Exercise & the heart

1. 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 EXERCISE AND THE HEART, Fifth Edition ISBN-13: 978-1-4160-0311-3 ISBN-10: 1-4160-0311-8 Copyright 2006, Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher (Elsevier, 1600 John F. Kennedy Boulevard, Suite 1800, Philadelphia, PA, 19103-2899). Library of Congress Cataloging-in-Publication Data Froelicher, Victor F. Exercise and the heart/Victor F. Froelicher, Jonathan Myers.5th ed. p.;cm Includes bibliographical references and index. ISBN 1-4160-0311-8 1. Exercise tests. 2. Heart function tests. 3. HeartDiseasesDiagnosis. I. Myers, Jonathan, 1957- II. Title. [DNLM: 1. Heart Diseasesrehabilitation. 2. Exercise Testmethods. 3. Exercise Therapymethods. 4. Exertion. WG 141.5.F9 F926e 2006] RC683.E.E94F76 2006 616.120754dc22 2005051641 Editor: Susan F. Pioli Senior Editorial Assistant: Joan Ryan Publishing Services Manager: Joan Sinclair Project Manager: Mary Stermel Design Direction: Gene Harris Marketing Manager: Dana Butler Printed in the United States of America Last digit is the print number: 10 9 8 7 6 5 4 3 2 1 Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practi- tioners, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the publisher nor the authors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher

2. To Susan, my wife and best friend. VFF To my two older brothers, Chris and Tim, who are no longer with us. Their intellect eluded me but was always and continues to be a source of motivation and inspiration. JM

3. Welcome to the fifth edition of Exercise and the Heart. Since the fourth edition, there have been numerous important documents published, including an update of the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines on exercise testing, the American Thoracic Society/American College of Chest Physicians Statement on Cardiopulmonary Exercise Testing, an AHA Scientific Statement on Exercise and Heart Failure, an AHA Scientific Statement on Physical Activity in the Prevention of Cardiovascular Disease, new editions of the American Association of Cardiovascular and Pulmonary Rehabilitation Guidelines, and the American College of Sports Medicine Guidelines on Exercise Testing and Prescription. Relevant information from these updated documents has been incorporated into this fifth edition. The necessity of practicing evidence-based medicine makes it critical that all of us defer to the panels of experts who write these guidelines. In rare cases in which the guidelines are inconsistent or we offer an opinion or recommendation that dif- fers from the guidelines, we alert the reader. As the field of cardiology has continued to evolve, it is important to note some of the new or changed acronyms in medicine. HF has been recommended as the acronym to replace CHF, because CHF has confusingly repre- sented either chronic or congestive (acute) heart failure. PCI (percutaneous coronary intervention) has replaced PTCA, because currently many techniques in addition to balloon angioplasty are performed by interventionalists. AED (automated external defibrillator) and ICD (implantable cardiac defibrillator) are used for the new biphasic defibrillator products. CRT (cardiac resynchronization therapy) is an implantable pacemaker for improving cardiac function that is often combined with an ICD. ACS (acute coronary syndrome) is the term now widely used to describe the spectrum of conditions associated with acute myocardial ischemia, including unstable angina pectoris and non-Q wave MIs. In this edition, weve tried to incorporate the influence of the remarkable advances in cardiology in the subject matter. These advances are listed below (not in order of impact), because each by themselves has strongly influenced exercise testing, exercise training, and clinical exercise physiology. 1. Designation of ACSs 2. Biomarkers for ischemia and volume overload/left ventricular dysfunction at point of contact (troponin and brain natri- uretic peptide [BNP]) 3. Advances in percutaneous coronary inter- ventions (PCI) culminating in drug-eluting stents that have greatly reduced stent failure 4. Evidence-based recommendations that PCI is better than thrombolysis for acute myocardial infarction 5. Medications that convincingly improve survival in patients with heart disease vii preface

4. viii Preface 6. Pacemakers for CRT 7. Further advances in exercise training for patients with heart failure and other groups previously excluded from rehabilitation 8. The basic role of endothelial function in maintaining cardiovascular health and how it is affected by exercise training 9. Human genomics studies related to sudden death (LQT1) and training (ACE) 10. Advances in cardiac defibrillators (implantable and portable units) These advances have actually interacted with one another, so it is best to address them in groupings that impact health care in a similar fashion. We address those that impact the diagnostic use of exercise testing first. Many patients who required diagnostic exercise testing after the first appearance of symptoms now have the diagnosis made based on an elevation of troponin. They frequently go straight to cardiac catheterization. Many cardiologists believe that advances in PCI make the noninvasive diagnosis of ischemic chest pain moot, because angiography can be used to make the diagnosis and treat the problem by averting all steps in between. The lowered restenosis rate associated with drug-eluting stents has removed, in their minds, all the reasons not to diagnose and fix the problem all in one relatively low-risk procedure. However, it is important to keep in mind that health care costs continue to rise and fewer people are insured or able to afford this invasive approach. As clinicians continue to deal with the problems of cost-efficacy, we contend that the exercise test remains the most logical gatekeeper to more expensive and/or invasive diagnostic tests. When a biomarker that can be measured at point of contact becomes val- idated as a way to increase the sensitivity of the test along with multivariate scores, reasonable clinicians apply the exercise test first. Although some would disagree, we contend that the art of medical decision making and the use of noninvasive tests are currently more important than ever. Next, let us consider the advances in health care that affect the prognostic use of exercise testing. PCI for acute myocardial infarction has been shown to be better for improving prognosis and lessening myocardial damage than thrombolysis. The reason this is so is that it is more effective than thrombolytic drugs in opening coronary arteries blocked by thrombosis. Improved patency rates mean that follow-up exercise testing is less likely to be needed routinely after MI to determine who needs coronary angiography. However, when the patient and physician want or need individualized prognostic information, there is no test more valuable than the standard exercise test. Several recent studies have confirmed that exercise capacity alone has independent and significant prognostic power regardless of the patients clinical history. Surprisingly, the next two items, which relate to patients with HF, have resulted in new ideas regarding cardiovascular physiology. First, HF results in major metabolic and cellular changes that can be improved by an exercise program. These alterations have provided interesting insights into the exercise response, because changes in endothelial function appear to be a major contributor to these improvements. Second, implanted synchro- nous pacemakers have been shown to improve both ventricular function and exercise capacity. This is somewhat surprising, because previously it was thought that myocyte damage was the pri- mary event leading to LV dysfunction and that conduction disturbances were a result of this. However, improvement in function resulting from correction of dysynchrony suggests that damage to the conduction system can be the cause of LV dysfunction and impair exercise capacity. There are two important bench findings that are impacting our understanding of cardiac pathophysiology. First, regular exercise can have a powerful effect on endothelial dysfunction, and now this mechanism is proposed as one of the major beneficial actions that exercise has on health. Second, we are only on the threshold of using human genomics to understand exercise and the heart. Congenital diseases that cause exercise- related sudden death have been localized to specific genes (for instance, LQT1). The ACE gene appears to be an important determinant of the response to exercise training. Finally, advances in defibrillators have had an important impact on exercise for the public. Biphasic units resulting in lower energy needs for defibrillation, long-life lithium batteries, and smart arrhythmia algorithms are the basis for these advances. Cardiopulmonary resuscitation (CPR) has been improved by AEDs, and they are now widely used by the public, resulting in better outcomes following arrhythmic events. These devices are now ubiquitous and are mandatory at gyms and sporting events; importantly, the AHA has developed guidelines for their use in health clubs. However, studies on the number of sudden cardiac deaths (50,000/year in the United States; approximately one fifth of the number estimated initially and used as the impetus for AEDs) and

