The administration of peripheral vasodilators produces hemodynamic and clinical improvement in patients with refractory congestive heart failure. The response to these agents in our experience, however, has been variable. Our previous work has established at least 4 determinant factors of major importance in modulating the responses observed: (1) the degree of preservation of compensatory mechanism which are activated by and serve to counteract the peripheral vasodilation; (2) the subvalvular left ventricular end-diastolic dimension which reflects either ventricular volume or the severity of mitral regurgitation; (3) the dose of the vasodilator agent; (4) the pretreatment hemodynamic state. We propose to examine the mechanisms behind these determinant factors, how they interact to modulate the responses observed and to evaluate if other factors are operative as well. Fifty patients with heart failure will be evaluated by invasive hemodynamic monitoring. Each will receive 3 vasodilator drugs (hydralazine, nitroglycerin and nitroprusside) intravenously and in step wise increments to permit construction of dose responses curves. Hemodynamic variables, ventricular and regurgitation volumes and plasma catecholamines and renin activity will be determined prior to and during drug therapy. Differences in the responses observed will be analyzed in terms of variations in the determinant factors before and after therapy. Determinant factors will then be enhanced or depressed by trimethopan camsylate, phenylephrine or indomethacin and the administration of vasodilator agents repeated; the resultant shifts in the dose response curves will be related to changes in the determinant factors. Maintenance therapy with hydralazine and/or isosorbide dinitrate will then be instituted, and repeat evaluation of important variables will be performed at specified intervals by invasive and non-invasive testing. In this way, we will be able to identify specific factors which can be utilized clinically in selecting those patients most likely to respond favorably to acute administration of vasodilator therapy and which may be employed as clinical markers in the long term followup of patients with heart failure treated with these drugs.
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