J. Meller

Hemodynamic patterns of response during long-term captopril therapy for severe chronic heart failure.

To determine the relationship between the early and late hemodynamic effects of captopril in patients with severe heart failure, we performed serial right heart catheterizations in 51 such patients who were treated with the drug for 2 to 8 weeks. Four hemodynamic patterns of response were observed. Nine patients had minimal responses initially (type I); six failed to improve during long-term treatment, but three showed delayed hemodynamic benefits. Twenty-eight patients had initial beneficial drug effects that were sustained after 48 hr and after 2 to 8 weeks (type II). In seven patients, first doses of captopril produced marked beneficial responses, but these became rapidly attenuated after 48 hr; nevertheless, continued therapy for 2 to 8 weeks was accompanied by spontaneous restoration of the hemodynamic effects of first doses of the drug, i.e., triphasic response (type III). In the remaining seven patients, attenuation of initial response was not reversed by prolonged captopril therapy; hemodynamic variables after 2 to 8 weeks had returned to their pretreatment values, i.e., drug tolerance (type IV). Plasma renin activity was lower in patients with minimal responses (0.6 +/- 0.2 ng/ml/hr) and was higher in patients with triphasic responses (9.4 +/- 2.5 ng/ml/hr) than in patients with types II and IV response patterns (4.4 +/- 0.7 and 2.8 +/- 0.5 ng/ml/hr, respectively; both p less than .05). Although first-dose effects of captopril are frequently sustained, the occurrence of delayed, attenuated, and triphasic responses indicates that a complex and variable relationship may exist between the early and late hemodynamic effects of vasodilator drugs in patients with severe heart failure.

Determinants of drug response in severe chronic heart failure. 1. Activation of vasoconstrictor forces during vasodilator therapy.

Vasodilator drugs activate neurohumoral forces that produce peripheral vasoconstriction and tachycardia and probably cause the rebound events observed upon abrupt withdrawal of therapy. To determine their role in limiting therapeutic vasodilator responses, these reactive forces were measured in 40 patients with severe chronic heart failure by quantifying the magnitude of rebound change (MRC) after nitroprusside withdrawal. Group 1 patients (n = 22), who had minimal reactive vasoconstriction (MRC ⩽27%), showed marked hemodynamic effects with nitroprusside (4.5 μg/kg/min) and isosorbide dinitrate (40 mg orally), associated with significant decreases in heart rate with both drugs (p < 0.001). Despite administration of the same doses of both drugs, group 2 patients (n = 18), who had marked rebound changes (MRC > 27%), showed significantly smaller changes in cardiac index, systemic vascular resistance and mean arterial pressure (p < 0.001), associated with no change or increases in heart rate. Rebound events were attenuated and the responses to nitroprusside and nitrates were enhanced in four patients in whom these drugs were readministered after pretreatment with i.v. phentolamine (0.3 mg/min). We conclude that activation of neurohumoral forces can limit the hemodynamic responses to vasodilator administration; this supports the use of combination therapy of direct-acting vasodilators and neurohumoral antagonists in selected patients with severe chronic heart failure.

Oral vasodilator therapy for chronic heart failure: a plea for caution.

For patients with severe congestive heart failure who continue to experience dyspnea and fatigue at rest or on minimal exertion despite optimal therapy with digitalis and diuretic agents, the supplemental use of vasodilator agents has provided a new and promising approach to therapy. Such patients generally have a greatly decreased cardiac output and an elevated left ventricular filling pressure at rest, associated with a greatly increased systemic vascular resistance and heightened venous tone. By directly relaxing venous capacitance vessels, vasodilators can reduce ventricular filling pressures and ventricular volumes; by directly relaxing arterial resistance vessels, these agents can reduce impedance to left ventricular ejection and enhance stroke volume. The enhancement of cardiac output is of primary importance because the essential feature distinguishing heart failure that is responsive or resistant to diuretic drugs is not simply the elevation of ventricular filling pressure but the adequacy of peripheral perfusion. Accordingly, whereas the use of digitalis and diuretic agents can result in satisfactory clinical improvement in most patients with congestive heart failure, such a regimen may not be satisfactory by itself in patients with low cardiac output at rest. Sodium nitroprusside produces marked and rapid hemodynamic improvement in patients with severe heart fai1ure.l However, because it can be administered