Richard R. Miller

Propranolol-withdrawal rebound phenomenon. Exacerbation of coronary events after abrupt cessation of antianginal therapy.

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.

Pharmacological mechanisms for left ventricular unloading in clinical congestive heart failure. Differential effects of nitroprusside, phentolamine, and nitroglycerin on cardiac function and peripheral circulation.

We compared cardiocircolatory actions of the com monly employed systemic vasodilators, intravenous (iv) nitroprusside (NP), Iv phentolamine (PH), and subliagoal 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 catbeterization showed a decline in end-diastolic pressure with NTG (19 to 8 mm Hg) which was greater (P < 0.05) than with NP and PH (21 to 11). Cardiac index increased (P < 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 < 0.001) during NP and PH (1,475 to 1,200 dynes sec cm-5) but was unchanged (1,487) by NTG. Plethysmographkally, forearm vascular resistance (FVR) decreased (P < 0.01) with NP and PH (61.6 to 39.1 mm Hg/ml per 100 g/min) bat not (52.4) by NTG. The decreases in venous tone (VT) with NTG (18.2 to 9.3 mn Hg/ml) and NP (183 to 9.8) were greater (P < 0.05) than with PH (18.8 to 13.1). FVR/VT percent changes of 0.%, 1.62, and 033 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.

Clinical use of sodium nitroprusside in chronic ischemic heart disease. Effects on peripheral vascular resistance and venous tone and on ventricular volume, pump and mechanical performance.

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 < 0.05) and significantly (P < 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 < 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 < 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 < 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 on both systemic arterial and venous smooth muscle. These LV unloading effects of nitroprusside in chronic congestive heart failure are most beneficial in patients with marked pump dysfunction and greatly elevated LVEDP and peripheral vascular resistance.

Efficacy of ambulatory systemic vasodilator therapy with oral prazosin in chronic refractory heart failure. Concomitant relief of pulmonary congestion and elevation of pump output demonstrated by improvements in symptomatology, exercise tolerance, hemodynamics and echocardiography.

The long-term efficacy of the new oral vasodilator, prazosin (PZ), was evaluated in nine patients with refractory heart failure due to chronic coronary heart disease. Ventricular function was assessed by cardiac catheterization, echocardiography, and treadmill testing; symptomatic evaluation was carried out for two to four months. One hour following 2-7 mg PZ, control left ventricular filling pressure was reduced (32 to 18 mm Hg, P < 0.001) for a 6 hour period. After two weeks of PZ 2 to 7 mg four times daily, echographic end-diastolic dimension fell (5.7 to 5.4 cm, P < 0.001) whileshortening fraction increased (27.6 to 30.2%, P < 0.005). Treadmill exercise duration increased from 209 to 317 seconds (P < 0.001). Symptoms diminished throughout the duration of follow-up (mean 94 days) with improvement in NYHA functional class (3.7 to 2.2, P < 0.001). Thus, prazosin possesses sustained nitroprusside-like balanced dilator actions on the systemic arterialand venous systems and is effective in the ambulatory management of chronicsevere heart failure.

Comparison of effects of nitroprusside and prazosin on left ventricular function and the peripheral circulation in chronic refractory congestive heart failure.

We compared cardiocirculatory actions of nitroprusside (NP) to prazosin (PZ) in eleven chronic coronary patients with refractory congestive heart failure. Each drug equally lowered systemic arterial pressures mildly while heart rate was unaltered. NP decline (P < .001) in left ventricular filling pressure (28 to 17 mm Hg) and rise (P < .005) in cardiac index (2.20 to 2.96 L/min/m2) were similar to PZ (30 to 17) and (2.08 to 3.00). PZ and NP equally enhanced cardiac efficiency of stroke work and myocardial oxygen consumption index. Total systemic vascular resistance declined (P < .001) the same with NP and PZ. Forearm vascular resistance (FVR) and venous tone (FVT) diminished equally with NP and PZ. Similar FVR/FVT percent changes of 0.88 and 0.64 with NP and PZ indicated relatively balanced systemic arteriolovenous relaxation. Sinze PZ effects persisted six hours with symptomatic improvement, oral PZ is the best vasodilator for long-term use, extending in-hospital NP-like actions to ambulatory heart failure therapy.

