Effects of Exercise Training on Abnormal Ventilatory Responses to Exercise in Patients with Chronic Heart Failure

Transcription

1 EXERCISE AND ABNORMAL VENTILATION IN CHF CHF SEPTEMBER/OCTOBER Effects of Exercise Training on Abnormal Ventilatory Responses to Exercise in Patients with Chronic Heart Failure Patients with chronic heart failure frequently report shortness of breath during daily activities as their primary symptom. In recent years, many efforts have been made by researchers to explain the mechanisms that underlie the characteristic heightened ventilatory response to activity in patients with chronic heart failure. The degree to which the ventilatory response to exercise is heightened parallels the severity of the disease, and measuring the ventilatory gas exchange response to exercise can help quantify the patient s response to therapy. Prior to the 1990s, patients with chronic heart failure were generally discouraged from participating in programs of exercise training. However, in the last decade, studies have demonstrated that exercise training is quite safe for these patients, and a multitude of benefits have been reported. Among the benefits of training are improvements in the abnormal ventilatory response to exercise. Although many mechanisms could potentially explain this response, it appears most likely that this improvement after training is due to a reduction in lactate accumulation and an attenuation of the heightened muscle receptor reflex response that occurs in chronic heart failure. This article reviews the mechanisms of dyspnea in chronic heart failure, along with recent studies assessing the effects of training on abnormal ventilatory responses to exercise in these patients. (CHF. 2000;6: ,255) 2000 by CHF, Inc. Jonathan Myers, PhD From the Cardiology Division, Palo Alto Veterans Administration Health Care System, and Stanford University, Palo Alto, CA Address for correspondence reprint/requests: Jonathan Myers, PhD, Palo Alto VA Health Care System, Cardiology Division, 111C, 3801 Miranda Avenue, Palo Alto, CA Manuscript received May 5, 2000; accepted May 23, 2000 A hallmark feature of patients with chronic heart failure (CHF) is exercise intolerance characterized by fatigue, shortness of breath, or both. The degree of exercise intolerance is important to characterize in patients with CHF, since it has implications for morbidity, disability, and prognosis, and is often the reason a patient seeks medical attention. As, exercise intolerance is an important clinical feature in these patients, therapeutic interventions are largely aimed at improving this symptom. Once thought to be contraindicated in patients with CHF, exercise training is now commonly employed in these patients, and a wide range of benefits, including improved exercise capacity, has been demonstrated over the last decade. 1,2 On the surface, the explanation for exercise intolerance in CHF appears simple. The heart s impaired pumping capacity delivers inadequate amounts of oxygen to the working muscle, leading to inadequate energy supply, lactate accumulation, shortness of breath, and fatigue. However, the exercise response in CHF is far more complex than commonly thought just 10 years ago. An abundance of evidence has accumulated to suggest that cardiac pump function is poorly related to exercise capacity and symptom generation in CHF. Rather, it is generally thought that factors in the peripheral musculature, and not central hemodynamics, largely determine both shortness of breath and fatigue. These peripheral factors include abnormalities in endothelial function, vasodilatory capacity, distribution of cardiac output, heightened chemo- and ergoreceptor sensitivity, skeletal muscle histology, and oxidative enzyme activity. 3 5 A great deal of effort has also recently been directed toward abnormalities of the ventilatory response to exercise in CHF. Minute ventilation (VE) is markedly higher among patients with CHF than in normal subjects at any given level of exercise. 3 6 This has been expressed as a higher VE at matched exercise workloads, a higher VE at any given oxygen uptake, and a higher VE for any given level of CO 2 production (VE/VCO 2 slope). 7 9 The latter measurement is frequently used as an index of ventilatory drive, and has

