Showing papers by "Eugene Braunwald published in 1980"
TL;DR: The negative inotropic effects of verapamil are valuable in improving the symptoms and hemodynamic disturbances of hypertrophic cardiomyopathy and the role of these agents in treating arterial hypertension, unstable angina pectoris, acute myocardial infarction, and ischemia during cardiopulmonary bypass needs to be determined.
Abstract: The calcium channel blocking agents have multiple hemodynamic effects that make them potentially valuable in treating many cardiovascular disorders. They are potent dilators of coronary and peripheral arteries and in isolated tissue preparations exert potent negative inotropic, chronotropic, and dromotropic effects. In intact animals the peripheral arterial vasodilatation induces reflex-mediated adrenergic activity, which opposes the direct negative inotropic, chronotropic, dromotropic, and hypotensive effects. The individual calcium channel blockers have different relative potencies on various cardiovascular functions. The net hemodynamic and electrophysiologic effect of each agent, therefore, results from a complex interplay of direct and reflex phenomena. The clinical efficacy of these agents in classic angina pectoris relates to their ability to decrease afterload, myocardial contractility, and heart rate and increase coronary blood flow. The agents have been used to prevent coronary spasm in Prinzmetal's variant angina. The negative inotropic effects of verapamil are valuable in improving the symptoms and hemodynamic disturbances of hypertrophic cardiomyopathy. The role of these agents in treating arterial hypertension, unstable angina pectoris, acute myocardial infarction, and ischemia during cardiopulmonary bypass needs to be determined.
549 citations
TL;DR: Although ultrastructural evidence of myocardial cell damage was present in the subendocardium after 20-40 minutes of ischemia, ultrastsructuralevidence of microvascular damage was not prominent until 60-90 minutes after coronary artery occlusion, suggesting that ultrastructureural microv vascular damage is not a primary cause of ultraststructural myocardIAL cell injury.
Abstract: Both microvascular damage and myocardial cell injury occur after coronary occlusion, but the relationship of these two events is unclear; specifically, it is unknown whether microvascular damage causes myocardial cell injury. Dogs were subjected to coronary occlusion for 20, 40, 60, 90 or 180 minutes, after which subendocardial and subepicardial biopsies were obtained for electron and light microscopy of 1-mu sections. Of 312 biopsies of ischemic myocadium, 181 showed myocardial cell injury with no microvascular damage; 131 showed myocardial cell injury and microvascular damage; but none showed microvascular damage without myocardial cell injury. Although ultrastructural evidence of myocardial cell damage was present in the subendocardium after 20-40 minutes of ischemia, ultrastructural evidence of microvascular damage was not prominent until 60-90 minutes after coronary artery occlusion. Morphologic ultrastructural evidence of microvascular damage lagged behind myocardial cell injury, suggesting that ultrastructural microvascular damage is not a primary cause of ultrastructural myocardial cell injury.
493 citations
TL;DR: Clinical experience with nifedipine suggests that it is a highly effective drug for the treatment of coronary-artery spasm and variant angina.
Abstract: We report clinical experience with the coronary vasodilator nifedipine in 127 patients with symptoms of myocardial ischemia associated with electrocardiographic or angiographic evidence, or both, of coronary-artery spasm. In the majority of patients conventional antianginal therapy including nitrates and beta-adrenergic blockers failed, and in one third of the patients at least one episode of ventricular tachycardia developed during an attack of angina. Nifedipine (40 to 160 mg every 24 hours) significantly reduced the mean weekly rate of anginal attacks from 16 to two (P less than 0.001). Similar marked reductions in the nitroglycerin requirement were noted. In 63 per cent of the patients complete control of anginal attacks was achieved, and in 87 per cent the frequency of angina was reduced by at least 50 per cent. Nifedipine was generally well tolerated, with only 5 per cent of the patients requiring termination of the drug because of intolerable side effects. This experience with nifedipine suggests that it is a highly effective drug for the treatment of coronary-artery spasm and variant angina.
