Cardiopulmonary Exercise Test The Most Powerful Tool to Detect Hidden Pathophysiology

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1 REVIEW ARTICLE Cardiopulmonary Exercise Test The Most Powerful Tool to Detect Hidden Pathophysiology Hitoshi Adachi, 1 MD Summary The cardiopulmonary exercise test (CPX) is an essential examination for detecting pathophysiological derangement and determining treatment policy because it clarifies not only the changes of hemodynamics but also abnormality in the whole body during exercise where heart disease patients often feel symptoms. To utilize CPX effectively, we must understand each parameter, such as peak oxygen uptake (peak O2), peak O2/HR, and E/ CO2. In addition, comparison of each parameter, for example, peak O2 and E/ CO2, and peak O2 and peak O2/HR, is useful to detect the pathophysiological abnormalities. In this article, I will describe how CPX should be used in clinical settings. (Int Heart J Advance Publication) Key words:, Angina pectoris, Cardiac rehabilitation T he cardiopulmonary exercise test (CPX) is an exercise stress test with a long history. The test clarifies the pathophysiological mechanism underlying various unfavorable symptoms or conditions. The principles and technical procedures for CPX were mostly established by Prof. K. Wasserman and his colleagues 1) in the 1970s. The most important point to note is that only CPX can elucidate the pathophysiological changes that occur while performing an activity at various levels of difficulty. Because symptoms, such as chest pain, shortness of breath, and/or leg fatigue appear during exercise in heart disease patients, we cannot disregard the possibility of heart disease even if the results of the examination at rest are negative. Therefore, for patients with such symptoms, it is necessary to perform an exercise test. However, CPX has obviously been underused to date. It is only used to evaluate peak oxygen uptake in patients with severely impaired cardiac functions, so as to determine whether the patient is a candidate for heart transplantation, or to determine the anaerobic threshold (AT) for exercise training. In this review, I would like to discuss why CPX is necessary for the management of the complications in heart disease patients, and how CPX can be used in the field of cardiology. I hope this will help many readers to develop an interest in CPX and begin to use this test routinely. Principles of CPX Preparation: A gas analyzer is the principal equipment for CPX. A breath-by-breath gas analyzer is necessary in a clinical setting. Additionally, a cycle-ergometer or treadmill ergometer, as an exercise load device, and an electrocardiograph are necessary. If the facility has many patients with severe heart failure, a cycle-ergometer is required to produce a sufficiently weak load because the exercise capability of these patients is very low. What is calculated during gas exchange analysis?: The gas analyzer measures the oxygen and carbon dioxide content in a gas. Using inspired and expired gas, oxygen uptake ( O2) and carbon dioxide output ( CO2) are calculated. The gas analyzer also measures tidal volume (TV) and respiratory rate (RR). From these measurements, minute ventilation ( E) is calculated. Using O2, CO2, E, and heart rate (HR), E/ CO2, E/ O2, R (gas exchange ratio), and O2/HR are calculated. A breath-by-breath gas analyzer also measures the partial pressure of end-tidal oxygen and carbon dioxide (PETO2 and PETCO2)). Ramp exercise protocol: CPX is usually performed using a ramp protocol (Figure 1). This protocol clarifies how much oxygen uptake is required when various disorders are induced. For example, we can confirm how much exercise intensity induces angina pectoris, and determine the severity of the disorder. Then, we can specify how much daily activity can be performed safely. For example, if the ischemic threshold is above the anaerobic threshold (AT), angina pectoris is not severe. Cardiac