Unraveling new mechanisms of exercise intolerance in chronic heart failure. Role of exercise training

Despite remarkable progress in the therapeutic approach of patients with chronic heart failure (CHF), exercise intolerance remains one of the hallmarks of the disease. During the past two decades, evidence has accumulated to underscore the key role of both endothelial dysfunction and skeletal muscle wasting in the process that gradually leads to physical incapacity. Whereas reverse ventricular remodeling has been attributed to aerobic exercise training, the vast majority of studies conducted in this specific patient population emphasize the reversal of peripheral abnormalities. In this review, we provide a general overview on underlying pathophysiological mechanisms. In addition, emphasis is put on recently identified pathways, which contribute to a deeper understanding of the main causes of exercise tolerance and the potential for reversal through exercise training. Recently, deficient bone marrow-related endothelial repair mechanisms have received considerable attention. Both acute exercise bouts, as well as exercise training, affect the mobilization of endothelial progenitor cells and their function. The observed changes following exercise training are believed to significantly contribute to improvement of peripheral endothelial function, as well as exercise capacity. With regard to skeletal muscle dysfunction and energy deprivation, adiponectin has been suggested to play a significant role. The demonstration of local skeletal muscle adiponectin resistance may provide an interesting and new link between the insulin resistant state and skeletal muscle wasting in CHF patients.     

Ventilatory mechanisms of exercise intolerance in chronic heart failure.

Mechanisms that have been suggested to underlie the abnormal ventilatory response to exercise in patients with chronic congestive heart failure (CHF) include high pulmonary pressures, ventilation-perfusion mismatching, early metabolic acidosis, and abnormal respiratory control. To evaluate the role that ventilation and gas exchange play in limiting exercise capacity in patients with CHF, data from 33 patients with CHF and 34 normal subjects of similar age who underwent maximal exercise testing were analyzed. Maximal oxygen uptake was higher among normal subjects (31.7 +/- 6 ml/kg/min) than among patients with CHF (17.7 +/- 4 ml/kg/min; p less than 0.001). The ventilatory equivalent for oxygen, expressed as a percentage of maximal oxygen uptake, was 25% to 35% higher among patients with CHF compared with normal subjects throughout exercise (p less than 0.01). A steeper component effect of ventilation on maximal oxygen uptake was observed among normal subjects compared with patients with CHF, which suggests that a significant portion of ventilation in CHF is wasted. Maximal oxygen uptake was inversely related to the ratio of maximal estimated ventilatory dead space to maximal tidal volume (VD/VT) in both groups (r = -0.73, p less than 0.001). Any given oxygen uptake at high levels of exercise among patients with CHF was accompanied by a higher VD/VT, lower tidal volume, and higher respiratory rate compared with normal subjects (p less than 0.01). Relative hyperventilation in patients with CHF started at the beginning of exercise and was observed both below and above the ventilatory threshold, which suggests that the excess ventilation was not directly related to earlier than normal metabolic acidosis. Thus abnormal ventilatory mechanisms contribute to exercise intolerance in CHF, and excess ventilation is associated with both a higher physiologic dead space and an abnormal breathing pattern. The high dead space is most likely due to ventilation-perfusion mismatching in the lungs, which is related to poor cardiac output, and the abnormal breathing pattern appears to be an effort to reduce the elevated work of breathing that is caused by high pulmonary pressures and poor lung compliance.     

Blood flow redistribution and exercise intolerance in chronic heart failure]

We examined blood flow redistribution during exercise and its significance on exercise intolerance in chronic heart failure. Sixty-three patients with chronic heart diseases underwent symptom-limited maximal multistage exercise using a supine ergometer. We measured oxygen intake (VO2) and cardiac index (CI) using Fick's principle and leg flow with the thermodilution method at rest and during exercise. Patients were categorized in 5 groups according to their VO2 max; i.e., control group (n = 12), having normal right-sided cardiac pressure during exercise; A group (n = 8), having an abnormal right-sided pressure elevation, but normal exercise tolerance VO2 max greater than 20 ml/min/kg; B group (n = 19) VO2 max 20-15; C group (n = 17) also 15-10; and D group (n = 7), VO2 less than 10 ml/min/kg. At maximal exercise, the CI max and leg flow max were similar between the control and A groups; whereas, they decreased in the order of groups B, C and D. The ratio of leg flow/CI increased by 5 times from rest to maximal exercise in all groups, although the values at rest and at maximal exercise were similar among all groups. The relationship between CI and leg flow during exercise was linear in each individual patient. The coefficient of this regression line was extremely high (r = 0.98 +/- 0.02). Therefore, we calculated each regression line, leg flow = (a).CI +/- (b), with the gradient (a) as an index of blood flow redistribution to working skeletal muscles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Big endothelin and chronic heart failure

