Exercise intolerance in patients with chronic heart failure

Progress in

Cardiovascular Diseases VOL XXXVIII, NO 1

JULY/AUGUST 1995

Exercise I n t o l e r a n c e in P a t i e n t s With Chronic Heart Failure Martin J, Sullivan and Mary H. Hawthorne Patients with chronic heart failure (CHF) experience significant morbidity because of dyspnea and fatigue with activities of daily living. Although central hemodynamic abnormalities are the hallmark of this disorder, investigators have not shown a relationship between left ventricular ejection fraction or exercise pulmonary capillary wedge pressure and exercise intolerance in this disorder. Recent studies have focused on the contributions of pulmonary abnormalities and alterations in peripheral vasomotor control and skeletal muscle in exercise intolerance in this disorder. Early anaerobic metabolism occurs in patients with CHF and appears to be caused by a combination of reduced

skeletal muscle blood flow and decreased aerobic enzyme content in skeletal muscle. Atrophy in skeletal muscle and alterations in skeletal muscle fiber typing are accompanied by alterations in contractile function in skeletal muscle, These results suggest that exercise intolerance in patients with CHF is multifactorial, and that research efforts must consider central hemodynamic abnormalities, pulmonary abnormalities, and alterations in peripheral blood flow and skeletal muscle biochemistry and histology. The present review will explore current research in this area and develop a model for understanding exercise intolerance in CHF.

HRONIC H E A R T failure (CHF) is a major cause of morbidity and mortality in the United States, with an estimated 300,000 new cases occurring each year. 1 A recent study by Schocken et al 2 indicates that 2,000,000 patients in the United States have CHF. In most of these patients CHF is caused by left ventricular (LV) systolic dysfunction because of corona~ artery disease, hypertension, or idiopathic dilated cardiomyopathy. 3 In recent years, the incidence of this clinical syndrome has not decreased, despite a decrease in the rate of new cases of coronary artery disease and better treatment of systemic hypertension) In fact, a study by Ghali et al 4 has actually shown an increase in ageadjusted hospital discharge rates for CHF that may reflect both an increased disease incidence and better survival rates. Although prolongation of life is an important goal in the treatment of these patients, therapy must also aim at improving functional disability. There are two major causes of symptoms in this disorder, (1) congestion caused by fluid overload and (2) exercise intolerance, often with disabling dyspnea and fatigue. Present therapy with loop diuretics, digoxin, and vasodilators can often relieve fluid overload in the majority of ambulatory patients with this disorder, making exercise

intolerance an important limitation in a large group of these patients. Efforts aimed at developing effective new therapies in CHF are limited currently by our incomplete understanding of the pathophysiologic basis of exercise intolerance in this disorder. Although central hemodynamic abnormalities are, by definition, the initiating pathophysiologic events in the CHF syndrome, it has been a uniform finding that the degree of LV systolic dysfunction as measured by LV ejection fraction (EF) does not correlate with exercise tolerance or symptom status. 5-14These results suggest that there is a complex interplay

C

Copyright © 1995 by W.B. Saunders Company

From the Department of Medicine, Division of Cardiology, The Center for Living, and the Department of Nursing, Duke University Medical Center and the Durham Veterans Administration Medical Center, Durham, NC. Supported by Grant No. HL- 54314 from the National Heart, Lung. and Blood Institute, Bethesda, MD, and by General Medical Research Funds from the Veterans Administration Medical Center, Durham, NC. MJ.S. was supported by an established investigatorship from the American Heart Association. Address reprint requests to Martin Y. Sullivan, MD, Duke University Medical Center, Division of Cardiology, Box 3022, Durham, NC 27710. Copyright © 1995 by W.B. Saunders Company 0620-0033/95/3801-000155. 00/0

Progressin Cardiovascular Diseases, Vol XXXVIII, No 1 (July/August), 1995: pp 1-22

1

2

SULLIVAN AND HAWTHORNE

between central hemodynamic factors (systolic and diastolic LV dysfunction, LV and right ventricular [RV] filling pressures, cardiac output, pericardial restraint, and RV function), peripheral factors (skeletal muscle blood flow, histology, biochemistry, and contractile function), and pulmonary factors (respiratory muscle fatigue, air flow limitations, and hyperpnea) in determining exercise capacity in patients with CHF. Although recent research has improved our basic understanding of exercise in this disorder, a large number of unanswered questions remain in this area. This report will review our understanding of exercise testing and the roles of central hemodynamic and peripheral factors in determining exercise intolerance in CHF. EXERCISE TESTING IN CHRONIC HEART FAILURE

Several investigators s,12-14 have shown that exertional symptom status is related to a decrease in maximal exercise capacity as indicated by measurement of oxygen consumption (V02) at peak exercise. This finding is because of the relationship between exercise intensity relative to maximum and perceived exertion in a given individual. As exercise intensity approaches peak V02, in both normal subjects and in patients, symptoms of dyspnea and muscle fatigue occur that can be reproducibly rated using a perceived exertion scale. Although this model may not account for symptoms during isometric exercise or isotonic exercise using small muscle groups, it serves as a useful framework for understanding exercise intolerance during isotonic activities involving large muscle groups. Although there are a number of limitations to using peak V02 measurements in patients with CHF, maximal exercise testing is an established technique in the evaluation of CHF. This technique is valuable in the determination of functional capacity before and after an intervention, disease severity, and prognosis. The derived information has been shown to be valuable in optimal timing of cardiac transplantation. 15,16 In addition, maximal exercise testing provides the patient and clinician with data that can be used to confidently plan exercise training and activities of daily living. 171s Peak Vo2 reflects the central hemodynamic, peripheral circulatory, metabolic, and pulmonary consequences of heart failure. Because the

central arteriovenous oxygen difference at peak exercise tends to be no different in patients with CHF when compared with that for normal individuals, peak V02 correlates closely with maximum cardiac output and serves as an indirect measure of stroke volume. 6-8 Because good test-retest reproducibility exists for peak V02 measurements, 8,19-22 this parameter has been used to quantitate functional limitations in patients with CHF. Several studies have shown that categorical measures, such as New York Heart Association (NYHA) functional class, lack the precision to detect small yet clinically significant changes in patient status, especially after an intervention. 23-25 Several studies have shown that patients frequently experience a significant deterioration in maximal exercise performance preceding clinical decompensation, 15,26pointing to the link between peak V02 and symptoms. Maximal exercise testing with measurement of peak Voz has several limitations. Although, V02 determinations are accurate in identifying patients with severe disease, discrimination of patients into NYHA classes II or III is more difficult, z7 It has also been argued that, for patients with severe dysfunction, such testing yields very little additional information to the clinician. Most exertional symptoms occur during low-level exercise. Patients with CHF perform most exercise at levels below peak V02; therefore, maximal testing only indirectly assesses exercise performance during levels of activity likely to be encountered during daily life. Anecdotal experience indicates that patients may experience excessive fatigue for hours or days after maximal exercise, 25 and maximal exercise testing may be frightening to patients with cardiac illnesses. In addition, such procedures as expired gas analysis require the necessary equipment and trained personnel. Either treadmill or bicycle ergometry protocols may be used for maximal exercise testing. Graded bicycle ergometry generally yields values for peak V02 10% to 15% less than treadmill testing but allows for quantification of submaximal and maximal exercise work rates. 25,28 In addition to being less cumbersome and expensive, patients tested by bicycle are more stable than those tested on the treadmill; it is easier to monitor hemodynamics and the electrocardiogram without the upper body motion encoun-

EXERCISE AND HEART FAILURE

tered with treadmill testing. Bicycle ergometry may also be more appropriate for heart failure patients with low levels of physical fitness (those who are deconditioned) or for those patients who cannot stand or walk because of weakness. 29 THE VENTILATORY ANAEROBIC THRESHOLD

Most laboratories use symptom-limited peak V02 and not maximal V02 (which requires a plateau in VQ with increasing work) in assessing functional capacity in CHF. One of the limitations of peak V02 testing in CHF is that determinations are not entirely independent of the patient's motivation. In normal subjects, the ventilatory anaerobic threshold (VAT) defines a point during exercise at which the ratio of ventilation (Ve) to V02 begins to increase because of the generation of excess carbon dioxide through the buffering of blood lactate by bicarbonate. 3°,31Although there is debate concerning the precise physiologic meaning of the VAT, it occurs at 40% to 90% of peak V02 and corresponds with an increase in blood lactate of 1 to 2 mmol/L.2° Exercise at work intensities below the VAT is accompanied by steady state V02 kinetics and stable blood lactate levels and can be sustained for long periods of time, whereas exercise above the VAT is accompanied by an upward drift in V02 and an increase in blood lactate levels and cannot be sustained for long periods of time. 3°,31 Thus, in normal subjects, the VAT represents a noninvasive indicator of skeletal muscle metabolism that is not dependent on motivation during exercise, which defines domains of high- and low-intensity exercise in an individual subject. Previous studies have identified that the VAT can be determined in most patients with CHF using either ventilatory equivalents or, possibly, the V-slope method and have suggested that this parameter may be useful in monitoring the response to interventions in patients with this disorder. 8,14,19,2°,3°,32-34Although there is a heightened ventilatory response to exercise in CHF, 35 several laboratories have shown that the VAT can be reproducibly determined in these patients. 8'1°'19'20'32-34Previous studies in our laboratory have shown that the V02 at which the VAT occurs can be increased by exercise training in patients with CHF. 33This finding was accompanied by a significant reduction in blood lactate accumulation during submaximal exercise and

3

an increase in exercise tolerance at a fixed submaximal work rate. These results indicate that, as in normal subjects, the VAT can be used to assess the results of an intervention that has a significant effect on blood lactate accumulation in this disorder and that it is linked to submaximal exercise tolerance. Although the VAT represents a potentially valuable parameter for assessing exercise tolerance, it has been difficult for some laboratories to reliably determine the VAT in patients with CHF. 14 Automated computerized approaches to determining the VAT generally have not been reliable. Irregular ventilatory patterns along with short exercise durations may make VAT measurement difficult or impossible to determine, especially in patients with severe CHF. The exercise protocol used also has an important effect on the VAT determination.2° It is also possible that pharmacologic interventions may improve peak Vo2 and symptoms in CHF without altering lactate metabolism. These factors have limited the utility of using the VAT to monitor the response to therapy in CHF. THE 6-MINUTE WALK TEST

The 6-minute walk test estimates functional capacity in chronically ill individuals by measuring the distance an individual can traverse over a 6-minute period. 36This test is thought to more closely correspond to the demands of everyday activities than other types of submaximal testing. McGavin and colleagues37 first used a 12-minute test to evaluate functional capacity in patients with significant pulmonary dysfunction unable to tolerate traditional methods of exercise testing. The validity and reproducibility of this test have been well established for the assessment and treatment of patients with chronic respiratory diseases 37-41 and, consequently, has been used as an outcome measure in many studies of patients with pulmonary diseases. Guyatt and associates42 were the first clinicians to report using the 6-minute walk test to measure exercise capacity in patients with CHF. In several sequential studies, these researchers documented statistically significant and small-tomoderate correlations with three other measures of functional capacity, NYHA class (r = -0.45), exercise capacity (r = 0.42), and scores on the Specific Activity Scale (r = -0.37),

