Richard R. Miller

Effects on anginal symptoms of sudden withdrawal of large doses of propranolol or placebo were evaluated in 20 patients in a double-blind crossover efficacy trial requiring sudden cessation of the agent. With propranolol, 160 to 320 mg per day for six and 12 weeks, no patients had increased angina or nitroglycerin use, and there were no hospitalizations or deaths. However, within two weeks of discontinuance of propranolol, untoward ischemic events developed in 10 patients. Six had serious withdrawal complications: intermediate coronary syndrome in three, and ventricular tachycardia, fatal myocardial infarction, and sudden death in one each. In four patients discontinuance of placebo increased anginal symptoms; in the remaining 10, ischemic symptoms were not provoked. The rebound phenomenon was related to degree of pre-propranolol angina and relief of pain by the agent. Thus, chronically administered propranolol should be gradually reduced, and activity restricted during its withdrawal.

We compared cardiocirculatory actions of the commonly employed systemic vasodilators, intravenous (iv) nitroprusside (NP), iv phentolamine (PH), and sublingual nitroglycerin (NTG), causing left ventricular (LV) unloading in 29 chronic coronary subjects with congestive failure to determine whether they produce disparate responses in LV function by different relaxing actions on systemic resistance and capacitance beds. Each drug equally lowered systemic arterial pressures to a small extent, whereas heart rate rose slightly with NTG. Cardiac catheterization showed a decline in end-diastolic pressure with NTG (19 to 8 mm Hg) which was greater (P less than 0.05) than with NP and PH (21 to 11). Cardiac index increased (P less than 0.05) during NP (2.68 to 2.93 liters/min per m2) and PH (2.60 to 3.02) but was unchanged (2.83) by NTG. Stroke work increased with PH, ejection fraction rose with NP and PH, and mean ejection rate increased with each, whereas pressure-time per minute fell and end-diastolic volume decreased with each agent. Total systemic vascular resistance declined (P less than 0.001) during NP and PH (1,475 to 1,200 dynes sec cm-5) but was unchanged (1,487) by NTG. Plethysmographically, forearm vascular resistance (FVR) decreased (P less than 0.01) with NP and PH (61.6 to 39.1 mm Hg/ml per 100 g/min) but not (52.4) by NTG. The decreases in venous tone (VT) with NTG (18.2 to 9.3 mm Hg/ml) and NP (18.5 to 9.8) were greater (P less than 0.05) than with PH (18.8 to 13.1) FVR/VT percent changes of 0.96, 1.62, and 0.53 with NP, PH, and NTG indicated balanced systemic arteriolovenous relaxation by iv NP, greater arteriolar dilation with iv PH, and predominant venous dilation by sublingual NTG. Thus, vasodilators produce disparate modifications of LV function by their differing alterations of preload and impedance, which are dependent upon relative extents of relaxation of systemic resistance and capacitance vessels characteristic of each agent as used clinically.

To elucidate the hemodynamic effects of prazosin, an antihypertensive agent, in congestive heart failure, we studied 10 patients with ischemic cardiomyopathy and severe ventricular dysfunction. After an oral dose of 2 to 7 mg, heart rate was unchanged (P>0.05). One hour after prazosin administration, mean arterial pressure declined from 95 to 78 mm Hg (P<0.001); left ventricular filling pressure declined from 30 to 18 mm Hg (P<0.001), cardiac index increased from 2.1 to 2.9 liters per minute per square meter (P<0.001), and systemic vascular resistance fell from 2074 to 1156 dynes sec cm-5 (P<0.001). In both forearms vascular resistance and venous tone were reduced (86 to 48 mm Hg per ml per 100 g per minute, and 59 to 18 mm Hg per ml, respectively [P<0.001]). All responses persisted for at least six hours (P< 0.01). Prazosin benefits severe congestive heart failure by inducing a sustained fall of both cardiac preload and impedance. (N Engl J Med 297:303–307, 1977)

We used first-pass radionuclide angiocardiography to assess filling fraction during the first third of diastole, peak filling rate and peak filling rate during the first third of diastole as indexes of left ventricular diastolic performance at rest and after upright bicycle exercise in 32 normal patients and 68 patients with coronary artery disease. The mean filling fraction was unchanged from rest to exercise in normal patients (47+/- 15% vs 46 +/- 13%; NS). Even in 49 coronary patients with normal (greater than or equal to 50%) ejection fraction at rest, filling fraction was less than that in normal patients at rest (35 +/- 11% vs 47 +/- 15%, p less than 0.001). Despite similar resting heart rates, patients with coronary disease had lower (p less than 0.001) peak filling rate and peak filling rate during the first third of diastole than normal patients. With exercise, filling fraction decreased (p less than 0.001) from the resting value in coronary patients. These data suggest that (1) indexes of diastolic performance can be noninvasively assessed at rest and during exercise using first-pass radionuclide angiocardiography, (2) abnormalities in early diastolic performance are often present at rest in patients with coronary artery disease despite normal systolic performance, and (3) exercise-induced ischemia results in increased early diastolic dysfunction in patients with coronary disease.

Although hemodynamic benefit has been shown with sodium nitroprusside (NP) in acute coronary pump failure, complete understanding of the mechanisms of action of the agent on the cardiocirculation and its value in chronic ventricular dysfunction are lacking. This investigation evaluates the effects of NP on the systemic and regional arterial and venous beds and on cardiac dynamics, ventricular volumes, contractile state and myocardial energetics in long-standing congestive heart failure. Twelve patients with chronic coronary pump dysfunction received NP infusion to lower systolic pressure to 95-105 mm Hg. Left ventricular (LV) function was assessed directly by angiographic volumes and high fidelity pressure, and peripheral circulatory dynamics were determined simultaneously by forearm arterial and venous plethysmography. NP reduced mean arterial pressure (MAP) from 88.2 to 73.4 mm Hg (P less than 0.05) and significantly (P less than 0.05) enhanced the variables of LV performance: LV end-diastolic pressure (EDP) diminished from 18.5 to 9.9 mm Hg; ejection fraction rose from 0.47 to 0.55; percent of LV segmental shortening increased; and isovolumic and ejection indices of contractility improved. Concomitantly, NP reduced the indices of myocardial oxygen demands of ventricular tension time index and LVED volume index. These salutary effects on LV performance and energetics occurred secondary to peripheral arterial and venous dilation (P less than 0.05) produced by NP: total systemic vascular resistance was lowered from 1590 to 1310 dynes sec cm--5; forearm vascular resistance diminished from 46 to 37 mm Hg/ml/100 gm/min; and forearm venous tone fell from 14.2 to 10.1 mm Hg/cc. Depressed stroke index (SI) and cardiac index (CI) increased (P less than 0.05) with NP: despite the fall in LVEDP, when ventricular filling pressures with the agent were at levels slightly above normal. Dextran infusion given with NP to restore LVEDP to moderately elevated values increased SI and CI (P less than 0.05) when NP alone produced no change in stroke output. Thus, the peripheral vasodilator properties of nitroprusside improve LV function by reducing impedance to ventricular ejection, while MVO2 is diminished by decreasing LV preload and afterload through relaxing actions