scintigraphy is one of the most prevalent and reliable examinations to detect myocardial ischemia. It can detect myocardial ischemia in more than 90% of patients. However, during exercise-stress scintigraphy, the patient is forced to pedal until their peak performance capacity, where they feel chest pain. Afterward, an isotope is injected and a myocardial scintigraphy image is taken. That is, cardiac scintigraphy only reveals whether myocardial From the 1 Department of Cardiology, Gunma Prefectural Cardiovascular Center, Gunma, Japan. Address for correspondence: Hitoshi Adachi, MD, Department of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12, Kameizumi, Maebashi, Gunma , Japan. h-adachi@ops.dti.ne.jp Received for publication May 12, Revised and accepted May 14, Released in advance online on J-STAGE September 30, doi: /ihj All rights reserved by the International Heart Journal Association. 1

2 2 Adachi IntHeartJ Advance Publication Figure 1. Model of ramp protocol. Warm-up is usually 3 to 4 minutes. The ramp intensity is set to complete the exercise test after 8 to 12 minutes. AT indicates anaerobic threshold; RCP, respiratory compensation point; and R, gas exchange ratio. Table I. Comparison of CPX, Scintigraphy and Stress Echocardiography Modality Comparison with activity intensity Skill CPX Can compare with daily activity ++ Scintigraphy Only at the peak exercise intensity ++ Dobutamine-stress echocardiography Impossible +++ Table II. Determinant Factors for Oxygen Uptake (V 4 O2) Factor Pulmonary function Pulmonary circulation Cardiac function Peripheral circulation Skeletal muscle function Autonomic nerve function Representative disease COPD Lung fibrosis CTEPH PAH Pleural effusion IHD Valve disease PAD Muscle dystrophy Beta-adrenergic receptor blocker Anemia Anemia CTEPH indicates chronic thromboembolic pulmonary hypertension; PAH, pulmonary arterial hypertension; IHD, ischemic heart disease; and PAD, pulmonary arterial disease. ischemia occurs at the peak exercise intensity. If the subject does not require vigorous performance near their peak capacity in daily life, the findings from cardiac scintigraphy are less useful. Dobutamine-stress echocardiography is also recommended to detect myocardial ischemia. The sensitivity of the examination is excellent if the examiner is an expert. However, we cannot evaluate the severity of angina pectoris from this test because the dose of dobutamine does not indicate the exercise intensity. We can only confirm the presence or absence of myocardial ischemia. On the other hand, CPX using a ramp protocol reveals the intensity at which myocardial ischemia occurs (Table I). Significance of Each Parameter Oxygen uptake ( O2): Oxygen uptake is the principal parameter obtained from CPX. Oxygen is necessary to produce ATP in the working muscle. Oxygen uptake decreases in the event of alveolar hypoventilation, pulmonary arterial flow limitation, cardiac dysfunction, peripheral vascular insufficiency, skeletal muscle dysfunction, and blood flow redistribution. 2) That is, this parameter reflects the pulmonary function, cardiac function skeletal muscle function, pulmonary and peripheral vascular function, and autonomic nerve function (Table II). During steady state exercise (Figure 2), a certain period of time is necessary before oxygen uptake reaches a steady state. This period is divided into two phases. Phase I lasts for approximately 15 seconds, during which oxygen uptake increases because the transport of blood from the lungs to the periphery increases. Next, oxygen uptake increases exponentially until it reaches a plateau in Phase II. The duration required to reach the plateau depends on the subject s exercise tolerance. This length of time is