4

a self-report measure of activity that approximates NYHA class. 42 There is an important training effect, with the 6-minute walk test that stabilizes over the first two testing intervals. 37,42 Hence, valid use of the 6-minute walk test should include a practice session to minimize variability; the level of coaching or encouragement also significantly influences subject performance.43 Several subsequent studies have also evaluated the use of the 6-minute walk test as a measure of functional capacity in heart failure. 44-48 In addition to providing data on functional capacity, Dracup and associates 44 have shown that results of the 6-minute walk test predicted depression and hostility scores among patients with CHF, suggesting a link between functional capacity and the psychosocial impact of CHF. Lipkin and associates 48 conducted a test of 26 stable heart failure patients (NYHA class II-III) by measuring peak V02 and distance walked on the 6-minute test. Again, a statistically significant and clinically meaningful relationship was found between these variables. Of interest is the finding that the relationship between performance and disease severity was curvilinear, with greater discriminating capacity among the sicker patients. Therefore, the investigators concluded that the 6-minute walk test is a useful test for screening and monitoring patients with moderate-to-severe CHF but is not as valuable for monitoring patients with mild functional impairment. Research conducted by both Gorkin 47 and Bittner, 45 using large subsets of the Studies of Left-Ventricular Dysfunction registry, have contributed significantly to our understanding of the validity and usefulness of the 6-minute walk test to evaluate patients with LV dysfunction. Gorkin and associates 47 examined a sample of 318 patients; they documented significant relationships between the walk test and two measures of functional impairment, the Functional Status Scale (r = -0.59) and the Dyspnea Scale (r = 0.44). Other smaller but significant relationships were also found between the walk test results and the following variables used to assess quality of life: (1) the Minnesota Living with Heart Failure Scale (r = -0.39); (2) health perceptions (r = -0.32); and (3) emotional distress ( r - - - 0 . 2 8 ) . The current evidence suggests that, if administered properly, the 6-minute

SULLIVAN AND HAWTHORNE

walk test may provide information that is complimentary to that obtained from maximal exercise testing with measurement of expired gas analysis. THE PROGNOSTIC VALUE OF EXERCISE TESTING IN HEART FAILURE

Four major sets of variables have emerged as mortality predictors in heart failure: functional capacity, hemodynamic variables, the presence and severity of arrhythmia, and the degree of neurohumoral activation. 36Assessment of functional capacity provides important prognostic information with which clinicians can select treatment and predict patient outcomes and responses to care. a5,49,5°Several studies outlined in Table 1 have shown the relationship of functional capacity to survival. 9,51-55 Szlachcic and associates 9 reported the first research that examined the determinants of exercise tolerance and their relationship to prognosis. The sample included 27 men with chronic heart failure; 16 patients were NYHA functional class III, 6 were class II, and 5 were class IV. Both rest and exercise hemodynamic measures (including EFs, cardiac output, and arterial and pulmonary artery pressures) were obtained along with exercise capacity measured by maximal oxygen consumption (peak Vo2) during upright bicycle ergometry. The subjects in this study were then followed for 1 year. Group I patients (peak Vo2 < 10 mL/kg/min; severe impairment) had significantly higher mortality (77%) compared with that for patients in group II (peak Vo2 > 10 mL/kg/min; 21%; P < .001). More recent studies show that the ability to achieve a peak Vo2 of more than 20 mL/kg/min and a VAT of more than 14 mL/kg/min is associated with a good prognosis. Those patients unable to achieve a Vo2 of 10 mL/kg/min and VAT of 8 mL/kg/min have a poor prognosis. Peak Vo2 values between 10 to 20 mL/kg/ min have variable prognostic implications depending on the study. The results of these studies suggest that measuring peak Vo2 provides valuable prognostic information in the assessment of patients with CHF. Bittner and associates 45 followed a subset of 242 patients from the Studies of Left-Ventricular Dysfunction registry to assess the prognostic value of the 6-minute walk test. There were four end points used during this analysis: (1) all

EXERCISE AND HEART FAILURE Table 1. Exercise Testing and Survival in Patients with Heart Failure Author(s)

Date

Szlachcic et al9

1985

Likoff et a152

1987

Cohn and Rector 53

1988

Pilote et a154

1989

Mancini et a P

1991

Stevenson et a155

1993

Study Population

Summary of Findings

27 patients grouped by Vo2 into groups; those with severely impaired tolerance (Vo~ < 10 mL/min/kg) and those with V02 between 10 and 18. 295 patients with average MET level of 6 were stratified by functional capacity. V-HeFT-1 trial; total exercise duration and peak 02 consumption were measured in 642 patients with mild-to-moderate heart failure. 115 patients with low EF ( < 35%) post-Ml were followed for 2 months to 7 years. Patients were assigned to 1 of 3 groups based upon V02 I: patients accepted for transplant VO2 less or equal to 14, n = 35. I1: patients considered too well for transplant. Vo2 > 14, n = 52. Ill: patients with low function, rejected for transplantn = 27. Bicycle exercise peak V02 determinations were examined in 333 patients referred for cardiac transplant, mean EF < 35%, for predictive value regarding outcomes: SCD, hemodynamic death, and deterioration to UrgTx.

77% 1-year mortality rate for patients with low VOz; versus 21% for less impaired group (P < .001). Exercise capacity was associated with survival, however, was not an independent predictor in patients with mild-to-moderate heart failure. Both exercise duration and peak V02 consumption were univariate predictors of survival, with V02 a more powerful predictor. Exercise capacity, assessed via treadmill 1 month after infarction, was a significant predictor of death and reinfarction. Patients with preserved exercise capacity had survivat rates comparable with transplant group; patients in group 3 had significantly lower survival rates; V02 was best predictor of survival. Researchers conclude that transplant can be safely deferred in patients with severe LV dysfunction with Vo2 > 14. Using life-table analysis, lower peak V02 predicted risk for death and UrgTx but not SCD. Cox analysis showed low peak V02 to be an independent predictor of total mortality..

Abbreviations: MET, metabolic rate; MI, myocardiol infarction; SCD, sudden cardiac death; UrgTx, urgent transplant.

cause mortality; (2) all hospitalizations; (3) hospitalizations for heart failure; and (4) death or hospitalization for heart failure. Patients were grouped by the researchers into the following four levels of performance: level I, < 300 m; level II, 300 to 374.9 m; level IlI, 375 to 449.9 m; and level IV, 450 m or greater. Using these groupings and the study end points, logistic regression analysis (with age, sex, cause of failure, and NYHA class as variables) showed that distance achieved in the 6-minute walk test was inversely related to mortality. Distance walked emerged as only one of two statistically significant independent predictors of mortality, with EF being the second predictive variable. Moreover, distance walked emerged as an equally strong predictor, with EF and gender as a predictor of hospitalization for CHF. Bittner and associates 45 found that each 120-m decrement in distance walked (approximately onehalf block) resulted in a 160% increase in hospitalization rate. These findings support the use of this test as a valid and useful predictor of survival in this patient group. In addition to predictions of mortality, there is also evidence that measures of functional

capacity are helpful in selecting appropriate treatment. 15,16,55For instance, the results of the work by the CASS investigators showed increased survival benefit for patients selected for surgical revascularization based on risk stratification via exercise testing. 56And more recently, Mancini and associates 15 have found that exercise testing with Vo2 determinations are helpful in distinguishing those patients who are likely to benefit from transplantation from those who can be safely deferred. This group of researchers examined three groups of patients: group I, patients accepted for heart transplant (n = 35); group II, patients considered too well for transplant (n = 52; Vo2 > 14); and group III, patients with low peak Vo2 ( < 10 mL/kg/min) who were rejected for transplant (n = 27). All three groups were comparable with respect to NYHA functional class, EF, and cardiac index. Patients with preserved exercise capacity (group II) had cumulative 1- and 2-year survival rates (94% and 84%, respectively) that were equal to the transplanted group. In contrast, patients rejected for transplant (group III) had significantly lower survival rates, 47% at 1 year and 32% at 2 years. Patients awaiting transplant

6

SULLIVAN AND HAWTHORNE

(group I) had a survival rate of 70% at 1 year compared with the survival rate of patients with V02 measurements greater than 14 (group II). In this study, peak V02 was the best predictor of survival. The investigators concluded that cardiac transplantation can be safely deferred in ambulatory patients with severe LV dysfunction and peak exercise V02 of greater than 14 mL/ min/kg. Figure 1 shows mortality in all patients in the study grouped by peak V02. PULMONARY LIMITATIONS IN CHF

Patients with CHF often report dyspnea during low-level physical activity. Dyspnea, which may be defined as an unpleasant awareness of breathing inappropriate for the level of physical activity, is a complex psychophysiologic phenomenon that may be mediated by a number of mechanisms,s7-59 According to Wasserman and CasaburP 7 these can be classified as (1) stimuli from vascular receptors, (2) mechanical stimuli including respiratory muscle stretch, pulmonary hyperinflation, and simulation of juxtapulmonary receptors (J-receptors), (3) hypoxemia, hypercapnia, and acidosis, (4) movement of the extremities, and (5) psychogenic factors. Studies have also suggested that chemoreceptors in skeletal muscle may also cause hyperpnea and possibly breathlessness, thus providing a link between peripheral metabolism and dyspnea during exercise.58 Studies have shown that proprioceptive input from the diaphragm and respiratory muscles signaling a disturbance in respiratory loading, termed length-tension inappropriateness, s7,s9,6° is an important contribut-

PEAKVO2 (rnt,,/kg,/m]n) 100: 75-

~

)18 ....

-

.

.

.

.

)14 418 (14)10

.

~'~'°'x. i

50\\=---= 110 25-

0

I

[

I

I

3

6

9

12

15

Fig 1. Survival curves of patients with CHF referred for cardiac transplantation, categorized by peak Vo2 (Reprinted with permission. TM [Circulation.] Copyright 1991 American Heart Association.)

ing factor to this symptom. It is felt that the increased work of breathing during exercise may cause increased respiratory muscle loading that, in turn, triggers proprioceptive impulses in these muscles mediating dyspnea. Macklem and coworkers61 have suggested that respiratory muscle fatigue may also play an important role in exertional breathlessness. Although studies have defined a large number of experimental conditions that can elicit dyspnea, it has been difficult to identify the primary factor responsible for exertional breathlessness in normal subjects or in a number of clinical conditions including CHF. Studies in animals by Paintal et a162 have shown that stimulation ofjuxtapulmonary receptors causes reflex hyperpnea via vagal efferents. Because J-receptors may be stimulated by increased pulmonary interstitial pressure, it has long been held that the primary mechanism responsible for exercise intolerance in this disorder has been increased pulmonary wedge pressure during exercise that stimulates pulmonary J-receptors causing reflex hyperventilation and also hypoxia, which, in turn, causes dyspnea. 63 Although increased pulmonary capillary wedge pressure is an important cause of dyspnea in patients with acute heart failure, several lines of evidence support the concept that increased intrapulmonary pressures are not the primary cause of exercise intolerance in stable ambulatory patients with CHF. Most patients with severe systolic LV dysfunction discontinue bicycle exercise because of muscle fatigueY ,64 Resting pulmonary capillary wedge pressure has been shown to have a modest inverse correlation with peak V02, but peak exercise pulmonary capillary wedge pressure is not related to peak V02.9,6s,66 Although hypoxia may occur with acute pulmonary edema, numerous studies have shown that arterial hypoxia does not occur during exercise in stable ambulatory patients with CHF. &35,64,67,68 Although excess ventilation (Ve), as indicated by an increased ratio of Ve to Vc02 (Ve/Vc02), occurs during exercise in patients with CHF, it is not closely correlated with rest or exercise pulmonary wedge pressure. 3s,64 Studies by Rubin et a167 have shown that the ratio of pulmonary dead space to tidal volume (VDS/VT) is elevated in patients with CHF. Studies in our laboratory3s extended these findings by showing that excess ventilation (Ve/Vc02) is inversely related to the VDs/VT

