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Principles of Exercise Testing and Interpretation Including Pathophysiology and Clinical Applications Fifth Edition 000i-0xvi_Was...

Principles of Exercise Testing and Interpretation Including Pathophysiology and Clinical Applications Fifth Edition 000i-0xvi_Wasserman_29774_FM.indd i 9/24/11 3:06:17 AM 000i-0xvi_Wasserman_29774_FM.indd ii 9/24/11 3:06:17 AM  Principles of Exercise Testing and Interpretation Including Pathophysiology and Clinical Applications Fifth Edition Karlman Wasserman, MD, PhD Kathy E. Sietsema, MD Professor of Medicine, David Geffen School of Medicine at UCLA Professor of Medicine, David Geffen School of Medicine at UCLA Division of Respiratory and Critical Care Physiology and Medicine Chief, Division of Respiratory and Critical Care Physiology Department of Medicine and Medicine Harbor–UCLA Medical Center Department of Medicine Torrance, California Harbor-UCLA Medical Center Torrance, California James E. Hansen, MD Professor of Medicine, David Geffen School of Medicine at UCLA Xing-Guo Sun, MD Division of Respiratory and Critical Care Physiology and Medicine Professional Research Scientist Department of Medicine Division of Respiratory and Critical Care Physiology and Medicine Harbor–UCLA Medical Center Department of Medicine Torrance, California Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center Darryl Y. Sue, MD Torrance, California Professor of Medicine, David Geffen School of Medicine at UCLA Division of Respiratory and Critical Care Physiology and Medicine Brian J. Whipp, PhD, DSc Department of Medicine Emeritus Professor of Physiology, St. George’s Hospital Harbor–UCLA Medical Center Medical School Torrance, California University of London, United Kingdom and University of California Los Angeles, School of Medicine William W. Stringer, MD Los Angeles, California Professor of Medicine, David Geffen School of Medicine at UCLA Chair, Department of Medicine Harbor–UCLA Medical Center Torrance, California 000i-0xvi_Wasserman_29774_FM.indd iii 9/24/11 3:06:17 AM  Acquisitions Editor: Frances R. DeStefano Product Manager: Leanne Vandetty Production Manager: Alicia Jackson Senior Manufacturing Manager: Benjamin Rivera Marketing Manager: Kimberly Schonberger Design Coordinator: Teresa Mallon Production Service: Absolute Service, Inc. © 2012 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business Fourth Edition © 2005 by LIPPINCOTT WILLIAMS & WILKINS Third Edition © 1999 by LIPPINCOTT WILLIAMS & WILKINS Second Edition © 1994 by Lea & Febiger Two Commerce Square 2001 Market Street Philadelphia, PA 19103 USA LWW.com All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. Printed in China Library of Congress Cataloging-in-Publication Data 9781609138998 1609138996 Principles of exercise testing and interpretation : including pathophysiology and clinical applications / Karlman Wasserman... [et al.]. — 5th ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-60913-899-8 (hardback : alk. paper) I. Wasserman, Karlman. [DNLM: 1. Exercise Test. 2. Physical Exertion—physiology. 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Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6 pm, EST. 10 9 8 7 6 5 4 3 2 1 000i-0xvi_Wasserman_29774_FM.indd iv 9/24/11 3:06:17 AM  To Our Families 000i-0xvi_Wasserman_29774_FM.indd v 9/24/11 3:06:17 AM 000i-0xvi_Wasserman_29774_FM.indd vi 9/24/11 3:06:17 AM  Preface I n this fifth edition of Principles of Exercise Testing and Interpretation, as in earlier editions, we attempt to develop conceptual advances in the physiology and ology. In particular, Chapters 2, 3, 4, 5, and 10 provide extensive information about changes in arterial, mixed venous, and femoral vein blood gases and arterial lactate pathophysiology of exercise, particularly as related to the during lower extremity exercise. These chapters are valu- practice of medicine. The underlying theme of the book able for differentiating the function of the peripheral from continues to be the recognition that the most important central circulations and describe mechanisms that enable requirement for exercise performance is transport of oxy- favorable shifts in the oxyhemoglobin and CO2 dissocia- gen to support the bioenergetic processes in the muscle tion curves to optimize arterial-venous differences and cells (including, of course, the heart) and elimination minimize changes in muscle capillary PO2 and PCO2. of the carbon dioxide formed as a byproduct of exercise The gas exchange responses to exercise can indicate metabolism. Thus, appropriate cardiovascular and ven- to the investigator which organ(s) are functioning poorly tilatory responses are required to match those of muscle and which are functioning well. Because the pattern of respiration in meeting the energy demands of exercise. the gas exchange response is characteristic of the disease As depicted by the logo on the book cover, normal process, it can enable a clinical diagnosis. For instance, exercise performance requires an efficient coupling of cardiopulmonary exercise testing might not only detect external to internal (cellular) respiration. Appropriate cardiovascular limitation, but could also be used to distin- treatment of exercise intolerance requires that patients’ guish which cardiovascular disease restricts the patient’s symptoms be thought of in terms of a gas exchange defect exercise performance when several might coexist, such between the cell and the environment. The defect may as coronary artery disease, chronic heart failure, and pe- be in the lungs, heart, peripheral or pulmonary circula- ripheral vascular disease. Chapter 8 describes a flowchart tions, the muscles themselves, or there may be a combi- approach to assist in making a clinical diagnosis, using nation of defects. Thus, we describe the pathophysiology the physiological data obtained during cardiopulmonary in gas transport and exchange that affect any site in the exercise testing. It is likely that no test in medicine can cardiorespiratory coupling between the lungs and the be used to diagnose the broad spectrum of diseases, while muscles. quantifying severity of organ dysfunction or improvement We illustrate how cardiopulmonary exercise testing in the pathophysiology of exercise intolerance, better and can provide the means for a critical evaluation by the more cheaply than cardiopulmonary exercise testing. As clinician-scientist of the functional competency of each a referral center for problematic cases, we are often im- component in the coupling of cellular to external respira- pressed with the revelations of pathophysiology provided tion, including the cardiovascular system. To achieve this, by cardiopulmonary exercise testing. clinical cases are used to illustrate the wide spectrum of This book describes how to evaluate the patient with pathophysiology capable of causing exercise intolerance. exercise intolerance using the physiology and pathophys- The primary symptoms causing exercise intolerance, iology of exercise gas exchange as frames of reference. typically dyspnea and/or fatigue, are shown to have a ra- The absence of detailed electrocardiographic displays tional pathophysiological basis. Without cardiopulmonary in this book should not be interpreted to mean that the exercise testing, the treatment of patients with exer- authors do not regard the electrocardiogram (ECG) to be cise intolerance may be improperly focused because the an essential component of exercise testing. On the con- pathophysiology causing the exercise intolerance may not trary, we routinely record and analyze a 12-lead ECG be well understood by the physician working within the throughout the exercise test. However, interpretation