Investigative Electrocardiography in Epidemiological Studies and Clinical Trials

296 Pages·2007·1.841 MB·English

by  Pentti Rautaharju MD, PhD, Farida Rautaharju PhD (auth.)

Investigative Electrocardiography in Epidemiological Studies and
Clinical Trials
Pentti Rautaharju and Farida Rautaharju
Investigative
Electrocardiography in
Epidemiological Studies
and Clinical Trials
Pentti Rautaharju, MD, PhD Farida Rautaharju, PhD
Wake Forest University School of Medicine Covance Cardiac Safety Services
Winston-Salem, North Carolina Reno, Nevada
USA USA
British Library Cataloguing in Publication Data
Rautaharju, P. (Pentti)
Investigative electrocardiography in epidemiological studies and clinical trials
1. Electrocardiography 2. Heart – Diseases – Epidemiology 3. Clinical trials
I. Title II. Rautaharji, Farida
616.1'207547
ISBN-13: 9781846284656
ISBN-10: 1846284651
Library of Congress Con trol Number: 2006926452
ISBN-10: 1-84628-465-1 eISBN 1-84628-481-3 Printed on acid-free paper
ISBN-13: 978-1-84628-465-6
© Springer-Verlag London Limited 2007
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Preface
This book on investigative electrocardiography is addressed to investigators who are
using electrocardiology as a research tool in epidemiological or clinical research or
in investigations on possible adverse responses of new pharmacological agents. The
primary emphasis of the book is on prognostic implications of ECG abnormalities in
the conditions covered, including the prevalence and incidence of ECG abnormalities in
contrasting populations.
We excluded from our book cardiac disorders with a relatively low population preva-
lence that otherwise may be of great clinical interest. We also decided to exclude acute
myocardial infarction because we had only limited resources available on this topic from
our population studies and from those clinical trials in which we have personally par-
ticipated in the classifi cation of trial endpoints within the framework of an ECG research
center.
Clinical trials are a relatively new area of electrocardiology. However, electrocardio-
graphy has become a most valuable research tool in clinical trials and in investigations
on morbidity and mortality risk associated with various clinical and subclinical condi-
tions. It has also become a crucial research tool in investigating adverse cardiac events
associated with administration of new drugs. Evaluation of QT prolongation plays a
central role in these investigations. As a possible marker of malignant arrhythmias, it is
used by regulating agencies in their decision process for approval of new pharmacologi-
cal agents.
Part 1 of this book begins with an account of ventricular excitation and repolarization
(Chapter 1), followed by Chapter 2 composed to facilitate the understanding of ECG
leads. Chapter 3 is a review of ionic channel functions in relation to ECG waveforms and
their role in drug effects. Heart rate and heart rate variability evaluation is covered next
(Chapter 4). Arrhythmic conditions selected include epidemiological aspects of atrial
fl utter and fi brillation and other atrial dysrhythmias (Chapter 5) and the role of ectopic
ventricular complexes (Chapter 6). Chapter 7 provides insights and a critical evaluation
of electrocardiographic left ventricular hypertrophy, and Chapter 8 covers ventricular
conduction defects. The last three chapters cover epidemiological aspects of old myo-
cardial infarction (Chapter 9), the importance of primary repolarization abnormalities
(Chapter 10), and fi nally, a critical evaluation of QT prolongation and QT dispersion
(Chapter 11). An important component in this last chapter is the establishment of
appropriate adjustment functions for QT interval, to overcome critical problems associ-
ated with the traditional Bazett’s formula and other power functions currently used for
QT rate adjustment.
vii
viii Preface
Each chapter starts with a synopsis summarizing the importance of the topic. The
main text in each chapter covers the mechanism, classifi cation problems, prevalence and
incidence, and predictive value of the abnormality.
Part 2 of the book contains an extensive series of tables listing normal standards
by gender, age (40–79 years), and ethnicity (Caucasian white and African–American),
established from large groups of healthy North-American populations. No previous
properly established normal standards are available for African–American men and
women or for older white women, and only limited standards are available for vectorial
parameters of ECG waves for any of these subgroups. These normal standards are pre-
sented as fi ve sections: Section A, ECG intervals; Section B, ECG wave amplitudes;
Section C, ECG vector components and spatial magnitudes at normalized time scale;
Section D, ECG amplitudes at 10-ms intervals; and Section E, repolarization waveform
vectors.
Many individuals have signifi cantly contributed to the effort that was required for the
completion of this book. The authors have closely collaborated for over a quarter of a
century in operating a central ECG laboratory that has been in charge of computer
analysis of major national health surveys conducted by the US National Center for
Health Statistics and a series of large cardiovascular observational studies and clinical
trials sponsored by the US National Heart, Lung, and Blood Institute. The authors wish
to express their gratitude to the sponsors and participants of these studies, principal
investigators, and their supporting staff. Our participation in several large clinical trials
sponsored by the pharmaceutical industry has also been a valuable experience that has
benefi ted the composition of this book.
The authors wish to acknowledge the collaborative efforts of the personnel of the
central ECG laboratory that has operated in different locations under the name EPICARE.
In particular, Dr. Ron Prineas, Dr. Zhu-Ming Zhang, and Charles Campbell, Wake Forest
University, NC, and James Warren, Dalhousie University, have provided important
support for this undertaking. The collaboration and friendship of Dr. Henry Blackburn
since the earliest years of cardiovascular epidemiology has provided an important intel-
lectual stimulus throughout these years.
Pentti Rautaharju and Farida Rautaharju
Contents
Part 1 Investigative Electrocardiography in Epidemiological Studies and
Clinical Trials
Chapter 1
Cardiac Excitation and Repolarization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Chapter 2
Electrocardiographic Lead Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Chapter 3
Normal and Arrhythmogenic Ionic Channel Mechanism . . . . . . . . . . . . . . . . . . . . 29
Chapter 4A
Heart Rate and Heart Rate Variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Chapter 4B
Methodological Considerations in Heart Rate Variability Analysis . . . . . . . . . . . . 68
Chapter 5
Supraventricular Dysrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Chapter 6A
Ectopic Ventricular Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Chapter 6B
Record Length, Spontaneous Variability and Suppression of Ectopic
Ventricular Complex Activity by Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Chapter 7A
Left Ventricular Hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Chapter 7B
Normal Standards for Cornell Voltage, Cornell Product and
Sokolow–Lyon Voltage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
ix
x Contents
Chapter 8
Prolonged Ventricular Excitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Chapter 9A
Old Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
Chapter 9B
Attributable Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
Chapter 10A
Primary Repolarization Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Chapter 10B
Procedures for Determination of the Spatial QRS/T Angle from
Conventional ECG Measurements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
Chapter 11
QT Prolongation and QT Dispersion – a Critical Evaluation . . . . . . . . . . . . . . . . . 202
Part 2 Normal ECG Standards for Adults by Gender, Age, and Ethnicity
Section A
ECG Intervals: Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Section B
ECG Wave Amplitudes: Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
Section C
ECG Vector Components and Spatial Magnitudes at Normalized
Time Scale: Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Section D
ECG Amplitudes at 10 ms Intervals: Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Section E
Repolarization Waveform Vectors: Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Part 1
Investigative Electrocardiography in
Epidemiological Studies and Clinical Trials