EXERCISE AND HEART FAILURE

7

(r = 0.78, P < .01) and that P a c o 2 levels were normal in CHF at rest and during exercise. These results indicate that ventilatory control mechanisms are intact in patients with CHF. Hyperpnea occurs during exercise in CHF to maintain eucapnea in the face of increased VDs/VT; ventilation is not driven by reflex mechanisms including stimulation of pulmonary J-receptors. Although it is possible that exerciseinduced hyperkalemia69 or stimulation from skeletal muscle metaboreceptors58,7°may play a role in dyspnea in CHF, these factors do not cause hypocapnic hyperventilation. It is interesting to note that peak exercise Ve/Vco2 was inversely related to peak exercise cardiac output (r = -0.49, P < .01) in our patients, suggesting that pulmonary hypoperfusion and not increased LV filling pressures may contribute to excess ventilation by worsening VDS/VT abnormalitiesY This might occur through ventilation-perfusion (V/Q) mismatching, with high V/Q ratios for some lung segments. When patients with CHF are grouped according to their primary limiting symptom (dyspnea versus fatigue) during bicycle exercise, there are no differences in peak pulmonary capillary wedge pressures in those limited primarily by fatigue compared with those limited by dyspnea (Fig 2). Examination of Fig 2 also shows that a significant number of ambulatory patients with CHF have normal peak pulmonary capillary wedge pressures (defined as < 16 mm Hg in previous studies in normal sub60 O .j

r/I

40

<3 <>

ul

~

20

0

0 Palllnll l i m i t e d by dyspnea ( 2 2 z 13 mmHg)

Patlerltl limited by fatigue ( 2 0 -+ 12 mmHg)

Fig 2. Peak exercise pulmonary capillary wedge pressure during bicycle exercise in patients with CHF grouped according to primary limiting symptom. (Reprinted with permission from Sullivan M J, Cobb FR: Central hemodynamic response to exercise in patients with chronic heart failure. Chest 101:340S346S, 1992 [suppl]Y s}

0.120 - - 0 NORMAL O - - I I CHF

t ~

a

_~ 0.08I-Z

0 0.04-

9 0.00

I

REST

9~ " "

I

I

I

25 50 75 WORKLOAD(WATTS)

I

MAXIMAL

Fig 3. Diaphragmatic work of breathing assessed by time tension intervals during exercise testing in patients with CHF and in normal subjects. [Reprinted with permission/6 [Circulation,] Copyright 1992 American Heart Association,)

jects). 71,72 Even though many of these patients

had normal peak LV filling pressures, they still showed major reductions in peak Vo2. Thus, exertional dyspnea and fatigue may occur at low absolute levels of exercise in CHF even with normal LV filling pressures. A number of studies have shown that restrictive pulmonary function abnormalities and an increased work of breathing are present in patients with CHF. 35,63,73-76 Mancini et a176-78 examined pulmonary function tests, transdiaphragmatic pressure, inspiratory and expiratory time, ratings of dyspnea and fatigue, and accessory muscle oxygenation (by near infrared spectrophotometry) at rest and during exercise in patients with CHF and in normal subjects. As shown in Fig 3, the diaphragmatic work of breathing as reflected by tension time intervals was increased in patients at rest and during exercise. However, transcutaneous phrenic nerve stimulation immediately after exercise showed no evidence of diaphragmatic fatigue in patients. Patients with CHF showed progressive respiratory muscle deoxygenation, whereas normal subjects did not alter near-infrared deflection values during exercise. 76,78 This finding is consistent with previous s t u d i e s 79-81 that have identified skeletal muscle hypoperfusion and early anaerobic metabolism during isotonic exercise involving large muscle groups in patients with this disorder. These results suggest that the decreased cardiac output response to exercise in CHF may also cause hypoperfusion of respiratory muscles, which, in turn, may lead to early respiratory muscle fatigue during exercise. Borg scale ratings of dyspnea at a given work rate

8

were inversely related to FEV1 (which was reduced in patients) and maximal inspiratory pressure and were directly related to tension time index and near-infrared absorption changes (reflecting respiratory muscle deoxygenation). These results suggest that pulmonary mechanics may play a role in exertional dyspnea in patients with CHF. It is interesting to note that perceived dyspnea at a given relative percentage of peak Vo2 was no different in patients versus normal subjects. Although it is possible that dyspnea is mediated in part by early respiratory muscle fatigue in CHF, these results suggest that diaphragmatic fatigue (as measured by peak twitch tension to transcutaneous phrenic nerve stimulation) does not occur during exercise in patients with CHF. The clinician is often faced with deciding whether a patient has exertional dyspnea because of cardiac or pulmonary disease. This is complicated by the finding that patients with CHF generally have mild restrictive pulmonary function abnormalities. 3s,6s,82Patients with both chronic obstructive pulmonary disease and CHF have excess ventilation during exercise, as indicated by an increase in Ve/Vc02 during exercise. Previous studies have examined the relationship of exercise ventilatory variables to resting pulmonary function studies including maximal voluntary ventilation in patients with CHF versus that in patients with chronic obstructive pulmonary disease. 82,83In a study by Nery et al, s2patients with chronic lung disease all discontinued exercise with a ratio of peak exercise Ve to maximal voluntary ventilation (dyspnea index) of greater than 0.80, whereas all patients with CHF and all normal subjects had a ratio that was less than 0.80 at peak exercise. Although patients with chronic lung disease may have a decrease in Pa02 during exercise, studies have consistently shown that patients with CHF maintain Pa02 with exercise. 7'8'35'68 Although determination of the dyspnea index is important in discriminating dyspnea from cardiac versus pulmonary disease, there may be alterations in pulmonary physiology in patients with CHF that may make this distinction more difficult. Cabanes et a184 have shown that patients with severe CHF may have bronchial hyperresponsiveness to cholinergic agonists. Although this cholinergic hyperresponsiveness was not found by Eichacker et al as in patients with

SULLIVAN AND HAWTHORNE

class IV CHF, it is possible that obstructive airway disease may play a role in producing dyspnea in some patients with CHF. Although patients with chronic lung disease and CHF both have exertional dyspnea, it appears that in the majority of patients the underlying mechanisms are somewhat different in these two disorders. ROLE OF CENTRAL HEMODYNAMICS

Studies by Hickam and Cargill 86 in 1947 were some of the first to show that cardiac output was reduced and systemic arteriovenous oxygen ( A V o 2 ) difference was increased at a given Vo2 in patients with CHF. This was followed by more systematic investigations by Epstein et al, 87 Ross et al, .8 and Sonnenblick et al, 89 which examined LV systolic performance and filling pressures during exercise in patients with CHF. These studies, combined with the work of Bruce et al, 9° Taylor et al, 9° and Mitchell et al, 92 established the concept that peak Vo2 could be used as an objective measure of exercise performance in patients with CHF and that central hemodynamic abnormalities played an important role in exercise intolerance in this disorder. Several investigators have shown that, in patients with systolic LV dysfunction, peak exercise LV EF is not related to peak exercise go2 .5"14'93Although this has been interpreted to indicate that abnormalities in cardiac function are not important in determining exercise tolerance, it is likely that this finding is because of the relatively small role of EF in determining the variability in cardiac output in groups of patients preselected with low LV EF. An important concept in investigating the role of central hemodynamics in contributing to exercise intolerance in CHF is that it is likely that LV and RV filling pressures and cardiac output at a given work rate are the variables that effect symptoms during exercise. Of these variables, it is likely that cardiac output is the most important. Cardiac output (CO), which is the product of heart rate (HR) and stroke volume (SV), is determined not only by LV contractility, but by several factors including changes in LV enddiastolic volume (EDV) and the mitral regurgitation fraction (MRF) as follows: CO = H R x SV or CO = H R x [ L V E D V x L V E F x (1 - MRF)]. Weber et al 8 provided the first systematic

EXERCISE AND HEART FAILURE

9

assessment of the relationships of peak tgrO2, central hemodynamics, and metabolism in patients with CHF because of LV dysfunction. This g r o u p 8'94'95 a n d o t h e r s 6-11,14,79,9°,96 have consistently shown a close linear relationship between peak exercise cardiac output and peak V Q in patients with CHF. Although peak cardiac output and peak Vo2 would be expected to be related regardless of the role of central hemodynamics in exercise intolerance, previous studies by Weber et aP indicate that the slope of the increase in cardiac output versus Vo2 is lower in patients with the most severe disability. Studies in our laboratory have also shown that cardiac output during submaximal exercise (300 killopond meters [kpm]/min) is closely related to peak Vo2 (r = 0.74, P < .01) in patients with this disorder. 97 This finding suggests that the slope of the cardiac output response during submaximal exercise is an important determinant of peak exercise tolerance in this disorder. This is likely because of the fact that reductions in exercise cardiac output are responsible for decreased perfusion of working skeletal muscle, which, in turn, is a potent stimulus for early A

t

'c16~ E

anaerobic metabolism. %Although early anaerobic metabolism is likely an important mechanism causing fatigue in this disorder, it is also possible that the reduced cardiac output response may lead to accumulation of metabolites in muscle or hypoperfusion of vital organs during exercise that may effect skeletal muscle excitation contraction. 99 Although the precise links between decreased cardiac output and exercise intolerance have not been defined, it appears the reduced cardiac output response to exercise plays an important role in limiting peak Vo2 in this disorder. Studies in patients with CHF have consistently shown a reduction in cardiac output and stroke volume at a given work rate, and a lower peak heart rate when compared to normal subjects. 8,12,14,35,68,79,96Figure 4 shows the central hemodynamic response in patients with CHF when compared with that in normal subjects. 79 In patients with severe systolic LV dysfunction and CHF, heart rate is increased during submaximal exercise (Fig 4A), with a 20% reduction in peak heart rate in patients when compared with that in normal subjects. 79 Chronotropic incomB

I

t,

® m

0

100

0 @

8

2

,.r-

t

t. . . . . . .

0 1

1

1

I

I

l

I

C

I

I

I

I

I

I

I

I

D

E 120 ~.. @

E O

•

60

O

t|

i

i

~st

150

300

oc~ 450 6,00 750 l CHF MAX

900 l NL MAX

I

1

Rest

150

l

3O0 450 A

CHF MAX

600

I

=

75O 900 A

NL MAX

. p<.O5 Patients vs. Normal8 f p<.01 Patients vs. Normals Fig 4. Central hemodynamic responses to bicycle exercise in patients with CHF and in normal subjects. (Reprinted with permissionY 9 [Circulation.] Copyright 1989 American Heart Association.)

