Leptin and the ventilatory response to exercise in heart failure

OBJECTIVES: The aim of the study was to test the hypothesis that leptin is involved in the regulation of ventilatory responses to exercise in chronic heart failure (CHF). BACKGROUND: Exercise-induced hyperventilation is a negative prognostic factor in CHF. Studies in animals suggest that leptin, a hormone secreted by adipocytes, contributes to the regulation of respiration. Plasma leptin levels are elevated in non-cachectic CHF, suggesting the possibility that leptin might be involved in dysregulation of ventilation in CHF. METHODS: We studied 50 patients with stable CHF without cachexia. All subjects underwent anthropometric measurements, resting echocardiography, pulmonary function tests, and a cardiopulmonary exercise test. The ventilatory response to exercise was assessed by calculating the VE/VCO(2) and VE/VO(2) slopes (VE = ventilation per unit time, VCO(2) = carbon dioxide production, VO(2) = oxygen consumption). RESULTS: Using a multiple regression model, leptin was significantly and positively correlated with both VE/VCO(2) slope (regression coefficient = 0.87, F = 39.32, p < 0.001) and VE/VO(2) slope (regression coefficient = 0.84, F = 24.04, p < 0.001). This correlation was independent of age, gender, body mass index, body fat, ejection fraction, New York Heart Association functional class, pulmonary function, plasma norepinephrine, angiotensin II, brain natriuretic peptide levels, and medications. Also, the greatest VE/VCO(2) slope was seen in subjects in the highest tertile of leptin. CONCLUSIONS: Leptin is an independent predictor of VE/VCO(2) slope in heart failure, and may be a link between metabolic, cardiovascular, and respiratory abnormalities in CHF.     

The effect of aspirin on the ventilatory response to exercise in chronic heart failure

INTRODUCTION: Patients with chronic heart failure (CHF) experience breathlessness and fatigue on exercise. One of the abnormalities seen on maximal exercise testing is an increased ventilatory response to exercise (VE/VCO(2) slope). The cause of this is unknown, but is likely to be due to a combination of interacting peripheral and central factors. Recent data have demonstrated a relation between VE/VCO(2) slope and prostaglandin levels in contracting muscles. The present study examined the influence of the presence of a potent non-selective prostaglandin inhibitor, aspirin, on the ventilatory response to exercise in a group of patients with CHF. METHODS: We investigated the ventilatory response to exercise of 120 consecutive patients in sinus rhythm attending a specialist heart failure clinic. We excluded those taking clopidogrel (six patients) and those on both warfarin and aspirin or taking other non-steroidal anti-inflammatory agents (five patients). The other 109 patients were grouped according to whether they were taking aspirin (n=52 (48%)) or not (n=57 (52%)). Each patient underwent echocardiography to assess left ventricular function, and exercise testing with metabolic gas exchange to derive peak oxygen consumption (pVO(2)) and the VE/VCO(2) slope. RESULTS: The groups were similar in terms of age, (67 (13) vs. 66 (12) years; P=0.34) drug use, heart failure aetiology, left ventricular function (ejection fraction; 33.3 (9.4) vs. 31.8 (9.9)%; P=0.05)) and exercise tolerance (pVO(2); 20.4 (5.3) vs. 19.9 (6.0); P=0.68, and VE/VCO(2) slope; 35.4 (6.2) vs. 35.7 (9.3); P=0.73). There was no difference in the ventilatory response to exercise or the symptoms of breathlessness between the two groups. CONCLUSIONS: Aspirin does not appear to affect exercise performance in CHF.     

Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure

Minute ventilation, respiratory rate, and metabolic gas exchange were measured continuously during maximal symptom limited treadmill exercise in 30 patients with stable chronic heart failure. The ventilatory response to exercise was assessed by calculation of the slope of the relation between minute ventilation and rate of carbon dioxide production. There was a close correlation between the severity of heart failure, determined as the maximal rate of oxygen consumption, and the ventilatory response to exercise. Reanalysis of the data after correction for ventilation of anatomical dead space did not significantly weaken the correlation but reduced the slope of the relation by approximately one third. These results show that the increased ventilatory response to exercise in patients with chronic heart failure is largely caused by mechanisms other than increased ventilation of anatomical dead space. This finding supports the concept that a significant pulmonary ventilation/perfusion mismatch develops in patients with chronic heart failure and suggests that the magnitude of this abnormality is directly related to the severity of chronic heart failure.     