2 244 EXERCISE AND ABNORMAL VENTILATION IN CHF been shown to reflect the severity of CHF 7 and prognosis. 9 Any attempt to explain the exercise limitation in CHF must also include an explanation for the increased ventilatory response to exercise. Mechanisms that have been put forth to explain this response include increased intrapulmonary pressures, elevated physiologic dead space, early metabolic acidosis, altered ventilatory control, abnormal breathing patterns, including rapid, shallow respiration, and heightened sensitivity of receptors in the muscle. 3 7,10 Despite a great deal of research directed toward this area, a complete explanation of the mechanisms(s) underlying these abnormal ventilatory responses to exercise in patients with CHF is lacking. Mechanism of Abnormal Exercise Ventilation In attempting to explain dyspnea in CHF, it is interesting to note that pulmonary function per se does not limit exercise in these patients. A large breathing reserve at peak exercise has been repeatedly observed; this is the ratio of maximal exercise VE to maximal voluntary ventilation at rest, and is also termed the VE/MVV ratio or dyspnea index. In other words, as occurs in a normal individual, 20% 40% of the CHF patient s ventilatory capacity remains, even at maximal levels of exertion. In addition, a decrease in arterial oxygen saturation, another marker of symptomatic pulmonary disease, rarely occurs in CHF. Thus, although some patients with CHF clearly have abnormal pulmonary hemodynamics, pulmonary function generally does not limit exercise. Pulmonary Wedge Pressure. Elevated pulmonary wedge pressure (PCW) is common in patients with CHF and is thought to decrease lung compliance and to stimulate pulmonary juxtacapillary receptors, which stimulate ventilation. 12,14,15 Traditionally, elevations in PCW have therefore been thought to be the main cause of hyperventilation and consequent exertional dyspnea. Several investigators have attempted to quantify the role of PCW as a cause of dyspnea during exercise in patients with CHF. Interestingly, many recent studies have found exercise capacity to be related to PCW at rest 8,16,17 but not during exercise. 16,17 Moreover, acute pharmacologically-induced reductions in pulmonary wedge pressure do not significantly reduce the ventilatory response to exercise. 16 These findings suggest that hyperventilation during exercise in patients with CHF is not, in fact, related to increases in PCW. Although pulmonary hypertension is frequently seen in patients with heart failure, exercise does not appear to be limited by ventilatory manifestations of elevated pulmonary pressures. CHF SEPTEMBER/OCTOBER 2000 Estimated Ventilatory Dead Space to Tidal Volume Ratio. The ventilatory requirement for a given level of work also depends on the ineffective fraction of tidal volume (V T ), that is, the ventilatory dead space (V d ). This ratio, V d /V T, is frequently elevated in patients with CHF, suggesting a ventilation-perfusion mismatch, and is one mechanism that underlies the hyperventilatory response to exercise in these patients. Higher than normal V d /V T values during exercise have been attributed primarily to increases in physiologic dead space, which are largely due to a reduction in pulmonary blood flow via reduced cardiac output. 6 8,18,19 The elevated V d /V T makes breathing inefficient because greater ventilation is required to maintain arterial oxygen. Early Lactate Accumulation. A striking feature of the exercise response in the patient with CHF is early lactate accumulation. Numerous investigators have associated early lactate accumulation in the blood with metabolic acidosis, hyperventilation, and exercise intolerance in patients with CHF. 3,4,8,18,20 Lactate that accumulates in the blood during exercise must be buffered to maintain physiologic ph, and the bicarbonate buffering process yields a secondary source of CO 2, which stimulates ventilation. Chemo- and Ergoreceptor Sensitivity. A recent paradigm suggests the presence of a specific ventilatory signal arising from the exercising muscle, which is abnormally enhanced in CHF. 5,10,21,22 These signals appear to contribute to the abnormal hemodynamic, autonomic, and ventilatory responses to exercise that characterize CHF. Afferent fibers present in the skeletal muscle (ergoreceptors) are sensitive to metabolic changes related to muscular work. These receptors appear to mediate circulatory adaptations occurring in the early stages of exercise, are stimulated by metabolic acidosis, and are partially responsible for sympathetic vasoconstriction. 