Methods Heart Rate Variability Heart Rate Turbulence Baroreflex PowerPoint Presentation

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF)

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT)

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF)

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file”

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read.

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns

Slide 32 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet

Slide 33 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram

Slide 34 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size)

Slide 35 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size)

Slide 36 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events.

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart

Slide 41 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences.

Slide 42 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated

Slide 43 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron.

Slide 44 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies.

Slide 45 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA

Slide 46 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions.

Slide 47 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined

Slide 48 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives

Slide 49 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms

Slide 50 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses

Slide 51 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV

Slide 52 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV

Slide 53 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV

Slide 54 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97

Slide 55 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV

Slide 56 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms.

Slide 57 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz

Slide 58 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min)

Slide 59 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min) Ground Rules for Measuring Frequency Domain HRV Only normal-to-normal (NN) intervals included At least one normal beat before and one normal beat after each ectopic beat is excluded Cannot reliably compute HRV with >20% ectopic beats With the exception of ULF, HRV in a 24-hour recording is calculated on shorter segments (5 min) and averaged.

Slide 60 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min) Ground Rules for Measuring Frequency Domain HRV Only normal-to-normal (NN) intervals included At least one normal beat before and one normal beat after each ectopic beat is excluded Cannot reliably compute HRV with >20% ectopic beats With the exception of ULF, HRV in a 24-hour recording is calculated on shorter segments (5 min) and averaged. Longer-Term HRV Total Power (TP) Sum of all frequency domain components. Ultra low frequency power (ULF) At >every 5 min to once in 24 hours. Reflects circadian, neuroendocrine, sustained activity of subject, and other unknown rhythms. Frequency Domain HRV

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min) Ground Rules for Measuring Frequency Domain HRV Only normal-to-normal (NN) intervals included At least one normal beat before and one normal beat after each ectopic beat is excluded Cannot reliably compute HRV with >20% ectopic beats With the exception of ULF, HRV in a 24-hour recording is calculated on shorter segments (5 min) and averaged. Longer-Term HRV Total Power (TP) Sum of all frequency domain components. Ultra low frequency power (ULF) At >every 5 min to once in 24 hours. Reflects circadian, neuroendocrine, sustained activity of subject, and other unknown rhythms. Frequency Domain HRV Intermediate-term HRV Very low frequency power (VLF) At ~20 sec-5 min frequency Reflects activity of renin-angiotensin system, vagal activity, activity of subject. Exaggerated by sleep apnea. Abolished by atropine Low frequency power (LF) At 3-9 cycles/min Baroreceptor influences on HR, mediated by SNS and vagal influences. Abolished by atropine. Frequency Domain HRV

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min) Ground Rules for Measuring Frequency Domain HRV Only normal-to-normal (NN) intervals included At least one normal beat before and one normal beat after each ectopic beat is excluded Cannot reliably compute HRV with >20% ectopic beats With the exception of ULF, HRV in a 24-hour recording is calculated on shorter segments (5 min) and averaged. Longer-Term HRV Total Power (TP) Sum of all frequency domain components. Ultra low frequency power (ULF) At >every 5 min to once in 24 hours. Reflects circadian, neuroendocrine, sustained activity of subject, and other unknown rhythms. Frequency Domain HRV Intermediate-term HRV Very low frequency power (VLF) At ~20 sec-5 min frequency Reflects activity of renin-angiotensin system, vagal activity, activity of subject. Exaggerated by sleep apnea. Abolished by atropine Low frequency power (LF) At 3-9 cycles/min Baroreceptor influences on HR, mediated by SNS and vagal influences. Abolished by atropine. Frequency Domain HRV Short-term HRV High frequency power (HF) At respiratory frequencies (9-24 cycles/minute, respiratory sinus arrhythmia but may also include non-respiratory sinus arrhythmia). Normally abolished by atropine. Vagal influences on HR with normal patterns. Frequency Domain HRV