Impaired glucose tolerance worsens exercise capacity and ventilatory response to exercise in patients with chronic heart failure

BACKGROUND: There is increasing evidence for the importance of peripheral abnormalities in the pathogenesis and progression of heart failure (HF). Recently, glucose and insulin metabolism abnormalities have been intensively investigated in patients with HF. AIM: To investigate whether coexistence of impaired glucose tolerance (IGT) may decrease exercise tolerance and influence ventilatory response to exercise in patients with systolic HF. METHODS: Maximal cardiopulmonary exercise test with evaluation of peak VO2 and VE/VCO2 slope and oral glucose tolerance test were performed in 64 clinically stable patients with HF and LVEF <45%. RESULTS: Impaired glucose tolerance was diagnosed in 26 (41%) patients and normal glucose tolerance (NGT) in 38 (59%) patients. There were no significant differences in baseline clinical characteristics or LVEF between groups. There were significant differences in peak VO2 between IGT and NGT (15.4+/-4.1 vs. 18.7+/-4.2 ml/kg/min respectively; p=0.003) and VE/VCO2 slope (35.7+/-7.3 vs. 31.8+/-5.7 respectively; p=0.02). The IGT was independently related to peak VO2 and VE/VCO2 slope in multivariate regression analysis. CONCLUSION: The IGT is associated with worse exercise capacity and ventilatory response to exercise in patients with HF.     

The mechanisms underlying the increased ventilatory response to exercise in chronic stable heart failure.

Chronic heart failure is a common clinical condition with a high mortality and morbidity. Patients with the condition suffer from shortness of breath and fatigue on exercise. This article reviews the recent advances made in the understanding of the pathophysiology of chronic heart failure and explores further possible research options.     

Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure.

Minute ventilation, respiratory rate, and metabolic gas exchange were measured continuously during maximal symptom limited treadmill exercise in 30 patients with stable chronic heart failure. The ventilatory response to exercise was assessed by calculation of the slope of the relation between minute ventilation and rate of carbon dioxide production. There was a close correlation between the severity of heart failure, determined as the maximal rate of oxygen consumption, and the ventilatory response to exercise. Reanalysis of the data after correction for ventilation of anatomical dead space did not significantly weaken the correlation but reduced the slope of the relation by approximately one third. These results show that the increased ventilatory response to exercise in patients with chronic heart failure is largely caused by mechanisms other than increased ventilation of anatomical dead space. This finding supports the concept that a significant pulmonary ventilation/perfusion mismatch develops in patients with chronic heart failure and suggests that the magnitude of this abnormality is directly related to the severity of chronic heart failure.     

The increased ventilatory response to exercise in chronic heart failure: relation to pulmonary pathology.

OBJECTIVE: To assess the exercise limitation of patients with chronic heart failure (CHF) and its relation to possible pulmonary and ventilatory abnormalities. SETTING: A tertiary referral centre for cardiology. METHODS: The metabolic gas exchange responses to maximum incremental treadmill exercise were assessed in 55 patients with CHF (mean (SD) age 57.9 (13.0) years; 5 female, 50 male) and 24 controls (age 53.0 (11.1) years; 4 female, 20 male). Ventilatory response was calculated as the slope of the relation between ventilation and carbon dioxide production (VE/VCO2 slope). RESULTS: Oxygen consumption (VO2) was the same at each stage in each group. Ventilation (VE) was higher in patients at each stage. Patients had a lower peak VO2 and a steeper VE/VCO2 slope than controls. Dead space ventilation as a fraction of tidal volume (VD/VT) was higher in patients at peak exercise, but dead space per breath was greater in controls at peak exercise (0.74 (0.29) v 0.57 (0.17) litres/breath; P = 0.002). End tidal CO2 was lower in patients at all stages, and correlated with peak VO2 (r = 0.58, P < 0.001). Alveolar oxygen tension was higher in patients at each stage than in controls. CONCLUSIONS: Patients with CHF have an increased ventilatory response at all stages of exercise. Although this is accompanied by an increase in VD/VT, there is hyperventilation relative to blood gases. It is more likely that the excessive ventilation is not due to a primary pulmonary pathology, but rather, the increase in dead space is likely to be a response to increased ventilation.     