5. Preface ix their location (most sudden deaths occur at home and not in public places) have led to some reassessment of their use. Randomized trials have demonstrated a survival benefit for ICDs in most patients with LV dysfunction. Now patients with these devices must be dealt with in the context of cardiac rehabilitation and exercise laboratory settings. The following is our strongest variance from the guidelines: Exercise testing should be used for screening healthy, asymptomatic individuals along with risk factor assessment. We plan to lobby with our colleagues on this point for the following reasons: A number of contemporary studies have demonstrated remarkable risk ratios for the combination of the standard exercise test responses and traditional risk factors. Other modalities without the favorable test characteristics of the exercise test are being promoted for screening. Physical inactivity has reached epidemic proportions, and the exercise test provides an ideal way to make patients conscious of their deconditioning and to make physical activity recommendations. Adjusting for age and other risk factors, each MET increase in exercise capacity equates to a 10% to 25% improvement in survival. With this fifth edition, we once again have assumed the writing by ourselves. Though it is obvious which one of us was the main author for the various chapters, we collaborated on all of them and take both blame and credit. With the volume of studies on exercise testing and training now all available on the world wide web, it is no longer practical to review in detail as many individual studies, however important they are. Although we have been careful to update our citations, we felt it necessary to keep the classic studies related to particular issues. Wherever possible, we have tried to summarize the major studies in tables, followed by a comment and then our overall view or recommendation on a given issue. Once again we feel it is important to provide the following precepts in the preface regarding methodology even though the details are in the chapters: The treadmill protocol should be adjusted to the patient; one protocol is not appropriate for all patients. Exercise capacity should be reported in METs, not minutes of exercise. Hyperventilation before testing is not indi- cated but can be used at another time if a false- positive test is suspected. ST measurements should be made at ST0 (J-junction), and ST depression should be considered abnormal only if horizontal or downsloping; most clinically important ST depression occurs in V5, particularly in patients with a normal resting ECG. Patients should be placed supine as soon as possible post exercise without a cool-down walk in order for the test to have its greatest diagnostic value. The 2- to 4-minute recovery period is critical to include in analysis of the ST response. Measurement of systolic blood pressure during exercise is extremely important, and exertional hypotension is ominous; at this point, only manual blood pressure measurement techniques are valid. Age-predicted heart rate targets are largely useless because of the wide scatter for any age; a relatively low heart rate can be maximal for a given patient and submaximal for another. The Duke Treadmill Score should be calculated automatically on every test except for the elderly. Other predictive equations and heart rate recovery should be considered a standard part of the treadmill report. To ensure the safety of exercise testing and reassure the noncardiologist performing the test, the following list of the most dangerous circumstances in the exercise testing lab should be considered: Testing patients with aortic valvular disease or obstructive hypertrophic cardiomyopathy (ASH or IHSS) should be done with great care. Aortic stenosis can cause cardiovascular collapse, and these patients may be difficult to resuscitate because of the outflow obstruction; IHSS can become unstable due to arrhythmia. Because of these conditions, a physical exam including assessment of systolic murmurs should be done before all exercise tests. If a significant murmur is heard, an echocardiogram should be considered before performing the test. When patients without diagnostic Q-waves on their resting ECG exhibit exercise-induced

6. x Preface ST segment elevation (i.e., transmural ischemia), the test should be stopped; this can be associated with dangerous arrhythmias and infarction. This occurs in about 1 of 1000 clinical tests. A cool-down walk is advisable in the following instances: 1. When a patient with an ischemic cardiomyopathy exhibits significant chest pain due to ischemia, because the ischemia can worsen in recovery 2. When a patient develops exertional hypotension accompanied by ischemia (angina or ST depression) or when it occurs in a patient with a history of HF, cardiomyopathy, or recent MI 3. When a patient with a history of sudden death or collapse during exercise develops PVCs that become frequent Appreciation of these circumstances can help avoid any complications in the exercise lab. As in previous editions, there are many pre- medical and medical students, graduate students, residents, fellows, visiting professors, and inter- national medical graduates who have contributed to the studies discussed in this book. They are too numerous to mention individually, but their work is cited extensively in this edition. One of the most gratifying things about what we do is to have the opportunity to host these individuals and gain the friendships that result through the inevitable battles that occur in trying to answer a research question. Because of this, we have maintained a wide range of contacts around the world, and many of them continue to collaborate with us. A few individuals in particular warrant men- tioning here, because their contributions to this edition are significant. They include Paul Dubach from Switzerland, Euan Angus Ashley from Scotland (now a Stanford cardiology fellow), and Kari Saunamaki from Denmark. Takuya Yamazaki was our most recent research fellow from Japan (of a list of many), and his desk is currently occu- pied by Tan Swee Yaw from Singapore. Notable PhDs who keep a close eye on our science are Barry Franklin, Paul Ribisl, and Bill Herbert. We have profited both personally and professionally by our association with all of these individuals and treasure the friendships that began through research collaboration. Given this background, we are targeting this book as a reference for the clinical aspects of exercise testing and training. It is meant for the serious student, academic, or health care provider who wants to have available much of the knowledge in this field summarized in one source. Hopefully it will find an appropriate niche on the shelves in many exercise labs, cardiac rehabilitation depart- ments, and educational training programs. We have tried to incorporate the latest available guidelines, position statements, and meta-analyses. Our love of the subject has led to the incorporation of details that some could consider minutia yet we might have missed some work considered important by our colleagues. We hope you enjoy this book and that it is helpful to you. Victor F. Froelicher Jonathan Myers

7. 1 C H A P T E R one Basic Exercise Physiology Exercise physiology is the study of the physiologic responses and adaptations that occur as a result of acute or chronic exercise. Exercise is the bodys most common physiologic stress, and it places major demands on the cardiopulmonary system. For this reason, exercise can be considered the most practical test of cardiac perfusion and function. Exercise testing is a noninvasive tool to evaluate the cardiovascular systems response to exercise under carefully controlled conditions. The adaptations that occur during an exercise test allow the body to increase its resting metabolic rate up to 20 times, during which time cardiac output may increase as much as six times. The magnitude of these adjustments is dependent upon age, gender, body size, type of exercise, fitness, and the presence or absence of heart disease. Although major adaptations are also required of the endocrine, neuromotor, and thermoregula- tory systems, the major focus of this chapter is on the cardiovascular response and adaptations of the heart to acute exercise. Cardiovascular adaptations to chronic training in humans and animals are reviewed in Chapter 12. It is important to understand two basic principles of exercise physiology with regard to exercise testing. The first is a physiologic principle: total body oxygen uptake and myocardial oxygen uptake are distinct in their determinants and in the way they are measured or estimated (Table 1-1). Total body or ventilatory oxygen uptake (VO2) is the amount of oxygen that is extracted from inspired air as the body performs work. Conversely, myocardial oxygen uptake is the amount of oxygen consumed by the heart muscle. Accurate measurement of myocardial oxygen consumption requires the placement of catheters in a coronary artery and in the coronary venous sinus to measure oxygen content. The determinants of myocardial oxygen uptake include intramyocardial wall tension (left ventricular pressure end-diastolic volume), contractility, and heart rate. It has been shown that myocardial oxygen uptake can be reasonably estimated by the product of heart rate and systolic blood pressure (double product). This information is valuable clinically because exercise-induced angina often occurs at the same myocardial oxygen demand (double product) and thus is a useful physiologic variable when evaluating therapy. When it is not the case, the influence of other factors should be suspected, such as a recent meal, abnormal ambient temperature, or coronary artery spasm. The second principle of exercise physiology is one of pathophysiology: considerable interaction takes place between the exercise test manifestations of abnormalities in myocardial perfusion and function. The electrocardiographic response to exercise and angina are closely related to myocardial ischemia (coronary artery disease), whereas exercise capacity, systolic blood pressure, and heart rate responses to exercise can be determined by the presence of myocardial ischemia, myocardial dysfunction, or responses in the periphery. Exercise-induced ischemia can cause cardiac dysfunction that results in exercise impairment and an abnormal systolic blood pressure response. Often it is difficult to separate the impact of

8. ischemia from the impact of left ventricular dysfunction on exercise responses. An interaction exists that complicates the interpretation of the exercise test findings. The variables affected by both myocardial ischemia and ventricular dysfunction (i.e., exercise capacity, maximal heart rate, and systolic blood pressure) have the greatest prognostic value. The severity of ischemia or the amount of myocardium in jeopardy is known clinically to be inversely related to the heart rate, blood pressure, and exercise level achieved. However, neither resting nor exercise ejection fraction nor a change in ejection fraction during exercise correlates well with measured or estimated maximal oxygen uptake, even in patients without signs or symptoms of ischemia.1,2 Moreover, exercise- induced markers of ischemia do not correlate well with one another. Silent ischemia (i.e., markers of ischemia presenting without angina) does not appear to affect exercise capacity in patients with coronary heart disease. Although not conclusive, radionuclide studies support this position.3 Cardiac output is generally considered the most important determinant of exercise capacity, but studies suggest that in some patients with heart disease, the periphery plays an important role in limiting exercise capacity.1,4 Concepts of Work. Because exercise testing fun- damentally involves the measurement of work, there are several concepts regarding work that are important to understand. Work is defined as force moving through a given distance (W = F D). If muscle contraction results in mechanical move- ment, then work has been accomplished. Force is equal to mass times acceleration (F = M A). Any weight, for example, is a force that is under- going the resistance provided by gravity. A great deal of any work that is performed involves over- coming the resistance provided by gravity. The basic unit of force is the newton (N). It is the force that, when applied to a 1-kg mass, gives it an acceleration of 1 m multiplied by sec2 . Since work is equal to force (in newtons) times distance (in meters), another unit for work is the newton meter (Nm). One Nm is equal to one joule (J), which is another common expression of work. Because work is nearly always expressed per unit of time (i.e., as a rate), an additional unit that becomes important is power, the rate at which work is performed. The bodys metabolic equivalent (MET) of power is energy. Therefore, it is easy to think of work as anything with weight moving at some rate across time (which is often analogous to distance). The common biologic measure of total body work is the oxygen uptake, which is usually expressed as a rate (making it a measure of power) in liters per minute. MET is a term commonly used clinically to express the oxygen requirement of the work rate during an exercise test on a treadmill or cycle ergometer. One MET is equated with the resting metabolic rate (;3.5 mL of O2/kg/min), and a MET value achieved from an exercise test is a multiple of the resting metabolic rate, either measured directly (as oxygen uptake) or estimated from the maximal workload achieved using standardized equations.5 Energy and Muscular Contraction. Muscular contraction is a complex mechanism involving the interaction of the contractile proteins actin and myosin in the presence of calcium. The British scientist A.F. Huxley proposed that the myosin and actin filaments in the muscle slid past one another as the muscle fibers shortened during contraction. Huxley won the Nobel Prize for this concept, which is still generally considered correct. The source of energy for this contraction is supplied by adenosine triphosphate (ATP), which is produced in the mitochondria. ATP is stored as two products, adenosine diphosphate and phosphate, at specific binding sites on the myosin heads. The sequence of events that occurs when a muscle contracts has three other major players: calcium and two inhibitory proteins, troponin and tropomyosin. Voluntary muscle contraction begins with the arrival of electrical impulses at the myoneural junction, initiating the release of calcium ions. Calcium is released into the 2 E X E R C I S E A N D T H E H E A R T TABLE 1-1. Two basic principles of exercise physiology Myocardial oxygen consumption ;Heart rate systolic blood pressure (determinants include wall tension left ventricular pressure volume; contractility; and heart rate) Ventilatory oxygen consumption (VO2) ;External work performed, or cardiac output a-VO2 difference* * The arteriovenous O2 difference is approximately 15 to 17 vol% at maximal exercise in most individuals; therefore, VO2 max generally reflects the extent to which cardiac output increases.