425 citations
TL;DR: Preliminary trials of long-term therapy with oral verapamil for control of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia suggest that this agent is effective for therapy of these arrhythmias.
Abstract: Calcium ions play an important role in the cardiovascular system. They are involved in electrophysiologic processes, link excitation to muscular contraction, control energy storage and utilization, and constrict vascular smooth muscle in coronary and systemic arteries. A new group of pharmacologic agents that block the passage of calcium ions across cell membranes has been developed. These agents act during the slow inward current of cellular depolarization. The most extensive clinical experience has been obtained with four of these agents: verapamil, nifedipine, perhexiline, and diltiazem. Verapamil, which has profound electrophysiologic effects on the slow inward current, is emerging as a valuable antiarrhythmic agent. Re-entrant supraventricular arrhythmias, such as paroxysmal supraventricular tachycardia, are particularly amenable to treatment with intravenous verapamil. Preliminary trials of long-term therapy with oral verapamil for control of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia suggest that this agent is effective for therapy of these arrhythmias.
341 citations
TL;DR: End-systolic volume is an easily determinable parameter of left ventricular function which appears to provide a measure for the onset of myocardial dysfunction in patients with these lesions and has major prognostic importance.
291 citations
TL;DR: Two methods to reduce the ordering of laboratory and radiologic tests by medical residents in their first postgraduate year by dividing the residents into three groups are studied.
Abstract: We studied two methods to reduce the ordering of laboratory and radiologic tests by medical residents in their first postgraduate year. Dividing the residents into three groups, we compare...
281 citations
TL;DR: Brief temporary coronary artery occlusions not associated with anatomic evidence of necrosis may result in prolonged abnormalities of ATP concentration and significant depletion of the total purine pool in the ischemic subendocardium and subepicardium.
Abstract: Changes in myocardial purine metabolism were studied after temporary coronary artery occlusion and subsequent reperfusion in the dog. Sequential myocardial biopsies were performed to allow for measurements of ATP, adenine nucleotide, nucleoside, and base concentrations after 15 min of ischemia, and after 90 min and 72 hr of reperfusion following this period of ischemia. Control, nonischemic sites were also sampled. After 15 min of coronary occlusion, subendocardial ATP concentrations (reported in nmol/mg of protein; mean ± SEM) were depressed in the ischemic zone at 19.9 ± 3.5 compared to 38.1 ± 2.8 in the nonischemic zone (P < 0.001). Subepicardial ATP concentrations also were depressed at 27.0 ± 2.2 in ischemic sites compared to subepicardial nonischemic sites (40.0 ± 4.0, P < 0.005). After 90 min of reperfusion ATP concentrations remained depressed in the previously ischemic subendocardium 26.8 ± 4.2 (P < 0.025 vs. nonischemic sites). After 72 hr of reperfusion, ATP was still depressed in the previously ischemic subendocardium at 29.2 ± 2.5 (P < 0.025 vs. nonischemic) and subepicardium (27.9 ± 3.3, P < 0.05 vs. nonischemic). Total purines were determined as the sum of ATP, ADP, AMP, adenosine, inosine, and hypoxanthine. After 15 min of occlusion, the total purine pool in the ischemic subendocardium tended towards being lower than in the nonischemic zone (42.0 ± 5.9 vs. 53.8 ± 5.2, not significant) but in the ischemic subepicardium the total purine pool was similar to that in the nonischemic zone. After 90 min of reperfusion the previously ischemic subendocardial purine pool was reduced compared to the nonischemic zone (39.0 ± 4.8, P < 0.025). Total purines were also depleted in both the subendocardium and subepicardium of previously ischemic zones after 72 hr of reperfusion (44.5 ± 2.9 and 40.0 ± 4.4, respectively, P < 0.05). Histologic analysis of the previously ischemic tissue revealed no evidence of necrosis. Therefore, brief temporary coronary artery occlusions not associated with anatomic evidence of necrosis may result in prolonged abnormalities of ATP concentration and significant depletion of the total purine pool.