10

petence has been shown in CHF by several investigators as an important contributing factor to reduced peak Vo2. 6,8,1°°,1°1 Although the mechanisms responsible for chronotropic incompetence in patients with severe systolic LV dysfunction have not been defined, abnormal reflex control of heart rate or adrenergic receptor alterations may be responsible. Studies by Colucci et al ml have shown that sinoatrial node sympathetic responsiveness is decreased in CHF because of postsynaptic [3-adrenergic desensitization. Cardiac output and stroke volume are reduced in patients when compared with that in normal subjects at rest and during exercise (Fig 4B and C), and central arteriovenous oxygen difference is increased in patients at rest and during submaximal exercise (Fig 4D). Mean systolic arterial blood pressure is decreased at maximal exercise in patients versus that in normal subjects but is not different at rest or at a given submaximal workrate. Mean pulmonary capillary wedge pressure is increased in patients at rest and during exercise, although a significant number of patients have normal LV filling pressures. Studies by Higginbotham et al m2 have examined the relationship of these variables to peak cardiac output in 40 patients with CHF because of severe LV systolic dysfunction. Peak heart rate was inversely related to peak cardiac output (r = -0.42, P < .05) indicating that chronotropic incompetence plays a role in determining the variability of peak cardiac output in this disorder. Although heart rate was only weakly to modestly related to peak cardiac output, exercise stroke volume was closely related to peak cardiac output (r = 0.72, P < .01). Several other groups have shown that the stroke volume response appears to be the primary factor determining the cardiac output response to exercise and plays an important role in determining exercise tolerance in patients with CHF because of severe systolic LV dysfunction. This is consistent with the findings of Weber et al 8 that stroke volume was lowest in patients with the most severe exercise intolerance. ROLE OF THE FRANK-STARLINGMECHANISM Measurements at rest have shown abnormalities in diastolic function in patients with severe LV systolic dysfunction. 1°3 Studies by Higginbotham et al 1°4 and by Shen et al 1°5 suggest that

SULLIVAN AND HAWTHORNE

use of the Frank-Starling mechanism plays an important role in augmenting stroke volume in a significant number of patients with LV systolic dysfunction and CHF. LV volumes were examined at rest and during maximal upright exercise in patients with severe LV dysfunction (LV EF, 21% + 9%) and in normal subjects using rightheart catheterization and simultaneous measurement of multigated radionuclide angiography, with calculation of end-diastolic volume from the Fick stroke volume and LV EF. 1°4Although exercise stroke volume was lower in patients with severe systolic dysfunction when compared with that of normal Subjects at rest and during exercise, the relative increase in stroke volume from rest to peak exercise was 48% in patients (25 to 37 mL/m 2) and 42% in normal subjects (41 to 58 mL/m2). Although part of the increase in stroke volume in normal subjects was attributable to an increase in LV EF with exercise, stroke volume increased in patients even though there was no change in LV EF. This was because of a greater increase in LV enddiastolic volume in patients (34 mL/m 2, from 153 mL/m 2 to 187 mL/m 2) when compared with that of normal subjects (11 mL/m 2, from 68 mL/m 2 to 77 mL/m2; P < .05). The increase in LV end-diastolic volume for a given increase in pulmonary capillary wedge pressure, a rough measure of LV compliance, was actually higher in patients when compared with that of normal subjects. It should be noted that mitral regurgitation, which may have been present during exercise in patients, would tend to underestimate the volume changes; therefore, the actual differences in LV end-diastolic changes between the groups may have been larger. Thus, patients with severe LV systolic dysfunction actually increase stroke volume by the same relative amount as normal subjects and accomplish this by use of the Frank-Starling mechanism without increasing LV EF. Patients increased LV end-diastolic volume almost three times as much as normal subjects during exercise, which played an important role in augmenting cardiac output in the face of impaired contractile reserve. Although most patients with severe LV systolic dysfunction use the Frank-Starling mechanism to increase stroke volume during exercise, some patients may not increase LV enddiastolic volume during exercise because of

EXERCISE AND HEART FAILURE

either diastolic LV dysfunction or pericardial constraint. JanickP °6 has shown that many patients with CHF show pericardial constraint during exercise, as indicated by an equilibration of the rate of increase in right atrial and pulmonary capillary wedge pressures during exercise. These patients showed no increase in stroke volume from rest to peak exercise, probably because of an inability to further increase LV end-diastolic volume. Ventricular interdependence and pericardial constraint may in part explain the finding by Baker et al 1°7that RV EF is significantly correlated with peak Vo2 in patients with LV systolic dysfunction. Patients with the lowest RV EF tend to have the highest RV afterload,~04 suggesting the presence of LV diastolic dysfunction or pericardial constraint. This, combined with high RV end-diastolic volumes, may limit the use of the Frank-Starling mechanism to increase LV stroke volume. HEART FAILURE BECAUSE OF DIASTOLIC LV DYSFUNCTION

Previous studies suggest that a significant minority (10% to 25%) of patients with classical CHF symptoms have normal LV systolic function. 1°8-11° To examine the potential role of diastolic LV dysfunction on the stroke volume response to exercise, we examined the central hemodynamic response to exercise in 7 patients with exercise intolerance and normal systolic LV function with 10 age-matched normal subjects. 111 These patients had classic CHF signs and symptoms, had documented previous pulmonary edema, and had no significant valvular abnormalities or coronary artery stenosis. Peak Vo2 was reduced in patients when compared with that of normal subjects (11.6 ___4.0 v 22.7 _+ 6.1 mL/kg/min; P < .01), which is consistent with severe exercise intolerance. Cardiac index and stroke volume index were no different at rest but were decreased in patients versus normal subjects during exercise. In contrast to the 25% to 40% increase in stroke volume during exercise observed in normal subjects, patients did not increase stroke volume with exercise. Both central arteriovenous oxygen difference and heart rate tended to be increased during submaximal exercise in patients. There was no difference in LV EF or LV end-systolic volume in the two groups, indicating normal ventricular contractile function in patients (Fig

11

5A and B). Although LV end-diastolic volume was not different at rest in the two groups, it was lower in patients during exercise and did not increase in this group from rest to exercise (Fig 5C). Pulmonary capillary wedge pressure was increased in patients versus normal subjects at rest and during exercise (Fig 5D), whereas the ratio of pulmonary capillary wedge pressure to LV end-diastolic volume was markedly increased in patients during exercise (Fig 5F). Mean arterial pressure was no different in the two groups (Fig 5E). There was a marked increase in LV filling pressures in patients without an increase in LV end-diastolic volume, suggesting severe LV diastolic dysfunction. Thus, stroke volume did not increase during exercise primarily because LV end-diastolic volume remained unchanged despite high LV filling pressures. These data show that diastolic LV dysfunction, even in the presence of normal systolic LV performance, may lead to significant reductions in exercise tolerance because of a decrease in the cardiac output-to-work rate relationship during exercise. It is also interesting to note that central hemodynamics during exercise may be quite similar in groups of patients with CHF symptoms whether they have primarily systolic or diastolic LV dysfunction. ROLE OF MITRAL REGURGITATION

Many patients with severe systolic LV dysfunction and CHF have secondary mitral regurgitation because of progressive ventricular dilation. Recent studies by Keren et a1112and Hamilton et a1113have shown that inotropic or vasodilator therapy may improve hemodynamics by reducing the mitral regurgitation fraction. It is possible that this is an important mechanism by which drug therapy improves cardiac output at rest or during exercise in dilated cardiomyopathy. Stevenson et a1114examined stroke counts by radionuclide ventriculography and cardiac output via thermodilution during upright exercise before and after vasodilator therapy in 10 patients with severe CHF because of systolic LV dysfunction. The calculated mitral regurgitation fraction during exercise before vasodilator therapy was 48% and decreased to 21% after vasodilator therapy (P < .05). Total stroke volume (left atrial plus aortic flow) was not changed at rest or during exercise after therapy, but forward stroke volume was significantly in-

12

_• LL

SULLIVAN AND HAWTHORNE

~< ¢D

A

4o

80 O ~

g ~ ~o LU

.3

B

100

>

E

40

20 ¢/1

20

Io UA

0

D

C

1D

m

c

Q.

9o

'

t

t ......

f

t .....

32

cE

24

>"

16

e~

o~

,4(}

g

I I UJ i

30

I

I

I

I

I

E

E~

F

"~ ~ 120 '~

g s a2

~

I(30

g 8O 60

I

l

I

1

I

I

R.st

15[)

300

450

600

750

MAX

NL MAX

_Eu~

g

Relt

WORKLOAD (kpm/min.)

creased after vasodilator therapy without a change in LV EF. This study supports the view that, in certain patients with severe heart failure, mitral regurgitation plays an important role in determining the forward stroke volume response to exercise, and that vasodilator therapy improves hemodynamics in CHF, in part, by reducing mitral regurgitation. PERIPHERAL LIMITATIONS TO EXERCISE

Studies in the 1950s and 1960s showed that arteriovenous oxygen difference was increased and lactate accumulation was increased at a given work rate during isotonic exercise in patients with CHF when compared with that of normal subjects. 34,H5 Weber et a194 has shown that blood lactate increased most quickly in patients with the most severely reduced exercise tolerance. During exercise in normal subjects, skeletal muscle mass, oxidative enzyme and substrate content, and fiber type, along with

150

300

450

~T

600

7.$0 A

Nt

MAX MAX WORKLOAD (kpm/min.)

Fig 5. Central hemodynamic responses to bicycle exercise in patients with classic CHF and normal LV systolic function and in normal subjects, (Reprinted with permission of the American College of Cardiology [Journal of the American College of Cardiology, 1991, 17:1065-1072]. m }

adrenergic activation, and the delivery of oxygen and substrates have been identified as important determinants of the onset of anaerobic metabolism at a particular work rate. u6 Studies over the past two decades have identified hypoperfusion of working skeletal muscle as an important cause of early anaerobic metabolism in this disorder. 79-81 Studies by Zelis and colleagues 117J18 showed that both rest and exercise arm blood flow were reduced in CHF accompanied by an increase in vascular resistance. These investigators also showed that the vasodilator response to adrenergic blockade, ischemia, and direct arterial vasodilators were decreased in patients with CHF. H7,H8Although increased vasoconstriction because of increased neurohumoral activation 93,119,12° or decreased endogenous vasodilation 121-124likely contribute to this response, these results suggest that increased vascular stiffness was responsible, in part, for increased vasomotor tone in CHF. This

EXERCISE AND HEART FAILURE

is supported by the findings that the capillary basement membranes could be thickened in CHF, 125 that diuresis restores about 30% of vasomotor responsiveness, 126 and that vascular stiffness reverses slowly after cardiac transplantation. 127This concept is supported by the findings of LeJemtel et a181that leg blood flow does not increase during 1- versus 2-legged exercise in patients with moderate-to-severe CHF. Wilson et a180'128132 have provided a number of important studies that have measured leg blood flow using the thermodilution technique in patients with CHF. These investigators found that leg blood flow at peak exercise was related to peak V02 and functional class and that reduced leg blood flow was associated with increased blood lactate levels during submaximal exercise. Studies in our laboratory 79showed that peak leg blood flow was closely related to peak V02 in both patients and normal subjects, and that cardiac output and leg blood flow were reduced both at rest and during exercise in CHF patients. Leg vascular resistance was markedly elevated in patients at rest and during exercise, whereas arterial blood pressure and flow to nonexercising tissues was maintained. This suggests that increased skeletal muscle vasomotor tone is an autoregulatory mechanism that prevents hypotension or hypoperfusion of vital organs in the face of a decreased cardiac output. Wilson and colleagues ~°,128-132also explored the relationship of decreased leg blood flow to metabolism in skeletal muscle during bicycle exercise in patients with CHF. These studies examined leg blood flow and metabolism during exercise before and after the use of vasodilators 128,129or adrenergic blockade. 131These studies generally showed that exercise cardiac output and leg blood flow were increased with acute drug administration without altering peak Vo2, exercise duration, or leg lactate production. These results were confirmed by this group in a study 133 showing that the acute administration of dobutamine did not improve calf phosphocreatinine-to-inorganic phosphate ratios despite immediate improvements in leg blood flow. This concept is supported by studies in our laboratory examining central hemodynamics and leg blood flow in patients with moderate CHF without edema during 1- and 2-1egged bicycle exercise. 134 In normal subjects, during intense

13

exercise, leg blood flow is increased during l-legged exercise because cardiac output can increase to meet the demands of a small muscle mass. In our patients, during l-legged exercise, single leg blood flow was increased at a given work rate as compared with blood flow during 2-legged exercise. This improvement in blood flow was accompanied by a decrease in leg arteriovenous oxygen difference, supporting the concept that skeletal muscle oxygen delivery was improved during l-legged exercise. Despite this improvement, blood lactate levels were unchanged with l-legged exercise. These results suggest that, although perfusion is decreased in skeletal muscle in CHF, intrinsic alterations in skeletal muscle play an important role in determining metabolism and oxygen use in CHF. This concept is supported by a recent study by Wilson et a1132 showing that a minority of patients with CHF maintain leg blood flow at normal levels during exercise. Despite normal perfusion, these patients have early lactate production and significant reductions in peak g o 2.