In a group of 124 patients the authors investigated the importance of assessment of plasma levels of big endothelin and endothelin 1 in patients with chronic heart failure as compared with other currently used non-invasive parameters. A six fold increase of plasma levels of both substances was found in patients in functional class NYHA IV as compared with patients in class NYHA II-III. But even patients in the milder stage of NYHA had twice as high values as compared with the standard of the healthy population. Similarly patients with interstitial pulmonary oedema had a twice as high level of both parameters as compared with patients who had a normal finding on X-ray or merely a redistribution of the pulmonary vascularization. The sensitivity of assessment of plasma levels is such that this examination could become part of the basic diagnosis.     

Plasma endothelin in chronic heart failure.

BACKGROUND. Endothelins are recently characterized vasoconstrictor peptides. As chronic heart failure (CHF) is characterized by peripheral arteriolar and renal vasoconstriction, we have measured venous plasma endothelin-like immunoreactivity ("endothelin") in patients with this syndrome. METHODS AND RESULTS. Compared with age- and sex-matched healthy volunteers (mean +/- SEM plasma endothelin concentration 6.4 +/- 0.3 pmol/l, n = 16), patients with severe CHF had elevated peripheral venous endothelin concentrations (12.4 +/- 0.6 pmol/l, n = 47, p less than 0.01). Plasma endothelin did not increase with exercise in normal subjects or in patients. Plasma endothelin concentration (mean, 13.4 +/- 0.9 pmol/l) did not correlate with plasma atrial natriuretic factor concentration (mean, 88.9 +/- 11.9 pg/ml) in patients with CHF (n = 21). There was also no correlation between plasma endothelin and serum urea or between endothelin and serum creatinine in patients with CHF (n = 34). There was, however, significant renal extraction of endothelin (aorta, 11.1 +/- 0.8 pmol/l; renal vein, 8.8 +/- 0.6 pmol/ml; p = 0.02) in patients with CHF (n = 13). CONCLUSIONS. Evidence suggests that circulatory endothelin concentrations in the range 5-40 pmol/l are vasoactive. Consequently, the endothelin concentrations found in patients with CHF may be of pathophysiological significance.     

Role of respiratory function in exercise limitation in chronic heart failure

OBJECTIVE: To test the hypothesis that respiratory function contributes to limit maximal exercise performance in patients with chronic heart failure by using the technique of dead space loading during exercise. DESIGN: Blinded subjects underwent two maximal incremental exercise tests in random order on an upright bicycle ergometer: one with and one without added dead space. SETTING:: Tertiary-care university teaching hospital. SUBJECTS: Seven patients with stable chronic heart failure (mean +/- SEM left ventricular ejection fraction, 27 +/- 3%). RESULTS: Subjects were able to significantly increase their peak minute ventilation during exercise with added dead space when compared with control exercise (57.4 +/- 5.9 vs 50.0 +/- 5.6 L/min; p < 0.05). Peak oxygen uptake, workload, heart rate, and exercise duration were not significantly different between the added dead space and control tests. Breathing pattern was significantly deeper and slower at matched levels of ventilation during exercise with added dead space. CONCLUSION: Because patients with chronic heart failure had significant ventilatory reserve at the end of exercise and were able to further increase their maximal minute ventilation, we conclude that respiratory function does not contribute to limitation of exercise in patients with chronic heart failure.     