Relation between hemodynamic and ventilatory responses in determining exercise capacity in severe congestive heart failure

The cause of exercise intolerance in congestive heart failure is unclear. Hemodynamic and ventilatory responses were measured during symptomatic maximal upright bicycle exercise in 28 patients with chronic severe left ventricular failure who achieved a maximal oxygen uptake of only 12 +/- 4 ml/min/kg (+/- standard deviation). All patients reached anaerobic metabolism as the respiratory exchange ratio rose and arterial pH fell significantly. Pulmonary capillary wedge pressure increased from 20 +/- 10 mm Hg at rest to 38 +/- 9 mm Hg at peak exercise and cardiac index increased from 2.51 +/- 0.73 to 4.54 +/- 1.65 liters/min/m2 (both p less than 0.001). Systemic vascular resistance decreased, but pulmonary vascular resistance did not change during exercise. Despite the marked pulmonary venous hypertension at peak exercise, blood gases were unchanged (PaO2, 96 +/- 15 mm Hg; PaCO2, 35 +/- 7 mm Hg). Systemic arterial oxygen content increased from 16 +/- 2 to 17 +/- 2 vol% (p less than 0.01). Changes in pulmonary capillary wedge pressure did not correlate with changes in arterial oxygen content. Results were similar whether patients were limited by dyspnea or fatigue. Thus, exercise intolerance in patients with severe left ventricular failure is associated with marked elevation of pulmonary capillary wedge pressure and anaerobic metabolism without hypoxemia or altered carbon dioxide tension. These findings suggest that exercise ability in congestive heart failure is more dependent on cardiac output than on ventilatory consequences of pulmonary congestion.     

A critical threshold of exercise capacity in the ventilatory response to exercise in heart failure

During exercise patients with chronic left heart failure ventilate more than normal individuals at the same workload; the ratio of minute ventilation to minute production of carbon dioxide (VE/VCO2) is increased. The relation between increased VE/VCO2, severity of heart failure, and exercise capacity has not been defined. VE/VCO2 was measured in 47 patients with chronic left heart failure (New York Heart Association grades II and III) and in 1009 healthy controls. Exercise capacity was assessed by peak oxygen consumption (VO2max) during progressive exercise. In the controls VO2max ranged from 25 to 93 ml/kg/min; VE/VCO2 was 17-36 and did not correlate with VO2max. In chronic left heart failure the VO2max ranged from 9 to 29 ml/kg/min; VE/VCO2 was 22-42 and correlated strongly with VO2max. End tidal carbon dioxide and respiratory rate at peak exercise were similar in the controls and patients with chronic left heart failure. The increase in VE/VCO2 on exercise in chronic left heart failure indicates increased physiological dead space, presumably caused by a ventilation-perfusion mismatch. In the controls and patients with chronic left heart failure the relation of VE/VCO2 to VO2max was curvilinear with a threshold of VO2max below which VE/VCO2 started to rise above the normal range. This point of inflection may be explained by the existence of a critical level of cardiac function necessary to perfuse adequately all lung zones on exercise.     

A critical threshold of exercise capacity in the ventilatory response to exercise in heart failure.