3 IntHeartJ Advance Publication HOW TO INTERPRET AND HOW TO USE CPX 3 Figure 2. Oxygen uptake during a constant stress test. Figure 3. Oxygen uptake pattern during a ramp protocol. The solid line is a normal pattern. When the ratio of work rate (watt) to oxygen uptake (ml/minute) is 1/10, the slope of work load and oxygen uptake is parallel. The small dotted line is the pattern for an obese subject. The thick dotted line is for a heart failure patient, and the dashed line is for a myocardial ischemia patient. called the time constant (τ), and reflects the ability for cardiopulmonary adjustment. Therefore, heart failure patients and older individuals have longer time constants. This parameter predicts the prognosis for heart disease patients. 3) After the oxygen uptake increases exponentially, it reaches a plateau if the exercise intensity is beneath the AT. This is called Phase III. With an incremental exercise protocol, oxygen uptake increases linearly during a ramp, and continues to increase by ml/minute for one watt. 4) There are three abnormal patterns of oxygen uptake increase during ramp tests (Figure 3). One is an upward displacement of oxygen uptake. This pattern is observed in obese subjects, who have higher than expected O2 values throughout the exercise. These subjects need more oxygen to move their heavier legs, resulting in greater O2 (Figure 3, line A). As previously described, the steepness of oxygen uptake is approximately 10 ml/minute. 4) In patients with diminished oxidative enzyme activity in skeletal muscle such as chronic heart failure or deconditioning, the steepness of O2 decreases (Figure 3, line B). The third abnormal O2 pattern is the hockey stick pattern. With mild to moderate exercise intensity, O2 increases as usual, but abruptly stops increasing near the peak intensity. This pattern is observed in patients with myocardial ischemia, diastolic and/or systolic ventricular dysfunction, mitral/tricuspid valve regurgitation, and other disorders, under conditions of restricted heart rate increase such as when taking beta-adrenergic receptor blockers 5) (Figure 3, line C). Peak O2 is one of the most powerful indicators of a patient s prognosis. 6,7) In addition, it is one of the most important parameters to determine whether the patient is a candidate for heart transplantation. Cardiac function during exercise - O2/HR, E/ CO2, PETCO2: Stroke volume can be evaluated using O2/HR (oxygen pulse). 8) Since O2 is the product of cardiac output and the volume of oxygen utilization (c(a-v)o2 difference), and c(a-v)o2 difference at the peak exercise is constant, peak O2/HR is equal to the product of stroke volume and a constant value. We can even calculate stroke volume at a given work rate. 8) O2/HR increases gradually during ramp exercise. At

4 4 Adachi IntHeartJ Advance Publication Figure 4. Sample of V 4 O2/HR, stroke volume, heart rate and cardiac output. SV indicates stroke volume; and CO, cardiac output. Table III. Mechanisms That Reduce V 4 O2 /HR Increase Mechanisms Myocardial ischemia Diastolic dysfunction Systolic dysfunction Mitral/tricuspid regurgitation approximately 50-60% of peak exercise intensity, the steepness of the line decreases (Figure 4). When it stops increasing and does not reach the predicted value, we should consider the possibility that something occurred at this point. Usually, this phenomenon occurs in patients with cardiac diastolic dysfunction, systolic dysfunction, moderate to severe myocardial ischemia, and/or mitral or tricuspid valve regurgitation (Table III). Myocardial ischemia induces cardiac dysfunction. If coronary arterial stenosis is severe enough to induce myocardial dysfunction, O2/HR does not reach the standard value. However, if coronary arterial stenosis is not so severe for the myocardial ischemia to affect the whole ventricular function, O2/HR reaches a normal value. That is, O2/HR can be used to evaluate the severity of angina pectoris. Usually, when the heart rate increases, the diastolic duration diminishes. Assuming the systolic duration (QT interval on ECG) and PQ interval do not shorten during exercise, and are fixed at 400 mseconds and 200 mseconds, respectively, when the heart rate reaches 100/minute, there is no interval between the T wave and P wave. That is, ventricular relaxation and atrial contraction occur simultaneously. This phenomenon reduces the effect of the atrial kick. A healthy heart can adjust to systolic and diastolic agile movements. However, a diseased heart cannot do so. As a result, the cardiac pump function decreases when tachycardia occurs. That is, patients with diastolic and systolic dysfunction sometimes show an early flattening of the slope during a ramp exercise. 