260 citations
TL;DR: The amrinone-induced hemodynamic improvement in patients with congestive heart failure secondary to coronary artery disease was associated with reductions in MVO2 and CBF and no evidence of myocardial ischemia.
Abstract: Amrinone has been shown to exhibit a potent inotropic effect in patients with heart failure secondary to congestive cardiomyopathy, but its effects on myocardial oxygen consumption (MVO2) and coronary blood flow (CBF) are unknown. Accordingly, the hemodynamic, myocardial metabolic and ECG responses to amrinone (2.5 mg/kg i.v. over 1 hour) were measured in nine patients with congestive heart failure secondary to coronary artery disease. Increases were observed in cardiac index (1.3 +/- 0.4 to 2.2 +/- 0.7 l/min/m2) and left ventricular stroke work (10.6 +/- 3.0 to 19.2 +/- 6.3 g-m/m2), and decreases in mean pulmonary wedge (31 +/- 5 to 26 +/- 4 mm Hg), mean pulmonary artery (44 +/- 8 to 36 +/- 7 mm Hg) and mean right atrial pressures (18 +/- 4 to 10 +/- 4 mm Hg), myocardial arteriovenous oxygen difference (129 +/- 19 to 109 +/- 17 ml/l), CBF (215 +/- 117 to 178 +/- 84 ml/min) and MVO2 (27 +/- 14 to 19 +/- 9 ml/min). All changes were significant (p less than 0.01). No significant changes occurred in aortic mean pressure, heart rate, myocardial lactate extraction or ECG, and no patient developed angina. In explaining the decline in MVO2, it is possible that the increase in contractility was more than offset by the reductions in preload and afterload. The amrinone-induced hemodynamic improvement in patients with congestive heart failure secondary to coronary artery disease was associated with reductions in MVO2 and CBF and no evidence of myocardial ischemia.
204 citations
TL;DR: There is evidence that repeated administration of prazosin to patients with severe congestive heart failure results in tolerance to its initial salutary effects as a vasodilator.
Abstract: There is evidence that repeated administration of prazosin to patients with severe congestive heart failure results in tolerance to its initial salutary effects as a vasodilator. Therefore, we used a randomized, double blind protocol to evaluate the clinical effectiveness of 2 months of continuous prazosin therapy in 22 patients with severe congestive heart failure. After 2 months, the patients treated with prazosin showed significant improvement in mean New York Heart Association functional class (3.7 ± 0.2 to 2.3 ± 0.2, p
179 citations
TL;DR: The presence of a border zone of cells which are in the reversible phase of myocardial injury following coronary artery occlusion allows for salvage of ischaemic myocardium by a number of interventions which include reperfusion a variety of pharmacological agents, and physical and haemodynamic interventions.
Abstract: Over the past decade major advances have been made in the understanding of myocardial infarction largely through the use of animal models of ischaemia and infarction. Ultrastructural and biochemical aspects of reversible versus irreversible ischaemic injury have helped to clarify the nature of ischaemic cell death. The presence of a border zone of cells which are in the reversible phase of myocardial injury following coronary artery occlusion allows for salvage of ischaemic myocardium by a number of interventions. These interventions include reperfusion a variety of pharmacological agents, and physical and haemodynamic interventions. Several clinical studies have shown that these interventions may be beneficial in the treatment of patients with acute myocardial infarction.
147 citations
TL;DR: This autoradiographic method using 99mTc-labeled human albumin microspheres is useful in delineating the area of ischemia after coronary artery occlusion and in evaluating the efficacy of pharmacologic agents designed to protect ischemic myocardium.
