Pulmonary function, cardiac function, and exercise capacity in a follow-up of patients with congestive heart failure treated with carvedilol.

BACKGROUND: Chronic heart failure causes disturbances in ventilation and pulmonary gas transfer that participate in limiting peak exercise oxygen uptake (VO(2p )). The beta-adrenergic receptor blocker carvedilol improves left ventricular (LV) function and not VO(2p). This study was aimed at investigating the pulmonary response to changes in LV performance produced by carvedilol in patients with chronic heart failure. METHODS: Twenty-one patients with New York Heart Association class II to III heart failure were randomly assigned (2 to 1) to carvedilol (25 mg twice daily, n = 14) or placebo (n = 7) for 6 months. Rest forced expiratory volume (FEV(1)), vital capacity, total lung capacity, carbon monoxide diffusing capacity, its alveolar-capillary membrane component, pulmonary venous and transmitral flows (for monitoring changes in LV end-diastolic pressure), LV diastolic and systolic dimensions, stroke volume, ejection fraction, and fiber shortening velocity were measured at baseline and at 3 and 6 months. VO(2p), peak ratio of dead space to tidal volume (VD/VT(p)), ventilatory equivalent for carbon dioxide production (VE/VCO(2)), and VO(2) at anaerobic threshold (VO(2at)) were also determined. RESULTS: FEV(1), vital capacity, total lung capacity, carbon monoxide diffusing capacity, and the alveolar-capillary membrane component were impaired in chronic heart failure compared with 14 volunteers and did not vary with treatment. Carvedilol reduced end-diastolic pressure, end-diastolic diameter, and end-systolic diameter and increased ejection fraction, stroke volume, and fiber shortening velocity without affecting VO(2p), VO(2at), VD/VT(p), or VE/VCO(2) at 3 and 6 months. Placebo did not produce significant changes. CONCLUSIONS: In chronic heart failure carvedilol ameliorates LV function at rest and does not significantly affect ventilation and pulmonary gas transfer or functional capacity. These results suggest that improvement in cardiac hemodynamics with carvedilol does not reverse pulmonary dysfunction. Persistent lung impairment might have some role in the failure of carvedilol to improve exercise performance.

[A failed improvement in pulmonary function and exercise capacity with carvedilol in congestive heart failure despite an excellent effect on left ventricular function]. / Mancato miglioramento della funzione polmonare e della capacità di esercizio con carvedilolo nello scompenso cardiaco congestizio, nonostante un eccellente effetto sulla funzione ventricolare sinistra.

This study was aimed at investigating in chronic heart failure (CHF) the effects that beta-blockade with carvedilol may have on lung function, and their relationship with left ventricular (LV) performance and peak exercise oxygen uptake (VO2p). CHF causes disturbances in ventilation and pulmonary gas transfer (stress failure of alveolar-capillary membrane) that participate in limiting VO2p. Carvedilol improves LV function and not VO2p. Twenty-one NYHA functional class II-III patients were randomized (2 to 1) to carvedilol (25 mg bid., 14 patients) or placebo (7 patients) for 6 months. Rest forced expiratory volume (FEV1), vital capacity (VC), total lung capacity (TLC), carbon monoxide diffusing capacity (DLCO), its alveolar-capillary membrane component (DM), pulmonary venous and transmitral flows (for monitoring changes in LV end-diastolic pressure, EDP), LV diastolic (EDD) and systolic (ESD) dimensions, stroke volume (SV), ejection fraction (EF), fiber shortening velocity (VCF) were measured at baseline and at 3 and 6 months. VO2p, peak ratio of dead space to tidal volume (VD/VTp), ventilatory equivalent for CO2 production (VE/VCO2), VO2 at anaerobic threshold (VO2at) were also determined. FEV1, VC, TLC, DLCO, DM were impaired in CHF compared to 14 volunteers, and did not vary with treatment. Carvedilol reduced EDP, EDD, ESD, and increased EF, SV, VCF, without affecting VO2p, VO2at, VD/VTp, VE/VCO2, at 3 and 6 months. Placebo was ineffective. In CHF, carvedilol exerts neutral effects on ventilation and pulmonary gas transfer and ameliorates LV function at rest. This proves that antifailure treatment may not be similarly effective on cardiac and pulmonary function; and does not contradict the possibility that persistence of lung impairment may contribute to lack of improvement in exercise performance with carvedilol.