9) This flattening often occurs at a heart rate of 110/minute (Figure 5). E/ CO2 and PETCO2 (Figure 6) are determined by the degree of ventilation-perfusion mismatch (V/Q mismatch). If patient does not have severe pulmonary dysfunction, these parameters are indicators of pulmonary arterial perfusion and cardiac output. 10) That is, when pulmonary arterial perfusion decreases, V/Q mismatch increases, and minute ventilation at a given work rate and E/ CO2 become greater. 11,12) In addition, when the volume of the pulmonary arterial perfusion is small, or the amount of carbon dioxide in the pulmonary arterial flow becomes smaller, the partial pressure of alveolar CO2 (PACO2) diminishes. Since end-tidal gas primarily consists of alveolar gas, PETCO2 is equal to PACO2. A smaller amount of PETCO2 is an indicator of less CO2 production in the body and/or pulmonary arterial perfusion, or in other words, the cardiac output (Figure 7). Cardiac rehabilitation is reported to improve these parameters. 13) Because the heart rate is included in O2/HR, the collection of data during the use of beta-adrenergic receptor blockers should be avoided. Further, as the maximum and minimum values of E/ CO2 and PETCO2 are obtained at the respiratory compensation point (RCP), when the examination is stopped before RCP, these parameters do not indicate cardiac output. The characteristics of each parameter are shown in Table IV. Indicators of shortness of breath - TV-RR slope, Ti/ Ttot, breathing reserve: Shortness of breath during exercise is induced by pathological responses to exercise. Excessively rapid RR, excessively augmented minute ventilation, and diminished breathing reserve are the main causes (Table V). Typically, the RR increases abruptly at the AT (Fig-

5 IntHeartJ Advance Publication HOW TO INTERPRET AND HOW TO USE CPX 5 Figure 5. Tachycardia and diastolic function. In patients with impaired cardiac function, the reduction in QT and PQ interval during exercise is small. Therefore, in patients with tachycardia, early diastole and late diastole increase while pump function decreases. Figure 6. V 4 EE/V 4 CO2, V 4 E/V 4 O2, PETCO2, and PETO2 during a ramp protocol. V 4 E/V 4 O2 and PETO2 reach a nadir at AT. V 4 E/V 4 CO2 and PETCO2 start to rise or decrease at RCP. ure 8A, B). However, if the RR at rest is faster than a normal value and the rate of increase during lighter intensity exercise is greater, this is called a rapid and shallow breathing pattern, which is one of the main causes of shortness of breath (Figure 8C). This condition often induces shortness of breath during mild activity. 14) Arapid and shallow breathing pattern can be improved by cardiac rehabilitation. 15) Ventilation is regulated by the sensitivity of respiratory chemoreceptors and the ergo reflex in skeletal muscles. The sensitivity of respiratory chemoreceptors increases when the sympathetic nerve is activated and/or acidosis occurs. These conditions often occur in heart failure patients as well as in exceedingly sedentary individuals whose skeletal muscles are atrophic. These subjects experience shortness of breath throughout mild to vigorous activity. Usually, subjects stop pedaling during CPX because they experience severe leg fatigue or are unable to continue pedaling due to weak leg power. However, patients with chronic obstructive pulmonary disease (COPD) or restrictive lung disease experience shortness of breath that is more severe than the leg fatigue, and the shortness of breath limits their results. These patients cannot perform more intense activity because they literary cannot breathe more. In patients with lung disease, ventilatory limitations sometimes determine exercise tolerance. In severe COPD patients, the difference between maximal voluntary ventilation (MVV) and peak VE becomes so small (less than

