Long-term, dose-dependent effects of spironolactone on left ventricular function and exercise tolerance in patients with chronic heart failure.

OBJECTIVES: This study was designed to assess the effects of spironolactone (SP) on left ventricular (LV) function and exercise tolerance in patients with chronic heart failure (CHF). BACKGROUND: In severe heart failure (HF), SP improves survival, but the underlying mechanisms are not clear. METHODS: We randomized 106 outpatients with HF to SP (12.5 to 50 mg/day) (group 1) or control (group 2). Complete echocardiography and cardiopulmonary exercise testing were performed at baseline and 12 months after randomization. RESULTS: Left ventricular end-systolic volume at baseline and at follow-up was 188 +/- 94 ml and 171 +/- 97 ml in group 1 and 173 +/- 71 ml and 168 +/- 79 ml in group 2 (treatment group-by-time interaction, p = 0.03). Left ventricular ejection fraction at baseline and at follow-up was 33 +/- 7% and 36 +/- 9% in group 1 and 34 +/- 7% and 34 +/- 9% in group 2 (treatment group-by-time interaction, p = 0.02). At baseline, 9 patients in group 1 and 3 patients in group 2 had a restrictive mitral filling pattern, a marker of severe diastolic dysfunction; at follow-up, 3 patients in group 1 and no patient in group 2 improved their pattern. No patient in group 1 and 4 patients in group 2 worsened their pattern (chi-square, p = 0.02). Peak oxygen consumption increased significantly in patients treated with 50 mg of SP and decreased in group 2 (17.7 +/- 5.2 vs. 18.5 +/- 5.9 and 19.1 +/- 5.6 vs. 17.9 +/- 5.3, respectively; analysis of variance, p = 0.01). CONCLUSIONS: Spironolactone improves LV volumes and function; furthermore, it improves exercise tolerance at the highest administered dose. Our data might explain the mortality reduction during aldosterone antagonism in patients with HF.

Ischemic etiology of heart failure identifies patients with more severely impaired exercise capacity.

BACKGROUND: Peak oxygen uptake (peak VO2) and the regression slope of ventilation against CO2 production during exercise (VE/VCO2 slope) are powerful prognostic indicators in patients with chronic heart failure (CHF). Our purpose was to evaluate the influence of CHF etiology on peak VO2 and VE/VCO2 slope, independently of demographic, clinical, Doppler-echocardiographic and neurohormonal factors. METHODS: Data were collected from 239 CHF patients referred for a cardiopulmonary exercise test as part of their clinical evaluation. Patients were stratified according to their CHF etiology (ischemic versus non-ischemic). RESULTS: The etiology of heart failure was ischemic in 143 patients (60%) and non-ischemic in 96 (40%). Patients with ischemic etiology, compared with those with non-ischemic etiology, showed a lower peak VO2 (15.4+/-4.2 versus 17.8+/-4.8 ml/kg/min, p<0.0001) and a steeper VE/VCO2 slope (38.1+/-6.8 versus 34+/-5.3, p<0.0001). In the univariate model, age (r=-0.36, p<0.0001), female sex (r=-0.21, p=0.001), ischemic CHF etiology (r=-0.26, p<0.0001) and NYHA class (r=-0.52, p<0.0001) correlated with peak VO2. At multivariate analysis, ischemic CHF etiology (beta=-0.23, p=0.001) was a predictor of peak VO2 (R(2)=0.49) independently of age (beta=-0.23, p=0.001), female sex (beta=-0.25, p=0.0006) and NYHA class (beta=-0.31, p<0.0001). Similarly, ischemic etiology (beta=0.29, p=0.001) predicted the VE/VCO2 slope (R(2)=0.38) independently of E/A ratio (beta=0.27, p=0.01) and resting heart rate (beta=0.22, p=0.01). CONCLUSIONS: Etiology of heart failure may influence the functional capacity and the ventilatory response to exercise.

Elevated serum uric acid levels are associated with diastolic dysfunction in patients with dilated cardiomyopathy.

OBJECTIVE: To assess whether serum uric acid, which is a marker of impaired oxidative metabolism, might correlate with left ventricular systolic and diastolic dysfunction in patients with chronic heart failure (CHF). BACKGROUND: Uric acid levels, which are frequently elevated in patients with CHF, correlate with leg vascular resistance. The effects of elevated levels of uric acid on cardiac function in patients with CHF have never been evaluated. METHODS: We studied 150 outpatients with CHF who came to our heart failure clinic. Patients underwent a complete echo-Doppler examination, with measurement of mitral E wave and mitral A wave velocities, E/A ratio, E wave deceleration time (DtE), left ventricular volumes, ejection fraction, and stroke volume. A restrictive mitral filling pattern (RMFP) was defined as either E/A ratio >2 or E/A >1 and DtE <140 milliseconds. RESULTS: Mean age was 62.2 +/- 7.8 years (86% male); 24 patients (16%) had an RMFP. Patients with an RMFP had significantly higher uric acid levels compared with patients without RMFP (0.48 +/- 0.14 mmol/L vs 0.38 +/- 0.08 mmol/L, respectively, P <.001). Uric acid levels correlated significantly with mitral E wave velocity (r =.22, P <.01), E/A ratio (r =.21, P <.05), DtE (r =.26, P <.01), and RMFP (P =.0001). There was no correlation between uric acid and left ventricular volumes, ejection fraction, or stroke volume. In a multivariate model, uric acid predicted DtE independently of renal function, diuretic dose, and left ventricular volumes. CONCLUSION: Elevated uric acid levels are associated with diastolic dysfunction in CHF. Xanthine oxydase inhibition in patients with CHF might theoretically result in an improvement of diastolic function.

Skeletal muscle abnormalities in chronic heart failure patients: relation to exercise capacity and therapeutic implications.

Recent studies suggest that changes in the periphery, like those occurring in the skeletal muscles of patients with chronic heart failure, might play an important role in the origin of symptoms and exercise intolerance in this condition. Biochemical and histologic changes in the skeletal muscles of chronic heart failure patients relate with the degree of exercise intolerance better than hemodynamics parameters. A reduction in skeletal muscle mass represents another important determinant of exercise intolerance in chronic heart failure patients. The relationship between skeletal muscle changes and exercise intolerance suggests the possibility of modifying the peripheral changes in order to improve functional capacity in chronic heart failure patients. Recent studies have shown that the administration of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers can improve the properties of the skeletal muscles. Similarly, exercise training allows improvement in peak oxygen consumption, which parallels important biochemical and histologic changes in the skeletal muscles.