[Inhibition of the neurohumoral axis after intravascular fluid depletion in congestive heart failure with water retention: mechanisms of the perpetuation of the syndrome]. / Inibizione dell'asse neuroumorale dopo deplezione di fluido intravascolare nello scompenso cardiaco congestizio con ritenzione idrica: meccanismi di perpetuazione della sindrome.

Hypovolemia stimulates the sympathoadrenal and renin systems and water retention. In congestive heart failure (CHF) reduced cardiac output and blood pressure have been suggested to be perceived as a volume deficit, which, if persistent, would perpetuate humoral activation and fluid retention. In the aim of probing this hypothesis, we monitored in patients with CHF the neurohumoral response to reduction of the body fluid obtained by ultrafiltration. In 22 patients with advanced CHF and fluid retention, ultrafiltration was performed with a diafilter, which was part of an external venous circuit, whose flow was regulated to produce 500 ml/hour of ultrafiltrate (average total amount 3,122 +/- 1,199 ml) until right atrial pressure was reduced to 50% of baseline. Hemodynamics, plasma renin activity, norepinephrine and aldosterone were measured before and in the 48 hours after ultrafiltration. Soon after the procedure, associated with a 20% reduction of plasma volume and a moderate decrease of cardiac output and blood pressure (consistent with a diminished degree of filling of the arterial compartment), there was an obvious fall of norepinephrine, plasma renin activity and aldosterone. In the next 48 hours we recorded an increasing neurohumoral axis depression, in spite of recovery of plasma volume, cardiac output and blood pressure and a striking enhancement in urinary output. Changes in norepinephrine, plasma renin activity or aldosterone were not related to the combination of changes in plasma volume, cardiac output and blood pressure (variations in the state of arterial filling) and significantly correlated with the increase in urinary output and sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Apparent paradox of neurohumoral axis inhibition after body fluid volume depletion in patients with chronic congestive heart failure and water retention.

BACKGROUND: Hypovolaemia stimulates the sympathoadrenal and renin systems and water retention. It has been proposed that in congestive heart failure reduction of cardiac output and any associated decrease in blood pressure cause underfilling of the arterial compartment, which promotes and perpetuates neurohumoral activation and the retention of fluid. This study examined whether an intravascular volume deficit accounts for patterns that largely exceed the limits of a homoeostatic response, which are sometimes seen in advanced congestive heart failure. METHODS AND RESULTS: In 22 patients with congestive heart failure and water retention the body fluid mass was reduced by ultrafiltration and the neurohumoral reaction was monitored. A Diafilter, which was part of an external venous circuit was regulated to produce 500 ml/hour of ultrafiltrate (mean (SD) 3122 (1199) ml) until right atrial pressure was reduced to 50% of baseline. Haemodynamic variables, plasma renin activity, noradrenaline, and aldosterone were measured before and within 48 hours of ultrafiltration. After ultrafiltration, which produced a 20% reduction of plasma volume and a moderate decrease in cardiac output and blood pressure (consistent with a diminished degree of filling of the arterial compartment), there was an obvious decrease in noradrenaline, plasma renin activity, and aldosterone. In the next 48 hours plasma volume, cardiac output, and blood pressure recovered; the neurohumoral axis was depressed; and there was a striking enhancement of water and sodium excretion with resolution of the peripheral oedema and organ congestion. The neurohumoral changes and haemodynamic changes were not related. There were significant correlations between the neurohumoral changes and increase in urinary output and sodium excretion. CONCLUSIONS: In advanced congestive heart failure arterial underfilling was not the main mechanism for activating the neurohumoral axis and retaining fluid. Because a decrease in circulating hormones was associated with reabsorption of extravascular fluid it is likely that hypoperfusion and/or congestion of organs, such as the kidney and lung, reduce the clearance of circulating noradrenaline and help to keep plasma concentrations of renin and aldosterone raised. A positive feedback loop between fluid retention and plasma hormone concentrations may be responsible for progression of congestive heart failure.