22 Chua and colleagues 23 have also recently demonstrated that hypoxic chemosensitivity is increased in CHF, and that this heightened chemosensitivity is correlated with the VE/VCO 2 slope. The results of these enhanced ergoreflex and chemoreceptor responses are hyperventilation and heightened sympathetic outflow, which causes an increase in peripheral resistance and thus a decrease in muscle perfusion. Effect of Exercise Training on Abnormal Ventilation in CHF While exercise training programs for patients with CHF were discouraged prior to the 1990s due to concerns about safety and benefits, such programs have

3 EXERCISE AND ABNORMAL VENTILATION IN CHF CHF SEPTEMBER/OCTOBER now become an accepted part of the therapeutic regimen for CHF. From the evidence gathered in the multitude of studies published during the last decade, the benefits of exercise training in patients with CHF appear to be due primarily to adaptations in the peripheral musculature rather than the heart itself. 2,24,25 These studies have focused on exercise tolerance, skeletal muscle oxidative capacity, histologic changes in the muscle, endothelial function, remodeling of the myocardium after an infarction, and quality of life. 2 Training also appears to favorably modify the ventilatory response to exercise in CHF, although such data are comparatively sparse and the mechanism underlying this response has not been fully characterized. A partial normalization of exercise ventilation in CHF represents an important therapeutic achievement, since dyspnea is such an important cause of the exercise limitation and morbidity. Because an appreciation for these abnormal ventilatory responses to exercise and the benefits of training in CHF are relatively recent, only five studies have specifically addressed the influence of training on abnormal ventilatory responses to exercise in these patients All of these studies have demonstrated that training reduces VE at a matched 8,22,26 28 submaximal workload, but only two have attempted to explore the mechanisms involved. In a controlled trial of exercise training in patients with CHF, Coats and colleagues 26 assessed the slope of the relation between minute ventilation and the rate of carbon dioxide production (VE/VCO 2 ) throughout exercise, an index which has been shown to parallel the severity of CHF. 6,7,9 The VE/VCO 2 slope was reduced after 8 weeks of training (0.038±0.04 to 0.034±0.03, p<0.05). In addition, VE was reduced at matched submaximal workloads (25 and 50 watts) after training (Fig. 1). These changes were associated with a reduction in the sensation of breathlessness and the ease of performing daily activities, according to Likert symptom scores. Similarly, Sullivan et al 27 trained 12 CHF patients for 4 6 months and reported a reduction in the ventilatory response at submaximal levels throughout a progressive exercise test. During a symptom-limited, submaximal, constant work rate protocol, ventilation and CO 2 production were reduced at matched work rates (representing a mean of 79±11% of maximal capacity), even though the oxygen cost of the work (VO 2 ) was unchanged. Endurance time on this submaximal protocol increased by nearly 50%. Davey and colleagues 28 assessed the effects of a modest home-based training program (20-minute sessions 5 days/week for 8 weeks) on the ventilatory response to exercise in 22 patients with New York Heart Association Class I or II heart failure. After the training program, small but significant increases in work capacity (10% and 9% increases in peak watts and peak VO 2, respectively) were observed. However, submaximal endurance improved by a considerable 33%. Both VCO 2 and VE were reduced at matched submaximal workloads. As in the previous studies, the VE/VCO 2 slope decreased after training. Exercise tolerance in these patients was related to various measures of ventilatory efficiency. Piepoli et al 22 assessed the potential effects of exercise training on muscle afferents (peripheral