Slide 63 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min) Ground Rules for Measuring Frequency Domain HRV Only normal-to-normal (NN) intervals included At least one normal beat before and one normal beat after each ectopic beat is excluded Cannot reliably compute HRV with >20% ectopic beats With the exception of ULF, HRV in a 24-hour recording is calculated on shorter segments (5 min) and averaged. Longer-Term HRV Total Power (TP) Sum of all frequency domain components. Ultra low frequency power (ULF) At >every 5 min to once in 24 hours. Reflects circadian, neuroendocrine, sustained activity of subject, and other unknown rhythms. Frequency Domain HRV Intermediate-term HRV Very low frequency power (VLF) At ~20 sec-5 min frequency Reflects activity of renin-angiotensin system, vagal activity, activity of subject. Exaggerated by sleep apnea. Abolished by atropine Low frequency power (LF) At 3-9 cycles/min Baroreceptor influences on HR, mediated by SNS and vagal influences. Abolished by atropine. Frequency Domain HRV Short-term HRV High frequency power (HF) At respiratory frequencies (9-24 cycles/minute, respiratory sinus arrhythmia but may also include non-respiratory sinus arrhythmia). Normally abolished by atropine. Vagal influences on HR with normal patterns. Frequency Domain HRV Frequency Domain HRV LF/HF ratio-may reflect SNS:PNS balance under some conditions. Normalized LF power= LF/(TP-VLF)-correlates with SNS activity under some conditions. Normalized HF power=HF/(TP-VLF)-proposed as a measure of relative vagal control of HR. Increased for abnormal HRV. Ratio HRV

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min) Ground Rules for Measuring Frequency Domain HRV Only normal-to-normal (NN) intervals included At least one normal beat before and one normal beat after each ectopic beat is excluded Cannot reliably compute HRV with >20% ectopic beats With the exception of ULF, HRV in a 24-hour recording is calculated on shorter segments (5 min) and averaged. Longer-Term HRV Total Power (TP) Sum of all frequency domain components. Ultra low frequency power (ULF) At >every 5 min to once in 24 hours. Reflects circadian, neuroendocrine, sustained activity of subject, and other unknown rhythms. Frequency Domain HRV Intermediate-term HRV Very low frequency power (VLF) At ~20 sec-5 min frequency Reflects activity of renin-angiotensin system, vagal activity, activity of subject. Exaggerated by sleep apnea. Abolished by atropine Low frequency power (LF) At 3-9 cycles/min Baroreceptor influences on HR, mediated by SNS and vagal influences. Abolished by atropine. Frequency Domain HRV Short-term HRV High frequency power (HF) At respiratory frequencies (9-24 cycles/minute, respiratory sinus arrhythmia but may also include non-respiratory sinus arrhythmia). Normally abolished by atropine. Vagal influences on HR with normal patterns. Frequency Domain HRV Frequency Domain HRV LF/HF ratio-may reflect SNS:PNS balance under some conditions. Normalized LF power= LF/(TP-VLF)-correlates with SNS activity under some conditions. Normalized HF power=HF/(TP-VLF)-proposed as a measure of relative vagal control of HR. Increased for abnormal HRV. Ratio HRV 0.20 Hz 0.40 Hz 0 LF peak HF peak 24-hour average of 2-min power spectral plots in a healthy adult

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min) Ground Rules for Measuring Frequency Domain HRV Only normal-to-normal (NN) intervals included At least one normal beat before and one normal beat after each ectopic beat is excluded Cannot reliably compute HRV with >20% ectopic beats With the exception of ULF, HRV in a 24-hour recording is calculated on shorter segments (5 min) and averaged. Longer-Term HRV Total Power (TP) Sum of all frequency domain components. Ultra low frequency power (ULF) At >every 5 min to once in 24 hours. Reflects circadian, neuroendocrine, sustained activity of subject, and other unknown rhythms. Frequency Domain HRV Intermediate-term HRV Very low frequency power (VLF) At ~20 sec-5 min frequency Reflects activity of renin-angiotensin system, vagal activity, activity of subject. Exaggerated by sleep apnea. Abolished by atropine Low frequency power (LF) At 3-9 cycles/min Baroreceptor influences on HR, mediated by SNS and vagal influences. Abolished by atropine. Frequency Domain HRV Short-term HRV High frequency power (HF) At respiratory frequencies (9-24 cycles/minute, respiratory sinus arrhythmia but may also include non-respiratory sinus arrhythmia). Normally abolished by atropine. Vagal influences on HR with normal patterns. Frequency Domain HRV Frequency Domain HRV LF/HF ratio-may reflect SNS:PNS balance under some conditions. Normalized LF power= LF/(TP-VLF)-correlates with SNS activity under some conditions. Normalized HF power=HF/(TP-VLF)-proposed as a measure of relative vagal control of HR. Increased for abnormal HRV. Ratio HRV 0.20 Hz 0.40 Hz 0 LF peak HF peak 24-hour average of 2-min power spectral plots in a healthy adult Relationship of Time and Frequency Domain HRV SDNN Total Power SDANN Ultra Low Frequency Power SDNNIDX Very Low Frequency Power Low Frequency Power pNN50 High Frequency Power rMSSD