6 6 Adachi IntHeartJ Advance Publication Figure 7. Conception diagram showing how PETCO2 changes. In a normal alveolus (left panel, left alveolus), CO2 diffuses almost completely from the pulmonary artery (Pa) to the alveolus (A). While in insufficiently expanded and with increased dead space between artery and alveolus (left panel, right alveolus), diffusion of CO2 is less. Combined with these gases, PETCO2 near the mouth is approximately 40 mmhg. During exercise, CO2 production from the skeletal muscle, pulmonary arterial flow, and alveolar parameters related to breathing increase. Hence, PETCO2 increases. Table IV. Comparison of Peak V 4 O2/HR, VE/V 4 CO2 at RCP, PETCO2 at RCP Parameter Denotation Required condition Peak V 4 O2/HR Stroke volume Needs to perform peak exercise BB affects the result VE/V 4 CO2 at RCP Cardiac output Needs to perform exercise until RCP PETCO2 at RCP Cardiac output Needs to perform exercise until RCP Muscle mass affects the results BB indicates beta-adrenergic receptor blockers. Table V. Causes of SOB and CPX Results Parameter Value Basal disease V 4 E/V 4 CO2 at RCP 34 Breathing pattern Rapid and shallow TV/RR slope < 90 Cardiac surgery (Sternotomy) Obesity Breathing reserve Peak V 4 E/MVV > COPD MVV - Peak V 4 E < 11L/minute Peak TV = IC Restrictive lung disease Ti/Ttot Abrupt drop < 0.4 COPD (air trapping) 11 L/minute or 10-40% of the MVV) that the patient finds it difficult to continue pedaling. On the other hand, in restrictive lung disease patients, inspiratory capacity (IC) and peak TV become so close that the patient cannot continue pedaling. These parameters are called the breathing reserve (BR) (Figure 9). CPX also reveals how a subject breathes during exercise. As was previously described, the TV-RR relationship demonstrates the existence of the rapid and shallow breathing pattern. The time trend graph for O2, CO2, and E sometimes shows an oscillatory pattern (Figure 10). This ventilation pattern is often seen in heart failure patients. Exacerbated chemosensitivity, diminished blood flow velocity, and decreased PaCO2 relate to this phenomenon. In addition, if the cardiac function is severely deteriorated, and depends on afterload instead of preload, cardiac output rhythmically changes due to the fluctuation of the diameter of the aorta. This leads to the oscillatory patterns for O2, CO2, and E. The prognosis for patients with oscillatory ventilation is poor, 16,17) but cardiac reha-

7 IntHeartJ Advance Publication HOW TO INTERPRET AND HOW TO USE CPX 7 Figure 8. RR threshold and TV/RR relationship. The respiratory rate increases abruptly at the anaerobic threshold (AT) and respiratory compensation point (RCP). RR indicates respiratory rate; and TV, tidal volume. Figure 9. Breathing reserve. BR indicates breathing reserve; MVV, maximal voluntary ventilation; IC, inspiratory capacity; and V 4 E, minute ventilation. bilitation improves oscillatory ventilation. 18) The ratio of inspiratory time to whole respiratory time (Ti/Ttot) abruptly diminishes a few minutes before the peak exercise intensity in patients with pulmonary emphysema. Usually, Ti/Ttot is maintained between 0.4 and 0.5 in normal subjects (Figure 11A). However, in severe emphysema patients, the ratio abruptly decreases to nearly 0.35, and these patients cannot continue pedaling because of shortness of breath (Figure 11B). Severity of heart failure - AT, peak O2, E/ CO2, E versus CO2 slope, PETCO2, time constant (τ on): As heart failure becomes more severe, exercise tolerance worsens. That is, both the AT and peak O2 diminish. 