9. sarcoplasmic reticulum that surrounds the muscle filaments. The calcium binds to a special protein, troponin-C, which is attached to tropomyosin (another protein that inhibits the binding of actin and myosin), and actin. When calcium binds to troponin-C, the tropomyosin molecule is removed from its blocking position between actin and myosin. The myosin head then attaches to actin, and muscular contraction occurs. The main source of energy for muscular contraction, ATP, is produced by oxidative phosphorylation. The major fuels for this process are carbohydrates (glycogen and glucose) and free fatty acids. At rest, roughly equal amounts of energy are derived from carbohydrates and fats. Free fatty acids contribute greatly to the energy supply during low levels of exercise, but greater amounts of energy are derived from carbohydrates as exercise progresses. Maximal work relies virtually entirely on carbohydrates. Because endurance performance is directly related to the rate at which carbohydrate stores are depleted, major advantages exist for both: (1) having greater glycogen stores in the muscle and (2) deriving a relatively greater proportion of energy from fat during prolonged exercise. Both of these benefits are conferred with training. Oxidative phosphorylation initially involves a series of events that take place in the cytoplasm. Glycogen and glucose are metabolized to pyruvate through glycolysis. If oxygen is available, pyruvate enters the mitochondria from the sarcoplasm and is oxidized to a compound known as acetyl CoA, which then enters a cyclical series of reactions known as the Krebs cycle. By-products of the Krebs cycle are CO2 and hydrogen. Electrons from hydrogen enter the electron transport chain, yielding energy for the binding of phosphate (phosphorylation) from adenosine diphosphate to ATP. This process, oxidative phosphorylation, is the greatest source of ATP for muscle contraction. A total of 36 ATP molecules per glucose molecule are formed in the mitochondria during this process. The mitochondria can produce ATP for muscle contraction only if oxygen is present. However, at higher levels of exercise, total body oxygen demand may exceed the capacity of the cardiovascular system to deliver oxygen. Historically, anaerobic (without oxygen) glycolysis has been the term used to describe the synthesis of ATP from glucose under these conditions. Many researchers have superseded this term with more functional descriptions, such as oxygen independent, nonoxidative, or rapid glycolysis, because anaerobic incorrectly implies that glycolysis occurs only when there is an inadequate oxygen supply. Under such conditions, glycolysis progresses in the cytoplasm much the same way as aerobic metabolism until pyruvate is formed. However, electrons released during glycolysis are taken up by pyruvate to form lactic acid. Rapid diffusion of lactate from the cell inhibits any further steps in glycolysis. Thus, oxygen- independent glycolysis is inefficient; two ATP molecules per glucose molecule is the total yield from this process. The fact that lactate accumulates in the blood during rapid glycolysis is an important concept in exercise science. The relative exercise intensity in which lactate accumulation occurs is an important determinant of endurance performance. The degree to which lactate accumulates in the blood is related to exercise intensity and the extent to which fast-twitch (type IIB) fibers are recruited. This subject is discussed further in Chapter 3. Although lactate can contribute to fatigue by increasing ventilation and inhibiting other enzymes of glycolysis, it can also serve as an important energy source in muscles other than those in which it was formed, and it serves as an important precursor for liver glycogen during exercise.6-8 Muscle Fiber Types. The bodys muscle fiber types are classified on the basis of the speed with which they contract, their color, and their mitochondrial content. Type I, or slow-twitch fibers, are red in color and contain high concentrations of mitochondria. Type II, or fast-twitch fibers, are white in color and have low concentrations of mitochondria. Fiber color is related to the degree of myoglobin, which is a protein that both stores oxygen in the muscle and carries oxygen in the blood to the mitochondria. Not surprisingly, slow-twitch fibers with their high myoglobin content are more resistant to fatigue; thus, a muscle with a high percentage of slow- twitch fibers is well suited for endurance exercise. However, slow-twitch fibers tend to be smaller and produce less overall force than fast-twitch fibers. Fast-twitch fibers are generally larger and tend to produce more force, although they fatigue more easily. Research suggests that the speed of contraction for each fiber type is based largely on the activity of the enzyme myosin ATPase, which sits in the myosin head and to which ATP combines. It is important to note that although the two fiber types can be separated by distinct characteristics, both fibers function effectively for virtually all physical activities. Evidence also suggests that slow-twitch and fast-twitch fibers are not as dichotomous as previously thought. C H A P T E R 1 Basic Exercise Physiology 3

10. Myosin ATPase activity and speed of contraction of some slow-twitch fibers approximate those of fast-twitch fibers. Moreover, type II (fast-twitch) fibers have been further divided into three sub- categories: type IIA, type IIB, and type IIC. The type IIA fiber mimics the type I fiber in that it has a high capacity for oxidative metabolism. It has been suggested that the type IIA fiber actually is a type II fiber that has been adapted for endurance exercise, and endurance athletes are known to have a relatively large number of these fibers.9 The type IIB fiber is a true type II fiber in that it contains few mitochondria and is better adapted for short bursts of activity. The type IIC fiber is poorly understood; it may represent an uncommitted fiber, capable of adapting into one of the other fiber types. Historically, it has been thought that endurance athletes were obliged to be genetically endowed with larger percentages of type I fibers, and that the opposite was true of sprinters or jumpers. Numerous cross-sectional studies have confirmed these differences in fiber types between endurance and sprint-type athletes since the advent of the muscle biopsy technique. However, fiber types may in fact represent a continuum, with some capable of adapting toward the characteristics of another fiber. ACUTE CARDIOPULMONARY RESPONSE TO EXERCISE The cardiovascular system responds to acute exercise with a series of adjustments that assure (1) active muscles receive blood supply appropriate to their metabolic needs, (2) heat generated by the muscles is dissipated, and (3) blood supply to the brain and heart is maintained. This response requires a major redistribution of cardiac output along with a number of local metabolic changes. The usual measure of the capacity of the body to deliver and utilize oxygen is the maximal oxygen uptake (VO2 max). Thus, the limits of the cardiopulmonary system are historically defined by VO2 max, which can be expressed by the Fick principle: VO2 max = maximal cardiac output maximal arteriovenous oxygen difference Cardiac output must closely match ventilation in the lung in order to deliver oxygen to the working muscle. VO2 max is determined by the maximal amount of ventilation (VE) moving into and out of the lung and by the fraction of this ventilation that is extracted by the tissues: VO2 = VE (FiO2 FeO2) where VE is minute ventilation, and FiO2 and FeO2 are the fractional amounts of oxygen in the inspired and expired air, respectively. (For the moment, this equation is oversimplified, as the measurement of VO2 also requires a determination of expired CO2, as detailed in Chapter 3.) Therefore, the cardiopulmonary limits (VO2 max) are defined by (1) a central component (cardiac output) that describes the capacity of the heart to function as a pump and (2) peripheral factors (arteriovenous oxygen difference) that describe the capacity of the lung to oxygenate the blood delivered to it and the capacity of the working muscle to extract this oxygen from the blood. Figures 1-1 and 1-2 outline the many factors affecting cardiac output and arteriovenous oxygen difference. An abnormality in one or more of these components often characterizes the presence and extent of some form of cardiovascular or pulmonary disease. In the following, these models are reviewed in the context of the cardiovascular response to exercise. Central Factors Figure 1-1 shows the central determinants of maximal oxygen uptake. Heart Rate Sympathetic and parasympathetic nervous system influences underlie the cardiovascular systems first response to exercise, an increase in heart rate. Sympathetic outflow to the heart and sys- temic blood vessels increases and vagal outflow decreases. Of the two major components of cardiac output, heart rate and stroke volume, heart rate is responsible for most of the increase in cardiac output during exercise, particularly at higher levels. Heart rate increases linearly with workload and oxygen uptake. Increases in heart rate occur primarily at the expense of diastolic, not systolic time. Thus, at very high heart rates, diastolic time may be so short as to preclude adequate ventricular filling. The heart rate response to exercise is influenced by several factors, including age, type of activity, body position, fitness, the presence of heart disease, medications, blood volume, 4 E X E R C I S E A N D T H E H E A R T