of diagnostic spectrum of his or her subspecialty. Exertional the exercise ECG is beyond the scope of this book and is dyspnea and/or fatigue at unusually low levels of exercise thoroughly covered elsewhere. We therefore only provide can often be traced to abnormal coupling of the cardiopul- the interpretation of the ECG records in the case discus- monary mechanisms required for normal gas exchange. sions in Chapter 10. Therefore, by measuring gas exchange during cardiopul- To provide important background information on monary exercise tests, not only can the exercise limitation the interpretation of exercise tests, we devote the first be quantified, but the functional adequacy of the heart, three chapters to the bioenergetic and physiological prin- circulatory system, and lungs also can be established. ciples underpinning exercise performance. We apply Fortunately, this can usually be done noninvasively. this knowledge to establish specific variables that can be We believe that each chapter of this book makes orig- used to detect abnormalities in function during exercise inal contributions to the understanding of exercise physi- in Chapter 4. The pathophysiology of exercise limitation vii 000i-0xvi_Wasserman_29774_FM.indd vii 9/24/11 3:06:17 AM  viii PREFACE caused by diseases of the cardiovascular, respiratory, mus- calculations. Although of special importance to anyone culoskeletal, and other systems is presented in Chapter 5. wishing to establish a laboratory, this information can Chapter 6 describes how to prepare the patient for and how also be very helpful to the interpreter’s understanding of to perform a cardiopulmonary exercise test, with Chapter the technical aspects of the measurements and calcula- 7 providing an analysis of normal gas exchange values tions used in cardiopulmonary exercise testing. in both adults and children. In Chapter 8, an interpre- We designed the content of this book to help car- tive approach for making specific diagnoses is presented, diologists, pulmonologists, and exercise physiologists using flowcharts and physiological data derived from the maximize the knowledge gained from computerized mea- cardiopulmonary exercise test. Chapter 9 describes the surements of gas exchange during exercise. Thus, it is de- expanding applications in which the uses of cardiopul- signed as a guide for those who wish to use cardiopulmo- monary exercise testing have been applied. Importantly, nary exercise testing to (1) diagnose the pathophysiology this chapter describes certain clinical diagnoses that can of exercise limitation; (2) evaluate the severity of a pa- only be made by cardiopulmonary exercise testing. The tient’s pathophysiology; (3) evaluate the effect of medical final chapter consists of 110 cases (80 in the book and or surgical therapy; and (4) provide a physiological basis 30 online) in which cardiopulmonary exercise tests have for assessing training strategies for patients undergoing been of diagnostic and/or therapeutic value. Each was a exercise rehabilitation or athletes in training. This book referral case, studied to answer a specific clinical ques- spans the field of exercise from teaching basic concepts tion, or selected to make a teaching point with respect to in exercise physiology to providing a meaningful report the pathophysiology of specific diseases. for the medical record. Our goal was to write a compre- Detailed practical information is provided in the hensive yet practical book that could be used for multiple appendices to assist in the technical support of a new purposes by physiologists, cardiologists, pulmonologists, laboratory, testing the subject, and making necessary other physicians, and exercise technicians. 000i-0xvi_Wasserman_29774_FM.indd viii 9/24/11 3:06:18 AM  Acknowledgments We are very much indebted to Leah Kram for her highly Finally, we are grateful to our colleagues, our for- intelligent editing of the chapters of this fifth edition, as mer fellows and students, and the many physicians she has for prior editions. Her dedication to this book and scientists who have participated in our semiannual made its completion possible in a timely fashion. postgraduate course (practicum) in exercise testing and We are also indebted to William L. Beaver, PhD, for interpretation over the last 29 years, for which the four the analysis of oscillatory gas exchange of Case 14 of prior editions served as a syllabus. This fi fth edition Chapter 10. benefits from the many useful discussions we have had We also want to express our gratitude to Dr. Dan with former course participants, as well as the knowl- M. Cooper, Professor of Pediatrics at the University of edge gained from new research. These have served as California at Irvine, California, for his excellent contri- a milieu for improving our understanding of exercise bution to the section on exercise gas exchange in normal physiology and pathophysiology and have helped to children in Chapter 7. close the gap between physiologic knowledge and the In addition, we would like to express our apprecia- application of cardiopulmonary exercise testing to solve tion to Piergiuseppe Agostoni, Professor of Cardiology at clinical problems. the University of Milan, Milan, Italy, for his overreading K.W. is especially indebted to his wife, Gail, for tol- and helpful suggestions on the heart failure section in erating his diversions during innumerable evenings and Chapter 5. weekends in his effort to see this edition completed. ix 000i-0xvi_Wasserman_29774_FM.indd ix 9/24/11 3:06:18 AM 000i-0xvi_Wasserman_29774_FM.indd x 9/24/11 3:06:18 AM  Contents Preface vii Acknowledgments ix CHAPTER 1 Exercise Testing and Interpretation............................................... 1 CHAPTER 2 Physiology of Exercise......................................................... 9 CHAPTER 3 Changes in Blood Gases and pH during Exercise.................................... 62 CHAPTER 4 Measurements during Integrative Cardiopulmonary Exercise Testing...................... 71 CHAPTER 5 Pathophysiology of Disorders Limiting Exercise..................................... 107 CHAPTER 6 Clinical Exercise Testing...................................................... 129 CHAPTER 7 Normal Values............................................................ 154 CHAPTER 8 Diagnostic Specificity of Exercise Intolerance: A Flowchart Approach.................... 181 CHAPTER 9 Clinical Applications of Cardiopulmonary Exercise Testing............................ 194 CHAPTER 10 Case Presentations........................................................ 235 Case 1. Normal Man.............................................................. 238 Case 2. Normal Athletic Man....................................................... 241 Case 3. Normal Woman: Air and Oxygen Breathing Studies................................. 244 Case 4. Normal Man.............................................................. 249 Case 5. Exceptionally Fit Man with Mild Lung Disease..................................... 252 Case 6. Normal Subject: Cycle and Treadmill Studies...................................... 255 Case 7. Normal Subject: Before and After β-Adrenergic Blockade............................ 260 Case 8. Normal Subject: Immediate Effects of Cigarette Smoking............................. 265 Case 9. Active Normal Man with Suspected Cardiac Disease................................ 271 Case 10. Normal Sedentary Woman.................................................. 276 Case 11. Normal Aging Athletic Man................................................. 279 Case 12. Chronic Heart Failure: Nonischemic Cardiomyopathy............................... 