muscle, or ergoreflex, contributions to ventilation) in patients with CHF. The ergoreflex contribution was quantified by a post-handgrip regional circulatory occlusion technique. After 6 weeks of a forearm training protocol, the ergoreflex contribution to exercise VE was reduced by 58% (p<0.05 vs. controls). These unique findings not only appear to confirm the presence of a muscle ergoreflex stimulus to ventilation, but they also suggest that alterations in these muscle receptors play an important role in exercise intolerance in CHF. Previous studies have demonstrated that isolated training of the forearm results in greater submaximal endurance and substantially corrects the impaired oxidative capacity of the skeletal muscle in CHF. 29,30 The study by Piepoli et al 22 suggests that in addition, exercise training may reduce the heightened ergoreflex activity that contributes to excessive dyspnea and fatigue in CHF. Improvement in abnormal ventilation after training might also involve hemodynamic changes (reduced pulmonary pressures or improved ventilationperfusion matching), metabolic changes reflected by a reduction in lactate accumulation, a change in ventilatory control, or a change in the ventilatory pattern that makes breathing more efficient. Accurate evaluation of these mechanisms would require the simulta- Minute Ventilation (I/min) Rest 25W 50W Peak Exercise Load Figure 1. Minute ventilation at rest and at 25 watts, 50 watts, and peak exercise before (open boxes) and after (shaded boxes) exercise training in patients with CHF. *p<0.05 Before vs. after training. From Coats et al. 26

4 246 EXERCISE AND ABNORMAL VENTILATION IN CHF CHF SEPTEMBER/OCTOBER 2000 neous measurement of ventilatory gas exchange, invasive intrapulmonary pressures, cardiac output, and arterial blood gases. We recently performed a study in which theses variables were acquired simultaneously during upright exercise before and after a 2-month high intensity residential training program in patients with reduced ventricular function after a myocardial infarction. 8 In the residential training program, the patients performed two 1-hour walking sessions daily, and four 45-minute sessions of individually prescribed cycling weekly. This resulted in 29% and 39% increases in peak VO 2 and VO 2 at the lactate threshold, respectively, whereas no differences were observed among control subjects. Although no differences were observed within or between groups in resting ejection fraction, maximal cardiac output increased by 1.7 l/minute in the trained group, which contrasts with the results of several studies of CHF showing either no change after training 25,31,32 or a more modest increase in cardiac output, on the order of 1.0 l/minute. 26,27 Figure 2 illustrates the effects of training on oxygen uptake, heart rate, perceived exertion, and lactate responses throughout exercise. Figure 3 presents the effects of training on VE, VE/VO 2, respiratory rate, and tidal volume. Figure 4 shows the effect of the training program on the slope of the relationship between VE and VCO 2. Figure 5 illustrates the relationships between resting and maximal exercise pulmonary wedge pressures and peak oxygen uptake. Figure 6 presents the relationships between maximal exercise VE/VCO 2 and Figure 2. Influence of exercise training on oxygen uptake, perceived exertion, heart rate, and lactate at matched ramp work rates during exercise. Open squares represent baseline values and closed circles denote post-training. A main effect (p<0.01) was observed for all parameters except oxygen uptake. Figure 3. Influence of training on ventilatory responses to exercise at matched ramp work rates during exercise. Open squares indicate baseline values and closed squares indicate post-training. A significant reduction (p<0.01) was observed for VE/VO 2 (the relationship between minute ventilation and the oxygen cost). maximal values for cardiac output, PCW, V d /V T, and mean pulmonary artery pressure prior to beginning the training program. These results are discussed below, in the context of the mechanisms underlying exertional dyspnea in CHF. Baseline Ventilatory Response to Exercise. At baseline, arterial PCO 2 remained normal throughout exercise (falling from 34.0±3.8 to 30.9±4.2 mm Hg), and VE and VCO 2 were tightly coupled, suggesting that neural and chemoreceptor control of VE were normal. VE/VCO 2 was characteristically shifted upward (Fig. 4), which reflects a heightened V d /V T. 7 The heightened ventilatory response to exercise is also evidenced by an elevated VE/VO 2, particularly on the initial test (Fig. 3). Ventilation-Perfusion Mismatching. Ventilationperfusion mismatching has been identified as a major factor contributing to an increase in physiologic dead space (V d /V t ) in CHF. 3,4,7,18,19 Underlying this response is reduced pulmonary perfusion caused by an attenuated cardiac response to exercise. 