During exercise patients with chronic left heart failure ventilate more than normal individuals at the same workload; the ratio of minute ventilation to minute production of carbon dioxide (VE/VCO2) is increased. The relation between increased VE/VCO2, severity of heart failure, and exercise capacity has not been defined. VE/VCO2 was measured in 47 patients with chronic left heart failure (New York Heart Association grades II and III) and in 1009 healthy controls. Exercise capacity was assessed by peak oxygen consumption (VO2max) during progressive exercise. In the controls VO2max ranged from 25 to 93 ml/kg/min; VE/VCO2 was 17-36 and did not correlate with VO2max. In chronic left heart failure the VO2max ranged from 9 to 29 ml/kg/min; VE/VCO2 was 22-42 and correlated strongly with VO2max. End tidal carbon dioxide and respiratory rate at peak exercise were similar in the controls and patients with chronic left heart failure. The increase in VE/VCO2 on exercise in chronic left heart failure indicates increased physiological dead space, presumably caused by a ventilation-perfusion mismatch. In the controls and patients with chronic left heart failure the relation of VE/VCO2 to VO2max was curvilinear with a threshold of VO2max below which VE/VCO2 started to rise above the normal range. This point of inflection may be explained by the existence of a critical level of cardiac function necessary to perfuse adequately all lung zones on exercise.     

Relationship between B-type natriuretic peptide levels and ventilatory response during cardiopulmonary exercise test in patients with chronic heart failure

AIM: Aim of the study was to evaluate if brain natriuretic peptide (BNP) levels, a cardiac neurohormone well correlated with prognosis in chronic heart failure (CHF), are associated with enhanced ventilatory response to exercise, in ambulatory patients with intermediate peak oxygen uptake (PVO2). METHODS: Resting BNP was measured in 129 consecutive stable CHF patients with mild to moderate heart failure (90% New York Heart Association (NYHA) class II or III) and intermediate (10-18 mL/kg/min) PVO2, assessed during cardiopulmonary exercise test. Mean (SD) left ventricular ejection fraction (EF) and pulmonary systolic pressure (PAP) were 41 +/- 3% and 47 +/- 14 mmHg, respectively. The enhanced ventilatory response to exercise (EVR) was assessed as a slope of the relation between minute ventilation and carbon dioxide production (VE/VCO2 slope) > 35. RESULTS: Thirty-three over 129 patients (26%) had EVR. Mean BNP plasma level was 394 +/- 347 pg/mL. A significant correlation between BNP and EVR (r = 0.310; p < 0.01), was observed. In the logistic multivariate model, a BNP plasma level > 100 pg/mL had an independent predictive value for EVR (95% IC 1.68 to 10.5, Odds Ratio 4.23, p = 0.02). We found a significant correlation between BNP and PAP (r = 0.390; p < 0.001), and between PAP and EVR (r = 0.511; p < 0.01). CONCLUSIONS: In CHF patients with intermediate PVO2, plasma BNP is clearly related to the enhanced ventilatory response to exercise. In this subset, BNP levels could represent an effective alternative tool for the clinical assessment in patients with unreliable cardiopulmonary exercise test.     

Prognostic value of brain natriuretic peptide and enhanced ventilatory response to exercise in patients with chronic heart failure

Whether brain natriuretic peptide (BNP), combined with a cardiopulmonary exercise test (CPx) parameters or echocardiography improves prognostic stratification in mild-to-moderate systolic heart failure (HF) is currently unclear. In 156 consecutive stable outpatients with mild to moderate HF and left ventricular ejection fraction (LVEF) <40%, we assessed the impact of BNP assay, Doppler echocardiography and CPx on survival. Median BNP plasma levels were 207 [90–520] pg/mL. Mean LVEF was 33 ± 7%. Left bundle branch block (LBBB) was present in 52 patients (33%) and a restrictive filling pattern in 35 (22%). The slope of the relation between minute ventilation and carbon dioxide production (VE/VCO₂ slope) averaged 35 ± 8; an enhanced ventilatory response (EVR) to exercise (VE/VCO₂ slope >35) was found in 67 patients (43%). During 759 ± 346 days of follow-up, 24 patients died. By multivariate analysis, the strongest independent predictors of all-cause death among clinical, echocardiographic variables and BNP were LBBB and beta-blocker treatment. When CPx variables were added, the best predictors of mortality were LBBB, beta-blockade and VE/VCO₂ slope. This study highlights the value of a sequential approach, based on clinical, laboratory and functional data to identify high-risk HF patients. BNP assay might constitute a simple alternative tool for patients with an inability or with clinical contraindications to exercise, advanced physical deconditioning and unreliable CPx results. However, whenever feasible, CPx with assessment of EVR is recommended for a more accurate prediction of prognosis.     