Although acute increases in leg blood flow do not lead to improved peak Vo2, chronic increases may lead to improved exercise performance. In a placebo-controlled trial, Drexler et a1135examined leg blood flow, peak Vo2, metabolism, and central hemodynamics before and after acute and chronic administration (4 months) of angiotensin-converting enzyme (ACE) inhibitor therapy in patients with CHF. This study showed that an improvement in peak Vo2 with long-term but not short-term ACE inhibitor therapy was accompanied by increased peak exercise leg blood flow, leg V02, and an increase in femoral venous oxygen extraction. Mancini et a1136have also shown that peak leg blood flow increases in patients who improve exercise tolerance after chronic ACE inhibitor therapy. Studies in our laboratory have shown that exercise training improved peak V02 after 4 to 6 months in patients with CHF. 19 This was accompanied by an increase in peak exercise leg blood flow and a trend for peak cardiac output to increase, whereas there was no change in leg blood flow or cardiac output during submaximal exercise. In these patients, leg lactate production was significantly decreased after training, without any change in submaximal skeletal muscle perfusion. These results support the

14

SULLIVAN AND HAWTHORNE

concept that, in addition to oxygen delivery, skeletal muscle biochemistry and histology play an important role in determining the metabolic response to exercise in CHF. SKELETAL MUSCLE FUNCTION IN HEART FAILURE A growing body of literature suggests that skeletal muscle function is abnormal in patients with CHF. 137-150 Studies using forearm exercise 140,142,145and leg exercise 142with monitoring of metabolism via 31p-magnetic resonance imaging (MRI) have shown early reductions in pH and increases in inorganic phosphorus/phosphocreatine (Pi/PCr) in patients with CHF compared with those for normal subjects. Patients also showed an excessive decrease in pH for a given decrease in Pi/PCr, suggesting heightened glycolytic metabolism. Analysis of rest and exercise biopsy specimens of the vastus lateralis in patients with CHF and in normal subjects support this concept by showing a prominent increase in lactate, glucose, and glucose-6-PO4 in skeletal muscle during low-level exercise. I43 Studies by Wilson et a114° and Massie et a114~ showed that pH and Pi/PCr were reduced at a given work rate when compared with those for normal subjects even though arm blood flow (measured by plethysmography) was normal in patients. Massie et a1145then showed that skeletal muscle metabolism was abnormal in CHF patients when compared with that of normal subjects even after occlusion of blood flow. These results provide strong evidence that abnormal skeletal muscle metabolism occurs in CHF independent of reduced perfusion. In addition to abnormalities in metabolism, skeletal muscle contractile function may be altered in patients with CHF. Lipkin et a1147 showed a 55% reduction in isometric tension of the quadriceps femoris in patients with CHF when compared with that of normal subjects, although skeletal muscle size was not measured in this study. Several groups 151-153have shown that skeletal muscle atrophy is present in many patients with CHF, which may contribute to exercise intolerance. Both Minotti et a1153 and Magnusson et a1151 have shown atrophy of the thigh muscles in patients with CHF. These investigators showed that, although the force of a maximal voluntary contraction was reduced in patients, maximal force production per cross-

sectional area was normal in patients with CHF.151.153Mancini et a1152examined calf muscle volume and 24-hour urinary creatinine excretion in 62 patients with CHF. There was a reduction in the creatinine-to-height ratio in 68% of patients, suggesting reduced skeletal muscle mass. Calf muscle volume was reduced in patients and was weakly related to peak V02 (r = 0.42, P < .05), suggesting that skeletal muscle atrophy contributes to exercise intolerance in this disorder. This is supported by a recent study by Jondeau et a1154that examined peak V02 during leg and, then, leg combined with arm exercise in patients with moderate to severe CHF and in age-matched normal subjects. In contrast to normal subjects who did not increase peak V02 with the addition of arm exercise, patients with severe CHF (peak V02, < 15 mL/kg/min) had a 22% increase in peak V02 with combined arm and leg exercise. These results indicate that cardiac output is not the sole factor limiting exercise in patients with CHF and suggest that reduced skeletal muscle mass or reduced perfusion capacity in muscle plays an important role in limiting exercise tolerance. However, skeletal muscle atrophy does not explain all of the reduction in exercise tolerance in CHF. We examined 31p-MRI of the quadriceps during knee extensor exercise in patients with CHF and in normal subjects matched for quadriceps femoris mass (measured by serial 1H-MRI imaging). 155 Peak V02 was significantly reduced in patients versus that in normal subjects, and anaerobic metabolism occurred earlier in patients during exercise. Thus, significant decreases in exercise tolerance accompanied by altered skeletal muscle metabolism can occur in CHF patients even in the absence of skeletal muscle atrophy. Minotti et a115°have reported strong evidence that skeletal muscle contractile dysfunction is present in CHF. These investigators examined static and dynamic isokinetic endurance in patients with CHF and in normal subjects. They showed that static endurance, defined as the time it takes for force to decrease to 60% of maximum during a maximal voluntary isometric contraction, was reduced in patients versus that in normal subjects (40 _+ 14 v 77 _+ 29 s; P < .02). This is important because isometric contractions of greater than 60% of maximum generally occlude arterial inflow. Dynamic endurance,

EXERCISE AND HEART FAILURE

15

defined as the decrease in peak torque during 15 successive contractions, was reduced in patients even after occlusion of arterial inflow. A finding that provides a strong link between skeletal muscle performance and symptoms was that dynamic endurance was closely related to peak V02 in patients (Fig 6). These results provide strong evidence that skeletal muscle contractile dysfunction occurs independent of reduced perfusion and plays an important role in determining exercise performance in CHF. This concept is supported by studies that have shown biochemical and histologic alterations in skeletal muscle in patients with CHF. Lipkin et a1147 noted fiber atrophy with abnormal lipid deposition in fibers in patients with CHF. Studies in patients in our laboratory 146 have noted decreases in aerobic enzymes, and [3-hydroxyacyl-CoA-dehydrogenase with normal levels of glycolytic enzymes. There were decreases in the percent composition of type-I fibers and increases in type-IIb fibers when compared with that of normal subjects. 146 Individual muscle fibers were smaller, and the number of capillaries per fiber was reduced, although overall fiber diffusion distances were unchanged. In a preliminary report, Yancey et a1148 also showed a decrease in aerobic enzyme activity in patients with CHF. Mancini et a1144 have also shown increases in relative type-IIb fiber composition, fiber atrophy, and reduced [3-hydroxyacyl-CoAdehydrogenase in patients with CHF. Studies by Ralston et a1156have shown marked reductions in aerobic enzymes in patients with CHF when compared with that in healthy younger subjects. Drexler et a1149have shown reduced surface and 30

cq

I

o .O

.~

E E

20

,,

10

N

•

•% •

o

qln, •

•

r - 0.90 p < 0.001

0i

0.4

=

0.5

|

i

i

!

u

0.6

0.7

0.8

0.9

1.0

Is•kinetic Endurance at 90 Deg/S Fig 6. Relationship of peak Vo= with is•kinetic endurance in patients with chronic heart failure. (Reproduced from the Journal of Clinical Investigation, 1991, 88:2077-2082, by copyright permission of The American Society for Clinical Investigation. ~s0)

volume density of mitochondria and reduced capillary length density in skeletal muscle in CHF. Several groups have shown modest relationships between skeletal muscle changes and peak Vo2.139,146,149 Although reduced aerobic enzyme content in skeletal muscle has previously been shown to accelerate lactate production during exercise in humans and in animals, Mancini et a1144did not show a relationship between skeletal muscle enzyme activity and exercise metabolism in patients with CHF. In contrast, our laboratory 143 has shown a close inverse relationship (r = -0.74, P < .05) between citrate synthetase activity and submaximal exercise femoral venous lactate levels in patients with CHF (Fig 7), suggesting that alterations in aerobic enzymes in skeletal muscle play an important role in determining submaximal and maximal exercise performance in this disorder. This is supported by the finding of Drexler et a1149that changes in mitochondrial volume density were related to the changes in peak V02 in 11 patients who underwent serial biopsies accompanied by exercise testing before and after vasodilator therapy. Habitual exercise conditioning plays an important role in determining skeletal muscle composition in normal humans 157 and is likely an important factor leading to changes in skeletal muscle in CHF. However, it is important to note that not all of the changes observed in skeletal muscle in CHF are consistent with deconditioning. Previous studies in humans have not shown a shift in type-I fibers in skeletal muscle after deconditioning. 158,16°Although it is possible that chronic hypoxia plays a role in skeletal muscle alterations in this disorder, studies in patients with intermittent claudication do not show similar changes. 161,162 These results suggest that changes in skeletal muscle in CHF are not solely because of deconditioning or hypoxia, although the precise mechanisms responsible are not currently known. Although anaerobic metabolism in skeletal muscle is an important factor mediating exercise intolerance in this disorder, several lines of evidence suggest that this is not the sole factor mediating skeletal muscle fatigue in patients. (1) Wilson et a1163have acutely decreased lactate production during exercise in patients with CHF by giving dichloroacetate without improving symptoms or exercise performance. (2) Stud-

16

SULLIVAN A N D H A W T H O R N E

8

._.q

8

O r = -0.34 OO~~= 0.37

6

o

r = 0.35 p = 0.36

6 4

g 2

2 I 1.0

0

g

0.5

I 1.5

I 2.0

I

2.5

0

I 20

10

I 30

I 40

t 50

Femoral Venous 0 2 Saturation (%)

Leg Blood Flow (l/rain)

o

8

O

i11

r = -0.45 p = 0.22

o= 6

E ¢

LL

o

2 0 0.5

J 1.0

6

o J 1.5

O ~

r = -0.74 p = 0.02

O

2 J 2.0

J 2.5

Skeletal Muscle Capillary Density (average capillaries per fiber)

0 0.5

I 1.0

I 1.5

I 2.0

p 2.5

Skeletal Muscle Ctrate Synthetase (gM/g protein)

ies have not shown reduced anaerobic metabolism during submaximal exercise after successful vasodilator therapy. 135 (3) Blood lactate levels at peak exercise are consistently lower in patients versus those in normal subjects8,79-8°without an alteration in the blood-to-skeletal muscle lactate gradient, m (4) Studies show that during peak bicycle exercise limited by fatigue (femoral venous oxygen saturation, 21%; RER, 1.37), biopsy specimens of the vastus lateralis show higher PCr levels and lower lactate in skeletal muscle in patients versus those in normal subjects.143 These results are in contrast to 31p-MRI studies during smaller muscle exercise, which show similar pH and Pi/PCr ratios in patients and normal subjects at peak exercise, 14°,141and raise the possibility that the basis of fatigue in skeletal muscle may be altered in CHF during isotonic exercise involving large muscle groups. Fatigue in skeletal muscle, defined as the inability to maintain a given force, may be due to a number of metabolic, neural, and neuromuscular factors in normal subjects. 99 Minotti et a1164 have shown that twitch potentiation does not increase force generation during an isometric contraction in CHF, suggesting that central fatigue or decreased neural activation is not primarily responsible for early fatigue in this disorder. This is supported by Wilson et al, 165 who showed increased electromyography activ-

Fig 7. Relationships of leg blood flow, femoral venous oxygen staturation, skeletal muscle cappillary denisty, and citrate synthetase activity in skeletal muscle (vastus lateralis) w i t h blood lactate appearance at a fixed submaximal work rate in patients with CHF. (Reprinted with permissionJ 4~ [Circulation.] Copyright 1991 American Heart Association.)

ity at a given work rate in skeletal muscle in patients with CHF when compared with that of normal subjects. Although it is unlikely that central fatigue is present in CHF, it is possible that the physiologic basis of skeletal muscle fatigue may be altered in patients with this disorder. EXERCISE TRAINING IN CHF