285 xi 000i-0xvi_Wasserman_29774_FM.indd xi 9/24/11 3:06:18 AM  xii CONTENTS Case 13. Chronic Heart Failure: Before and after Therapy.................................. 288 Case 14. Chronic Heart Failure: Oscillatory Ventilation and Gas Exchange...................... 293 Case 15. Chronic Heart Failure: Cardiomyopathy with Intraventricular Conduction Delay........... 297 Case 16. Myocardial Ischemia: Undiagnosed Angina and Hypertension........................ 300 Case 17. Myocardial Ischemia: Atypical Chest Pain....................................... 303 Case 18. Myocardial Ischemia: Small Vessel Disease...................................... 306 Case 19. Myocardial Ischemia: Interim Development of Coronary Artery Disease over 3 Years....... 309 Case 20. Myocardial Ischemia: Coronary Artery Disease in a Previously Athletic Man.............. 314 Case 21. Peripheral Arterial Disease.................................................. 319 Case 22. Cardiovascular Impairment with Hypertension and Carboxyhemoglobinemia............. 322 Case 23. Rate Disturbance due to β-Adrenergic Blockade for Treatment of Systemic Hypertension.... 325 Case 24. Atrial Fibrillation with Rapid Ventricular Response during Exercise..................... 330 Case 25. Chronotropic Insufficiency with Escape Rhythm................................... 333 Case 26. Hypertrophic Cardiomyopathy with Postexercise Vasodepressor Syncope................. 336 Case 27. Mitral Insufficiency........................................................ 339 Case 28. Congenital Heart Disease Surgically Corrected in Infancy............................ 342 Case 29. Congenital Heart Disease: Surgically Corrected Transposition of the Great Arteries........ 345 Case 30. Patent Ductus Arteriosus with Left-to-Right Shunt................................. 348 Case 31. Patent Ductus Arteriosus with Right-to-Left Shunt (Eisenmenger Ductus)................ 352 Case 32. Eisenmenger Complex (Ventricular Septal Defect with Pulmonary Hypertension).......... 355 Case 33. Early Onset of Exercise Lactic Acidosis: Differentiating Circulatory from Muscular Impairment...................................................... 358 Case 34. Early Onset of Exercise Lactic Acidosis Suggesting Circulatory Impairment............... 362 Case 35. Pulmonary Hypertension with Patent Foramen Ovale............................... 367 Case 36. Idiopathic Pulmonary Hypertension before and after Treatment....................... 372 Case 37. Long-standing Idiopathic Pulmonary Hypertension: Serial Tests over 17 Years of Treatment..................................................... 378 Case 38. Idiopathic Pulmonary Hypertension............................................ 384 Case 39. Mixed Connective Tissue Disease with Pulmonary Involvement....................... 387 Case 40. Pulmonary and Systemic Vasculitis: Air and Oxygen Breathing Studies.................. 391 Case 41. Scleroderma with Pulmonary and Pulmonary Vascular Involvement.................... 397 Case 42. Severe Pulmonary Vascular Disease Secondary to Sarcoidosis: Air and Oxygen Breathing Studies......................................................... 400 Case 43. Exercise-Induced Pulmonary Hypertension Secondary to Left Ventricular Diastolic Dysfunction....................................................... 405 Case 44. Intrapulmonary Right-to-Left Shunt due to Pulmonary Arteriovenous Fistulae............. 408 Case 45. Mild Chronic Bronchitis with Normal Exercise Performance.......................... 412 Case 46. Emphysema with Mild Airway Obstruction....................................... 415 Case 47. Severe Emphysema........................................................ 418 Case 48. Emphysema with Pulmonary Vascular Disease.................................... 421 Case 49. Severe Emphysema and Bronchitis: Air and Oxygen Breathing Studies.................. 424 Case 50. Bullous Emphysema: Before and after Bullectomy................................. 429 Case 51. Chronic Obstructive Lung Disease with a History of Heart Failure...................... 434 Case 52. Mild Obstructive Airway Disease with Disproportionate Exertional Dyspnea.............. 438 Case 53. Mild Pulmonary Asbestosis.................................................. 442 Case 54. Severe Pulmonary Asbestosis................................................ 445 Case 55. Idiopathic Interstitial Lung Disease............................................ 448 Case 56. Interstitial Lung Disease.................................................... 451 000i-0xvi_Wasserman_29774_FM.indd xii 9/24/11 3:06:18 AM  CONTENTS xiii Case 57. Sarcoidosis.............................................................. 454 Case 58. Interstitial Pneumonitis: Before and after Corticosteroid Therapy...................... 457 Case 59. Interstitial Pulmonary Fibrosis: Air and Oxygen Breathing Studies..................... 463 Case 60. Obesity Contributing to Ventilatory Limitation.................................... 469 Case 61. Extrapulmonary Restriction: Ankylosing Spondylitis................................ 473 Case 62. Extrapulmonary Restriction: Scoliosis........................................... 476 Case 63. McArdle Disease.......................................................... 479 Case 64. Myopathy with Exertional Rhabdomyolysis...................................... 483 Case 65. Congenital Mitochondrial Myopathy........................................... 486 Case 66. Mitochondrial Myopathy.................................................... 489 Case 67. Mixed Disorder: Chronic Bronchitis and Obesity................................... 492 Case 68. Mixed Disorder: Peripheral Arterial Disease, Anemia, Carboxyhemoglobinemia, and Cardiac Dysfunction.................................................... 495 Case 69. Mixed Disorder: Mild Interstitial Lung Disease, Obstructive Airway Disease, and Myocardial Ischemia.................................................... 498 Case 70. Mild Interstitial Lung Disease, Silent Myocardial Ischemia, and Uncontrolled Systemic Hypertension..................................................... 501 Case 71. Mixed Disease: Aortic Stenosis, Mitral Stenosis, and Obstructive Airway Disease.......... 505 Case 72. Mixed Disorder: Obstructive Airway Disease, Talc Pneumoconiosis, and Pulmonary Vascular Disease.......................................................... 509 Case 73. Mixed Disorder: Peripheral Arterial Disease and Obstructive Lung Disease............... 512 Case 74. Exercise Testing for Staging and Prognosis in Chronic Heart Failure.................... 517 Case 75. Exercise Testing in Preoperative Evaluation for Lung Cancer Resection.................. 521 Case 76. Exercise Testing for Evaluation of Work Fitness: Extreme Obesity...................... 524 Case 77. Exercise Testing for Assessment before and after Pulmonary Rehabilitation for Chronic Obstructive Pulmonary Disease......................................... 527 Case 78. Evaluation of Unexplained Dyspnea: A Morbidly Obese Asthmatic..................... 533 Case 79. Evaluation of Unexplained Dyspnea: Thromboembolic Pulmonary Vascular Disease........ 536 Case 80. Evaluation of Unexplained Dyspnea: An Obese Woman at Risk for Pulmonary Hypertension..... 539 Cases 81–110. Visit solution.lww.com/exercisetesting5e for exclusive online-only access. Appendix A. Symbols and Abbreviations 542 Appendix B. Glossary 544 Appendix C. Calculations, Formulas, and Examples 549 Appendix D. Placement of a Brachial Artery Catheter 557 Appendix E. Tables and Nomogram 559 Index 563 000i-0xvi_Wasserman_29774_FM.indd xiii 9/24/11 3:06:18 AM 000i-0xvi_Wasserman_29774_FM.indd xiv 9/24/11 3:06:18 AM  Principles of Exercise Testing and Interpretation Including Pathophysiology and Clinical Applications Fifth Edition 000i-0xvi_Wasserman_29774_FM.indd xv 9/24/11 3:06:18 AM 000i-0xvi_Wasserman_29774_FM.indd xvi 9/24/11 3:06:18 AM  CHAPTER 1 Exercise Testing and Interpretation CELL RESPIRATION AND BIOENERGETICS................. 