Hemodynamic assessment of oral peripheral vasodilator therapy in chronic congestive heart failure: prolonged effectiveness of isosorbide dinitrate.

To evaluate the effectiveness of oral vasodilator therapy in chronic congestive heart failure, 20 mg of isosorbide dinitrate or placebo was administered orally in double-blind fashion to 25 patients with congestive heart failure. In 15 patients receiving isosorbide dinitrate, pulmonary arterial wedge pressure decreased 5 minutes to 5 hours after drug administration; the peak reduction was observed at 1 hour (from 23 to 14 mm Hg; P less than 0.001). Wedge pressure decreased to normal (12 mm Hg or less) in 8 of the 15 patients (Group I) but remained greater than 12 mm Hg in 7 (Group II). Reductions in mean systemic arterial pressure, systemic vascular resistance and pressure-time per minute also occurred. Indexes of pump output were unchanged in the 15 who received isosorbide dinitrate but tended to decrease slightly in Group I. Stroke index (from 23 to 26 cc/m2) and stroke work index (from 21.4 to 24.1 g-m/m2) increased slightly but significantly (P less than 0.05) in Group II. Thus the prinicpal hemodynamic action of isorbide dinitrate is marked and sustained reduction in left ventricular filling pressure without pronounced effect on cardiac output. This agent should be used in congestive heart failure primarily for relief of congestive symptoms.

Combined dopamine and nitroprusside therapy in congestive heart failure. Greater augmentation of cardiac performance by addition of inotropic stimulation to afterload reduction.

The hemodynamic benefits of combining administration of dopamine with nitroprusside (NP) were evaluated in nine patients with chronic congestive heart failure due to ischemic, idiopathic myocardial or valvular cardiac disease. NP alone (68 μg/min) produced decline in left ventricular end-diastolic pressure (LVEDP) from 25.4 to 14.1 mm Hg (P < 0.01) but modest increase in cardiac index (CI) from 2.41 to 3.02 L/min/m2 (P < 0.05). Dopamine alone (6 μg/kg/min) caused an elevation of CI to 3.36 (P < 0.01) but without decrease of LVEDP. Simultaneous infusion of the two agents resulted in favorable alterations in both hemodynamic variables: LVEDP decreased to 15.7 (P < 0.01) and CI increased to 3.52 (P < 0.01). It is concluded that dopamine substantially enhances the effectiveness of nitroprusside therapy in congestive heart failure by providing concomitantly the principal beneficial actions of the vasodilator and dopamine used separately. Thus combined dopamine with NP treatment considerably raises low CI while markedly reducing elevated LVEDP and provides a potentially efficacious pharmacologic modality for the treatment of severe congestive heart failure due to left ventricular dysfunction.

Electrocardiographic and Cineangiographic Correlations in Assessment of the Location, Nature and Extent of Abnormal Left Ventricular Segmental Contraction in Coronary Artery Disease

The relationship between the resting electrocardiogram and left ventricular contractile pattern, as documented by angiography, was evaluated in 123 patients with coronary artery disease who underwent left ventriculography. Dyssynergy was present in 73/77 (95%) patients with pathologic Q waves on ECG recordings in contrast to 11/46 ( 24%; P < 0.01) without Q waves. The location of Q waves correlated well with the site of abnormal ventricular motion: antero-apical dyssynergy in 40/40 (100%) patients with anterior myocardial infarction (MI) and infero-apical dyssynergy in 25/28 (89%) with inferior MI. Four contraction patterns were defined: 1) normal motion-39 patients (35 without Q waves, four with inferior or posterior Q waves); 2) segmental hypokinesis-37 patients (six without Q, 31 with Q); 3) segmental akinesis-26 patients (four without Q, 22 with Q); and 4) localized dyskinesis-aneurysm in 21 patients (only one without Q, 20 with Q). The presence of ST elevation and T wave inversion (ST↑ - T↓) along with Q waves were associated with dyskinesis or akinesis in 18/19 (95%) patients. The Q wave location reflected the type of dyssynergy: 32/40 (80%) patients with anterior MI had akinesis or dyskinesis, while 18/28 (64%) patients with inferior MI exhibited hypokinesis. Lateral extension of the Q wave in an anterior MI was related to the dyssynergy type (average V lead: 4.9 in dyskinesis and 3.3 in hypokinesis; P < 0.05) and extent (dyssynergy area /LV silhouette: 31% with Q to V3 and 58% to V5 or V6; P < 0.05). Dyssynergy area was larger in isolated anterior than inferior MI (42% and 23% of LV perimeter; P < 0.05) and largest in the anterior-inferior MI (68%; P < 0.05). Dyssynergy was more extensive with Q and ST↑-T↓ than with Q alone (48% and 33% LV perimeter; P < 0.05). Thus, specific QRS and ST-T wave alterations, when monitoring coronary disease, accurately predict characteristics of LV dyssynergy: Q identifies its presence and location and Q with ST↑-T↓ estimates its nature and extent.