19) This is not only due to the impaired cardiac function but also due to deteriorated skeletal muscle function and endothelial cell function, as well as abnormal autonomic nerve function. In addition, due to the increased ventilation-perfusion (V/Q) mismatch, E/ CO2 at RCP and the E versus CO2 slope increases, while PETCO2 at RCP decreases. Impaired cardiovascular response in heart failure patients leads to a prolonged time constant (τ on) and the prognosis for patients with abnormal parameters is poor ) CPX parameters related to the severity of heart failure are shown in Table VI. Detecting the state of autonomic function - Heart rate analysis: In heart disease, the state of autonomic nerve function is an important factor for determining the prognosis. Therefore, clarifying how much the sympathetic and parasympathetic nerve function is activated is useful to treat patients. At rest and during mild exercise, heart rate is regulated by parasympathetic nerve function. Therefore, a rapid heart rate at rest is a sign of attenuated parasympathetic nerve function. During moderate to vigorous exercise intensity, sympathetic nerve activity regulates the heart rate. In other words, in the event of exaggerated sympathetic nerve activity, ΔHR/ΔWR diminishes. This is called chronotropic incompetence. Usually, the heart rate increase during a ramp exercise is approximately 0.6

8 8 Adachi IntHeartJ Advance Publication Figure 10. Oscillatory ventilation. Oscillation in V 4 E is defined as follows: a cycle length of approximately 80 seconds, amplitude > 15% of resting V 4 E, and duration > 60% or 66% of exercise duration. Rarely, there exists a patient whose heart rate does not increase during a ramp exercise although their autonomic nerve activity does not change (Figure 13). In patients with pacemakers who have sick sinus syndrome or some kind of arrhythmia such as atrial tachycardia, the heart rate stays nearly constant. In patients with severe heart failure, and those that have undergone open heart surgery or heart transplantation, the increase of heart rate during a ramp exercise is blunted (Table VII). Figure 11. Ti/Ttot. Ti/Ttot is the ratio of inspiratory rate (Ti) against total ventilation period (Ttot). beats/minute per watt (Figure 12A). In chronotropic incompetence, this value becomes lower than 0.6. An impaired heart rate response to the exercise is another sign of exaggerated sympathetic nerve function. Characteristically, this is often observed in heart failure patients (Figure 12B). Beta-adrenergic receptor blocker administration results in a lower resting heart rate and a lower heart rate response to exercise (Figure 12C). Exercise training for chronic heart failure patients improves the heart rate at rest and the chronotropic incompetence (Figure 12D). Comparison of Each Parameter AT and peak O2: Usually, AT and peak O2 decrease similarly. If %peak O2 is lower than %AT, there are 4 possible mechanisms. One is patient motivation. If the subject stops pedaling below the peak intensity, %peak O2 becomes smaller than %AT. The next mechanism is the problem of the subject s muscle power. When a patient s muscle power is too weak, he/she sometimes cannot pedal an ergometer sufficiently. As for the linearity of the O2 increase, oxygen uptake increases linearly during the examination unless the subject s pedaling speed decreases. 23) If the increase in stroke volume during exercise decreases, and the subject s heart rate response is blunted primarily due to beta-adrenergic receptor blocker administration, %peak O2 also becomes smaller than %AT. Deteriorated cardiac output improvement during exercise reduces the oxygen uptake by working skeletal muscle. However, when the increase in stroke volume does not match the oxygen demand of the working muscle, the heart rate usually increases to increase the blood flow and oxygen supply. Therefore, in cases of limited heart rate increase, %peak O2 becomes smaller than %AT. This is the third mechanism.