18 The inverse association between the ventilatory response to exercise (VE/VCO 2 ) and maximal cardiac output in our study (Fig. 6) suggests that decreased pulmonary perfusion did in fact underlie an increased physiologic dead space by increasing ventilation-perfusion mismatching. A better matching of ventilation and perfusion, and thus a reduction in V d /V T, could, in theory, be accomplished by either an improvement in cardiac output or a reduction in physiologic dead space. We

5 EXERCISE AND ABNORMAL VENTILATION IN CHF CHF SEPTEMBER/OCTOBER Figure 4. The slope of the relationship between minute ventilation and VCO 2 before (open circles) and after (closed circles) training in the exercise group (0.33 before vs after, p<0.01). hypothesized that an increase in maximal cardiac output with training observed in some previous studies 26,27 would parallel a reduction in physiologic dead space. Although a substantial increase in maximal cardiac output occurred in the trained group, we did not observe a significant reduction in the ratio of dead space to tidal volume, making improved ventilation-perfusion matching an unlikely explanation for the improved ventilatory response to exercise. Efficiency of Ventilation. The significant reductions in VE/VO 2 (Fig. 3) and the reduction in the slope of the relationship between VE and VCO 2 (Fig. 4) confirm a beneficial effect of exercise training on the efficiency of ventilation during exercise. These measures are well recognized indices of ventilatory efficiency and have been used as markers of the severity of CHF. 6,7,9 Breathing Pattern. Rapid, shallow respiration is characteristic of the response to exercise in patients with CHF, 6,33,18 and it has been suggested that this breathing pattern reflects an effort on the part of the patient to reduce the work of breathing. 12 This response has been expressed as the ratio of tidal volume to respiratory rate. 6,33 Initially, our patients demonstrated a ratio of tidal volume to breathing rate which was similar to that observed in previous studies among patients with CHF, 6,33 and training had only a slight effect on this relationship. The overall reduction in the ventilatory requirement for work (VE/VO 2 ) that we observed after training was attributable mainly to a lower respiratory rate, whereas tidal volume remained relatively unchanged (Fig. 3). Training had only minimal effects on the breathing pattern. Figure 5. The relationships between resting and maximal exercise pulmonary wedge pressures and peak oxygen uptake among patients in both groups before randomization. Metabolic Acidosis. Previous studies have demonstrated that exercise training causes a delay in the lactate or ventilatory threshold in normal subjects 34,35 and in patients who have sustained a myocardial infarction. 36,37 A delay in the threshold of hyperventilation would be particularly important in patients with CHF, because dyspnea is such an important limitation to their daily activities. 38 Whether training causes a reduction in lactate production or an increase in the rate of lactate clearance has been debated, but clearly training delays lactate accumulation during exercise. 39 Our data confirm the work of others 6,40 with respect to both a delay in the lactate threshold (39% increase in VO 2 at the lactate threshold) and an overall reduction in the slope of the relationship between blood lactate and work rate throughout exercise (Fig. 2). Because ventilation is an important component of perceived effort, 41 it follows that a marked reduction in perceived exertion was observed throughout exercise after training (Fig. 2). Pulmonary Pressures. Relatively weak relationships were observed between resting and exercise PCW, peak VO 2, and the ventilatory requirement for exercise (Fig. 5), confirming previous assertions that stimulation of pulmonary receptors does not underlie abnormal ventilatory responses to exercise. The influence of exercise training on pulmonary vascular pressures has been disputed. Some studies have demonstrated increases in left ventricular filling pressures during exercise after training in this population, 31,32 whereas others have shown decreases 32,42 or