11. and environment. Of these, the most important factor is age; a decline in maximal heart rate occurs with increasing age.10 This decline appears to be due to intrinsic cardiac changes rather than to neural influences. It should be noted that there is a great deal of variability around the regression line between maximal heart rate and age; thus, age-related maximal heart rate is a relatively poor index of maximal effort (see Chapter 5). Maximal heart rate is unchanged or may be slightly reduced after a program of training. Resting heart rate is frequently reduced after training as a result of enhanced parasympathetic tone. Stroke Volume. The product of stroke volume (the volume of blood ejected per heartbeat) and heart rate determines cardiac output. Stroke volume is equal to the difference between end-diastolic and end-systolic volume. Thus, a greater diastolic filling (preload) will normally increase stroke volume. Alternatively, factors that increase arterial blood pressure will resist ventricular outflow (afterload) and result in a reduced stroke volume. During exercise, stroke volume increases up to approximately 50% to 60% of maximal capacity, after which increases in cardiac output are due to further increases in heart rate. The extent to which increases in stroke volume during exercise reflect an increase in end-diastolic volume or a decrease in end-systolic volume, or both, is not entirely clear but appears to depend upon ventricular function, body position, and intensity of exercise. In healthy subjects, stroke volume increases at rest and during exercise after a period of exercise training. Although the mechanisms have been debated, evidence suggests that this adaptation is due more to increases in preloadand possibly local adaptations that reduce peripheral vascular resistance than to increases in myocardial contractility. In addition to heart rate, end-diastolic volume is determined by two other factors: filling pressure and ventricular compliance. C H A P T E R 1 Basic Exercise Physiology 5 FIGURE 1-1 Central determinants of maximal oxygen uptake. (From Myers J, Froelicher VF: Hemodynamic determinants of exercise capacity in chronic heart failure. Ann Intern Med 1991;115:377-386.) FIGURE 1-2 Peripheral determinants of maximal oxygen uptake. The a-V O2 difference is the difference between arterial and venous oxygen. Hb, hemoglobin; PAO2, partial pressure of alveolar oxygen; VE, minute ventilation. (From Myers J, Froelicher VF: Hemodynamic determinants of exercise capacity in chronic heart failure. Ann Intern Med 1991;115:377-386.)

12. Filling Pressure. The most important determinant of ventricular filling is venous pressure. The degree of venous pressure is a direct consequence of the amount of venous return. The Frank- Starling mechanism dictates that, within limits, all the blood returned to the heart will be ejected during systole. As the tissues demand greater oxygen during exercise, venous return increases, which in turn increases end-diastolic fiber length (preload), resulting in a more forceful contraction. Venous pressure increases as exercise intensity increases. Over the course of a few beats, cardiac output will equal venous return. A number of other factors affect venous pressure, and therefore filling pressure, during exercise. These factors include blood volume, body position, and the pumping action of the respiratory and skeletal muscles. A greater blood volume increases venous pressure and therefore end-diastolic volume by making more blood available to the heart. Because the effects of gravity are negated, filling pressure is greatest in the supine position. In fact, stroke volume generally does not increase from rest to maximal exercise in the supine position. The intermittent mechanical constriction and relaxation in the skeletal muscles during exercise also enhance venous return. Finally, changes in intrathoracic pressure that occur with breathing during exercise facilitate the return of blood to the heart. Ventricular Compliance. Compliance is a measure of the capacity of the ventricle to stretch in response to a given volume of blood. Specifically, compliance is defined as the ratio of the change in volume to the change in pressure. The diastolic pressure/volume relation is curvilinear; that is, at low end-diastolic pressures, large changes in volume are accompanied by small changes in pressure, and vice versa. At the upper limits of end-diastolic pressure, ventricular compliance declines; that is, the chamber stiffness increases as it fills. Because of the difficulty in measuring end-diastolic pressure during exercise, few data are available concerning ventricular compliance during exercise in humans. End-systolic volume is a function of two factors: contractility and afterload. Contractility. Contractility describes the forceful- ness of the hearts contraction. Increasing contractility reduces end-systolic volume, which results in a greater stroke volume and thus greater cardiac output. This process is precisely what occurs with exercise in the normal individual; the percentage of blood in the ventricle that is ejected with each beat increases, owing to an altered cross-bridge formation. Contractility is commonly quantified by the ejection fraction, the percentage of blood ejected from the ventricle during systole using radionuclide, echocardiographic, or angiographic techniques. Despite its wide application as an index of myocardial contractility, ejection fraction has been repeatedly shown to correlate poorly with exercise capacity. Afterload. Afterload is a measure of the force resisting the ejection of blood by the heart. Increased afterload (or aortic pressure, as is observed with chronic hypertension) results in a reduced ejection fraction and increased end- diastolic and end-systolic volumes. During dynamic exercise, the force resisting ejection in the periphery (total peripheral resistance) is reduced by vasodilation, owing to the effect of local metabolites on the skeletal muscle vasculature. Thus, despite even a fivefold increase in cardiac output among normal subjects during exercise, mean arterial pressure increases only moderately. Volume Response to Exercise. Results of studies evaluating the volume response to exercise have varied greatly. Although the advent of radionuclide techniques in the 1970s offered promise for the noninvasive assessment of ventricular volumes during exercise, the results have been disappointing. Because of technical limitations, most of these studies have been performed in the supine position. Early studies employing radionuclide or echocardiographic techniques during supine exercise among normal subjects reported that end-diastolic volume remained constant or diminished slightly,11-14 increased in the order of 27%,15 or varied greatly depending on the subject.16-18 Among patients with coronary artery disease exercised in the supine position, increases in end-diastolic volume were observed among patients with exercise-induced angina, whereas end-diastolic volume did not change in patients who were asymptomatic. Sharma et al19 and Jones et al20 reported increases in both end-diastolic and end-systolic volumes in patients who developed angina during exercise. Slutsky et al11 reported that end-diastolic volume remained unchanged in patients with coronary artery disease whether or not they developed angina. Manyeri and Kostuk21 reported large increases in both end-systolic and end-diastolic volumes during supine exercise among 20 patients with coronary artery disease, 13 of whom developed angina during exercise. 6 E X E R C I S E A N D T H E H E A R T

13. The ventricular volume response to upright exercise also varies greatly, even in similar populations. The results of some of the major studies in this area are listed in Table 1-2. Among normal subjects, end-diastolic volume has been reported to increase greatly,15,21,22 increase moderately,23-27 or decrease slightly during upright exercise.28-31 End-diastolic volume has been reported to increase in the range of 8% to 56% among patients with coronary artery disease, and end- systolic volume has been shown to increase in the range of 16% to 94% in response to upright exercise.21,23,32-37 Among normal subjects, end- systolic volume has generally been reported to decrease in response to maximal upright exercise (range 4% to 79%).21,23-33,38 Higginbotham et al,22 however, observed a 48% increase in end-systolic volume among normal subjects; others have reported lesser increases. Less is known about the ventricular response to upright exercise in patients with chronic heart failure. Sullivan et al,39 Tomai et al,31 and Delahaye et al40 all observed increases in both end-systolic and end-diastolic volumes from rest to peak exercise ranging between 10% and 20% in patients with left ventricular dysfunction. The inconsistent results concerning the ventricular volume response to both supine and upright exercise have led investigators to raise questions concerning the validity of radionuclide techniques for assessing ventricular function. For example, Jensen et al41 studied the individual variability of radionuclide ventriculography in patients with coronary artery disease with repeat testing for more than 1 year. Although differences in end-diastolic volume measurements between initial and repeat testing were small, the standard deviations of the individual differences between tests at rest and peak exercise were large, on the order of 38 and 49 mL, respectively. Variability in the ejection fraction and end-systolic volume responses to exercise were of a similar magnitude. In light of the apparent shortcomings of the radionuclide techniques, investigators have C H A P T E R 1 Basic Exercise Physiology 7 TABLE 1-2. Ventricular volume response to upright exercise using radionuclide of echocardiographic techniques Percent Percent Investigator Population Technique change EDV change ESV Rerych et al 197823 Normals (n = 30) RN Increase 10 Decrease 35 CAD (n = 20) RN Increase 56 Increase 94 Freeman et al 198134 Normals (n = 10) RN Increase 25 Increase 10 CAD (n = 22) RN Increase 30 Increase 38 Wyns et al 198228 Normals (n = 10) RN Decrease 8 Decrease 65 Manyeri and Kostuk 198321 Normals (n = 22) RN Increase 31 Decrease 22 Crawford et al 198333 CAD (n = 10) Echo Increase 8 Increase 22 CAD (n = 20) RN Increase 45 Increase 48 Kalischer et al 198436 CAD (n = 18) RN Increase 27 Increase 48 CAD (n = 10) RN Increase 24 Increase 38 Hakki and Iskandrian 198543 Mixed (n = 117) RN Increase 15 Shen et al 198535 Normals (n = 17) RN Increase 22 Increase 27 CAD (n = 14) RN Increase 26 Increase 29 Higginbotham et al 198622 Normals (n = 24) RN Increase 45 Increase 48 Iskandrian and Hakki 198624 Normals (n = 41) RN Increase 6 Decrease 35 Plotnick et al 198627 Normals (n = 30) RN Increase 4 Decrease 50 Renlund et al 198729 Normals (n = 13) RN Decrease 3 Decrease 79 Sullivan et al 198839 CHF (n = 20) RN Increase 20 Increase 20 Ginzton et al 198938 Normals (n = 14) Echo Decrease 26 Decrease 48 Younis et al 199025 Normals (n = 9) RN Increase 17 Decrease 4 Goodman et al 199126 Normals (n = 15) RN Increase 19 Decrease 14 Myers et al 199137 CAD (n = 8) Echo Increase 16 Increase 16 Schairer et al 199230 Normals (n = 15) Echo Decrease 4 Decrease 52 Tomai et al 199232 Normals (n = 12) RN Decrease 8 Decrease 42 Tomai et al 199331 Normals (n = 10) RN Decrease 8 Decrease 43 CHF (n = 10) RN Increase 12 Increase 14 Delahaye et al 199740 CHF (n = 13) RN Increase 15 Increase 23 Lapa-Bula et al 200241 CHF (n = 10) Echo Increase 4 Decrease 5 CAD, coronary artery disease; CHF, chronic heart failure; Echo, echocardiography; EDV, end-diastolic volume or end-diastolic volume index; ESV, end-systolic volume or end-systolic volume index; RN, radionuclide ventriculography.