Studies examining exercise training in patients with CHF and severe systolic LV dysfunction have provided important information on the mechanisms of exercise intolerance in CHF. Although exercise has previously been felt to be contraindicated in patients with CHF, at least 10 studies have now shown that training improves peak Vo2 and symptoms of C H F . 137'166"175 Exercise training represents a potentially important therapy in CHF that likely acts primarily through effects in skeletal muscle. Studies in our laboratory have shown that, after 4 to 6 months of cardiac rehabilitation, patients improved peak Vo2 by 23% and developed a training bradycardia and an increase in peak AVoz difference without significant changes in exercise cardiac o u t p u t . 19,33 This was accompanied during submaximal exercise by a marked decrease in arterial and femoral venous lactate accumulation without a change in leg blood flow or femoral venous oxygen saturation. Patients

EXERCISE AND HEART FAILURE

showed an increase in V02 at the anaerobic threshold, improved symptoms, and a marked increase in endurance time at a fixed submaximal work rate. These results highlight the important effect of skeletal muscle on peak V02 in CHF. This is supported by the results of Minotti et al, 174 who examined arm metabolism, blood flow, and muscle size before and after local training in patients with CHF. During submaximal exercise after training, anaerobic metabolism was delayed without changes in blood flow or muscle mass. Coates et al, 167,a7°in a randomized cross-over trial, also showed improved peak V02 with training that was accompanied by an improved quality of life. An important finding in this study was that adrenergic activation assessed by 3Hnorepinephrine spillover and by spectral analysis of heart rate variability was decreased in patients after training. This has important consequences because therapies similar to exercise training that reduce neurohumoral activation in CHF generally confer long-term morbidity and mortality benefits. Resistance training of smaller muscle groups has also been shown to improve functional capacity in these patients, a66 Studies by Davies et a169have shown that exercise training reduces hyperkalemia during exercise in patients with CHF, which may lead to decreased fatigue during low-level exercise. A recent study by Kavanaugh et aP 72 found an increase in peak V02 after training in patients with severe CHF (peak V02 < 15 mL/kg/min). In this study, changes in peak V02 were closely related to improvements in quality of life. These studies indicate that exercise training improves peak V02 and symptoms to a degree that is similar to the effects of vasodilator therapy. ~73 It appears that exercise training improves exercise tolerance in CHF mainly through effects on skeletal muscle without major improvement in central hemodynamics. These results support the concept that peripheral factors play an important role in determining the response to therapy in this disorder. SUMMARY

Studies over the past 10 years have significantly furthered our understanding of the pathophysiology of exercise intolerance in patients with CHF. Functional capacity, as assessed by

17

exercise testing, has emerged as an important prognostic variable that can be used to guide treatment. The consistent finding that increased pulmonary capillary wedge pressure does not seem to be responsible for exercise intolerance in most ambulatory patients with CHF has led to a search for pulmonary and skeletal muscle etiologies for fatigue and dyspnea in this disorder. Although LV EF does not correlate with peak V02 in preselected patients with severe LV systolic dysfunction, this does not necessarily indicate that central hemodynamic factors do not play a role in determining functional capacity in CHF. Cardiac output and stroke volume at both submaximal and maximal exercise are both related to peak V02. The finding that LV EF is not related to peak V02 likely reflects the modest contribution of variability in LV EF and the more significant contributions of heart rate, LV end-diastolic volume, and mitral regurgitation fraction on the cardiac output response to exercise. Although abnormal heart function is the primary initiating event in the syndrome of CHF, there is now clear evidence that peripheral abnormalities play a role in exercise intolerance in CHF. This is underscored by the finding that exercise training can improve functional class and both maximal and submaximal exercise intolerance without altering cardiac output EF, LV filling pressures, or leg blood flow during submaximal exercise. Numerous studies have also shown that vasodilator therapy, which has immediate salutary hemodynamic benefits does not improve symptoms or peak V02 for weeks to months after initiating treatment. In addition to alterations in vasomotor tone and increased vascular stiffness in peripheral vessels in CHF that may act to further decrease perfusion, a growing body of literature has shown significant alterations in skeletal muscle biochemistry, histology, contractile function, and size that appear to have an important effect on exercise tolerance in CHF. At present, it appears that exercise intolerance in CHF is caused by a complex interaction of abnormalities in central hemodynamics leading to decreased cardiac output, pulmonary function, peripheral blood flow, and skeletal muscle composition and function that must all be taken into consideration when evaluating the effects of new therapies in this disorder.

18

SULLIVAN AND HAWTHORNE

REFERENCES

1. Smith, WM: Epidemiology of congestive heart failure. Am J Cardio155:3A-8A, 1985 2. Schocken DD, Arrieta MI, Leverton PE, et al: Prevalence and mortality rate of congestive heart failure in the United States. J Am Coll Cardio120:301-306, 1992 3. Sullivan M J: Congestive heart failure: Trends in epidemiology and therapy, in Kennedy G, Crawford M (eds): Congestive Heart Failure: Current Clinical Issues (ed 1). New York, NY, Futura, 1994, pp 1-15 4. Ghali JK, Cooper R, Ford E: Trends in hospitalization rates for heart failure in the United States, 1973-1986. Arch Intern Med 150:769-773, 1990 5. Benge W, Litchfield RL, Marcus ML: Exercise capacity in patients with severe left ventricular dysfunction. Circulation 61:955-959, 1980 6. Higginbotham MB, Morris KG, Conn EH, et al: Determinants of variable exercise performance among patients with severe left ventricular dysfunction. Am J Cardiol 51:52-60, 1983 7. Franciosa JA, Park M, Levine TB: Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure. Am J Cardiol 47:33-39, 1981 8. Weber KT, Kinasewitz GT, Janicki JS, et al: Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation 65:1213-1223, 1982 9. Szlachcic J, Massie BM, Kramer BI, et al: Correlates and prognostic implication of exercise capacity in chronic congestive heart failure. Am J Cardio155:1037-1042, 1985 10. Metra M, Raddino R, Dei Cas L, et al: Assessment of peak oxygen consumption, lactate and ventilatory thresholds and correlation with resting and exercise hemodynamic data in chronic congestive heart failure. Am J Cardiol 65:1127-1133, 1990 11. Marantz PR, Tobin JN, Wassertheil-Smoller S, et al: The relationship between left ventricular systolic function and congestive heart failure diagnosed by clinical criteria. Circulation 77:607-612, 1988 12. Fransciosa JA, Leddy CL, Wilen M, et al: Relation between hemodynamic and ventilatory responses in determining exercise capacity in severe congestive heart failure. Am J Cardio153:127-134, 1984 13. Weber KT, Janicki JS: Cardiopulmonary Exercise Testing. Philadelphia, PA, Saunders, 1986 14. Cohen-Solal A, Caviezell B: Cardiopulmonary exercise testing in chronic heart failure. Heart Failure t0:46-57, 1994 15. Mancini DM, Eisen H, Kussmal W, et al: Value of peak oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 83:778-786, 1991 16. Brooks SE, Rodeheffer RJ: Prognostic features in patients with congestive heart failure and selection criteria for cardiac transplantation. Mayo Clin Proc 67:485-492, 1992 17. Evart CK, Stewart KJ, Kelemen MH, et al: Usefullness of self efficacy in predicting over-exertion during programed exercise in coronary artery disease. Am J Cardio157:557-561, 1986 18. Frolicher ESS, King SC, Woods SL, et al: Exercise

testing, in Underhill SL, et al (eds): Cardiac Nursing. Philadelphia, PA, Lippincott, 1989, pp 418-430 19. Sullivan MJ, Higgenbotham MB, Cobb FR: Exercise training in patients with severe left ventricular dysfunction. Hemodynamic and metabolic effects. Circulation 78:506515, 1988 20. Simonton CA, Higginbotham MB, Cobb FR: The ventilatory threshold: Quantitative analysis of reproducibility and relation to arterial lactate concentration in normal subjects and in patients with chronic heart failure. Am J Cardio162:100-107, 1988 21. Elborn JS, Stanford CF, Nicolls DP: Reproducibility of cardiovascular parameters during exercise in patients with chronic heart failure. Eur Heart J 11:75-81, 1990 22. Dickstein K, Aarsland S, Snapin S: Reproducibility of cardiopulmonary exercise testing in men following myocardial infarction. Eur Heart J 9:948-954, 1988 23. Hanson P: Exercise testing and training in patients with chronic heart failure. Med Sci Sports Exerc 26:527-537, 1994 24. Rector TS, Kubo SH, Cohn JN: Patients self assessment of their congestive heart failure. Heart Failure 1:189209, 1987 25. Dubach P, Froelicher VF: Cardiac rehabilitation for heart failure patients. Cardiology 76:368-373, 1989 26. Packer M, Pitt B: Which objective measurements parallel the courses of disease progression in patients with congestive heart failure. J Am Coll Cardiol 11:202A, 1988 (abstr) 27. Hlaff-Nelson CL, Herndon JE, Mark DB, et al: Relation of clinical and angiographic factors to functional capacity as measured by Duke Activity Status Index. Am J Cardio168:973-975, 1991 28. Myers J, Froelicher VF: Exercise testing. Cardiol Clin 11:199-213, 1993 29. Graves JE, Pollack ML: Exercise testing in cardiac rehabilitation. Cardiol Clin 11:253-266, 1993 30. Wasserman K: Coupling of exernal to cellular respiration during exercise: the wisdom of the body revisited. Am J Physiol 266:E519-E539, 1994 31. Brooks GA: Anaerobic threshold: Review of the concept and directions for future research. Med Sci Sports Exerc 17:22-31, 1985 32. Matsumura N, Nishijima H, Kojima S, et al: Determination of anaerobic threshold for assessment of functional state in patients with chronic heart failure. Circulation 68:306-367, 1983 33. Sullivan MJ, Higginbotham MB, Cobb FR: Exercise training in patients with chronic heart failure delays ventilatory anaerobic threshold and improves submaximal exercise performance. Circulation 79:324-329, 1989 34. Wasserman K, McIlroy MB: Detecting the threshold of anaerobic metabolism in cardiac patients during exercise. Am J Cardiol 14:844-848, 1964 35. Sullivan MJ, Higginbotham MB, Cobb F: Increased exercise ventilation in patients with chronic heart failure: Intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation 77:552-559, 1988 36. Gradman AH, Deedwania PC: Predictors of mortality in patients with heart failure. Cardiol Clin 12:25-35, 1994

EXERCISE AND HEART FAILURE

37. McGavin CR, Gnpta SP, McHardy GJR: Twelveminute walking test for assessing disability in chronic bronchitis. Br Med J 1:822-823, 1976 38. Butland RJA, Pang J, Gross ER, et al: Two, six and 12 minute walking tests in respiratory disease. Br Med Jr 284:1607-1608, 1982 39. McGavin CR, Artvinli M, Naoe H, et al: Dyspnea, disability and estimate of exercise performance in respiratory disease. Br Med J 2:241-243, 1978 40. Morgan AD, Peck DF, Buchanan DR, et al: Effect of attitudes and beliefs on exercise tolerance. Br Med J 286:171-173, 1983 41. Mungall IPF, Hainsworth R: Assessment of respiratory function in patients with chronic obstructive lung disease. Thorax 34:254-258, 1979 42. Guyatt GH, Sullivan MJ, Thompson PJ, et al: The 6-minute walk: A new measure of exercise capacity in patients with chronic heart failure. Can Med J 132:919-923, 1985 43. Guyatt GH, Pugsley SO, Sullivan MJ, et al: Effect of encouragement on walking test performance. Thorax 39:818822, 1984 44. Dracup K, Walden JA, Stevenson LW, et al: Quality of life with advanced heart failure. J Heart Lung Transplant 11:272-279, 1992 45. Bittner V, Weiner DH, Yusuf S, et al: Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. JAMA 270:17021707, 1993 46. Rozdovec A, Papouchado M, James MA, et al: The relationship of symptoms to performance in paced patients with breathlessness. Eur Heart J 10:63-69, 1989 47. Gorkin L, Norvell NK, Rosen RC, et al: Assessment of quality of life as observed from baseline data of the studies of left-ventricular dysfunction (SOLVD) trial quality of life substudy. Am J Cardiol 71:1069-1073, 1993 48. Lipkin DP, Scriven AJ, Crake T, et al: Six minute walking test for assessing exercise capacity in chronic heart failure. Br Med J 292:653-655, 1986 49. Younis LT, Chaitman BR: Prognostic value of exercise testing. Cardiol Clin 11:229-240, 1993 50. Wenger NK: Patients with left ventricular dysfunction and congestive heart failure, in Wenger NK, Hellerstein HK (eds): Rehabilitation of the Coronary Patient. New York, NY, Churchill Livingstone, 1992, pp 403-413 51. Cleland JGF, Dargie HJ: Mortality in heart failure: Clinical variables of prognostic value. Br Heart J 58:572582, 1987 52. Likoff MJ, Chandler SL, Kay HR: Clinical determinants of mortality in chronic congestive heart failure. Am J Cardio159:634-638, 1987 53. Cohn JN, Rector TS: Prognosis of congestive heart failure and predictors of mortality. Am J Cardiol 62:16361641, 1988 54. Pilote L, Silberberberg J, Lisbona R, et al: Prognosis in patients with low left ventricular ejection fraction. Circulation 80:1636-1641, 1989 55. Stevenson LW, Steimle AE, Chelimsky-Saffallick C, et al: Outcomes predicted by peak oxygen consumption during evaluation of 333 patients with advanced heart failure. Circulation 88:I-94, 1993 (suppl I, abstr)