Respiratory muscle function and exercise intolerance in heart failure

Inspiratory muscle weakness (IMW) is prevalent in patients with chronic heart failure (CHF) caused by left ventricular systolic dysfunction, which contributes to reduced exercise capacity and the presence of dyspnea during daily activities. Inspiratory muscle strength (estimated by maximal inspiratory pressure) has independent prognostic value in CHF. Overall, the results of trials with inspiratory muscle training (IMT) indicate that this intervention improves exercise capacity and quality of life, particularly in patients with CHF and IMW. Some benefit from IMT may be accounted for by the attenuation of the inspiratory muscle metaboreflex. Moreover, IMT results in improved cardiovascular responses to exercise and to those obtained with standard aerobic training. These findings suggest that routine screening for IMW is advisable in patients with CHF, and specific IMT and/or aerobic training are of practical value in the management of these patients.     

Apoptosis in skeletal myocytes of patients with chronic heart failure is associated with exercise intolerance

OBJECTIVES: The purpose of the study was to investigate if apoptosis occurs in skeletal muscle myocytes and its relation to exercise intolerance in patients with chronic heart failure (CHF). BACKGROUND: Intrinsic abnormalities of skeletal muscle frequently limit exercise tolerance in CHF patients. Recently, apoptosis has been detected in cardiac myocytes of patients with CHF, suggesting that apoptosis may contribute to the reduced contractile force. The presence and regulation of apoptosis in skeletal myocytes of patients with CHF remains to be defined. METHODS: Skeletal muscle biopsies (m. vastus lateralis) of 34 CHF patients (New York Heart Association functional class II-III) and eight age-matched healthy control subjects were analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling for the presence of apoptosis, and by immunohistochemistry and videodensitometrical quantification for inducible nitric oxide synthase (iNOS) and Bcl-2 expression. Maximal oxygen consumption (VO2max) was determined by ergospirometry. RESULTS: Apoptosis was detected in 16/34 (47%) patients with CHF and in none of the healthy subjects. Patients with apoptosis-positive skeletal muscle myocytes exhibited a significantly lower VO2max (12.0 +/- 3.7 vs. 18.2 +/- 4.4 ml/kg/min; p = 0.0005), a higher iNOS expression (6.8 +/- 3.6 vs. 3.7 +/- 2.6% iNOS-positive stained tissue area; p = 0.015) and a lower Bcl-2 expression (1.0 +/- 0.3 vs. 1.4 +/- 0.4% Bcl-2-positive tissue area; p = 0.03) as compared with patients with apoptosis-negative biopsies. CONCLUSIONS: These results indicate that apoptosis is frequently found in skeletal muscle obtained from CHF patients, which is associated with significant impairment of functional work capacity. In skeletal muscle of these patients, iNOS and Bcl-2 are possibly involved in the regulation of apoptosis.     

Pulmonary hypertension and exercise intolerance in patients with heart failure

OBJECTIVES: This study was undertaken to investigate the relationship between pulmonary hypertension and exercise performance in patients with heart failure. BACKGROUND: The exercise capacity of patients with heart failure is frequently reduced. Pulmonary hypertension may contribute to this exercise intolerance by impairing blood flow through the pulmonary circulation. METHOD: Three hundred twenty patients with heart failure underwent upright treadmill exercise testing with hemodynamic monitoring. The incidence of pulmonary hypertension and the relationship between pulmonary vascular resistance (PVR) and exercise cardiac output and minute oxygen consumption (VO2) were examined. RESULTS: Pulmonary vascular resistance was normal (<1.5 Wood Units; Group 1) in 28% of the patients, mildly elevated (1.5 to 2.49 Wood Units; Group 2) in 36%, moderately elevated (2.5 to 3.49 Wood Units; Group 3) in 17% and severely elevated (>3.5 Wood Units; Group 4) in 19%. Increasing PVR was associated with significantly lower peak exercise VO2 (Group 1: 13.9+/-3.7; 2:13.7+/-3.4; 3: 11.8+/-2.4; 4: 11.5+/-2.6 L/min, p<0.01 Groups 3 and 4 vs. 1) and lower peak exercise cardiac output (Group 1: 10.0+/-2.8, 2:9.0+/-3.0; 3: 7.4+/-2.1; 4: 6.3+/-2.0 L/min, p<0.05, Groups 2, 3 and 4 vs. 1). The pulmonary wedge pressure decreased during exercise, consistent with impaired left ventricular filling, in 36% of patients with severe pulmonary hypertension (Group 4) versus only 13% of patients with normal PVR (p<0.01). CONCLUSIONS: Pulmonary vascular resistance is frequently increased in heart failure and is associated with a reduced cardiac output response to exercise, suggesting that pulmonary hypertension impairs exercise performance in heart failure.     