14. employed alternative methods for quantifying ventricular function during exercise. Crawford et al33 evaluated the feasibility and reproducibility of two-dimensional echocardiography for assessing left ventricular function during exercise. A 9% test-retest difference in end-diastolic volume was demonstrated. End-diastolic volume was reported unchanged from rest to peak exercise in patients with coronary disease, but it increased significantly (20%) from rest to peak exercise in normal subjects. Ginzton et al38 compared athletes with sedentary subjects during upright exercise using two-dimensional echocardiography. After a slight increase in end-diastolic volume submaximally in both groups, end- diastolic volume decreased 39% and 35% at peak exercise among athletes and sedentary subjects, respectively. Although both groups decreased end-systolic volume progressively during exercise, the reduction was greater among the athletes (70% versus 52%). Thus, the ventricular volume response to exercise is not entirely clear, but it appears to depend upon the type of disease, method of measurement (radionuclide or echocardiographic), type of exercise (supine versus upright), and exercise intensity (submaximal versus maximal). Much of the disagreement on this issue can no doubt be attributed to differences in the exercise level at which measurements were taken. With this in mind, some rough generalizations may be made concerning changes in ventricular volume in response to upright exercise. In normal subjects, the response from upright rest to a moderate level of exercise is an increase in both end-diastolic and end-systolic volumes of about 15% and 30%, respectively. As exercise progresses to a higher intensity, end-diastolic volume probably does not increase further,27 but end-systolic volume decreases progressively. At peak exercise, end-diastolic volume may even decline somewhat, while stroke volume is maintained by a progressively decreasing end-systolic volume. Based on six studies that have quantified the volume response of patients with coronary artery disease in the upright position,21,23,34-37 end-diastolic volume has been reported to increase 16% to 56% during exercise. The increase in end-systolic volume has been reported to range from 16% to 48%. An exception, however, is a study performed by Rerych et al23 that reported a 94% increase in end-systolic volume. Sullivan et al,39 Tomai et al,31 and Delahaye et al40 reported approximately 20% increases in both end-systolic and end-diastolic volumes from rest to maximal exercise during upright exercise among patients with chronic heart failure, whereas Lapu-Bula et al42 reported that volumes changed minimally during exercise. Few other data are available for this group in the upright position. Peripheral Factors (a-VO2 Difference) Figure 1-2 shows the peripheral determinants of maximal oxygen uptake. Oxygen extraction by the tissues during exercise reflects the difference between the oxygen content of the arteries (generally 18 to 20 mL O2/100 mL at rest) and oxygen content in the veins (generally 13 to 15 mL O2/100 mL at rest, yielding a typical a-VO2 difference at rest of 4 to 5 mL O2/100 mL, ;23% extraction). During exercise, this difference widens as the working tissues extract greater amounts of oxygen; venous oxygen content reaches very low levels and a-VO2 difference may be as high as 16 to 18 mL O2/100 mL with exhaus- tive exercise (exceeding 85% extraction of oxygen from the blood at VO2 max). Some oxygenated blood always returns to the heart, however, as smaller amounts of blood continue to flow through metabolically less active tissues that do not fully extract oxygen. Generally, a-VO2 difference does not explain differences in VO2 max between subjects who are relatively homogenous. That is, a-VO2 difference is generally considered to widen by a relatively fixed amount during exercise, and differences in VO2 max have been historically explained by differences in cardiac output. However, some patients with cardiovascular or pulmonary disease exhibit reduced VO2 max values that can be attributed to a combination of central and peripheral factors. Determinants of Arterial Oxygen Content. Arterial oxygen content is related to the partial pressure of arterial oxygen, which is determined in the lung by alveolar ventilation and pulmonary diffusion capacity, and in the blood by hemoglobin content. In the absence of pulmonary disease, arterial oxygen content and saturation are usually normal throughout exercise, even at very high levels. This is true even for patients with severe coronary disease or chronic heart failure. However, often patients with symptomatic pulmonary disease neither ventilate the alveoli adequately nor diffuse oxygen from the lung into the bloodstream normally, and a decrease in 8 E X E R C I S E A N D T H E H E A R T

15. arterial oxygen saturation during exercise is one of the hallmarks of this disorder. Arterial hemoglobin content is also usually normal throughout exercise. Naturally, a condition such as anemia would reduce the oxygen-carrying capacity of the blood, along with any condition that would shift the O2 dissociation curve leftward, such as reduced 2, 3-diphosphoglycerate, PCO2, or elevated temperature. Determinants of Venous Oxygen Content. Venous oxygen content reflects the capacity to extract oxygen from the blood as it flows through the muscle. It is determined by the amount of blood directed to the muscle (regional flow) and capillary density. Muscle blood flow increases in proportion to the increase in work rate and thus the oxygen requirement. The increase in blood flow is brought about not only by the increase in cardiac output, but also by a preferential redistribution of the cardiac output to the exercising muscle. A reduction in local vascular resistance facilitates the greater skeletal muscle flow. In turn, locally produced vasodilatory mechanisms, along with neurogenic dilatation resulting from higher sympathetic activity, mediate the greater skeletal muscle blood flow. A marked increase in the number of open capillaries reduces diffusion distances, increases capillary blood volume, and increases mean transit time, facilitating oxygen delivery to the muscle. Cross-sectionally, fit individuals have a greater skeletal muscle capillary density than sedentary subjects. In addition, fit subjects may have a greater capacity to redistribute blood flow toward the working muscle and away from nonexercising tissue. The converse is true in many patients with cardiovascular disease. For example, one of the characteristics of the patient with chronic heart failure is an exaggeration of the deconditioning response. These patients exhibit a reduced capacity to redistribute blood, a reduced capacity to vasodilate in response to exercise or following ischemia, and a reduced capillary-to-fiber ratio. SUMMARY The major cardiopulmonary adaptations that are required of acute exercise make exercise testing a very practical test of cardiac perfusion and function. The rather remarkable physiologic adaptations that occur with exercise have made exercise a valuable research medium not just for the study of cardiovascular disease, but also for studying physical performance in athletes and for studying the normal and abnormal physiology of other organ systems. A major increase and redistribution of cardiac output underlies a series of adjustments that allow the body to increase its resting metabolic rate as much as 10 to 20 times with exercise. The capacity of the body to deliver and utilize oxygen is expressed as the maximal oxygen uptake. Maximal oxygen uptake is defined as the product of maximal cardiac output and maximal arteriovenous oxygen difference. Thus, the cardiopulmonary limits are defined by (1) a central component (cardiac output) that describes the capacity of the heart to function as a pump and (2) peripheral factors (arteriovenous oxygen difference) that describe the capacity of the lung to oxygenate the blood delivered to it and the capacity of the working muscle to extract this oxygen from the blood. Hemodynamic responses to exercise are greatly affected by the type of exercise being performed, by whether or not disease is present, and by the age, gender, and fitness of the individual. Coronary artery disease is characterized by reduced myocardial oxygen supply, which, in the presence of an increased myocardial oxygen demand, can lead to myocardial ischemia and reduced cardiac performance. Despite years of study, a number of dilemmas remain with regard to the response to exercise clinically. Although myocardial perfusion and function are intuitively linked, it is often difficult to separate the impact of ischemia from that of left ventricular dysfunction on exercise responses. Indices of ventricular function and exercise capacity are poorly related. Cardiac output is considered the most important determinant of exercise capacity in normal subjects and in most patients with cardiovascular or pulmonary disease. However, among patients with disease, abnormalities in one or several of the links in the chain that defines oxygen uptake contribute to the determination of exercise capacity. The transport of oxygen from the air to the mitochondria of the working muscle cell requires the coupling of blood flow and ventilation to cellular metabolism. Energy for muscular contraction is provided by three sources: stored phosphates (ATP and creatine phosphate), oxygen- independent glycolysis, and oxidative metabolism. Oxidative metabolism provides the greatest source of ATP for muscular contraction. Muscular contraction is accomplished by three fiber types that differ in their contraction speed, color, and mitochondrial content. The duration and intensity C H A P T E R 1 Basic Exercise Physiology 9