1 FACTORS LIMITING EXERCISE.......................... 5 WHY MEASURE GAS EXCHANGE TO EVALUATE Fatigue............................................. 5 CARDIOVASCULAR FUNCTION AND Dyspnea............................................ 5 CELLULAR RESPIRATION?........................... 2 Pain................................................ 6 NORMAL COUPLING OF EXTERNAL TO EVIDENCE OF SYSTEMIC DYSFUNCTION UNIQUELY CELLULAR RESPIRATION............................ 3 REVEALED BY INTEGRATIVE CARDIOPULMONARY WHAT IS CARDIOPULMONARY EXERCISE TESTING?......... 4 EXERCISE TESTING................................ 6 CARDIAC STRESS TEST AND PULMONARY STRESS TEST: SUMMARY......................................... 7 NOMENCLATURE FALLACIES........................ 4 PATTERNS OF CHANGE IN EXTERNAL RESPIRATION (OXYGEN UPTAKE AND CARBON DIOXIDE OUTPUT) AS RELATED TO FUNCTION, FITNESS, AND DISEASE...... 4 The energy to support life, with its changing levels of of creatine phosphate (phosphocreatine, PCr), and an- physical and metabolic activity, is obtained from the oxi- aerobic (non-O2-requiring) oxidation of glycogen or glu- dation of metabolic substrate. Oxygen (O2) is the key that cose by pyruvate to yield lactic acid—or, more precisely, unlocks the energy from metabolic substrate by serving as the lactate ion and its associated proton. Each of these the proton acceptor in the oxidative processes that yield processes is critically important for the normal exer- high-energy compounds. The energy is located in the cise response, and each plays a different role in the total bond(s) of a phosphate anion in high-energy compounds, bioenergetic response. mainly as adenosine triphosphate (ATP). Splitting of The aerobic oxidation of carbohydrate and fatty these high-energy phosphate bonds (~P) is controlled by acids provides the major source of ATP regeneration enzymatic reactions at the myofibril such that the energy and becomes the unique source in the steady state of released is transduced into mechanical energy for mus- moderate-intensity exercise. In a normally nourished cular contraction. individual, about five-sixths of the energy comes from Because the reserve of ~P in the cell is quite small aerobic oxidation of carbohydrate and one-sixth comes relative to the needs, ~P production—and therefore from fatty acids.3,8,20 To sustain a given level of exercise, O2 consumption—must increase to sustain exercise. the cardiorespiratory response must be adequate to sup- Because there is a relatively precise relation between the ply the O2 needed to regenerate, aerobically, all the ATP O2 consumption and ~P production, measurement of O2 needed for the activity. Local stores of PCr are a source of consumption provides insight into the rate of ~P expended high-energy phosphate in the early phase of exercise and for physical work. account for much of the O2 deficit during the first minutes of exercise and the recovery repayment of the O2 debt.7,16 PCr is rapidly hydrolyzed by creatine (Cr) kinase to Cr CELL RESPIRATION AND BIOENERGETICS and inorganic phosphate (Pi). The energy released in this reaction is used to regenerate ATP at the myofibril during The most immediate requirement of exercise is the release early transient phase of exercise (Fig. 1.2). Subjects with of the energy of the terminal ~P of ATP to fuel its energy less fitness for aerobic exercise have a greater decrease in demands. The bioenergetic processes for the regeneration PCr at a given work rate, or O2 consumption, than a more of ATP in the muscle is achieved by three mechanisms fit subject. PCr, like adenosine diphosphate, is intimately (Fig. 1.1): aerobic (O2-requiring) oxidation of substrates linked to the control of O2 consumption. Thus, the pro- (primarily glycogen and fatty acids), anaerobic hydrolysis file of change of PCr is often considered to be a proxy 1 001-008_Wasserman_29774_Chapter_01.indd 1 9/24/11 12:22:04 AM  A formação de bicarbonato/CO², é influenciada pela quebra do PCr: PH> = CO² + H ~> HCO³- 2 PRINCIPLES OF EXERCISE TESTING AND INTERPRETATION hydrate and fatty acids, splitting of PCr and anaerobic ATP glycolysis). For instance, when the regeneration of ATP Aerobic: CHO oxidation is aerobic, O2 is consumed and carbon dioxide (CO2) is F.A. oxidation produced in proportion to the ratio of carbohydrate to Muscle fatty acid in the substrate being oxidized in the muscle Contraction cells. On the other hand, when PCr is split, it is converted to Cr and Pi. Because Cr is neutral in water, whereas PCr Anaerobic: CP → C + ~P reacts like a relatively strong acid, the splitting of PCr La accumulation decreases cell acidity. This reaction, therefore, consumes ADP CO2 produced from cellular metabolism by its conversion to bicarbonate (HCO −3) in the tissues.15,26 This reduces FIGURE 1.1. Sources of energy for adenosine triphosphate (ATP) CO2 output at the airway relative to O2 uptake, creat- regeneration from adenosine diphosphate (ADP). CHO, carbohydrate; ing a disparity between the early kinetics in V̇CO2 rela- FA, fatty acid; CP, creatine phosphate. tive to V̇O2 (to be discussed more thoroughly in Chapter 2).7,27 Finally, when high-energy phosphate is generated variable of muscle O2 consumption during the early pe- from anaerobic glycolysis, the H+ produced with lactate riod of exercise when its intracellular concentration is is buffered predominantly by HCO −3, thereby “consum- changing.2,6,13,16 ing” HCO −3 and adding CO2 to that produced by aerobic During the process of glycolysis, the coenzyme nic- metabolism. This is usually sufficient to increase V̇CO2 otinamide adenine dinucleotide (NAD+) is reduced to above V̇O2. NADH + H+. If it is not reoxidized aerobically at the mito- Because these different mechanisms in ATP regener- chondrial site of O2 utilization, NADH + H+ can be reoxi- ation have different effects on gas exchange, study of the dized anaerobically by pyruvate (NADH + H+ + pyruvate gas exchange responses to exercise can reveal informa- → NAD+ + lactate). Thus, pyruvate can serve as the oxi- tion regarding the kinetics of the relative contributions dant to regenerate NAD+ when the cell becomes O2 poor. of aerobic respiration, PCr hydrolysis, and anaerobic gly- The reoxidation of NADH + H+ to NAD+ is required for colysis to the total bioenergetic response. glycolysis to proceed. The energy produced by anaerobic glycolysis is rela- WHY MEASURE GAS EXCHANGE TO tively small per unit of glycogen and glucose consumed. Two molecules of lactate are produced with the consump- EVALUATE CARDIOVASCULAR FUNCTION tion of each six-carbon moiety of glycogen or glucose AND CELLULAR RESPIRATION? molecule. Because an H+ is produced with each lactate ion that accumulates, anaerobic glycolysis has important Physical exercise requires the interaction of physiologi- implications with respect to acid–base balance, buffering cal control mechanisms to enable the cardiovascular and of lactic acid, hydrogen ion regulation, and gas exchange ventilatory systems to couple their behaviors to support during exercise. Gas exchange (O2 uptake [V̇O2] and CO2 their common function—that of meeting the increased output [V̇CO2]) is affected in a different way by each of the respiratory demands (O2 consumption [Q̇O2] and CO2 three sources of ATP regeneration (oxidation of carbo- production [Q̇CO2]) of the contracting muscles (Fig. 1.3). Thus, both systems are stressed during exercise to meet the increased need for O2 by the contracting muscles and the removal of metabolic