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BACKGROUND Sodium retention and hormonal activation are fundamental hallmarks in congestive heart failure. The present study was designed to assess the ability of patients with asymptomatic to mildly symptomatic heart failure and no signs or symptoms of congestion to excrete ingested sodium and to identify possible early abnormalities of hormonal and hemodynamic mechanisms related to sodium handling. METHODS AND RESULTS The effects of a high salt diet (250 mEq/day for 6 days) on hemodynamics, salt-regulating hormones, and renal excretory response were investigated in a balanced study in 12 untreated patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (NYHA class I-II, ejection fraction < 50%) (HF) and in 12 normal subjects, who had been previously maintained a 100 mEq/day NaCl diet. In normal subjects, high salt diet was associated with significant increases of echocardiographically measured left ventricular end-diastolic volume, ejection fraction, and stroke volume (all P < .001) and with a reduction of total peripheral resistance (P < .001). In addition, plasma atrial natriuretic factor (ANF) levels increased (P < .05), and plasma renin activity and aldosterone concentrations fell (both P < .001) in normals in response to salt excess. In HF patients, both left ventricular end-diastolic and end-systolic volumes increased in response to high salt diet, whereas ejection fraction and stroke volume failed to increase, and total peripheral resistance did not change during high salt diet. In addition, plasma ANF levels did not rise in HF in response to salt loading, whereas plasma renin activity and aldosterone concentrations were as much suppressed as in normals. Although urinary sodium excretions were not significantly different in the two groups, there was a small but systematic reduction of daily sodium excretion in HF, which resulted in a significantly higher cumulative sodium balance in HF than in normals during the high salt diet period (P < .001). CONCLUSIONS These results show a reduced ability to excrete a sodium load and early abnormalities of cardiac and hemodynamic adaptations to salt excess in patients with mild heart failure and no signs or symptoms of congestion.

Neurohormonal activation is a fundamental component in the pathophysiology of congestive heart failure. In fact it represents a mechanism consecutive to cardiac dysfunction that favours the development of congestion and of further heart failure through vasoconstriction and water and salt retention. The time of onset and the mechanisms responsible for neurohormonal activation in heart failure are not defined. This brief article reviews this topic and summarizes the findings of studies that investigated the dynamic adaptations of hormonal mechanisms in the milder or initial stages of heart failure. An early characterization and detection of the abnormalities of the hormonal responses to salt or volume changes may be useful for a better comprehension and the treatment of the initial stage of the disease.

To investigate whether the response of atrial natriuretic factor (ANF) to volume expansion is impaired in the early stages of dilated cardiomyopathy, the effects of saline load (SL; 0.25 ml/kg.min for 120 min) were assessed in 12 patients with dilated cardiomyopathy and asymptomatic to mildly symptomatic heart failure (HF) and in nine normal subjects (N). SL increased plasma ANF levels in N (from 14.3 +/- 2 to 19.5 +/- 3 and 26 +/- 4 pg/ml, at 60 and 120 min, respectively, P less than 0.001), but not in HF (from 42.9 +/- 9 to 45.9 +/- 9 and 43.9 +/- 8 pg/ml). Left ventricular end-diastolic volume (LVEDV) and stroke volume were increased (P less than 0.001) by SL in N but not in HF. Urinary sodium excretion (UNaV) increased in N more than in HF during SL, whereas forearm vascular resistance (FVR) did not change in N and increased in HF (P less than 0.001). In five HF patients SL was performed during ANF infusion (50 ng/kg, 5 ng/kg.min) that increased ANF levels from 37.1 +/- 10 to 146 +/- 22 pg/ml. In this group, SL raised both LVEDV (P less than 0.01) and ANF (P less than 0.05), whereas FVR did not rise. In addition, the UNaV increase and renin and aldosterone suppressions by SL were more marked than those observed in HF under control conditions. Thus, in patients with dilated cardiomyopathy and mild cardiac dysfunction, plasma ANF levels are not increased by volume expansion as observed in N. The lack of ANF response is related to the impaired cardiac adaptations. The absence of an adequate increase of ANF levels may contribute to the abnormal responses of HF patients to saline load.

BACKGROUND Angiotensin converting enzyme (ACE) inhibition exerts a favorable effect on the response to exercise in heart failure. This study was planned to define the influence of ACE inhibition on the adaptation to volume overload. METHODS AND RESULTS We studied the hemodynamic, hormonal, and renal responses to acute volume expansion (sodium chloride, 0.9%, 0.25 ml.kg-1.min-1 for 2 hours) in patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (New York Heart Association class I or II, ejection fraction < or = 50%). The patients were studied without any pretreatment (n = 14) or after 1 week of treatment with the oral ACE inhibitor quinapril at a dosage of 10 mg/day (n = 11). Seven patients were studied during constant intravenous infusion with nitroglycerin (0.1 micrograms.kg-1.min-1). The study groups had similar hemodynamic and clinical characteristics and hormonal profile at baseline evaluation. In the untreated patients, volume expansion did not increase left ventricular end-diastolic volume measured by echocardiography and was associated with a reduction in ejection fraction (p < 0.05) and with a paradoxical increase in forearm vascular resistance (p < 0.05) estimated by plethysmography. In addition, plasma atrial natriuretic factor did not change, and plasma norepinephrine was increased by saline loading. In contrast, in the patients treated with quinapril, volume expansion induced an increase of both left ventricular volumes (p < 0.001) without changing ejection fraction and reduced forearm vascular resistance (p < 0.05). In addition, in this group, plasma atrial natriuretic factor levels increased (p < 0.05) and plasma norepinephrine did not change during volume overload. During nitroglycerin infusion, volume expansion was associated with peripheral vasodilatation, increases of left ventricular volumes, and no change in ejection fraction. In this group, however, plasma atrial natriuretic factor levels did not change in response to volume overload. CONCLUSIONS We conclude that pretreatment with the ACE inhibitor quinapril significantly improves compromised responses to acute isotonic volume overload in patients with dilated cardiomyopathy and mild heart failure. The favorable influence of ACE inhibition on cardiovascular and hormonal responses to volume expansion seems to be related to the cardiac unloading produced by this treatment.