Slide 66 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min) Ground Rules for Measuring Frequency Domain HRV Only normal-to-normal (NN) intervals included At least one normal beat before and one normal beat after each ectopic beat is excluded Cannot reliably compute HRV with >20% ectopic beats With the exception of ULF, HRV in a 24-hour recording is calculated on shorter segments (5 min) and averaged. Longer-Term HRV Total Power (TP) Sum of all frequency domain components. Ultra low frequency power (ULF) At >every 5 min to once in 24 hours. Reflects circadian, neuroendocrine, sustained activity of subject, and other unknown rhythms. Frequency Domain HRV Intermediate-term HRV Very low frequency power (VLF) At ~20 sec-5 min frequency Reflects activity of renin-angiotensin system, vagal activity, activity of subject. Exaggerated by sleep apnea. Abolished by atropine Low frequency power (LF) At 3-9 cycles/min Baroreceptor influences on HR, mediated by SNS and vagal influences. Abolished by atropine. Frequency Domain HRV Short-term HRV High frequency power (HF) At respiratory frequencies (9-24 cycles/minute, respiratory sinus arrhythmia but may also include non-respiratory sinus arrhythmia). Normally abolished by atropine. Vagal influences on HR with normal patterns. Frequency Domain HRV Frequency Domain HRV LF/HF ratio-may reflect SNS:PNS balance under some conditions. Normalized LF power= LF/(TP-VLF)-correlates with SNS activity under some conditions. Normalized HF power=HF/(TP-VLF)-proposed as a measure of relative vagal control of HR. Increased for abnormal HRV. Ratio HRV 0.20 Hz 0.40 Hz 0 LF peak HF peak 24-hour average of 2-min power spectral plots in a healthy adult Relationship of Time and Frequency Domain HRV SDNN Total Power SDANN Ultra Low Frequency Power SDNNIDX Very Low Frequency Power Low Frequency Power pNN50 High Frequency Power rMSSD Non-Linear HRV Non-linear HRV characterize the structure of the HR time series, i.e., is it random or self-similar. Increased randomness of the HR time series is associated with worse outcomes in cardiac patients. Non-linear HRV measures are not available from commercial Holter systems.

Slide 67 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min) Ground Rules for Measuring Frequency Domain HRV Only normal-to-normal (NN) intervals included At least one normal beat before and one normal beat after each ectopic beat is excluded Cannot reliably compute HRV with >20% ectopic beats With the exception of ULF, HRV in a 24-hour recording is calculated on shorter segments (5 min) and averaged. Longer-Term HRV Total Power (TP) Sum of all frequency domain components. Ultra low frequency power (ULF) At >every 5 min to once in 24 hours. Reflects circadian, neuroendocrine, sustained activity of subject, and other unknown rhythms. Frequency Domain HRV Intermediate-term HRV Very low frequency power (VLF) At ~20 sec-5 min frequency Reflects activity of renin-angiotensin system, vagal activity, activity of subject. Exaggerated by sleep apnea. Abolished by atropine Low frequency power (LF) At 3-9 cycles/min Baroreceptor influences on HR, mediated by SNS and vagal influences. Abolished by atropine. Frequency Domain HRV Short-term HRV High frequency power (HF) At respiratory frequencies (9-24 cycles/minute, respiratory sinus arrhythmia but may also include non-respiratory sinus arrhythmia). Normally abolished by atropine. Vagal influences on HR with normal patterns. Frequency Domain HRV Frequency Domain HRV LF/HF ratio-may reflect SNS:PNS balance under some conditions. Normalized LF power= LF/(TP-VLF)-correlates with SNS activity under some conditions. Normalized HF power=HF/(TP-VLF)-proposed as a measure of relative vagal control of HR. Increased for abnormal HRV. Ratio HRV 0.20 Hz 0.40 Hz 0 LF peak HF peak 24-hour average of 2-min power spectral plots in a healthy adult Relationship of Time and Frequency Domain HRV SDNN Total Power SDANN Ultra Low Frequency Power SDNNIDX Very Low Frequency Power Low Frequency Power pNN50 High Frequency Power rMSSD Non-Linear HRV Non-linear HRV characterize the structure of the HR time series, i.e., is it random or self-similar. Increased randomness of the HR time series is associated with worse outcomes in cardiac patients. Non-linear HRV measures are not available from commercial Holter systems. Most commonly used measure of randomness is the short-term fractal scaling exponent (DFA1 or α1). Decreased DFA1  increased randomness of the HR. Another index is power law slope, a measure of longer term self-similarity of HR. Decreased slope  worse outcome. Normal DFA1 is about 1.1. DFA1<0.85 is associated with higher risk. Non-Linear HRV