Effects of exercise training on abnormal ventilatory responses to exercise in patients with chronic heart failure

Patients with chronic heart failure frequently report shortness of breath during daily activities as their primary symptom. In recent years, many efforts have been made by researchers to explain the mechanisms that underlie the characteristic heightened ventilatory response to activity in patients with chronic heart failure. The degree to which the ventilatory response to exercise is heightened parallels the severity of the disease, and measuring the ventilatory gas exchange response to exercise can help quantify the patient's response to therapy. Prior to the 1990s, patients with chronic heart failure were generally discouraged from participating in programs of exercise training. However, in the last decade, studies have demonstrated that exercise training is quite safe for these patients, and a multitude of benefits have been reported. Among the benefits of training are improvements in the abnormal ventilatory response to exercise. Although many mechanisms could potentially explain this response, it appears most likely that this improvement after training is due to a reduction in lactate accumulation and an attenuation of the heightened muscle receptor reflex response that occurs in chronic heart failure. This article reviews the mechanisms of dyspnea in chronic heart failure, along with recent studies assessing the effects of training on abnormal ventilatory responses to exercise in these patients. (c)2000 by CHF, Inc.     

The effects of long-term beta-blockade on the ventilatory responses to exercise in chronic heart failure

AIMS: Chronic heart failure (CHF) patients complain of breathlessness and fatigue. Beta-blockers improve symptoms, echocardiograpahic variables and prognosis in CHF, but their effect on exercise capacity remains unclear. The aim of this study was to describe the effects of long-term beta-blocker therapy on metabolic gas exchange variables and ventilation during exercise in CHF patients. METHODS: 42 patients with symptomatic heart failure due to left ventricular systolic dysfunction (ejection fraction 33.2 (8.2)) on loop diuretics and angiotensin-converting enzyme inhibitors or angiotensin II antagonists, underwent exercise testing with metabolic gas exchange. They were then initiated onto and uptitrated to the maximum tolerated dose of beta-blockers. After 1 year of follow-up, patients were invited back for repeat testing. RESULTS: 35 patients attended for repeat exercise testing. Four patients had died, and three had not tolerated beta-blockade. After 1 year, exercise time was increased (487 (221) vs. 500 (217), p<0.05), and peak oxygen consumption and V(E)/V(CO(2)) slope were unchanged (20.9 (5.0) vs. 20.0 (5.4), p=0.15 and 36.7 (8.3) vs. 37.3 (7.8), p=0.70). Peak ventilation, (61.5 (12.9) vs. 57.1 (13.4), p<0.05), peak carbon dioxide production (1629 (404) vs. 1496 (375), p<0.02) and hence respiratory exchange ratio (1.02 (0.08) vs. 0.98 (0.06) p<0.02) and p<0.05) were reduced. Submaximal oxygen consumption and carbon dioxide production were lower at matched workloads. The slope relating symptoms to ventilation (Borg/V(E) slope) was less steep following beta-blockade (0.18 (0.09) vs. 0.15 (0.06), p<0.05). CONCLUSION: Long term beta-blocker therapy increases exercise time but not peak oxygen consumption, and reduces peak carbon dioxide production. CHF patients are less symptomatic for a given ventilation during exercise following beta-blocker treatment.     

Neuro-hormonal activation predicts ventilatory response to exercise and functional capacity in patients with heart failure