9 IntHeartJ Advance Publication HOW TO INTERPRET AND HOW TO USE CPX 9 Table VI. CPX Parameters in Heart Failure Parameter Without BB With BB With BB + CRP Peak V 4 O2 low low slightly low - normal Anaerobic threshold low low slightly low - normal V 4 E/V 4 CO2 at RCP high high slightly high - normal V 4 E versus V 4 CO2 slope steep steep slightly steep - normal Peak V 4 O2/HR low normal - high normal - high PETCO2 at RCP low low slight low - normal HR at rest high normal - low normal - low HR response to exercise low low slightly low - normal Time constant prolonged prolonged slightly prolonged Respiratory pattern rapid and shallow slightly rapid and shallow slightly rapid and shallow - normal BB indicates beta-adrenergic receptor blockers; and CRP, cardiac rehabilitation program. Figure 12. Heart rate response to the exercise. The thick solid line (A) is the heart rate response of normal subjects. In heart failure, the resting heart rate increases and the response to exercise becomes blunted (thin solid line B). When a beta-adrenergic receptor blocker is used, line B moves to line C. After successful cardiac rehabilitation, chronotropic incompetence is ameliorated (dashed line D). Dotted line E is the heart rate response for patients who underwent heart transplantation. Additionally, if oxygenation enzyme activity deteriorates, oxygen uptake during exercise decreases. In particular, since oxygen consumption depends mainly on metabolic improvement above AT, the slope of oxygen uptake becomes shallower, resulting in the mismatch of %peak O2 and %AT. A comparison of AT and peak O2 is shown in Table VIII. Peak O2 versus peak O2/HR: Performing peak exercise is dependent on many factors, including sufficient cardiac, skeletal muscle, and vascular endothelial cell functions. On the other hand, peak O2/HR is regulated mainly by cardiac function. Therefore, when %peak O2/ HR is disproportionately smaller than %peak O2, cardiac function during exercise is assumed to be impaired. On the other hand, when %peak O2/HR is greater than % peak O2, the primary cause of impaired exercise tolerance is attributed to skeletal muscle dysfunction. Of course, if the subject is taking beta-adrenergic receptor blockers, this does not hold true, because beta-adrenergic receptor blockers cause a higher than expected O2/HR. 24) Peak O2 and E/ CO2 at RCP: As was described previously, the peak O2 is affected not only by cardiac pump function, but also by skeletal muscle function. On the other hand, E/ CO2 at RCP (minimum E/ CO2) is mainly determined by pulmonary blood flow in heart disease if the subject does not have severely impaired pulmonary function. Therefore, we can determine whether the impairment is in the heart or in the skeletal muscle. The relationship between %peak O2 and E/ CO2 at RCP is not linear, as is shown in Figure 14. A normal subject is plotted with open circles as A. A typical heart failure patient is plotted as B. The improvement of cardiac function without skeletal muscle function such as when using a left ventricular assist device changes the plot from BtoC. 25) After exercise training, the plot changes from C to D. When the V/Q mismatch is high, as seen in chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary arterial hypertension (PAH), or pleural effusion, the patient often presents as E. Clinical Application How to determine the appropriate AV delay: In cardiac resynchronization therapy (CRT), the optimal atrioventricular (AV) delay must be determined to obtain the most favorable effect. If the patient can walk a little, the optimal AV delay should be the value that results in the greatest cardiac output during exercise. The parameters for cardiac output and/or pulmonary blood flow during exercise are O2/HR and E/ CO2. CPX can reveal the greatest cardiac output during exercise. Because the exercise tolerance of a patient who requires CRT is very low, we use a watt load of 0 to 10. These loads are 1.5 to 2.5 METs, consistent with a highly sedentary daily activity. The setting of AV delay that shows the greatest O2/HR and lowest E/ CO2 at this intensity is adopted (Figure 15). How to determine the best rate response for the pacing device: The rate response is an important function that improves exercise tolerance. CPX is repeated a few times with different rate response patterns. The rate response setting that shows the greatest O2 and lowest E/ CO2 at a given work rate is the best setting. Because CPX must be performed repeatedly, CPX until exhaustion should be avoided. Beta-adrenergic receptor blocker or stimulator?: To determine whether a beta-blocker or a beta-stimulator is more favorable for patients who experience shortness of breath, respiratory pattern, breathing reserve, Ti/Ttot at peak exercise, peak O2/HR, and peak O2 are evaluated.

10 10 Adachi IntHeartJ Advance Publication Figure 13. The heart rate response of patients after open heart surgery during. A ramp protocol. Table VII. Causes of Diminished Heart Rate Response to Exercise Causes Beta-adrenergic receptor blocker Open heart surgery Transplanted heart Pacemaker Atrial flutter Atrial Tachycardia Supraventricular tachycardia Table VIII. Comparison of %anaerobic Threshold (AT) and %peak V 4 O2 Variable %AT > %peak V 4 O2 Diminished muscle power/ metabolism Rejection against CPX Impaired cardiac function under condition of BB usage After successful cardiac rehabilitation %AT < %peak V 4 O2 BB indicates beta-adrenergic receptor blockers. Figure 14. The graph of V 4 E/V 4 CO2 at RCP as a function of %peak V 4 O2.