6 248 EXERCISE AND ABNORMAL VENTILATION IN CHF CHF SEPTEMBER/OCTOBER 2000 Figure 6. The relationships between maximal exercise VE/VCO 2 and maximal values for cardiac output, pulmonary capillary wedge pressure (PCW), V d /V t, and mean pulmonary artery pressure (PA) in both groups at baseline. VE/VCO 2 =relationship between minute ventilation and the rate of carbon dioxide production; V d /V T =ratio of ventilatory dead space to tidal volume. no change. 27,31,43 We did not observe any changes in PCW, pulmonary artery pressure, or pulmonary vascular resistance in either the trained or control groups, and the relationships between pulmonary pressures, exercise capacity, and ventilation were similar before and after the study period in both groups. Mechanism of Reduced Ventilatory Response to Exercise One of the most important factors governing exercise tolerance in CHF is the level of ventilation that can be sustained. Exercise training has clearly been shown to be one intervention that reduces the ventilatory response to exercise and contributes to an increase in exercise tolerance. Because few studies have taken a mechanistic approach to this question, a complete explanation for the reduction in the ventilatory response to exercise requires further study. The study by Piepoli and coworkers 22 focused on muscle afferent receptor effects, e.g., those in the peripheral musculature, whereas our study 8 addressed central adaptations, e.g., pulmonary pressure changes, ventilation-perfusion matching, breathing patterns, and ventilatory control. According to the alveolar gas equation, ventilation is governed by three factors: 1) the PaCO 2 set point, i.e., the level at which PaCO 2 is regulated (ventilatory control); 2) the ratio of ventilation to perfusion (V d /V T ); and 3) CO 2 production, or VCO 2. In our study, ventilation and VCO 2 were tightly coupled, and PaCO 2 remained stable during exercise, as others have observed in patients with CHF. 18,44 These relationships did not change with training, suggesting that altered ventilatory control does not explain the reduced ventilatory response to exercise in these patients. However, a growing body of evidence suggests an important role of peripheral muscle receptors in stimulating ventilation. 5,10,21,22 This, along with the findings of Piepoli et al 22 demonstrating diminution of these signals after localized forearm training, suggest an alternative, peripheral contribution to ventilation, which adapts to training. Whether this adaptation occurs in response to more standardized aerobic training programs in these patients is unknown. We hypothesized that if exercise training would increase maximal cardiac output, as others had recently reported in CHF, 26,27 an improvement in V d /V T would occur via enhanced pulmonary blood flow. Although we observed a trend for a reduction in maximal V d /V T, the insignificant change in this response suggests that this mechanism does not contribute in a major way to the reduction in the ventilatory response to exercise. The third factor in the alveolar gas equation, CO 2 production, might be reduced after training through a reduction in lactate production, an increase in lactate removal, or both. The reduction in blood lactate levels after training has been considerable. 2,8,24,40 This is likely related to an improvement in skeletal muscle metabolism; patients with CHF are known to exhibit abnormalities in mitochondrial volume and oxidative enzymes, and training has been demonstrated to partially reverse these abnormalities. 