19

56. Weiner DA, Ryan TJ, McCabe CH, et al: Prognostic importance of a clinical profile and exercise test in medically treated patients with coronary artery disease. J Am Coll Cardiol 3:772-779, 1994 57. Wasserman K, Casaburi R: Dyspnea: Physiological and pathological mechanisms. Annu Rev Med 39:503-515, 1988 58. Hagberg JM, Coyle EF, Carroll JE, et al: Exercise hyperventilation in patients with McArdle's disease. J Appl Physio152:991-994, 1982 59. Fishman AP, Ledlie FJ: Dyspnea. Bull Eur Physiopathol Respir 15:789-796, 1979 60. Campbell EJM, Howell JBL: The sensation of breathlessness. Br Med Bull 19:36-40, 1976 61. Roussos CS, Macklem PT: Diaphragmatic fatigue in man. J Appl Physio143:189-197, 1977 62. Paintal AS: Mechanism of stimulation of type J pulmonary receptors. J Physio1203:511-517, 1969 63. Ingrain RH, McFadden ER: Respiratory changes during exercise in patients with pulmonary venous hypertension. Prog Cardiovasc Dis 19:109-115, 1976 64. Fink LI, Wilson JR, Ferraro N: Exercise ventilation and pulmonary artery wedge pressure in chronic stable congestive heart failure. Am J Cardio157:1358-1363, 1986 65. Lipkin DP, Canepa-Anson R, Stephens MR, et al: Factors determining symptoms in heart failure: Comparison of fast and slow exercise tests. Br Heart J 55:439-445, 1986 66. Massie BM: Exercise tolerance in congestive heart failure: Role of cardiac function, peripheral blood flow, and muscle metabolism and effect of treatment. Am J Med 84:75-82, 1988 (suppl 3A) 67. Rubin SA, Brown HV: Ventilation and gas exchange during exercise in severe chronic heart failure. Am Rev Respir Dis 129:63-64, 1984 68. Wilson JR, Ferraro N: Exercise intolerance in patients with chronic left heart failure: Relation to oxygen transport and ventilatory abnormalities. Am J Cardiol 51:1358-1363, 1983 69. Barlow CW, Qayyum MS, Davey PP, et al: Effect of physical training on exercise-induced hyperkalemia in chronic heart failure: Relation with ventilation and catecholamines. Circulation 89:1144-1152, 1994 70. Eiken O, Bjurstedt H: Dynamic exercise in man as influenced by experimental restriction of blood flow in the working muscles. Acta Physiol Scand, 1987;131:339-345. 71. Higginbotham MB, Morris KG, Williams RS, et al: Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Cire Res 58:281-291, 1986 72. Sullivan MJ, Cobb FR, Knight JD, et al: Central hemodynamic response to upright exercise in normal subjects: Stroke volume is augmented by similar mechanisms in men and women. Am J Cardio167:1405-1412, 1991 73. Gazetopoulos N, Davies H, Oliver C, et al: Ventilation and hemodynamics in heart disease. Br Heart J 28:1-15, 1986 74. Reed JW, Ablett M, Cotes JE: Ventilatory responses to exercise and to carbon dioxide in mitral stenosis before and after valvulotomy: Cause of tachypnea. Clin Sci Mol Med 54:9-16, 1978 75. Clark AL, Swan JW, Laney R, et al: The role of right

20

and left ventricular function in the ventilatory response to exercise in chronic heart failure. Circulation 89:2062-2069, 1994 76. Mancini DM, Henson D, LaManca J, et al: Respiratory muscle function and dyspnea in patients with chronic heart failure. Circulation 86:909-918, 1992 77. Wilson JR, Mancini D, Simson M, et al: Objective detection of muscle fatigue in patients with heart failure. Am J Cardiol 17:488-493, 1992 78. Mancini DM, Rerraro N, Nazzaro D, et al: Respiratory muscle deoxygenation during exercise in patients with heart failure demonstrated with near-infrared spectroscopy. J Am Coil Cardiol 18:492-498, 1991 79. Sullivan MJ, Knight JD, Higginbotham MB, et al: Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure: Muscle blood flow is reduced with maintenance of arterial perfusion pressure. Circulation 80:769-781, 1989 80. Wilson JR, Martin JL, Schwartz D, et al: Exercise intolerance in patients with chronic heart failure: Role of impaired nutritive flow to skeletal muscle. Circulation 69:1079-1087, 1984 81. LeJemtel TH, Maskin CS, Lucido D, et al: Failure to augment maximal limb blood flow in response to one-leg versus two-leg exercise in patients with severe heart failure. Circulation 74:245-251, 1986 82. Nery LE, Wasserman K, French W, et al: Contrasting cardiovascular and respiratory responses to exercise in mitral valve and chronic obstructive pulmonary disease. Chest 83:446, 1983 (abstr) 83. Wasserman K: Dyspnea on exertion: Is it the heart or the lungs? JAMA. 248:2039-2043, 1982 84. Cabanes LR, Weber SN, Matran R, et al: Bronchial hyperresponsiveness to methacholine in patients with impaired left ventricular function. N Engl J Med 320:13171322, 1989 85. Eichacker PQ, Seidelman MJ, Rothstein MS, et al: Methacholine bronchial reactivity testing in patients with chronic congestive heart failure. Chest 93:336-338, 1988 86. Hickam JB, Cargill WH: Effect of exercise on cardiac output and pulmonary arterial pressure in normal persons and in patients with cardiovascular disease and pulmonary emphysema. J Clin Invest 27:10-19, 1948 87. Epstein SE, Beiser GD, Stampfer M, et al: Characterization of the circulatory response to maximal upright exercise in normal subjects and patients with heart failure. Circulation 35:1049-1062, 1967 88. Ross J, Gault JH, Mason DT, et al: Left ventricular performance during muscular exercise in patients with and without cardiac dysfunction. Circulation 34:597-608, 1966 89. Sonnenblick EH, Braunwald E, Williams JF, et al: Effects of exercise on myocardial force-velocity relations in intact unanesthetized man: Relative roles of changes in heart rate, sympathetic activity and ventricular dimensions. J Clin Invest 44:2051-2062, 1965 90. Bruce RA, Kusumi F, Hosmer D: Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. Am Heart J 85:546562, 1973 91. Taylor HL, Buskirk E, Henschel A: Maximal oxygen intake as an objective measure of cardiorespiratory performance. J Appl Physiol 8:73-80, 1958

SULLIVAN AND HAWTHORNE

92. Mitchell J, Blomquist G: Maximal oxygen uptake. N Engl J Med 284:1018-1022, 1981 93. Francis GS, Goldsmith SR, Cohn JN: Relationship of exercise capacity to resting left ventricular performance and basal plasma norepinephrine levels in patients with congestive heart failure. Am Heart J 104:725-731, 1982 94. Weber KT, Janicki JS: Lactate production during maximal and submaximal exercise in patients with chronic heart failure. J Am Coll Cardiol 6:717-724, 1985 95. Weber K, Janicki JS: Cardiopulmonary exercise testing for evaluation of chronic heart failure. Am J Cardiot 55:22A-31A, 1985 96. Sullivan MJ, Cobb FR: Central hemodynamic response to exercise in patients with chronic heart failure. Chest 101:340S-346S, 1992 (suppl) 97. Sullivan MJ, Knight JD, Higginbotham MB, et al: Submaximal exercise cardiac output predicts peak Vo2 in patients with heart failure but not in normal subjects. Circulation 80:427, 1989 (suppl 2, abstr) 98. Idstrom JP, Subramanian VH, Chance B, et al: Oxygen dependence of energy metabolism in contracting recovering rat skeletal muscle. Am J Physiol 248:H48-H53, 1985 99. Green H J: Manifestations and sites of neuromuscular fatigue, in Taylor AW (ed): Biochemistry of Exercise, vol 21. Champaign, IL, Human Kinetics, 1990, pp 13-35 100. Hammond HK, Froelicher VF: Normal and abnormal heart rate responses to exercise. Prog Cardiovasc Dis 27:271-296, 1985 101. Colucci WS, Ribeiro JP, Rocco MB, et al: Impaired chronotropic response to exercise in patients with congestive heart failure: Role of postsynaptic [3-adrenergic desensitization. Circulation 80:314-323, 1989 102. Higginbotham MB, Sullivan MJ, Simpson CA, et al: Central and peripheral determinants of exercise limitation in patients with congestive heart failure. Circulation 74: 1788, 1986 (suppl 2, abstr) 103. Feldman MD, Alderman JD, Aroesty JM, et al: Depression of systolic and diastolic myocardial reserve during atrial pacing tacbycardia in patients with dilated cardiomyopathy. J Clin Invest 82:1661-1669, 1988 104. Higginbotham MB, Sullivan M J, Coleman RE, et al: Regulation of stroke volume during exercise in patients with severe left ventricular dysfunction: Importance of the Starling mechanism. J Am Coll Cardiol 9:58A, 1987 (abstr) 105. Shen WF, Roubin GS, Hirasawa K, et al: Left ventricular volume and ejection fraction response to exercise in chronic congestive heart failure: Difference between dilated cardiomyopathy and previous myocardial infarction. Am J Cardio155:1027-1031, 1985 106. Janicki JS: Influence of the pericardium and ventricular inter-dependence on left ventricular diastolic and systolic function in patients with heart failure. Circulation 82:15-20, 1990 (suppl 3) 107. Baker BJ, Wilen MM, Boyd CM, et al: Relation of right ventricular ejection fraction to exercise capacity in chronic left ventficular failure. Am J Cardiol 54:596-598, 1984 108. Soufer R, Wohlgelernter D, Vita N: Intact systolic left ventricular function in clinical congestive heart failure. Am J Cardio155:1032-1036, 1985 109. Topoi EJ, Traill TA, Fortuin NJ: Hypertensive