Afterload reduction therapy with nitroprusside in severe aortic regurgitation: Improved cardiac performance and reduced regurgitant volume

To assess the hemodynamic effects of afterload reduction in severe aortic regurgitation, nitroprusside was infused at cardiac catheterization in 12 patients with aortic regurgitation. Cardiac hemodynamics, angiographic variables and regurgitant volumes were quantified during control periods, and nitroprusside was infused to reduce systemic systolic pressure to 110 to 125 mm Hg. The following were reduced by the drug: systolic arterial pressure (from 154 +/- 6.4 to 115 +/- 2.3 mm Hg, P less than 0.001); left ventricular end-diastolic pressure (from 23 +/- 2.2 to 11 +/- 1.0 mm Hg, P less than 0.001); systemic vascular resistance (from 1,782 +/- 133 to 1,148 +/- 94 dynes sec cm-5, P less than 0.001); left ventricular end-diastolic volume (from 242 +/- 25 to 196 +/- 19 ml, P less than 0.001); aortic regurgitant fraction (from 0.53 +/- 0.05 to 0.44 +/- 0.06, P less than 0.01); and aortic regurgitant minute volume (from 5.5 +/- 0.10 to 4.3 +/- 0.09 liters/min, P less than 0.01). Effective cardiac index increased (from 2.49 +/- 0.19 to 3.10 +/- 0.24 liters/min per m2, P less than 0.01), and left ventricular ejection fraction rose (from 0.55 +/- 0.03 to 0.61 +/- 0.03, P less than 0.005). These data indicate that afterload reduction with nitroprusside in severe aortic regurgitation improves cardiac performance, greatly decreases left ventricular preload and reduces aortic regurgitant volume. Thus, nitroprusside therapy has special value in severe aortic regurgitation that is of particular benefit in critical clinical conditions.

Chronic stable inferior myocardial infarction: unsuspected harbinger of high-risk proximal left coronary arterial obstruction amenable to surgical revascularization.

Eighty-four patients with previous uncomplicated isolated inferior myocardial infarction underwent coronary arteriography to determine the prevalence and distribution of coronary stenoses in order to identify those patients at high risk for early death. Coronary risk factors and treadmill stress testing were evaluated as predictors of left coronary artery disease, and the clinical course was compared of patients undergoing coronary bypass surgery versus those treated medically. Of the 84 patients, 17 (20 percent) had one vessel stenosis (75 percent or more luminal narrowing), 29 (35 percent) had stenosis of two and 38 (45 percent) had stenosis of all three major coronary arteries. Fifty-three patients (63 percent) had stenosis of the proximal left anterior descending coronary artery including 8 with complete and 18 with subtotal occlusion. Of the 53 patients with proximal left anterior descending arterial stenosis, 42 (79 percent) had an operable condition (no distal obstruction) as did 36 (69 percent) of 52 with circumflex arterial stenosis. Although the presence of multiple coronary risk factors, particularly with a positive stress test, was predictive of multivessel stenosis, lack of risk factors and a negative exercise test were nonspecific. Of 45 patients followed up for 18 months, 14 who underwent, coronary bypass surgery were compared with 31 medically treated patients with similar cardiac function and coronary pathoanatomy. Ten surgically treated patients (71 percent) had reduced angina compared with nine medically treated patients (29 percent) ( P P P > 0.05). Thus, serious left coronary artery disease is highly prevalent as well as operable in patients with chronic inferior myocardial infarction. The latter condition thereby provides a clinically useful and sensitive marker of high risk coronary arterial stenosis.