16. of activity determine the extent to which these fuel sources and fiber types are called upon. R E F E R E N C E S 1. Myers J, Froelicher VF: Hemodynamic determinants of exercise capacity in chronic heart failure. Ann Intern Med 1991;115: 377-386. 2. McKirnan MD, Sullivan M, Jensen D, Froelicher VF: Treadmill performance and cardiac function in selected patients with coronary heart disease. J Am Coll Cardiol 1984;3:253-261. 3. Hammond HK, Kelley TL, Froelicher VF: Noninvasive testing in the evaluation of myocardial ischemia: Agreement among tests. J Am Coll Cardiol 1985;5:59-69. 4. Clark AL, Poole-Wilson PA, Coats AJ: Exercise limitation in chronic heart failure: Central role of the periphery. J Am Coll Cardiol 1996;28:1092-1102. 5. American College of Sports Medicine: Guidelines for Exercise Testing and Prescription, 6th ed. Philadelphia, Lea & Febiger, 1999. 6. Brooks GA: Intra- and extra-cellular lactate shuttles. Med Sci Sports Exerc 2000;32:790-799. 7. Brooks GA: Lactate shuttles in nature. Biochem Soc Trans 2002; 30:258-264. 8. Myers J, Ashley E: Dangerous curves: A perspective on exercise, lactate, and the anaerobic threshold. Chest 1997;111:787-795. 9. Saltin B, Henricksson J, Hugaard E, Andersen P: Fiber types and metabolic potentials of skeletal muscles in sedentary man and endurance runners. Ann NY Acad Sci 1977;301:3-29. 10. Hammond K. Froelicher VF: Normal and abnormal heart rate responses to exercise. Prog Cardiovasc Dis 1985;27:271-296. 11. Slutsky R, Karliner J, Ricci D, et al: Response of left ventricular volume to exercise in man assessed by radionuclide equilibrium angiography. Circulation 1979;60:565. 12. Cotsamire DL, Sullivan MJ, Bashore TM, Leier CV: Position as a variable for cardiovascular responses during exercise. Clin Cardiol 1987;10:137-142. 13. Stein RA, Michelli D, Fox EL, Krasnow N: Continuous ventricular dimensions in man during supine exercise and recovery. Am J Cardiol 1978;41:655-660. 14. Bevegard BS, Shepherd JT: Regulation of circulation during exercise in man. Physiol Rev 1967;47:178-213. 15. Poliner LR, Dehmer GJ, Lewis SE, et al: Left ventricular performance in normal subjects: A comparison of the responses to exercise in the upright and supine positions. Circulation 1980;62:528-534. 16. Bristow JD, Klosten FE, Farrahi C, et al: The effects of supine exercise on left ventricular volume in heart disease. Am Heart J 1966;71:319-329. 17. Adams KF, Vincent LM, McAllister SM, et al: The influence of age and gender on left ventricular response to supine exercise in asymptomatic normal subjects. Am Heart J 1987;113:732-742. 18. Granath A, Jonsson B, Strandall T: Circulation in healthy old men, studied by right heart catheterization at rest and during exercise in supine and sitting position. Acta Med Scand 1964; 176:425-446. 19. Sharma B, Goodwin JF, Raphael MJ, et al: Left ventricular angiography on exercise: A new method of assessing left ventricular function in ischemic heart disease. Br Heart J 1976; 38:59-70. 20. Jones R, McEwan P, Newman G, et al: Accuracy of diagnosis of coronary artery disease by radionuclide measurement of left ventricular function during rest and exercise. Circulation 1981;64:586-601. 21. Manyeri DE, Kostuk WJ: Right and left ventricular function at rest and during bicycle exercise in the supine and sitting positions in normal subjects and patients with coronary artery disease. Assessment by radionuclide ventriculography. Am J Cardiol 1983; 51:36-42. 22. Higginbotham MB, Morris KG, Williams RS, et al: Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res 1986;58:281-291. 23. Rerych SK, Scholz PM, Newman GE, et al: Cardiac function at rest and during exercise in normals and in patients with coronary heart disease. Evaluation by radionuclide angiography. Ann Surg 1978;187:449-464. 24. Iskandrian AS, Hakki AH: Determinants of the changes in left ventricular end-diastolic volume during upright exercise in patients with coronary artery disease. Am Heart J 1986;112: 441-446. 25. Younis LT, Melin JA, Robert AR, Detry JMR: Influence of age and sex on left ventricular volumes and ejection fraction during upright exercise in normal subjects. Eur Heart J 1990; 11:916-924. 26. Goodman JM, Lefkowitz CA, Liu PP, et al: Left ventricular functional response to moderate and intense exercise. Can J Sport Sci 1991;16:204-209. 27. Plotnick GD, Becker L, Fisher ML, et al: Use of the FrankStarling mechanism during submaximal versus maximal upright exercise. Am J Physiol 1986;251:H1101-H1105. 28. Wyns W, Melin JA, Vanbutsele RJ, et al: Assessment of right and left ventricular volumes during upright exercise in normal men. Eur Heart J 1982;3:529-536. 29. Renlund DG, Lakatta EG, Fleg JL, et al: Prolonged decrease in cardiac volumes after maximal upright bicycle exercise. J Appl Physiol 1987;63:1947-1955. 30. Schairer JR, Stein PD, Keteyian S, et al: Left ventricular response to submaximal exercise in endurance-trained athletes and sedentary adults. Am J Cardiol 1992;70:930-933. 31. Tomai F, Ciavolella M, Crea F, et al: Left ventricular volumes during exercise in normal subjects and patients with dilated cardiomyopathy assessed by first-pass radionuclide angiography. Am J Cardiol 1993;72:1167-1171. 32. Tomai F, Ciavolella M, Gaspardone A, et al: Peak exercise left ventricular performance in normal subjects and in athletes assessed by first-pass radionuclide angiography. Am J Cardiol 1992;70:531-535. 33. Crawford MH, Amon KW, Vance WS: Exercise 2-dimensional echocardiography. Quantitation of left ventricular performance in patients with severe angina pectoris. Am J Cardiol 1983; 51:1-6. 34. Freeman MR, Berman DS, Staniloff H, et al: Comparison of upright and supine bicycle exercise in the detection and evaluation of extent of coronary artery disease by equilibrium radionuclide ventriculography. Am Heart J 1981;102:182-189. 35. Shen WF, Roubin GS, Choong CY-P, et al: Left ventricular response to exercise in coronary artery disease: Relation to myocardial ischemia and effects of nifedipine. Eur Heart J 1985; 6:1025-1031. 36. Kalisher AL, Johnson LL, Johnson YE, et al: Effects of propranolol and timolol on left ventricular volumes during exercise in patients with coronary artery disease. J Am Coll Cardiol 1984; 3:210-218. 37. Myers J, Wallis J, Lehmann K, et al: Hemodynamic determinants of maximal ventilatory oxygen uptake in patients with coronary artery disease. Circulation 1991;84:II-150. 38. Ginzton LE, Conant R, Brizendine M, Laks MM: Effect of long- term high-intensity aerobic training on left ventricular volume during maximal upright exercise. J Am Coll Cardiol 1989;14: 364-371. 39. Sullivan MJ, Higginbotham MB, Cobb FR: Exercise training in patients with severe left ventricular dysfunction. Hemodynamic and metabolic effects. Circulation 1988;78:506-515. 40. Delahaye N, Cohen-Solal A, Faraggi M, et al: Comparison of left ventricular responses to the six-minute walk test, stair climbing, and maximal upright bicycle exercise in patients with congestive heart failure due to idiopathic dilated cardiomyopathy. Am J Cardiol 1997;80:65-70. 41. Lapu-Bula R, Robert A, Van Craeynest D, et al: Contribution of exercise-induced mitral regurgitation to exercise stroke volume and exercise capacity in patients with left ventricular systolic dysfunction. Circulation 2002;106:1342-1348. 42. Jensen DG, Genter F, Froelicher VF, et al: Individual variability of radionuclide ventriculography in stable coronary artery disease patients over one year. Cardiology 1984;71:255-265. 43. Hakki AH, Iskandrian AS: Determinants of exercise capacity in patients with coronary artery disease: Clinical implications. J Cardiac Rehabil 1985;5:341-348. 10 E X E R C I S E A N D T H E H E A R T

