Increased circulating atrial natriuretic factor concentrations in patients with chronic heart failure after inhibition of neutral endopeptidase: effects on diastolic function

Objective—±Candoxatrilat was used to raise atrial natriuretic factor (ANF) concentrations in patients with heart failure, and the effects on left ventricular systolic and diastolic function were studied to determine the contribution of peripheral and central mechanisms to the haemodynamic effects.Design—This was a single blind, randomised comparison of ±candoxatrilat and placebo in patients with mild heart failure. All patients received two intravenous doses of ±candoxatrilat and two placebo doses on four consecutive days.Setting—A teaching hospital department of cardiology.Patients—Six men (mean age 52 years) with mild heart failure (New York Heart Association class II) due to ischaemic heart disease (four patients) or dilated cardiomyopathy (two patients) were included. Mean ejection fraction was 37·5% and mean peak oxygen consumption was 20·4 ml/min/kg.Main outcome measures—Plasma ANF concentrations, haemodynamic indices and left ventricular diastolic function measured by early to atrial filling rate (E:A ratio) with Doppler echocardiography were determined before and after ±candoxatrilat and placebo.Results—±Candoxatrilat caused a threefold rise of plasma ANF compared with placebo (p < 0·005), but there was no significant change in heart rate, blood pressure, or cardiac output. Mean right atrial pressure fell from 6·7 to 4·7 mm Hg (NS) and pulmonary artery wedge pressure fell from 9·2 to 6·7 mm Hg (p < 0·05). Doppler echocardiographic measurements of transmitral blood flow showed a significant fall in peak early left ventricular filling velocity from 39·5 to 34·2 cm/s (p < 0·05), along with a non-significant rise in peak atrial filling velocity from 39·7–41·6 cm/s after ±candoxatrilat. The E:A ratio, a Doppler index of left ventricular diastolic function, fell from a mean of 1·04 to 0·87 (p < 0·05).Conclusions—±Candoxatrilat increased plasma ANF concentrations and reduced right atrial and pulmonary artery wedge pressures. No evidence of an improvement in left ventricular systolic or diastolic function was found, so the fall in preload was due to peripheral effects, either an increase in venous capacitance or a fall in circulating blood volume.