EXERCISE AND HEART FAILURE

hypertrophic cardiomyopathy of the elderly. N Engl J Med 312:277-283, 1985 110. Kessler KM: Heart failure with normal systolic function: Update of prevalence, differential diagnosis, prognosis, and therapy. Arch Intern Med 148:2109-2111, 1988 111. Kitzman DW, Higginbotham MB, Cobb FR, et al: Heart failure with normal systolic function: Diastolic dysfunction limits exercise cardiac output. J Am Coll Cardiot 17:1065-1072, 1991 112. Keren G, Katz S, Strom J, et al: Dynamic mitral regurgitation: An important determinant of the hemodynamic response to load alterations and inotropic therapy in severe heart failure. Circulation 80:306-313, 1989 113. Hamilton MA, Stevenson LW, Child JS, et al: Sustained reduction in valvular regurgitation and atrial volumes with tailored vasodilator therapy in advance congestive heart failure secondary to dilated (ischemic or idiopathic) cardiomyopathy. Am J Cardio167:259-236, 1991 114. Stevenson LW, Brunken RC, Belil D, et al: Afterload reduction with vasodilators and diuretics decreases mitral regurgitation during upright exercise in advanced heart failure. J Am Coil Cardiol 15:174-180, 1990 115. Donald KW, Wormald PN, Taylor SH, et al: Changes in the oxygen content of femoral venous blood and leg blood flow during leg exercise in relation to cardiac output response. Clin Sci 16:567-591, 1957 116. Ivy JL, Withers RT, Van Handel PJ, et al: Muscle respiratory capacity and fiber type as determinants of the lactate threshold. J Appl Physio148:523-527, 1980 117. Zelis R, Flaim SF: Alterations in vasomotor tone in congestive heart failure. Prog Cardiovasc Dis 24:437-459, 1982 118. Zelis R, Mason DT, Braunwald E: A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. J Clin Invest 47:960-970, 1968 119. Zelis R, David D: The sympathetic nervous system in congestive heart failure. Heart Failure 2:21-32, 1986 120. Wilson JR, Frey M J, Mancini DM, et al: Sympathetic vasoconstriction during exercise in ambulatory patients with left ventricular failure. Circulation 79:1021-1027, 1989 121. Katz SD, Biasucci L, Sabba C, et al: Impaired endotheium-mediated vasodilation in the peripheral vasculature of patients with congestive heart failure. J Am Coil Cardiol 19:918-925, 1992 122. Katz S, Schwarz M, Yuen J, et al: Impaired acetyicholine-mediated vasodilation in patients with congestive heart failure. Role of endothelium-derived vasodiating and vasconstricting factors. Circulation 88:55-61, 1993 123. Treasure CB, Vita JA, Cox DA, et al: Endotheliumdependent dilation of the coronary microvasculatnre is impaired in dilated cardiomyopathy. Circulation 81:772779, t990 124. Kaiser L, Spickard RC, Olivier NB: Heart failure depresses endothelium-dependent responses in canine femoral artery. Am J Physiol 256:H962-H967, 1989 125. Longhurst J, Capone R J, Zelis R: Evaluation of skeletal muscle capillary basement membrane thickness in congestive heart failure. Chest 67:195-198, 1975 126. Sinoway L, Minotti J, Musch T, et al: Enhanced metabolic vasodilation secondary to diuretic therapy in

21

decompensated congestive heart failure secondary to coronary artery disease. Am J Cardiol 60:107-111, 1987 127. Sinoway LI, Minotti JR, David D, et al: Delayed reversal of impaired vasodilation in congestive heart failure after heart transplantation. Am J Cardiol 61:1076-1079, 1988 128. Wilson JR, Ferraro N: Effect of the ReninAngiotensin System on limb circulation and metabolism during exercise in patients with heart failure. J Am Coll Cardiol 6:555-556, 1985 129. Wilson JR, Martin JL, Ferraro N, et al: Effect of hydralazine on perfusion and metabolism in the leg during upright bicycle exercise in patients with heart failure. Circulation 68:425-432, 1983 130. Wilson JR, Martin JL, Ferraro N: Impaired skeletal muscle nutritive flow during exercise in patients with heart failure: Role of cardiac pump dysfunction as determined by effect of dobutamine. Am J Cardio154:1308-1315, 1984 131. Wilson JR, Ferraro N, Wiener DH: Effect of the sympathetic nervous system on limb circulation and metabolism during exercise in heart failure. Circulation 72:72-81, 1985 132. Wilson JR, Mancini DH, Dunkman WB: Exertional fatigue due to skeletal muscle dysfunction in patients with heart failure. Circulation. 87:470-475, 1993 133. Mancini DM, Schwartz M, Ferraro N, et al: Effect of dobutamine ion skeletal muscle metabolism in patients with congestive heart failure. Am J Cardio165:1121-1146, 1990 134. Sullivan MJ, Cobb FR: Dynamic regulation of leg vasomotor tone in patients with chronic heart failure. J Appl Physio171:1070-1075, 1991 135. Drexler H, Banhardt U, Meinertz T, et al: Contrasting peripheral short-term and long-term effects of converting enzyme inhibition in patients with congestive heart failure: A double-blind, placebo-controlled trial. Circulation 79:491-502, 1989 136. Mancini DM, Davis L, Wexler JP, et al: Dependence of enhanced maximal exercise performance on in: creased peak skeletal muscle perfusion during long-term captopril therapy in heart failure. J Am CoU Cardiol 10:845-850, 1987 137. Wilson JR: Exercise intolerance in heart failure: Importance of skeletal muscle. Circulation 91:559-561, 1995 138. Minotti JR, Christoph I, Massie BM: Skeletal muscle function, morphology, and metabolism in patients with congestive heart failure. Chest 101:333S-339S, 1992 (suppl 5) 139. Zannad F, Chait Z: Skeletal muscle metabolic, morphohistological, and biochemical abnormalities in congestive heart failure. Heart Failure 10:58-66, 1994 140. Wilson JR, Fink L, Maris J, et al: Evaluation of energy metabolism in skeletal muscle of patients with heart failure with gated phosphorus-31 nuclear magnetic resonance. Circulation 71:57-62, 1985 141. Massie BM, Conway M, Yonge R, et al: 31P nuclear magnetic resonance evidence of abnormal skeletal muscle metabolism in patients with congestive heart failure. Am J Cardio160:309-315, 1987 142. Mancini DM, Ferraro N, Tuchler M, et al: Detection of abnormal calf muscle metabolism in patients with heart failure using phosphorus-31 nuclear magnetic resonance. Am J Cardiol 62:1234-1240, 1988

22

143. Sullivan MJ, Green HJ, Cobb FR: Aletered skeletat muscle metabolic response to exercise in chronic heart failure. Relation to skeletal muscle aerobic enzyme activity, Circulation 84:1597-1607, 1991 144. Mancini DM, Clyle E, Coggan A, et ah Contricution of intrinsic skeletal muscle changes in 31p NMR skeletal muscle metabolic abnormalities in patients with chronic heart failure. Circulation 80:1338-1346, 1989 145. Massie BM, Conway M, Rajagopalan B, et al: Skeletal muscle metabolism during exercise under ischemic conditions in congestive heart failure. Evidence for abnormalities unrelated to blood flow. Circulation 78:320-326, 1988 146. Sullivan M J, Green HJ, Cobb FR: Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 81:518-527, 1990 147. Lipkin DP, Jones DA, Round JM, et ah Abnormalities of skeletal muscle in patients with chronic heart failure. Int J Cardiol 18:187-195, 1988 148. Yancy CW, Parson D, Lane L, et al: Capillary density, fiber type and enzyme composition of skeletal muscle in congestive heart failure. J Am Coll Cardiol 13:38A, 1989 (abstr) 149. Drexler H, Riede U, Munzel T, et al: Alterations of skeletal muscle in chronic heart failure. Circulation 85:17511759, 1992 150. Minotti JR, Christoph I, Oka R, et ah Impaired skeletal muscle function in patients with congestive heart failure. Relationship to systemic exercise performance. J Clin Invest 88:2077-2082, 1991 151. Magnusson G, Isberg B, Karlberg KE, et al: Skeletal muscle strength and endurance in chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol 73:307-309, 1994 152. Mancini DM, Walter G, Reichek N, et al: Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 85:1364-1373, 1992 153. Minotti JR, Pillay P, Oka R, et al: Skeletal muscle size: Relationship to muscle function in heart failure. J Appl Physio175:373-381, 1993 154. Jondeau G, Katz SD, Zohman L, et al: Active skeletal muscle mass and eardiopulmonary reserve: Failure to attain peak aerobic capacity during maximal bicycle exercise in patients with severe congestive heart failure. Circulation 86(5):1351-1356, 1992 155. Sullivan MJ, Charles HC, Negro-Villar R, et al: Skeletal muscle anaerobic metabolism occurs independent of muscle atrophy in heart failure. Circulation 84:II-7, 1991 (suppl II, abstr) 156. Ralston MA, Merola AJ, Leier CV: Depressed aerobic enzyme activity of skeletal muscle in severe chronic heart failure. J Lab Clin Med 117:370-372, 1991 157. Alway SE, MacDougall JD, Sale DG, et al: Functional and structural adaptations in skeletal muscle of trained athletes. J Appl Physio164:1114-1120, 1988 158. Lindboe ChF, Platou ChS: Disuse atrophy of human

SULLIVAN AND HAWTHORNE

skeletal muscle: An enzyme histochemical study. Acta Neuropathol (Berl) 56:241-244, 1982 159. Hikida RS, Gollnick PD, Dudley GA, et al: Structural and metabolic characteristics of human skeletal muscle following 30 days of simulated microgravity. Aviat Space Environ Med 60:664-670, 1989 160. Green HJ, Sutton JR, Cymerman A, et al: Operation Everest II: adapations in human skeletal muscle. J Appl Physio166:2454-2461, 1989 161. Regensteiner JG, Wolfel EE, Brass EP, et al: Chronic changes in skeletal muscle histology and function in peripheral arterial disease. Circulation 87:413-421, 1993 162. Hedberg B, Angquist KA, Henriksson-Larsen K, et al: Fibre loss and distribution in skeletal muscle from patients with severe peripheral aterial insufficiency. Eur J Vasc Surg 3:315-322, 1989 i63. Wilson JR, Mancini DM, Ferraro N, et al: Effect of dichloroacetate on the exercise performance of patients with heart failure. J Am Coll Cardiol 12:1464-1469, 1988 164. Minotti JR, Pillay P, Chang L, et al: Neurophysiological assessment of skeletal muscle fatigue in patients with congestive heart failure. Circulation 86:903-908, 1992 165. Wilson JR, Mancini DM, Simson M: Detection of skeletal muscle fatigue in patients with heart failure using electromyography. Am J Cardio170:488-493, 1992 166. Douard H, Patel P, Broustet JP: Exercise training in patients with chronic heart failure. Heart Failure 10:80-87, 1994 167. Coats AJS, Adamopoulos S, Meyer T, et al: Effects of physical training in chronic heart failure. Lancet 335:6366, 1990 168. Lee AP, Ice R, Blessey R, et al: Long-term effects of physical training on coronary patients with impaired ventricular function. Circulation 15:1519-1526, 1979 169. Uren NG, Lipkin DP: Exercise training as therapy for chronic heart failure. Br Heart J 67:430-433, 1992 170. Coats AJS, Adanopoulos S, Radaeili A, et al: Controlled trial of physical training in chronic heart failure. Circulation 85:2119-2131, 1992 171. Jette M, Heller R, Landry F, et al: Randomized 4-week exercise program in patients with impaired left ventricular function. Circulation 84:1561-1567, 1991 172. Kavanagh T, Myers MG, Baigrie RS, et al: Cardiac respiratory training responses to a one-year walking program in patients with chronic heart failure. Eur Heart J 14:415, 1993 (suppl, abstr) 173. Minotti JR, Massie BM: Exercise training in heart failure patients: Does reversing the peripheral abnormalities protect the heart? Circulation 85:2323-2325, 1992 174. Minotti JR, Johnson EC, Hudson TL, et al: Skeletal muscle response to training exercise in congestive heart failure. J Clin Invest 86:751-758, 1990 175. Conn Eh, Williams RS, Wallace AG: Exercise responses before and after physical conditioning in patients with severely depressed left ventricular function. Am J Cardio149:296-300, 1982