Slide 68 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min) Ground Rules for Measuring Frequency Domain HRV Only normal-to-normal (NN) intervals included At least one normal beat before and one normal beat after each ectopic beat is excluded Cannot reliably compute HRV with >20% ectopic beats With the exception of ULF, HRV in a 24-hour recording is calculated on shorter segments (5 min) and averaged. Longer-Term HRV Total Power (TP) Sum of all frequency domain components. Ultra low frequency power (ULF) At >every 5 min to once in 24 hours. Reflects circadian, neuroendocrine, sustained activity of subject, and other unknown rhythms. Frequency Domain HRV Intermediate-term HRV Very low frequency power (VLF) At ~20 sec-5 min frequency Reflects activity of renin-angiotensin system, vagal activity, activity of subject. Exaggerated by sleep apnea. Abolished by atropine Low frequency power (LF) At 3-9 cycles/min Baroreceptor influences on HR, mediated by SNS and vagal influences. Abolished by atropine. Frequency Domain HRV Short-term HRV High frequency power (HF) At respiratory frequencies (9-24 cycles/minute, respiratory sinus arrhythmia but may also include non-respiratory sinus arrhythmia). Normally abolished by atropine. Vagal influences on HR with normal patterns. Frequency Domain HRV Frequency Domain HRV LF/HF ratio-may reflect SNS:PNS balance under some conditions. Normalized LF power= LF/(TP-VLF)-correlates with SNS activity under some conditions. Normalized HF power=HF/(TP-VLF)-proposed as a measure of relative vagal control of HR. Increased for abnormal HRV. Ratio HRV 0.20 Hz 0.40 Hz 0 LF peak HF peak 24-hour average of 2-min power spectral plots in a healthy adult Relationship of Time and Frequency Domain HRV SDNN Total Power SDANN Ultra Low Frequency Power SDNNIDX Very Low Frequency Power Low Frequency Power pNN50 High Frequency Power rMSSD Non-Linear HRV Non-linear HRV characterize the structure of the HR time series, i.e., is it random or self-similar. Increased randomness of the HR time series is associated with worse outcomes in cardiac patients. Non-linear HRV measures are not available from commercial Holter systems. Most commonly used measure of randomness is the short-term fractal scaling exponent (DFA1 or α1). Decreased DFA1  increased randomness of the HR. Another index is power law slope, a measure of longer term self-similarity of HR. Decreased slope  worse outcome. Normal DFA1 is about 1.1. DFA1<0.85 is associated with higher risk. Non-Linear HRV Detrended Fluctuation Analysis (DFA)