CO2. Therefore, by studying ex- ternal respiration in response to exercise, it is possible to address the functional competence or “health” of the organ systems coupling external to cellular respiration. Cardiopulmonary exercise testing (CPET) offers the investigator the unique opportunity to study the cellu- lar, cardiovascular, and ventilatory systems’ responses simultaneously under precise conditions of metabolic stress. Exercise tests in which gas exchange is not de- termined cannot realistically evaluate the ability of FIGURE 1.2. Scheme by which phosphocreatine (creatine phos- these systems to subserve their common major function, phate, PCr or Cr~P) supplies high-energy phosphate (~P) to adenosine which is support of cellular respiration. CPET allows diphosphate (ADP) at the myofibril. Because of its quantity in muscle, the investigator to distinguish between a normal and an PCr serves as a reservoir of readily available ~P as well as a shuttle abnormal response characteristic of disease, grade the mechanism to translocate ~P from mitochondria to the myofibril con- adequacy of the coupling mechanisms, and assess the tractile sites. ATP, adenosine triphosphate. effect of therapy on a diseased organ system. However, 001-008_Wasserman_29774_Chapter_01.indd 2 9/24/11 12:22:05 AM  CHAPTER 1: EXERCISE TESTING AND INTERPRETATION 3 be used to determine which of these defects is (or is pre- dominantly) responsible for the patient’s symptoms be- fore embarking on major therapeutic procedures directed at either one.31 NORMAL COUPLING OF EXTERNAL TO CELLULAR RESPIRATION Figure 1.3 schematizes the coupling of pulmonary (V̇O2 and V̇CO2) to cellular (Q̇O2 and Q̇CO2) respiration by the circulation. Obviously, the circulation must increase at a rate that is adequate to meet the O2 requirement (Q̇O2) of FIGURE 1.3. Gas transport mechanisms for coupling cellular (inter- the cells, and so cardiac output increases in proportion to nal) to pulmonary (external) respiration. The gears represent the func- the Q̇O2. In normal subjects, in the steady state, muscle tional interdependence of the physiologic components of the system. blood flow must increase by approximately 5 to 6 liters per The large increase in oxygen (O2) utilization by the muscles (Q̇O2) is liter of O2 consumption,24,32 depending on the hemoglo- achieved by increased extraction of O2 from the blood perfusing the bin concentration. Since 5 liters of arterial blood contain muscles, the dilatation of selected peripheral vascular beds, an increase approximately 1 liter of O2 when the hemoglobin concen- in cardiac output (stroke volume and heart rate), an increase in pulmo- tration is 15 g per dL, the normal steady-state circula- nary blood flow by recruitment and vasodilatation of pulmonary blood tory response must exceed this flow to meet the energy vessels, and finally, an increase in ventilation. Oxygen is taken up (V̇O2) requirement. O2 cannot be completely extracted from the from the alveoli in proportion to the pulmonary blood flow and degree muscle blood flow since a gradient for O2 diffusion must of O2 desaturation of hemoglobin in the pulmonary capillary blood. In be maintained between the end-capillary blood and myo- the steady state, V̇O2 = Q̇O2. Ventilation [tidal volume (VT) × breathing cyte24: If V̇O2 fails to increase at a rate appropriate to Q̇O2, frequency (f )] increases in relation to the newly produced CO2 (Q̇CO2) such as seen in diseases of the cardiovascular system,10,33 arriving at the lungs and the drive to achieve arterial CO2 and hydro- lactic acidosis will be a necessary consequence and often gen ion homeostasis. These variables are related in the following way: at a low work rate. V̇CO2 = V̇A × PaCO2/PB, where V̇CO2 is minute CO2 output, VA is minute Because the body’s total H+ is only on the order of alveolar ventilation, PaCO2 is arterial or ideal alveolar CO2 tension, 3.4 μmol, and the total H+ equivalent produced per minute and PB is barometric pressure. V̇O2, V̇CO2, Q̇O2, and Q̇CO2 are expressed from metabolism in the form of CO2, even for a moderate as standard temperature pressure dry (STPD). walking speed, is about 40,000 μmol/minute (approxi- The representation of uniformly sized gears is not intended to imply mately 10,000 times), elimination of the increased CO2 equal changes in each of the components of the coupling. For instance, must be accomplished quickly and precisely. Therefore, the increase in cardiac output is relatively small for the increase in to regulate arterial pH at physiological levels, the venti- metabolic rate. This implies an increased extraction of O2 from and CO2 latory control mechanism(s) must increase ventilation at loading into the blood by the muscles. In contrast, at moderate work a rate closely linked to the CO2 exchanged at the lungs intensities, minute ventilation increases in approximate proportion to and the degree of lactic acidosis. Thus, the ventilatory the new CO2 brought to the lungs by the venous return. The develop- control system is closely linked to the CO2-H+ and lac- ment of metabolic acidosis at heavy and very heavy work intensities tic acid production during exercise, with ventilation accelerates the increase in ventilation to provide respiratory compensa- increasing sufficiently to regulate arterial H+. There is tion for the metabolic acidosis. little deviation in the normal H+ response in humans because the ventilatory control mechanisms constrain the arterial H+ increase. A very slight respiratory acido- not only is it the most effective in this regard, but CPET sis, but typically not an alkalosis, can be encountered in is also one of the most inexpensive ways of diagnosing normal subjects during the non–steady state of moder- the pathophysiology of the cardiovascular and ventila- ate exercise19 and a metabolic acidosis is characteristic tory systems. at heavier work intensities. Ventilation must, therefore, In contrast to other diagnostic tests that evaluate one increase at a greater rate, relative to work rate, when a organ system, CPET evaluates each and every organ system lactic acidosis is superimposed on the respiratory acid essential for exercise simultaneously. An exercise test that (CO2) load. This is necessary to meet the demands of restricts its observations to the electrocardiogram (ECG) clearing the additional CO2 produced by the HCO −3 can only support a diagnosis of myocardial ischemia. buffering of the lactic acid. However, to reduce arterial However, this is imperfect with respect to sensitivity and PCO2 in order to constrain the fall in pH, ventilation must specificity. Furthermore, an individual patient may have increase at an even greater rate than V̇CO2.29 However, mixed defects (e.g., cardiac and pulmonary). CPET can the hyperventilatory response is typically inadequate to 001-008_Wasserman_29774_Chapter_01.indd 3 9/24/11 12:22:05 AM  4 PRINCIPLES OF EXERCISE TESTING AND INTERPRETATION avoid the development of arterial acidemia when lactate changes in intrathoracic pressure during breathing.4,9 increases during exercise.28 Although the cardiovascular and pulmonary gas ex- change responses to exercise tend to be relatively uniform and, to a large extent, predictable in normal subjects, WHAT IS CARDIOPULMONARY specific diseases affect the gas exchange responses in EXERCISE TESTING? specific ways, depending on the particular pathophysi- ology. Thus, the knowledgeable examiner cannot only CPET is an examination that allows the investigator to detect abnormality, but can often define the contribu- simultaneously study the responses of the cardiovascu- tory disease process. Because CPET is quantitative, it lar and ventilatory systems to a known exercise stress. also