Wasserman - Principles of Exercise Testing and Interpretation PDF

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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  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