Slide 69 -

Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min) Ground Rules for Measuring Frequency Domain HRV Only normal-to-normal (NN) intervals included At least one normal beat before and one normal beat after each ectopic beat is excluded Cannot reliably compute HRV with >20% ectopic beats With the exception of ULF, HRV in a 24-hour recording is calculated on shorter segments (5 min) and averaged. Longer-Term HRV Total Power (TP) Sum of all frequency domain components. Ultra low frequency power (ULF) At >every 5 min to once in 24 hours. Reflects circadian, neuroendocrine, sustained activity of subject, and other unknown rhythms. Frequency Domain HRV Intermediate-term HRV Very low frequency power (VLF) At ~20 sec-5 min frequency Reflects activity of renin-angiotensin system, vagal activity, activity of subject. Exaggerated by sleep apnea. Abolished by atropine Low frequency power (LF) At 3-9 cycles/min Baroreceptor influences on HR, mediated by SNS and vagal influences. Abolished by atropine. Frequency Domain HRV Short-term HRV High frequency power (HF) At respiratory frequencies (9-24 cycles/minute, respiratory sinus arrhythmia but may also include non-respiratory sinus arrhythmia). Normally abolished by atropine. Vagal influences on HR with normal patterns. Frequency Domain HRV Frequency Domain HRV LF/HF ratio-may reflect SNS:PNS balance under some conditions. Normalized LF power= LF/(TP-VLF)-correlates with SNS activity under some conditions. Normalized HF power=HF/(TP-VLF)-proposed as a measure of relative vagal control of HR. Increased for abnormal HRV. Ratio HRV 0.20 Hz 0.40 Hz 0 LF peak HF peak 24-hour average of 2-min power spectral plots in a healthy adult Relationship of Time and Frequency Domain HRV SDNN Total Power SDANN Ultra Low Frequency Power SDNNIDX Very Low Frequency Power Low Frequency Power pNN50 High Frequency Power rMSSD Non-Linear HRV Non-linear HRV characterize the structure of the HR time series, i.e., is it random or self-similar. Increased randomness of the HR time series is associated with worse outcomes in cardiac patients. Non-linear HRV measures are not available from commercial Holter systems. Most commonly used measure of randomness is the short-term fractal scaling exponent (DFA1 or α1). Decreased DFA1  increased randomness of the HR. Another index is power law slope, a measure of longer term self-similarity of HR. Decreased slope  worse outcome. Normal DFA1 is about 1.1. DFA1<0.85 is associated with higher risk. Non-Linear HRV Detrended Fluctuation Analysis (DFA) Power Law Slope