allows the severity of dysfunction to be graded. It This is possible because gas exchange at the airway is is our impression that, in contrast to Japan and Europe, a consequence of cardiac output and pulmonary blood CPET is a greatly underutilized diagnostic tool in the flow, as well as peripheral O2 extraction coupled to ven- United States. Likely, a great deal of money is wasted by tilation. Thus, the heart, with the circulation, couples gas performing available tests, which are not physiologically exchanges (O2 and CO2) of muscle respiration with that qualitative or quantitative in the diagnostic process, in at the lungs. The adequacy of the cardiovascular trans- contrast to CPET. It is often not appreciated that V̇O2 is port of O2 for known exercise work rates is described by equal to cardiac output (a cardiac function) and arterial- the lung gas exchange. venous O2 difference (a cardiac and peripheral vascular For CPET, the gas exchange measurements are ac- function). companied by the ECG, heart rate, and blood pressure measurements. Importantly, the cardiovascular measure- ments are interrelated with the gas exchange measure- PATTERNS OF CHANGE IN EXTERNAL ments. The interrelation adds meaning to the non–gas RESPIRATION (OXYGEN UPTAKE AND exchange measurements because it relates them to the CARBON DIOXIDE OUTPUT) AS RELATED actual energy expended during exercise rather than re- TO FUNCTION, FITNESS, AND DISEASE lying on indirect estimates. It also provides information regarding the stroke volume response to exercise by the This book is devoted largely to describing patterns of measure of the O2 extracted from each heartbeat at speci- gas exchange that relate to function, fitness, and disease fied work intensities. states. As described earlier, increases in external respira- tion (V̇O2 and V̇CO2) need to be intimately coupled to the increases in cellular respiration (Q̇O2 and Q̇CO2). CARDIAC STRESS TEST AND PULMONARY The proportional contributions of aerobic and an- STRESS TEST: NOMENCLATURE FALLACIES aerobic regeneration of ATP during exercise can often be inferred from measurements of external respiration. The authors would like to dispel a concept that remains For example, gas exchange kinetics differ in response to prevalent in clinical exercise testing—namely, that there exercise depending on whether work is performed above is cardiac stress testing and pulmonary stress testing. It or below the anaerobic threshold (AT) (Fig. 1.4). For is impossible to stress only the heart or only the lungs work performed below the AT (without a lactic acidosis), with exercise. Both the heart and lungs are needed to O2 flow through the muscles is adequate to supply all support the respiration of all living cells of the body and of the O2 needed for the aerobic regeneration of ATP in to maintain their energy requirements. The function of the steady state, and the patterns of V̇O2 and V̇CO2 in- the heart, the lungs, and the peripheral and pulmonary crease as shown in the right side of the Without Lactic circulations need to be coordinated in order to meet Acidosis panel of Figure 1.4. In contrast, if the O2 sup- the increased cellular respiratory demands of exercise. ply is inadequate to meet the total O2 need, lactic aci- Diseases of the heart cause both abnormal breathing dosis develops and the patterns of increase in V̇O2 and and gas exchange responses to exercise, as do disorders V̇CO2 change as shown in the right side of the With Lactic of the lungs. However, the patterns of the abnormal re- Acidosis panel of Figure 1.4. In the former state, work is sponses are usually different. This will be described in done in a true steady state, in which V̇O2 is equal to Q̇O2. later chapters. In the latter state, the cardiopulmonary system fails to Abnormalities of the heart might cause abnormali- transport enough O2 to meet the cellular O2 requirement, ties in lung gas exchange during exercise, with “pulmo- V̇O2 does not reach a steady state and work is performed nary symptoms.”11,14,22,30 Similarly, pulmonary disorders with a lactic acidosis. Consequently, V̇CO2 increases in might result primarily in abnormalities in cardiovascular excess of V̇O2 due to the CO2 release from HCO −3 as it responses to exercise because the heart is in the chest buffers lactic acid. and lung disease can limit cardiac filling, either because Individuals who are fit for endurance work do not of increased pulmonary vascular resistance or extreme develop a lactic acidosis until work rates are high relative 001-008_Wasserman_29774_Chapter_01.indd 4 9/24/11 12:22:05 AM  CHAPTER 1: EXERCISE TESTING AND INTERPRETATION 5 FACTORS LIMITING EXERCISE Symptoms that stop people from performing exercise are fatigue, dyspnea, and/or pain (e.g., angina or claudication). By observing external respiration during a quantitative exercise test in which large muscle groups are stressed (walking, running, or cycling), it can be determined if exercise tolerance is reduced and, if so, whether abnormal cardiovascular, ventilatory, or metabolic responses to ex- ercise account for the reduction. Fatigue A muscle is considered to fatigue when its force output decreases for a given stimulus. However, the exact mecha- nisms of muscle fatigue remain a topic of debate. Because lactic acidosis accompanies an increased rate of anaerobic ATP production and the Pi concentration increases in proportion to the time constant of the V̇O2 change, it is FIGURE 1.4. Scheme of coupling of external to cellular respiration tempting to attribute the fatigue to the intracellular conse- for constant-load exercise. The right side of the figure shows breath- quences of these mediators and possibly decreased levels by-breath data for 6 minutes of constant work rate exercise for work of ATP. Low cellular pH and increased Pi have been shown with and without lactic acidosis. Each study is an overlay of four to reduce force production via reduction of myofibrillar repetitions to reduce random noise in the data and enhance the calcium sensitivity and impaired calcium release from physiological features. Measurements of external respiration (right) the sarcoplasmic reticulum. However, regardless of the can be used as a basis for reconstructing the changes in muscle precise mechanisms,11 the consistent physiological sig- cellular respiration. The left side of the figure shows, schemati- nal for impending fatigue during exercise is the failure cally, the changes in muscle cellular respiration that would account of V̇O2 to reach a steady state and to meet the cellular O2 for the observed changes in external respiration. The factors that requirement. modulate the relationship between cellular respiration and external A number of investigators have measured V̇O2 during respiration are shown in the center. At the start of exercise, there increasing work rate exercise in both patients with heart is normally a step increase in both V̇ O2 and V̇ CO2 consequent to the failure and normal subjects10,21,33 and observed that V̇O2 abrupt increase in pulmonary blood flow due to an immediate in- increases more slowly, relative to the increase in work rate, crease in heart rate and stroke volume. After an approximate 15- before the onset of fatigue. This places further demands second delay, V̇ O2 and V̇ CO2 increase further when venous blood on anaerobic mechanisms of ATP regeneration. Although formed after exercise started, arrives at the lungs. At this early time, this phenomenon is seen as work rate is increased toward V̇ CO2 increases more slowly than V̇ O2. The slower rise in V̇ CO2 than peak V̇O2 in normal subjects, it is particularly notable in V̇ O2 is accounted for by utilization of CO2 in the production of HCO−3 heart