Long-term vasodilator therapy of chronic aortic insufficiency. A randomized double-blinded, placebo-controlled clinical trial.

Abstract

Although vasodilator drugs acutely reduce regurgitation and improve cardiac performance in aortic insufficiency, their long-term effects on left ventricular size and function are uncertain. Consequently, we performed a double-blinded, placebo-controlled trial using hydralazine in 80 minimally symptomatic patients who had clinically stable, moderate-to-severe aortic insufficiency. Patients randomized to hydralazine displayed a progressive reduction in left ventricular end-diastolic volume index (LVEDVI) measured by radionuclide angiography, the predetermined end point of the study. At 24 months, mean LVEDVI had been reduced by 30 38 ml/m2, an 18% reduction from baseline. In contrast, LVEDVI changed minimally in patients randomized to placebo, and the intergroup differences over time were statistically significant (p<0.03). The hydralazine group also experienced reductions in left ventricular end-systolic volume index and increases in ejection fraction that were significantly different (both p<0.01) from changes in placebo-treated patients. These findings show that long-term treatment with hydralazine reduces the volume overload in aortic insufficiency and suggest that such therapy may have a beneficial effect on the natural history of the disease. (Circulation 1988;78:92-103) P revious studies have shown that vasodilator drugs acutely reduce the regurgitant volume and improve cardiac performance in aortic insufficiency. 1-7 Consequently, vasodilator therapy has emerged as an important modality for the shortterm management of patients with this lesion. These findings also raise the possibility that long-term therapy may chronically reduce the volume overload to the left ventricle. maintain cardiac performance in or close to the normal range." However, prolonged volume overload often leads to deterioration in left ventricular performance so that later in the course, signs and symptoms of cardiac dysfunction frequently develop.8,'0 An intriguing prospect is that the prophylactic administration of a vasodilator drug during the stable plateau phase of volume overload might be able to reduce either the extent of left ventricular dilation or its progression. The present study was undertaken to test the hypothesis that long-term vasodilator therapy with oral hydralazine reduces the volume overload and, hence, the left ventricular end-diastolic volume in clinically stable, moderate-to-severe aortic insufficiency. It was conducted as a prospective, randomized, placebocontrolled, double-blinded trial with change in left ventricular volume measured by radionuclide angiography as the predetermined end point.

Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis

“…7,9 This is in contrast to clinical studies that have used hydralazine and achieved similar reductions in blood pressure but failed to offer the same clinical benefit as RAS inhibition. [48][49][50] In the present manuscript, we provide no explanation for this discrepancy. Taken together, these results suggest that blood pressure reduction may not be the sole factor influencing myocardial events such as fibrosis.…”

2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults

“…138 -141 Long-term treatment with a systemic vasodilator drug may be considered for those with severe aortic regurgitation who are deemed to be poor candidates for surgery. Several studies 142,143 have suggested that prolonged therapy with hydralazine and nifedipine in patients with severe aortic regurgitation and preserved LV function might act to minimize structural changes in the ventricle and thereby possibly delay the need for surgical intervention; however, these drugs are often poorly tolerated in this setting, and no trial has shown that these vasodilators can reduce the risk of HF or death (see ACC/AHA Guidelines for the Management of Patients With Valvular Heart Disease). 138 There are no long-term studies of vasodilator therapy in patients with severe asymptomatic mitral regurgitation.…”

2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease

“…This analysis is subject to the usual limitations of comparisons of different clinical series with different patient selection factors and different end points. For example, 1 series 270 represents patients receiving placebo in a randomized drug trial 278 that included some patients with "early" New York Heart Association (NYHA) functional class II symptoms (although none had "limiting" symptoms), and another 272 represents patients receiving digoxin in a long-term study comparing the effects of nifedipine with digoxin. In 2 studies, 274,276 LV function was not reported in all patients, and it is unclear whether all had normal LV systolic function at baseline.…”

“…304 -306,312 This is an inconsistent finding with a single oral dose of nifedipine. 308 -311 Reduced end-diastolic volume and increased ejection fraction have also been observed in small numbers of patients receiving long-term oral therapy with hydralazine and nifedipine for periods of 1 to 2 years 278,314 ; with nifedipine, these effects are associated with a reduction in LV mass. 272,314 Less consistent results have been reported with ACE inhibitors, depending on the degree of reduction in arterial pressure and end-diastolic volume.…”