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Heart Rate Variability to Assess Autonomic Function Phyllis K. Stein, Ph.D. Research Assistant Professor of Medicine and Director, HRV Lab Washington University School of Medicine, St. Louis, MO PART I Understanding ECGs and How the Heart Works Overview of Blood Circulation The Heartbeat Valves Valves Electrical Pathways Action Potential Basics 1 2 3 4 5 Resting voltage Resting voltage Cardiac Action Potential Components of the ECG ECG Measurements Autonomic Nervous System Effects on the Heart Parasympathetic Nervous System (PNS), inhibits cardiac action potentials Sympathetic Nervous System (SNS), stimulates cardiac action potentials Single Channel Normal ECG p wave QRS complex t wave A Normal 12 Lead ECG Atrial Premature Contraction (APC) Abnormal p wave Early QRS Atrial Bigeminy Atrial Fibrillation (AF) Normal ECG with Ventricular Premature Contractions (VPCs) VPCs Right Bundle Block (RBB) Wide QRS peak Dangerously Abnormal ECGS Ventricular Tachycardia (VT) Ventricular Fibrillation (VF) Keywords Atrium Ventricle SA node AV node ECG Components P wave QRS complex T wave Sympathetic Nervous System Parasympathetic Nervous System Vagal APC or SVE Bigeminy VPCs VT VF PART II Holter and Other Continuous ECG Data Patient wearing a Holter device. Heart Rate Variability (HRV) Lab Analyzes Data from Continuous Electronically-Stored ECGs Holter Monitor 2 or 3 channels of Simultaneous ECG signals Cassette Tape Flash Card Continuous ECG Data Also Obtained from Overnight Sleep Studies Sleep studies have many channels of data including ECG Data stored on a hard disk and file exported to a CD One channel is ECG Analysis of Stored ECG Signals Continuous ECG signal is digitized and loaded on the Holter scanner Holter scanner is a computer with special commercial software that can process ECGs Many other computer algorithms exist that can display and measure things from ECGs The Job of the Holter Scanner Read and display the stored ECG Identify the peak of each beat Accurately label each beat as normal, APC or VPC Measure the time between the peaks of each beat Create a report describing the recording Export the results as a “beat file” The QRS File MARS scanner exports “QRS” files. QRS file is a list of every detected event on the tape, with the time after the next event. Events can be normal beats, APCs, VPCs or just noise. QRS file is in binary format, so we need to convert it to something we can read. Digitized ECG Format .MIT Format Binary format Consists of a .HDR file and .SIG file .RAW file Binary format Does not contain any header info Can be reloaded onto MARS like tape .NAT file Actual file on MARS Can be reloaded into MARS “slot” and restore all original data and analyses The .MIB file QRS file from the MARS scanners are saved to “HRV.” “HRV” is the name of the Sun computer that does all HRV calculations. QRS file is converted to MIB file and stored on “HRV.” .MIB= machine-independent beatfile Heart rate variability is calculated from the .MIB file Example of the Beginning of a .MIB File # 13:46:03.726 Study code=8050MJP OK,1 Record number code=8050MJP1 Start time=13:41:00 First beat=13:46:03.726 Start date=02-May-03 Samples per second=128 Marquette conversion date=Thu Jun 10 13:19:17 2004 Marquette hardware revision=508 833 523 4.00 0.25 End header Q0.000000000 Q687.500000000 Q617.187500000 Q656.250000000 Q656.250000000 Q656.250000000 Q648.437500000 Q656.250000000 Q656.250000000 Q687.500000000 Q625.000000000 Q656.250000000 Q656.250000000 Q656.250000000 Q656.250000000 header Files Generated from the .MIB File All heart rate variability calculations are made and exported to an EXCEL spreadsheet with one row per subject Heart rate tachograms -beat-by-beat plots of heart rate vs. time HRV power spectral plots - graphical representation of HRV HRV Poincaré plots - graphical representations of HR patterns Part of an HRV Spreadsheet x-axis = time in minutes (0-10 minutes) y-axis for each 10-min plot is H (0-100 bpm in 5 cm) “x-axis” is mean HR for that 10-min segment Heart Rate Tachogram Hourly HRV Power Spectral Plots (much reduced in size) Hourly Poincaré plots (much reduced in size) Keywords Holter Scanner Beat file QRS File Binary .MIB Header Recognize: Tachograms Power spectral plots Poincaré plots Part III HRV in Detail Background (HRV) Decreased heart rate variability Abnormal heart rate variability Identify patients with autonomic abnormalities who are at increased risk of arrhythmic events. Simplified Model of Cardiovascular Autonomic Control Renin angiotensin system Heart Rate Cardiac output Blood pressure Parasympathetic Nervous system Sympathetic Nervous system How HRV Reflects the Effect of the Autonomic Nervous System of the Heart HR Fluctuations Fluctuations in HR (HRV) are mediated by sympathetic (SNS) and parasympathetic (PNS) inputs to the SA node. Rapid fluctuations in HR usually reflect PNS control only (respiratory sinus arrhythmia). Slower fluctuations in HR reflect combined SNS and PNS + other influences. Rapid Fluctuations in HR Are Vagally Mediated “Rapid” fluctuations in HR are at >10 cycles/min (respiratory frequencies) Vagal effect on HR mediated by acetylcholine binding which has an immediate effect on SA node. If HR patterns are normal, rapid fluctuations in HR are vagally modulated Acetylcholine Binding The Acetylcholine Neurotransmitter binds to a receptor on a muscle once released from a neuron. Slower Fluctuations in HR Reflect Both SNS and Vagal Influences “Slower” fluctuations in HR are <10 cycles per min. SNS effect on HR is mediated by norepinephrine release which has a delayed effect on SA node Both SNS and vagal nerve traffic fluctuate at >10 cycles/min, but the