17. 11 C H A P T E R two Exercise Testing Methodology Despite the many advances in technology related to the diagnosis and treatment of cardiovascular disease, the exercise test remains an important diagnostic modality. Its numerous applications, widespread availability, and high yield of clinically useful information continue to make it an important gatekeeper for more expensive and invasive procedures. However, the many different approaches to the exercise test have been a draw- back to its proper application. Excellent guidelines have been updated by organizations such as the American Heart Association, American Association of Cardiovascular and Pulmonary Rehabilitation, and American College of Sports Medicine. These guidelines are based on a multi- tude of research studies over the last 30 years and have led to greater uniformity in methods. Nevertheless, in many laboratories, methodology remains based on tradition, convenience, equipment, or personnel available. New technology, while adding convenience, has also raised new questions with regard to methodology. For example, all commercially available systems today depend upon computers. Do computer-averaged exercise electrocardio- grams (ECGs) improve test accuracy, and should the practitioner rely on this processed information or on the raw data? What about the many computerized exercise scores that now can so easily be calculated? Technology has changed the exercise-testing laboratory environment, and concerns such as these have arisen. Though many of these techniques are attractive, in many instances not enough data are yet available to validate them, so they should be used judiciously. Also, what about the various ancillary tests and the nonexercise stress modalities? In this chapter, we will address basic methodology and comment on the impact these advances in technology have had. We start by listing the advantages and disadvantages of exercise ECG testing. These considerations are important because the health care provider must evaluate the suitability of the various testing modalities in each situation. ADVANTAGES AND DISADVANTAGES OF EXERCISE ECG TESTING ADVANTAGES OF THE STANDARD EXERCISE ECG TEST 1. Low cost 2. Availability of trained personnel 3. Exercise capacity determined 4. Patient acceptability 5. Takes less than an hour to accomplish 6. Convenience 7. Availability 8. Long history of use, validation of responses, application of multivariate scores

18. SAFETY PRECAUTIONS AND RISKS The safety precautions outlined by the American Heart Association are very explicit in regard to the requirements for exercise testing. Everything necessary for cardiopulmonary resuscitation must be available, and regular drills should be performed to ascertain that both personnel and equipment are prepared for a cardiac emergency. The classic survey of clinical exercise facilities by Rochmis and Blackburn in 19711 showed exercise testing to be a safe procedure, with approximately only one death and five nonfatal complications per 10,000 tests. Perhaps because of an expanded knowledge concerning indications, contraindications, and endpoints, data suggest that maximal exercise testing is safer today than 30 years ago. In 1989, Gibbons et al2 reported the safety of exercise testing in 71,914 tests conducted over a 16-year period. The complication rate was 0.8 per 10,000 tests. In a recent survey of 71 exercise testing laboratories throughout the Veterans Administration Health Care System including 75,828 tests, we observed an event rate of 1.2 per 10,000 tests.3 The fact that the event rate was similar between a clinically referred population (the Veterans Administration, a higher risk group), and a generally healthier population2 underscores the fact that the test is extremely safe. Gibbons et al2 suggested that the low complication rate in their study was due to the inclusion of a cool-down walk, but we have observed a low rate of ventricular tachycardia,4 and a low overall complication rate3 despite having patients assume a supine position immediately after the test and despite exercising higher risk patients.This issue is addressed in more detail in Chapter 13, and a summary of these studies is presented in Table 13-6. However, it is important to note that there have been reports of complications, including acute infarctions and deaths, associated with exercise testing. Although the test is remarkably safe, the population referred for this procedure usually is at high risk for coronary events. Irving and Bruce5 have reported an association between exercise-induced hypotension and ventricular fibrillation. Shepard6 has hypothesized the following risk levels for exercise: (1) three or four times normal in a cross-country foot race, (2) 6 to 12 times normal when patients at risk for coronary artery disease (CAD) are performing unac- customed exercise, and (3) as high as 60 times normal when patients with existing CAD are performing exercise in a stressful environment, such as a physicians office. Cobb and Weaver7 estimated the risk to be over 100 times in the latter situation and point out the dangers of the recovery period. The risk of exercise testing in patients with CAD cannot be disregarded even with its excellent safety record. Studies documenting the risks of exercise training are presented in more detail in Chapter 12. Indications to stop an exercise test, in addition to the factors to consider in assessing the degree of exertion, are outlined in Table 2-1. Most problems can be avoided by having an experienced physician, nurse, or exercise physiologist standing next to the patient, measuring blood pressure, and assessing patient appearance during the test. The exercise technician should operate the recorder and treadmill, take the appropriate tracings, enter data on a form, and alert the physician to any abnormalities that may appear on the monitor scope. If the patients appearance is worrisome, if systolic blood pressure drops or plateaus, if there are alarming ECG abnormalities, if chest pain occurs and becomes worse than the patients usual pain, or if the patient wants to stop the test for any reason, the test should be stopped, even at a submaximal level. In most instances, a symptom- limited maximal test is preferred, but it is usually advisable to stop if 0.2 mV of additional ST-segment elevation occurs, or if 0.2 mV of flat or downsloping ST-segment depression occurs. In some patients estimated to be at high risk because of their clinical history, it may be appropriate to stop at a submaximal level, as it is not unusual for severe ST-segment depression, dysrhythmias, or both to occur in the postexercise period. If the measurement of maximal exercise capacity or other information is needed, it may be preferable to repeat the test later, once the patient has demonstrated a safe performance of a submaximal workload. Exercise testing should be an extension of the history and physical examination. A physician obtains the most information by being present to talk with, observe, and examine the patient in 12 E X E R C I S E A N D T H E H E A R T DISADVANTAGES OF EXERCISE ECG TESTING 1. Limited sensitivity and specificity 2. Inability to localize ischemia or coronary lesions. 3. No estimate of left ventricular (LV) function 4. Not suitable for certain patients. 5. Requires cooperation and the ability to walk or pedal a cycle ergometer.

19. conjunction with the test. A brief physical examination should always be performed to rule out any contraindications that exist. Accordingly, individuals who supervise exercise tests must have the cognitive and technical skills necessary to be competent to do so. The American College of Cardiology, American Heart Association, and the American College of Physicians, with broad involvement from other professional organizations involved with exercise testing, such as the American College of Sports Medicine, have outlined the cognitive skills needed to competently supervise exercise tests.8 These skills include knowledge of appropriate indications and contraindications to testing, an understanding of risk assessment, the ability to recognize and treat complications, and knowledge of basic cardiovascular and exercise physiology, along with the ability to interpret the test in different patient populations. The need for physician presence during exercise testing has been the subject of a great deal of discussion in the past. In many cases, exercise tests can be supervised by properly trained and competent exercise physiologists, physical thera- pists, nurses, physician assistants, or medical technicians who are working under the direct supervision of a physician. However, the physician must be in the immediate vicinity or on the prem- ises or the floor and available for emergencies.8,9 In situations where the patient is deemed to be at higher risk for an adverse event during exercise testing, the physician should be physically present in the exercise testing room to personally supervise the test. Such cases include, but are not limited to, patients with recent acute coronary syndrome or myocardial infarction (within 7 to 10 days), severe LV dysfunction, severe valvular stenosis (e.g., aortic stenosis), or known complex arrhythmias. The physicians reaction to signs or symptoms should be moderated by the information the patient gives regarding his or her usual activity. If abnormal findings occur at levels of exercise that the patient usually performs, then it may not be necessary to stop the test for them. Also, the patients activity history should help determine appropriate work rates for testing. CONTRAINDICATIONS Table 2-2 lists the absolute and relative contraindications to performing an exercise test. C H A P T E R 2 Exercise Testing Methodology 13 TABLE 2-1. Indications for terminating an exercise test and assessment of maximal effort Absolute Reasons or Indications to Terminate Acute myocardial infarction Severe anginachest pain score of 4 out of 4 Exertional hypotensiona drop in systolic blood pressure of 10 mmHg, or drop below the value obtained in the standing position prior to testing, particularly in patients who have heart failure, have had a prior myocardial infarction, or are exhibiting signs or symptoms of ischemia 1.0 mm ST elevation in leads without diagnostic Q waves Serious arrhythmiasventricular tachycardia, third-degree heart block Poor perfusion as judged by skin temperature and cyanosis Neurologic signsconfusion, lightheadedness, vertigo Technical problemsinability to interpret the ECG pattern; any malfunction of the recording or monitoring device; inability to measure the systolic blood pressure Patients request to terminate Relative Reasons or Indications to Terminate The following indications may be superseded if done so in the context of good clinical judgment. Increasing chest painchest pain score of 3 out of 4 2.0 mm horizontal or downsloping ST depression Pronounced fatigue or shortness of breath Wheezing Leg pain or claudication Increase in systolic blood pressure to 250 mmHg or increase in diastolic blood pressure to 115 mmHg Less serious arrhythmias than those in preceding list (frequent or mutifocal premature ventricular contractions, supraventricular tachycardia, bradyarrhythmias) Bundle branch block or another rate-dependent intraventricular conduction defect that cannot be distinguished from ventricular tachycardia Assessment of Maximal Effort As no single marker of effort is usually specifically indicative of a maximal effort, it is best to consider multiple responses. Borg scale 17-20 Signs of fatigue, profound shortness of breath, or exhaustion Age-predicted maximal heart rate, with a population-specific regression equation Expired gas measurements, including respiratory exchange ratio (>1.10)