BACKGROUND: Heart failure (HF) is characterised by reduced tolerance to effort, associated with progressive fatigue and dyspnoea. Neuro-hormonal activation is a hallmark of HF and influences its clinical evolution. AIM: To evaluate the relationship between neuro-hormonal activation, exercise capacity and ventilatory efficiency. METHODS AND RESULTS: 154 HF patients (127 males, 62 +/- 1 years) underwent cardiopulmonary exercise testing and resting blood sampling for assay of plasma brain natriuretic peptide (BNP), NT-proBNP, norepinephrine, epinephrine, aldosterone and plasma renin activity (PRA). BNP and NT-proBNP levels correlated with peak oxygen consumption (VO2) (both R = -0.53, p < 0.001), VE/VCO2 slope (R = 0.56; p < 0.001 and R = 0.58; p < 0.001, respectively) and maximum workload (R = -0.49; p < 0.001 and R = -0.47; p < 0.001, respectively). Norepinephrine correlated slightly less with peak VO2 (R = -0.38, p < 0.001), VE/VCO2 (R = 0.45; p < 0.001) and maximum workload (R = -0.35; p < 0.001). There was a significant inverse correlation between left ventricular ejection fraction and BNP (R = -0.48, p < 0.001), NT-proBNP (R = -0.42; p < 0.001) and norepinephrine (R = -0.43; p < 0.001). Weaker correlations were found for PRA, exercise parameters and ejection fraction. ROC curves showed that BNP was able to identify patients with peak VO2 < 14 ml/min/kg (cut-off 98 pg/ml, AUC 0.775) and a VE/VCO2 > 35 (cut-off 183 pg/ml, AUC 0.797), as well as NT-proBNP (cut-off 537 pg/ml, AUC 0.799 and cut-off 1010 pg/ml, AUC 0.768, respectively) and norepinephrine (cut-off 454 pg/ml, AUC 0.716 and cut-off 575 pg/ml, AUC 0.783, respectively). CONCLUSION: Haemodynamic impairment (as indicated by BNP and NT-proBNP plasma values) and sympathetic activation predict exercise capacity and ventilatory efficiency in HF patients.     

The effects of alpha and beta blockade on ventilatory responses to exercise in chronic heart failure

Objective: To assess the influence of acute α and β blockade on ventilation and symptoms of breathlessness during exercise in patients with chronic heart failure and in controls.     

Altered skeletal muscle metabolic response to exercise in chronic heart failure. Relation to skeletal muscle aerobic enzyme activity

BACKGROUND. Exertional fatigue, which frequently limits exercise in patients with chronic heart failure, is associated with early anaerobic metabolism in skeletal muscle. The present study was designed to examine the skeletal muscle metabolic response to exercise in this disorder and determine the relation of reduced muscle blood flow and skeletal muscle biochemistry and histology to the early onset of anaerobic metabolism in patients. METHODS AND RESULTS. We evaluated leg blood flow, blood lactate, and skeletal muscle metabolic responses (by vastus lateralis biopsies) during upright bicycle exercise in 11 patients with chronic heart failure (ejection fraction 21 +/- 8%) and nine normal subjects. In patients compared to normal subjects, peak exercise oxygen consumption was decreased (13.0 +/- 3.3 ml/kg/min versus 30.2 +/- 8.6 ml/kg/min, p less than 0.01), whereas peak respiratory exchange ratio and femoral venous oxygen content were not different (both p greater than 0.25), indicating comparable exercise end points. At rest in patients versus normals, there was a reduction in the activity of hexokinase (p = 0.08), citrate synthetase (p less than 0.02), succinate dehydrogenase (p = 0.0007), and 3-hydroxyacyl CoA dehydrogenase (p = 0.04). In patients, leg blood flow was decreased at rest, submaximal, and maximal exercise when compared to normal subjects (all p less than 0.05), and blood lactate accumulation was accelerated. In patients, during submaximal exercise blood lactate levels were not closely related to leg blood flow but were inversely related to rest citrate synthetase activity in skeletal muscle (r = -0.74, p less than 0.05). At peak exercise there were no intergroup differences in skeletal muscle glycolytic intermediates, adenosine nucleotides, or glycogen, whereas in patients compared to normal subjects less lactate accumulation and phosphocreatine depletion were noted (both p less than 0.05), suggesting that factors other than the magnitude of phosphocreatine depletion or lactate accumulation may influence skeletal muscle fatigue in this disorder. CONCLUSIONS. The results of the present study suggest that in patients with chronic heart failure reduced aerobic activity in skeletal muscle plays an important role in mediating the early onset of anaerobic metabolism during exercise. Our findings are consistent with the concept that reduced aerobic enzyme activity in skeletal muscle is, in part, responsible for determining exercise tolerance and possibly the response to chronic intervention in patients with chronic heart failure.