time constant for changes in SNS tone to affect HR is too long to affect HR at normal breathing frequencies. NE blinds to the beta-receptor (Alpha subunit of G-protein). After binding, G protein links to second messenger (adenyl cyclase) which converts ATP to cAMP. cAMP activates protein kinase A which breaks ATP to ADP+phosphate which phosphorylates the pacemaker channels and increases HR Sympathetic activation takes too long to affect RSA Assessment of HRV Approach 1 Physiologist’s Paradigm HR data collected over short period of time (~5-20 min), with or without interventions, under carefully controlled laboratory conditions. Approach 2 Clinician’s/Epidemiologists’s Paradigm Ambulatory Holter Recordings usually collected over 24-hours or less, usually on outpatients. Assessment of HRV Approaches 1 and 2 can be combined Longer-term HRV-quantifies changes in HR over periods of >5min. Intermediate-term HRV-quantifies changes in HR over periods of <5 min. Short-term HRV-quantifies changes in HR from one beat to the next Ratio HRV-quantifies relationship between two HRV indices. HRV Perspectives Sources of Heart Rate Variability Extrinsic Activity - Sleep Apnea Mental Stress - Smoking Physical Stress Intrinsic Periodic Rhythms Respiratory sinus arrhythmia Baroreceptor reflex regulation Thermoregulation Neuroendocrine secretion Circadian rhythms Other, unknown rhythms Ways to Quantify HRV Approach 1: How much variability is there? Time Domain and Geometric Analyses Approach 2: What are the underlying rhythms? What physiologic process do they represent? How much power does each underlying rhythm have? Frequency Domain Analysis Approach 3: How much complexity or self-similarity is there? Non-Linear Analyses Time Domain HRV SDNN-Standard deviation of N-N intervals in msec (Total HRV) SDANN-Standard deviation of mean values of N-Ns for each 5 minute interval in msec (Reflects circadian, neuroendocrine and other rhythms + sustained activity) Longer-term HRV SDNNIDX-Average of standard deviations of N-Ns for each 5 min interval in ms (Combined SNS and PNS HRV) Coefficient of variance (CV)- SDNNIDX/AVNN. Heart rate normalized SDNNIDX. Time Domain HRV Intermediate-term HRV Time Domain HRV rMSSD-Root mean square of successive differences of N-N intervals in ms pNN50-Percent of successive N-N differences >50 ms Calculated from differences between successive N-N intervals Reflect PNS influence on HR Short-term HRV Geometric HRV HRV Index-Measure of longer-term HRV From Farrell et al, J am Coll Cardiol 1991;18:687-97 Examples of Normal and Abnormal Geometric HRV Frequency Domain HRV Based on autoregressive techniques or fast Fourier transform (FFT). Partitions the total variance in heart rate into underlying rhythms that occur at different frequencies. These frequencies can be associated with different intrinsic, autonomically-modulated periodic rhythms. What are the Underlying Rhythms? One rhythm 5 seconds/cycle or 12 times/min 5 seconds/cycle= 1/5 cycle/second 1/5 cycle/second= 0.2 Hz What are the Underlying Rhythms? Three Different Rhythms High Frequency = 0.25 Hz (15 cycles/min Low Frequency = 0.1 Hz (6 cycles/min) Very Low Frequency = 0.016 Hz (1 cycle/min) Ground Rules for Measuring Frequency Domain HRV Only normal-to-normal (NN) intervals included At least one normal beat before and one normal beat after each ectopic beat is excluded Cannot reliably compute HRV with >20% ectopic beats With the exception of ULF, HRV in a 24-hour recording is calculated on shorter segments (5 min) and averaged. Longer-Term HRV Total Power (TP) Sum of all frequency domain components. Ultra low frequency power (ULF) At >every 5 min to once in 24 hours. Reflects circadian, neuroendocrine, sustained activity of subject, and other unknown rhythms. Frequency Domain HRV Intermediate-term HRV Very low frequency power (VLF) At ~20 sec-5 min frequency Reflects activity of renin-angiotensin system, vagal activity, activity of subject. Exaggerated by sleep apnea. Abolished by atropine Low frequency power (LF) At 3-9 cycles/min Baroreceptor influences on HR, mediated by SNS and vagal influences. Abolished by atropine. Frequency Domain HRV Short-term HRV High frequency power (HF) At respiratory frequencies (9-24 cycles/minute, respiratory sinus arrhythmia but may also include non-respiratory sinus arrhythmia). Normally abolished by atropine. Vagal influences on HR with normal patterns. Frequency Domain HRV Frequency Domain HRV LF/HF ratio-may reflect SNS:PNS balance under some conditions. Normalized LF power= LF/(TP-VLF)-correlates with SNS activity under some conditions. Normalized HF power=HF/(TP-VLF)-proposed as a measure of relative vagal control of HR. Increased for abnormal HRV. Ratio HRV 0.20 Hz 0.40 Hz 0 LF peak HF peak 24-hour average of 2-min power spectral plots in a healthy adult Relationship of Time and Frequency Domain HRV SDNN Total Power SDANN Ultra Low Frequency Power SDNNIDX Very Low Frequency Power Low Frequency Power pNN50 High Frequency Power rMSSD Non-Linear HRV Non-linear HRV characterize the structure of the HR time series, i.e., is it random or self-similar. Increased randomness of the HR time series is associated with worse outcomes in cardiac patients. Non-linear HRV measures are not available from commercial Holter systems. Most commonly used measure of randomness is the short-term fractal scaling exponent (DFA1 or α1). Decreased DFA1  increased randomness of the HR. Another index is power law slope, a measure of longer term self-similarity of HR. Decreased slope  worse outcome. Normal DFA1 is about 1.1. DFA1<0.85 is associated with higher risk. Non-Linear HRV Detrended Fluctuation Analysis (DFA) Power Law Slope Comparison of Normal and Highly Random HRV Plots