failure patients as they approach their symptom- associated with release of K+ by the muscle cell associated with the limited maximum work rate. splitting of PCr and perhaps other chemical reactions in the tissues that store some of the metabolic CO2. For work rates without a lactic acidosis, V̇ O2 reaches a steady state by approximately 3 minutes and Dyspnea V̇ CO2 by 4 minutes. For work rates with a lactic acidosis, V̇ O2 does Dyspnea is a common exercise-induced symptom of not reach a steady state by 3 minutes and may not reach a steady disease states. It occurs in patients with pathophysiology state before the subject fatigues. In contrast, V̇ CO2 kinetics remain that results in inefficient gas exchange due to ventilation– relatively unchanged, with the level of V̇ CO2 exceeding V̇ O2 after the perfusion mismatching (high physiological dead space), first several minutes of heavy-intensity exercise (see text for discus- low work rate lactic acidosis (e.g., low cardiac output re- sion of mechanisms). sponse to exercise), exercise-induced hypoxemia, and dis- orders associated with impaired ventilatory mechanics. to less fit subjects. Their V̇O2 kinetics are relatively rapid These pathophysiological changes can occur singly, but compared to less fit subjects.17 Patients with circulatory more commonly they occur in combinations. For exam- disorders usually have slow V̇O2 kinetics, even at rela- ple, patients with chronic obstructive pulmonary disease tively low work rates.12 Thus, the difference between the have a combination of impaired ventilatory mechanics that steady-state V̇O2 requirement and the actual V̇O2 during limits their maximal ability to ventilate their lungs and the transition from rest to exercise (i.e., the O2 deficit) var- ventilation–perfusion mismatching that causes ventilation ies depending on the subject’s fitness for aerobic work. to be inefficient in eliminating CO2-H+ equivalents from 001-008_Wasserman_29774_Chapter_01.indd 5 9/24/11 12:22:05 AM  6 PRINCIPLES OF EXERCISE TESTING AND INTERPRETATION the body. In addition, they may have exercise-induced hy- gas exchange responses occur when diseases of the car- poxemia that further stimulates ventilatory drive. diovascular or ventilatory systems, or both, decrease their Dyspnea also occurs in patients with left ventricu- effective functioning. Thus, the gas exchange responses lar failure. These patients have a low work rate lactic to exercise could indicate which organ(s) are functioning acidosis, as well as inefficient lung gas exchange due to poorly and which are functioning well. CPET provides ventilation–perfusion mismatching (high physiologic the means not only to distinguish between lung and dead space). Both of these mechanisms stimulate venti- cardiovascular disease, but also to distinguish one car- latory drive consequent to the inefficient elimination of diovascular disease from another as the cause of exercise CO2-H+ equivalents from the body. Any pathophysiology limitation. For instance, coronary artery disease, chronic that increases ventilatory drive can cause dyspnea. heart failure, and peripheral vascular disease have ab- Arterial hypoxemia is a common disorder in lung normal patterns of exercise gas exchange unique to each and pulmonary vascular diseases. If the oxygen ten- and, therefore, can be distinguished from each other.25 sion decreases during exercise, it stimulates the carotid The gas exchange measurements can confirm ischemia- body chemoreceptors to increase ventilatory drive. This induced left ventricular dysfunction during exercise and stimulus to ventilation can cause the symptom of dyspnea. the precise metabolic rate at which the ischemia and The carotid bodies are chemoreceptors that drive ventila- dysfunction take place. The unique ability of CPET to tion in response to both exercise arterial hypoxemia and detect pulmonary vasculopathy leading to pulmonary in acidemia.29 Mechanisms of dyspnea in health and dis- hypertension early in the course of disease, and to detect ease are discussed further in later chapters. an exercise-induced right-to-left shunt, is addressed in Chapters 5 and 9.23 The CPET in which gas exchange is measured with Pain the ECG, should be among the most sensitive tests to Pain in the chest, arm, or neck is the most common symp- evaluate causes of exercise intolerance because exercise tom of acute myocardial ischemia brought on by exercise amplifies the abnormal manifestations of the organs that (angina pectoris) in patients with coronary artery dis- couple external to cellular respiration (see Fig. 1.3). Also, ease. This is a reflection of an inadequate O2 supply to no test is likely to be capable of quantifying improvement the myocardium relative to the myocardial O2 demand. or worsening of these functions with greater sensitivity Reducing the O2 demand by decreasing myocardial work than a CPET. Thus, CPET—with gas exchange, ECG, or increasing myocardial O2 supply can eliminate an- blood pressure, and spirometric measurements—early ginal pain. These are established cardiologic therapeu- in the evaluation of the patient with exercise limitation tic practices for treating anginal pain. The successful would greatly reduce utilization of less sensitive diag- treatment of myocardial ischemia might be documented nostic tests, thereby decreasing medical costs. However, with CPET. maximal benefit cannot be obtained from a CPET unless Claudication occurs because of an O2 supply–demand the diagnosing physician is trained to recognize both the imbalance in the muscles of the lower exercising extremi- normal responses to exercise and the pathophysiological ties. Walking at a normal pace requires an increase in Q̇O2 changes brought about by disease states. of the muscles of locomotion of approximately 20-fold com- To facilitate recognition of the pattern of disease, we pared to rest. Therefore, the ability of muscle blood flow believe that the data collected during a cardiopulmonary to increase appropriately is critically important to enable exercise study should be displayed graphically, so that walking without ischemic pain. If stenotic, atherosclerotic the relationships between the functional variables can be changes in the conducting vessels to the lower extremity seen. We illustrate this approach in Chapter 10, showing limit the increase in leg blood flow in response to exer- CPET data from patients with a large variety of diseases. cise, an O2 supply–demand imbalance will occur. This will A nine-panel graphical display was developed to view result in critically low levels of O2 in the muscles,5 caus- critical variables simultaneously. This nine-panel graphi- ing local K+, lactate, and H+ accumulation secondary to the cal array is shown on a single page to provide a picture of ischemia. These accumulated metabolites are likely media- critical data needed to determine the physiologic state tors of the exercise-induced leg pain. The impaired blood of each of the links in the coupling of external to cellular supply will be reflected in slow O2 uptake kinetics.1 respiration. It was developed over time from an extensive practice experience. CPET makes important contributions to the diagnosis EVIDENCE OF SYSTEMIC DYSFUNCTION and treatment of patients, is relatively inexpensive, and has UNIQUELY REVEALED BY INTEGRATIVE a low morbidity. Therefore, it is surprising that it is not CARDIOPULMONARY EXERCISE TESTING used more frequently by specialists who treat patients with heart and lung diseases. Nevertheless, we do recognize Chapter 9 describes pathophysiologic diagnoses uniquely that it is becoming used with a greater frequency than in made by CPET. Obligatory changes in the normal exercise preceding years. We believe that it is likely that its greater 001-008_Wasserman_29774_Chapter_01.indd 6 9/24/11 12:22:06 AM  CHAPTER 1: EXERCISE TESTING AND INTERPRETATION 7 use in the future will result from the recognition that it 9. Hansen JE, Wasserman K. Pathophysiology of activity shortens time to diagnosis and reduces medical costs. limitation in patients with interstitial lung disease. Chest. 