11 IntHeartJ Advance Publication HOW TO INTERPRET AND HOW TO USE CPX 11 Figure 15. Response of V 4 E/V 4 CO2 and stroke volume to various AV delays. This is a sample from a patient with cardiac resynchronization therapy defibrillator (CRT) implantation. Her best AV delay was determined to be 200 mseconds/160 mseconds (Ap/As) through echocardiography measured on a bed in a recumbent position. We tested 3 AV delays to determine the most effective value during daily activity. When AV delay was set to Ap/As 130 mseconds/100 mseconds, V 4 E/V 4 CO2 was lowest and stroke volume was highest. Therefore, AV delay was set as 130/100. After that, her shortness of breath disappeared. Using these parameters, we can determine whether the patient s basal problem is in the lungs or in the heart. After that, we can select a beta-adrenergic receptor blocker or stimulator correctly. Should ASV be discontinued or not?: Since the publication of SERVE-HF, 26) the use of adaptive servo-ventilators (ASV) is being discontinued, although the favorable effect of ASV for Japanese heart failure patients was established by the SAVIOR-C 27) investigation. Following abrupt discontinuation of ASV usage, the exacerbation of heart failure is often experienced. To avoid inappropriate exacerbation, CPX should be performed before the discontinuation of ASV. If the patient still has an unstable respiratory pattern such as oscillatory ventilation or irregular respiration, and/or abnormal heart rate response, it means that the patient still has impaired cardiac function and severely deranged autonomic nerve function. Because ASV can improve these dysfunctions, ASV is determined to be sill necessary. It is important to remember that the effect of ASV for chronic heart failure is not only extinction of sleep apnea but also increasing the exercise tolerance by improving the cardiac output and autonomic nerve derangement. Determining the need for PCI for stable angina pectoris: If the patient has significant coronary arterial stenosis, CPX should be performed. If ST depression, flattening of O2/HR due to myocardial ischemia, and a sensation of chest pain occur during mild activity with optimal medical treatment, PCI or coronary artery bypass grafting (CABG) should be considered. If these responses are not observed until AT, interventional treatment should be avoided, because coronary stenosis does not induce angina pectoris during daily activity. Further, PCI sometimes induces new lesions due to the catheters and/or wires used. It must be kept in mind that diagnosis and determination of the severity of angina pectoris should be achieved not with fractional flow wire reserve (FFR) wires, but with symptoms during exercise. Acknowledgment This article was carefully checked by Dr. Karlman Wasserman who was formerly my boss, for which I am very grateful. Disclosures Conflicts of interest: None. References 1. Wasserman K, Whipp BJ, Koyl SN, Beaver WL. Anaerobic threshold and respiratory gas exchange during exercise. J Appl Physiol 1973; 35: Miyazaki A, Adachi H, Oshima S, Taniguchi K, Hasegawa A, Kurabayashi M. Blood flow redistribution during exercise contributes to exercise tolerance in patients with chronic heart failure. Circ J 2007; 71: Koike A, Koyama Y, Itoh H, Adachi H, Marumo F, Hiroe M. Prognostic significance of cardiopulmonary exercise testing for 10-year survival in patients with mild to moderate heart failure. Jpn Circ J 2000; 64: Hansen JE, Sue DY, Wasserman K. Predicted values for clinical exercise testing. Am Rev Respir Dis 1984; 129: S Yoshida S, Adachi H, Murata M, Tomono J, Oshima S, Kurabayashi M. Importance of compensatory heart rate increase during myocardial ischemia to preserve appropriate oxygen kinetics. J Cardiol 2017 (in press). 6. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991; 83: Stelken AM, Younis LT, Jennison SH, et al. Prognostic value of cardiopulmonary exercise testing using percent achieved of pre-

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