2,25,45 The mediation of exercise ventilation with training by a reduction in blood lactate has also been demonstrated in normals 46 and patients with COPD. 47 Lastly, a reduced tidal volume could also increase ventilation by raising the V d /V t ; anatomic dead space, although considered to be fixed in absolute terms, will be increased if a given tidal volume is ventilated more frequently (i.e., a high ratio of tidal volume to respiratory rate). In our study, training caused only a slight decrease in the ratio of maximal tidal volume to respiratory rate. Although the reduced ventilation throughout exercise was mediated primarily by a reduction in respiratory rate (Fig. 3), the overall breathing pattern does not appear to be altered significantly by training. Summary Dyspnea on exertion remains the hallmark symptom of patients with CHF, and heightened ventilation is related to the severity of heart failure. Most treat-

7 EXERCISE AND ABNORMAL VENTILATION IN CHF CHF SEPTEMBER/OCTOBER ment strategies are directed toward improving fatigue or mortality, but in recent years increasing attention has focused on ameliorating the heightened ventilatory response to exercise. Exercise training appears to partially normalize the ventilatory response to exercise primarily via two mechanisms: 1) reduced lactate accumulation; and 2) a reduction in the exaggerated ergoreflex response that characterizes CHF. Recent studies have greatly enhanced our understanding of the cardiopulmonary response to exercise in CHF, and a growing body of evidence suggests that training can improve abnormalities of ventilation in response to exercise in these patients. REFERENCES 1 Agency for Health Care Policy and Research. Clinical Practice Guidelines for Cardiac Rehabilitation, Piepoli MF, Flaiter M, Coats AJS. Overview of studies of exercise training in chronic heart failure: The need for a prospective randomized multicenter European trial. Eur Heart J. 1998;19: Sullivan MJ, Hawthorne, M. Exercise intolerance in patients with chronic heart failure. Prog Cardiovasc Dis. 1995;38: Myers J, Froelicher VF. Hemodynamic determinants of exercise capacity in chronic heart failure. Ann Intern Med. 1991;115: Harrington D, Coats AJS. Mechanisms of exercise intolerance in congestive heart failure. Curr Opin Cardiol. 1997;12: Myers I, Salleh A, Buchanan N, et al. Ventilatory mechanisms of exercise intolerance in chronic heart failure. Am Heart J. 1992;124: Wada O, Asanoi H, Miyagi K, et al. Importance of abnormal lung perfusion in excessive exercise ventilation in chronic heart failure. Am Heart J. 1992;125: Myers J, Dziekan G, Goebbels U, et al. Influence of high intensity training on the ventilatory response to exercise in patients with reduced ventricular function. Med Sci Sports Exerc. 1999;31: Chua TP, Ponikowski P, Harrington D, et al. Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol. 1997;29: Clark AL, Piepoli M, Coats AJS. Skeletal muscle and the control of ventilation on exercise: Evidence for metabolic receptors. Eur J Clin Invest. 1995;25: Gazetopolous N, Davies H, Oliver C, et al. Ventilation and hemodynamics in heart disease. Br Heart J. 1966;28: Ingram RH, McFadden ER. Respiratory changes during exercise in patients with pulmonary venous hypertension. Prog Cardiovasc Dis. 1976;19: Parker GW, Gorlin R. Immediate post-exercise vital capacity: A measure of increased pulmonary capillary pressure. Am J Med Sci. 1969;257: Reed JW, Ablett M, Cotes JE. Ventilatory response to exercise and to carbon dioxide in mitral stenosis before and after valvulotomy: Causes of tachypnea. Clin Sci Molec Med. 1978;54: Paintal AS. Mechanism of stimulation of type J pulmonary receptors. J Physiol (Lond). 1969;55: Fink L, Wilson J, Ferraro N. Exercise ventilation and pulmonary artery wedge pressure in chronic stable congestive heart failure. Am J Cardiol. 1986;5: Szlachcic J, Massie BN, Kramer BL, et al. Correlates and prognostic implication of exercise capacity in chronic congestive heart failure. Am J Cardiol. 1985;55: Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: Intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation. 1988;77: Buller NP, Poole-Wilson PA. Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure. Br Heart J. 1990;63: Sullivan MJ, Cobb FR. The anaerobic threshold in chronic heart failure: Relation to blood lactate, ventilatory basis, reproducibility, and response to exercise training. Circulation. 1990;81(suppl II):II47 II Clark AL, Poole-Wilson PA. Exercise limitation in chronic heart failure: Central role of the periphery. J Am Coll Cardiol. 