1996;109:1566–1576. 10. Kitzman DW, Higginbotham MB, Cobb FR, et al. Exercise SUMMARY intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling Organ dysfunction that limits exercise can usually be mechanism. J Am Coll Cardiol. 1994;17:1065–1072. detected by evidence of an abnormality in the coupling of 11. Kleber F, Reindl I, Wernecke K, et al. Dyspnea in heart fail- external (pulmonary) respiration to cellular respiration. ure. In: Wasserman K, ed. Exercise Gas Exchange in Heart Integrative CPETs in which gas exchange is measured dy- Disease. Armonk, NY: Futura Publishing; 1996. 12. Koike A, Hiroe M, Itoh H. Time constant for VO2 and other pa- namically at the airway rather than as a single steady-state rameters of cardiac function in heart failure. In: Wasserman measurement, can usually identify the pathophysiology K, ed. Cardiopulmonary Exercise Testing and Cardiovascular of reduced exercise tolerance. Discerning the pathophysi- Health. Armonk, NY: Futura Publishing; 2002. ology of the intolerance is often sufficient to make an ana- 13. Mahler M. First-order kinetics of muscle oxygen consump- tomical diagnosis. If not, it can suggest other tests that tion, and an equivalent proportionality between QO2 and could narrow the diagnostic choices. When the cause of phosphorylcreatine level: implications for the control of the patient’s exercise intolerance is not clinically obvious, respiration. J Gen Physiol. 1985;86:135–165. we believe that it is cost-effective to perform a CPET be- 14. Metra M, Raccagni D, Carini G, et al. Ventilatory and arte- fore proceeding with more invasive and expensive testing. rial blood gas changes during exercise in heart failure. In: As stated by the European Society of Cardiology, “The Wasserman K, ed. Exercise Gas Exchange in Heart Disease. full potentials of CPET in the clinical and research set- Armonk, NY: Futura Publishing; 1996. 15. Piiper J. Production of lactic acid in heavy exercise and ac- ting still remain largely underused.”18 Often new insights id-base balance. In: Moret PR, Weber J, Haissly J, et al., eds. are obtained into the disease processes of patients, par- Lactate: Physiologic, Methodologic and Pathologic Approach. ticularly in those patients with cardiovascular diseases. New York, NY: Springer-Verlag; 1980. Possibly, CPET covers a broader range of potential diag- 16. Rossiter HB, Ward SA, Doyle VL, et al. Inferences from noses than any test in medicine. Furthermore, it “ampli- pulmonary O2 uptake with respect to intramuscular [phos- fies” the manifestation of the basic disease process, which phocreatine] kinetics during moderate exercise in humans. thereby assists in the differential diagnosis of diseases J Physiol. 1999;518(pt 3):921–932. with similar symptoms. 17. Sietsema KE, Daly JA, Wasserman K. Early dynamics of O2 uptake and heart rate as affected by exercise work rate. 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Butler J, Schrijen F, Polu JM, et al. Cause of the raised wedge the proportion of dietary fat and carbohydrate on exer- pressure on exercise in chronic obstructive pulmonary dis- cise gas exchange on normal subjects. Am Rev Respir Dis. ease. Am Rev Respir Dis. 1988;138:350–354. 1989;139:1430–1434. 5. Bylund-Fellenius AC, Walker PM, Elander A, et al. 21. Sullivan MJ, Cobb FR. Relation between central and pe- Energy metabolism in relation to oxygen, partial pres- ripheral hemodynamics during exercise in patients with sure in human skeletal muscle during exercise. Biochem J. chronic heart failure. Circulation. 1989;80:769–781. 1981;200:247–255. 22. Sullivan MJ, Higginbotham MB, Cobb FR. Increased ex- 6. Chance B, Leigh J, Clark B, et al. 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J Appl Physiol. 1975;39:354–358. 1983;51:1639–1643. 001-008_Wasserman_29774_Chapter_01.indd 8 9/24/11 12:22:06 AM  CHAPTER 2 Physiology of Exercise SKELETAL MUSCLE: MECHANICAL PROPERTIES AND Identifying the Anaerobic Threshold by Gas Exchange....... 30 FIBER TYPES.................................... 10 Anaerobic, Lactate, and Lactic Acidosis Thresholds.......... 32 BIOENERGETICS.................................... 11 Altered Physiological Responses to Exercise above Sources of High-Energy PO4 and Cell Respiration........... 11 the Anaerobic Threshold............................ 33 Phosphocreatine Splitting Kinetics....................... 13 METABOLIC-CARDIOVASCULAR-VENTILATORY COUPLING... 39 Substrate Utilization and Regulation..................... 13 Sources of Adenosine Triphosphate Regeneration Reflected OXYGEN COST OF WORK............................. 16 in V̇O2 and V̇CO2 Kinetics............................ 39 Work Efficiency and Steady-State V̇O2.................... 17 Cardiovascular Coupling to Metabolism: V̇O2 Non–Steady State................................ 17 Muscle Oxygen Supply............................. 41 Power-Duration Curve and Critical Power................. 18 Ventilatory Coupling to Metabolism...................... 43 LACTATE INCREASE................................. 18 Effect of Dietary Substrate............................. 46 Lactate Increase as Related to Work Rate................. 18 CONTROL OF BREATHING............................ 48 Lactate Increase as Related to Time...................... 19 Arterial Hydrogen Ion Regulation........................ 48 Lactate Increase in Response to Increasing Work Rate....... 20 H + Balance......................................... 48 Mechanisms of Lactate Increase......................... 20 Physical Factors...................................... 49 Oxygen Supply, Critical Capillary PO2, and Lactate Increase... 22 Reflexes Controlling Breathing during Exercise............. 49 BUFFERING THE EXERCISE-INDUCED LACTIC ACIDOSIS..... 26 GAS EXCHANGE KINETICS............................ 52 THE ANAEROBIC THRESHOLD CONCEPT................. 29 Oxygen Uptake Kinetics............................... 52 The Anaerobic Threshold and Oxygen Uptake–Independent Carbon Dioxide Output Kinetics......................... 56 and –Dependent Work Rate Zones.................... 29 SUMMARY........................................ 56 The performance of muscular work requires the physi- Blood with normal hemoglobin of adequate concentration ological responses of the cardiovascular and ventilatory An effective pulmonary circulation through which the systems to be coupled with the increase in metabolic regional blood flow is matched to its ventilation rate; efficient coupling minimizes the stress to the com- Normal lung mechanics and chest bellows ponent mechanisms supporting the energy transfor- Ventilatory control mechanisms capable of regulat- mations. In other words, cellular respiratory (internal ing arterial blood gas tensions and hydrogen ion respiration) requirements can only be met by the inter- concentration action of physiological mechanisms that link gas ex- The response of each of the coupling links in the gas ex- change between the cells and the atmosphere (external change process is usually quite predictable and can be respiration) (see Fig. 1.3). Inefficient coupling increases used as a frame of reference for considerations of im- the stress to these systems and, when sufficiently severe, paired function. can result in symptoms that impair or limit work perfor- This chapter reviews the essentials of skeletal mance. Efficient ga