Salivary endothelin concentrations in the assessment of chronic heart failure

We have shown that salivary endothelin concentrations are raised in patients with chronic heart failure and indicate progression of disease severity through each New York Heart Association Functional Class. Furthermore, endothelin concentrations in saliva seem to discriminate between controls and patients with mild symptoms of chronic heart failure.     

A neural link to explain the "muscle hypothesis" of exercise intolerance in chronic heart failure.

BACKGROUND: In chronic heart failure the cause of exercise limitation is still unclear: ergoreceptors, muscle afferents sensitive to exercise metabolites, are proposed as a neural link between muscular abnormalities and the limited exercise responses in this syndrome. METHODS: In 92 stable patients with heart failure (34 in New York Heart Association class I, 27 in class II, and 31 in class III) and 28 age-matched normal controls, we assessed exercise tolerance (maximal upright bicycle) and ergoreflex activity (2 dynamic hand grips: one control and one followed by 3 minutes of local circulatory occlusion to isolate the ergoreflex component by metabolite trapping). RESULTS: Patients, with respect to the controls, showed reduced exercise tolerance (peak VO2: 20 vs 33 mL/kg/min), increased ergoreflex effects on ventilation (9 vs 4 L/min), systolic pressure (37 vs 13 mm Hg), and leg vascular resistance (45 vs 22 units) (all P <.005); with the progression of the symptoms, a progressive increase in ergoreflex contribution to the ventilatory response to exercise was observed. The indexes of exercise limitation during arm and leg exercise (ie, peak VO 2, V/VCO2 slope) correlated highly with the ergoreflex contribution to ventilatory response during handgrip test ( r 相似文献   

有氧运动治疗慢性心力衰竭

慢性心力衰竭是各种心脏疾病导致心功能不全的最终结局.近年来有氧运动疗法对慢性心力衰竭的治疗逐渐受到重视.慢性心力衰竭的治疗模式已由原来的药物治疗发展到药物-运动治疗模式[1,2].     

Renal handling of endothelin in patients with chronic heart failure

Chronic heart failure is characterized by increased renal extraction of endothelin (ET)-1 and unaltered handling of big ET-1. The renal extraction of ET-1 in patients with heart failure is closely related to elevations in pulmonary artery and pulmonary capillary wedge pressures.     

Predictors of exercise capacity in chronic heart failure

Abnormalities of skeletal muscle rather than of haemodynamicsmay be important determinants of exercise capacity in chronicheart failure. We investigated an array of indicators of centralhaemodynamics and peripheral muscle function to establish whichresting measurements predicted exercise performance. In 20 patients quadriceps strength, resting and peak leg bloodflow and leg muscle cross sectional area were measured. In 18patients average daytime blood pressure and pulse rate, haemodynamicvariables at rest and during exercise, and autonomic activitywere measured. There were correlations between peak oxygen consumptionand quadriceps strength (0.65; P=0.007), thigh muscle crosssectional area (r=0.63; P=0.004), and average daytime systolicblood pressure (r=0.66; P<0.01). There were no correlationswith indices of peripheral blood flow, measures of haemodynamicfunction, or autonomic function. Quadriceps strength was themost important individual correlate of exercise tolerance (r=0.73).With total muscle cross sectional area and left quadriceps strengthalso taken into consideration, 82% of the variation in peakoxygen consumption was explained. Of the haemodynamic variables,only average daytime systolic blood pressure predicted exerciseperformance. The resting variables that best predict exercise performancein chronic heart failure are measures of skeletal muscle functionand bulk, and average daytime systolic blood pressure. Thesefindings suggest that abnormalities in the periphery largelydetermine exercise performance in chronic heart failure, andthat the ability of the heart to generate an adequate bloodpressure response to daily activities is also predictive offunctional status.