1996;28: Piepoli M, Clark AL, Volterrani M. Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart failure. Effects of physical training. Circulation. 1996;93: Chua TP, Clark AL, Amadi A, et al. Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol. 1996;27: Dubach P, Myers J, Dziekan G, et al. Effect of exercise training on myocardial remodeling in patients with reduced ventricular function following myocardial infarction: Application of MRI. Circulation. 1997;95: Hambrecht R, Niebauer I, Fiehn E, et al. Physical training in patients with stable chronic heart failure: Effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles. J Am Coll Cardiol. 1995;25: Coats AJS, Adamopoulos S, Radaelli A, et al. Controlled trial of physical training in chronic heart failure. Exercise performance, hemodynamics, ventilation and autonomic function. Circulation. 1992;85: Sullivan MI, Higginbotham MB, Cobb FR. Exercise training in patients with severe left ventricular dysfunction. Hemodynamic and metabolic effects. Circulation. 1988;78: Davey P, Meyer T, Coats A, et al. Ventilation in chronic heart failure: Effects of physical training. Br Heart J. 1992;68: Stratton JR, Dunn JF, Adamopoulos S, et al. Training partially reverses skeletal muscle metabolic abnormalities during exercise in heart failure. J Appl Physiol. 1994;76: Minotti JR, Johnson EC, Hudson TL, et al. Skeletal muscle response to exercise training in congestive heart failure. J Clin Invest. 1990;86: Jette M, Helter R, Landry F, et al. Randomized 4-week exercise program in patients with impaired left ventricular function. Circulation. 1991;84: Scalvini S, Marangoni S, Volterrani M, et al. Physical rehabilitation in coronary patients who have suffered from episodes of cardiac failure. Cardiology. 1992;80: Clark AL, Chua TP, Coats AJS. Anatomical dead space, ventilatory pattern, and exercise capacity in chronic heart failure. Br Heart J. 1995;74: Davis JA, Frank MH, Whipp BI, et al. Anaerobic threshold alterations caused by endurance training in middle-aged men. J Appl Physiol. 1979;46: Ready AE, Quinney HA. Alterations in anaerobic threshold as the result of endurance training and detraining. Med Sci Sports Exerc. 1982;14: Hambrecht R, Niebauer J, Marburger C, et al. Various intensities of leisure time physical activity in patients with coronary artery disease: Effects on cardiorespiratory fitness and progression of coronary atherosclerotic lesions. J Am Coll Cardiol. 1993;22: Sullivan M, Ahnve S, Froelicher VF, et al. The influence of exercise training on the ventilatory threshold of patients with coronary heart disease. Am Heart J. 1985;109: Oka RK, Stotts NA, Dae MW, et al. Daily physical activity levels in congestive heart failure. Am J Cardiol. 1993;71: Myers J, Ashley E. Dangerous curves: A perspective on exercise, lactate, and the anaerobic threshold. Chest. 1997;111: Sullivan MJ, Higginbotham MB, Cobb FR. Exercise training in patients with chronic heart failure delays ventilatory anaerobic threshold and improves submaximal exercise performance. Circulation. 1989;79: Robertson RI, Noble BJ. Perception of physical exertion: Methods, mediators, and applications. Exerc Sport Sci Rev. 1997;25:

8 250 EXERCISE AND ABNORMAL VENTILATION IN CHF CHF SEPTEMBER/OCTOBER Tavazzi L, Ignone G. Short-term hemodynamic evolution and late follow-up of post-infarct patients with left ventricular dysfunction undergoing a physical training program. Eur Heart J. 1991;12: Dubach P, Myers J, Dziekan C, et al. Effect of high intensity exercise training on central hemodynamic responses to exercise in men with reduced left ventricular function. J Am Coll Cardiol. 1997;29: Weber KT, Kinasewitz CT, Janicki JS, et al. Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation. 1982;65: Hambrecht R, Fiehn E, Yu I, et al. Effects of endurance training on mitochondrial ultrastructure and fiber type distribution in skeletal muscle of patients with stable chronic heart failure. J Am Coll Cardiol. 1997;29: Casaburi R, Storer TW, Wasserman K. Mediation of reduced ventilatory response to exercise after endurance training. J Appl Physiol : Casaburi R. Mechanisms of the reduced ventilatory requirement as a result of exercise training. Eur Respir Rev. 1995;25:42 46.