20. Good clinical judgment should be foremost in deciding the indications and contraindications for exercise testing. In selected cases with relative contraindications, testing can provide valuable information even if performed submaximally. PATIENT PREPARATION Preparations for exercise testing include the following: 1. The patient should be instructed not to eat or smoke at least 2 to 3 hours prior to the test and to come dressed for exercise. 2. A brief history and physical examination (particularly for patients with systolic murmurs) should be performed to rule out any contraindications to testing (see Table 2-2). 3. Specific questioning should determine which drugs are being taken, and potential electrolyte abnormalities should be considered. The labeled medication bottles should be brought along so that they can be identified and recorded. It is generally no longer considered necessary for most patients to stop taking their beta-blockers prior to testing. If it is considered necessary to do so in selected patients, they should be stopped gradually in order to avoid the rebound phenomenon, which can be dangerous. The tapering of beta-blockers should be over- seen by a physician. 4. If the reason for the exercise test is not apparent, the referring physician should be contacted such that this gets clarified. 5. A 12-lead ECG should be obtained in both the supine and standing positions. The latter is an important rule, particularly for patients with known heart disease, since an abnormality may prohibit testing. On rare occasions, a patient referred for an exercise test will instead be admitted to the coronary care unit. 6. The patient should receive careful explana- tions of why the test is being performed and of the testing procedure, including its risks and possible complications. A demonstration should be provided of how to get on and off the treadmill and how to walk on it. The patient should be told that he or she can hold on to the handrails initially but then should use the rails only for balance (discussed in the following section). TREADMILL The treadmill should have front and side rails for patients to steady themselves, and some patients may benefit from the helping hand of the person administering the test. The treadmill should be calibrated at least monthly. Some models can be greatly affected by the weight of the patient and 14 E X E R C I S E A N D T H E H E A R T TABLE 2-2. Contraindications to exercise testing Absolute Acute myocardial infarction (within 2 days) Unstable angina not stabilized by medical therapy Uncontrolled cardiac arrhythmias causing symptoms or hemodynamic compromise Symptomatic severe aortic stenosis Uncontrolled symptomatic heart failure Acute pulmonary embolus or pulmonary infarction Acute myocarditis or pericarditis Relative* Left main coronary stenosis or its equivalent Moderate stenotic valvular heart disease Electrolyte abnormalities Uncontrolled arterial hypertension Tachyarrhythmias or bradyarrhythmias Hypertrophic cardiomyopathy and other forms of outflow tract obstruction Mental or physical impairment leading to inability to exercise adequately High-degree atrioventricular block *Relative contraindications can be superseded if benefits outweigh risks of exercise. In the absence of definitive evidence, a systolic blood pressure of 200 mmHg and a diastolic blood pressure of 110 mmHg are reasonable criteria.

21. will not deliver the appropriate workload to heavy patients. An emergency stop button should be readily available to the staff only. A small platform or stepping area at the level of the belt is advisable so that the patient can start the test by pedaling the belt with one foot prior to stepping on. After they become accustomed to the treadmill, patients should not grasp the front or side rails, as this decreases the work performed and thus the oxygen uptake, which increases exercise time, resulting in an overestimation of exercise capacity. Gripping the handrails also increases ECG muscle artifact. For patients who have difficulty letting go of the handrails, it is helpful to have them take their hands off the rails, close their fists, and extend one finger on each hand, touch- ing the rails only with those fingers in order to maintain balance while walking. Some patients may require a few moments before they feel com- fortable enough to let go of the handrails, but we strongly discourage grasping the handrails after the first minute of exercise. LEGAL IMPLICATIONS OF EXERCISE TESTING In any procedure with a risk of complications, it is advisable to make certain the patient understands the situation and acknowledges the risks. Some physicians feel that informing patients of the risks involved will occasionally make them overly anxious or discourage them from performing the test. Because of this, and the fact that a signed consent form does not necessarily protect a physician from legal action, there has been less insistence on consent forms. However, a great deal of case law exists suggesting that a written informed consent before the exercise test is important to protect the patient, physician, and institution. Establishment of physician-patient communication before and after performance of the exercise test should be the first legal consideration. A test should not be performed without first obtaining the patients informed consent, after the patient is made aware of the potential risks and benefits of the procedure. A physician may be held responsible in the event of a major untoward event, even if the test is carefully performed, in the absence of informed consent. The argument can be made that the patient would not have undergone the procedure had he or she been made aware of the risks associated with the test. After the test, responsibility rests with the physician for prompt interpretation and consideration of the implications of the test. Communication of these results to the patient is necessarywith advice concerning adjustments in lifestyleand this should be done immediately after the test is performed. The second consideration should be adherence to proper standards of care during performance of the test. Exercise testing should be carried out only by persons thoroughly trained in its administration and in the prompt recognition of problems that may arise. A physician trained in exercise testing and resuscitation should be readily available during the test to make judgments concerning test termination. Resuscitative equipment should always be available. As mentioned above, an updated joint position statement from several professional organizations was published in 2000, outlining the standards for physician competence for performing exercise testing.8 BLOOD PRESSURE MEASUREMENT Although numerous clever devices have been developed to automate blood pressure measurement during exercise, none can be recommended. The time-proven method of the physician hold- ing the patients arm with a stethoscope placed over the brachial artery remains the most reliable method to obtain the blood pressure. The patients arm should be free of the handrails so that noise is not transmitted up the arm. It is sometimes helpful to mark the brachial artery. An anesthesiologists auscultatory piece or an electronic microphone can be fastened to the arm. A device that inflates and deflates the cuff on the push of a button can also be helpful. If systolic blood pressure appears to be increasing sluggishly or decreasing, it should be taken again immediately. If a drop in systolic blood pressure of 10 to 20 mmHg or more occurs, or if it drops below the value obtained in the standing position prior to testing, the test should be stopped. This is particularly important in patients who have heart failure, a prior myocardial infarction, or are exhibiting signs or symptoms of ischemia. An increase in systolic blood pressure to 250 mmHg or an increase in diastolic blood pressure to 115 mmHg are also indications to stop the test. The clinical implications of abnormal blood pressure responses to the exercise test are discussed in detail in Chapter 5. C H A P T E R 2 Exercise Testing Methodology 15

22. ECG RECORDING INSTRUMENTS Many technologic advances in ECG recorders have taken place. The medical instrumentation industry has promptly complied with specifications set forth by various professional groups. Machines with high-input impedance ensure that the voltage recorded graphically is equivalent to that on the surface of the body despite the high natural impedance of the skin. There remains some concern about mismatching lead impedance, which can result in distortion. Optically isolated buffer amplifiers have ensured patient safety, and machines with a frequency response from 0 to 100 Hz are commercially available. The 0 Hz lower end is possible because DC coupling is technically feasible. Some ECG equipment has monitoring and diagnostic modes, particularly equipment used in coronary care units. The diagnostic mode follows diagnostic instrument specifications with a frequency response from 0.05 to 100 Hz. In the monitor mode, there can be distortion of the ECG. The monitor mode is available to lessen the effects of electrical interference, motion, and respiration on the ECG and should not be used for exercise testing. The type of distortion is affected by the ECG waveform that is presented. If the ECG waveform is a tall R wave without an S wave, the ST-segment distortion can be different than if there is an R wave followed by a large S wave. In general, an inadequate low-frequency response can greatly decrease the Q- and R-wave amplitude and create S waves. Alteration of the 25 to 45 Hz frequency response is the most common cause of ST-segment distortion found in tracings with abnormal ST segments. Some of the newer filtering techniques delay the appearance of the ECG signal on the monitor screen by several seconds. WAVEFORM AVERAGING Digital averaging techniques have made it possible to average ECG signals to remove noise. There is a need for consumer awareness in these areas, since most manufacturers do not specify how the use of such procedures modifies the ECG. Signal averaging can actually distort the ECG signal. These techniques are attractive because they can produce a clean tracing in spite of poor skin preparation. However, the common expression used by computer scientists, Garbage in, garbage out, has never been more applicable than to the computerized ECG. The clean-looking exercise ECG signal produced may not be a true represen- tation of the actual waveform and in fact may be dangerously misleading. Also, the instruments that make computer ST-segment measurements cannot be totally reliable as they are based on imperfect algorithms. For instance, the algorithm that measures QRS end at 70 or 80 msec after the peak of the R wave can hardly be valid, particularly with a changing heart rate. Because of physician insistence on having exercise tracings as clean as resting tracings, manufacturers have taken some worrisome steps with filtering and ECG presentation. One such approach is linked medians, in which averages are connected together at the same R-R interval as raw data. Even though these tracings are appropriately labeled, and often presented with a channel of raw data as well, most physicians do not realize that they are dealing with created waveforms instead of raw data. ECG PAPER RECORDERS For some patients it is advantageous to have a recorder with a slow paper speed option such as 5 mm/sec. This speed makes it possible to record an entire exercise test and reduces the likelihood of missing any dysrhythmias when specifically evaluating patients with these problems. A faster paper speed of 50 mm/sec can be helpful for making accurate ST-segment slope measurements. Many different types of ECG paper can be used. Wax-treated paper is known to retain an ECG image for 20 years or longer; however, it is pressure- sensitive and easily marked. Thermochemically treated paper is sturdy and resists marking. There are many different types of thermochemically treated paper, and the life expectancy of images recorded on them is usually adequate. However, at least one instance of ECG paper losing a recorded image resulted in legal action by a hos- pital against a manufacturer. Ceramic-coated paper is very sturdy and comparable in price to other ECG papers. It has a hard finish with a high contrast, which makes it durable and easy to interpret. Untreated paper is the cheapest ECG paper, but the ink-jet and carbon-transfer techniques characteristically produce

Exercise & the heart

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Transcript of Exercise & the heart