Abstract: Investigation of the efficacy of pharmacologic agents affecting myocardial infarct size after coronary artery occlusion is complicated by the variability of collateral flow among experimental animals which results in variability of infarct size. To overcome this difficulty, we developed an autoradiographic method to delineate the ischemic area at risk of necrosis after coronary artery occlusion and we invetigated the potential protective effect of a calcium antagonist verapamil. The left anterior descending coronary arteries of 25 barbiturate-anesthetized dogs were occluded. Thirty minutes later, highly radioactive human albumin microspheres labeled with 99mTc were injected into the left atrium. One hour after coronary artery occlusion, dogs were randomized to control or treated groups; the latter received a 0.2 mg/kg loading dose and 0.6 mg/kg per hr maintenance dose of verapamil intravenously. Eight hours after coronary artery occlusion, the dogs were killed, the hearts were excised, and the left ventricle was sectioned parallel to the atrioventricular groove; infarct size was determined planimetrically after incubation in triphenyl tetrazolium chloride. The slices were then exposed to high-speed x-ray film with image-enhancing screens. The percentage of left ventricle that was ischemic, as determined by planimetry of autoradiographs, was similar in treated and control animals (36.6 +/- 2.0% compared to 37.3 +/- 2.8%, respectively). Of the ischemic area, 92.0 +/- 4.3% was infarcted in control animals and 70.5 +/- 5.1% was infarcted in treated animals (P < 0.01). Thus, this autoradiographic method using 99mTc-labeled human albumin microspheres is useful in delineating the area of ischemia after coronary artery occlusion and in evaluating the efficacy of pharmacologic agents designed to protect ischemic myocardium. Verapamil, administered 1 hr after coronary artery occlusion, is effective in limiting infarct size.
TL;DR: The case of a 54-year-old woman with severe hypertrophic cardiomyopathy without obstruction, in whom treatment with the calcium-channel blocking agent nifedipine improved both diastolic c...
Abstract: WE report the case of a 54-year-old woman with severe hypertrophic cardiomyopathy without obstruction, in whom treatment with the calcium-channel blocking agent nifedipine improved both diastolic c...
TL;DR: Although orally administered amrinone shows promise as a potentially useful agent in the treatment of advanced heart failure, the safety of this drug remains to be established.
Abstract: The acute effects of an oral preparation of amrinone, a recently synthesized cardiotonic agent, were assessed noninvasively in nine patients who had advanced heart failure that persisted despite treatment with digitalis, diuretic drugs and afterload-reducing agents. All patients demonstrated an improvement In left ventricular ejection fraction determined by radionuclide ventriculography (20.3 ± 2.8 to 30.8 ± 4.8 percent [mean ± Standard error of the mean], p
TL;DR: Plasma norepinephrine levels were increased in 10 patients with severe heart failure before and after chronic prazosin therapy, and the cause of the increase is unclear and warrants further study.
Abstract: To ascertain whether increased sympathetic nervous system activity may contribute to the attenuation of prazosin's effect on congestive heart failure, we measured plasma norepinephrine levels in 10 patients with severe heart failure before and after chronic prazosin therapy. Norcpinephrine levels were increased in eight of 10 patients while supine (145 +/- 133 pg/mL; after, 481 +/- 376 pg/mL; P < 0.01); levels measured in five patients while upright were also increased (before, 351 +/- 238 pg/mL; after, 651 +/- 258 pg/mL; P < 0.05). Left ventricular ejection fraction measured by gated blood pool scan was increased from 16.9% +/- 8.1% to 25.4% +/- 11.3% (N = 10, P < 0.01). Mean systemic blood pressure and heart rate were unchanged. Increased plasma norepinephrine levels may attenuate prazosin's vasodilator action in heart failure. The cause of the increase in norepinephrine levels is unclear and warrants further study.
TL;DR: At the turn of the decade, the results of three major clinical trials concerned with the treatment of patients who have survived an acute myocardial infarction are being published.
Abstract: At the turn of the decade, the results of three major clinical trials concerned with the treatment of patients who have survived an acute myocardial infarction are being published. One of these, on...
TL;DR: Amrinone, when infused to produce positive inotropic effects equivalent to those of isoprenaline, is equally detrimental in increasing acute myocardial ischaemic injury in the non-failing canine heart, as manifest by augmentation of epicardial ST segment elevation and intramyocardial Pco 2 with both agents during coronary occlusion.
Abstract: This study was performed to assess the effects of the promising new inotropic agent amrinone on acute myocardial ischaemic injury in the anaesthetised, non-failing canine heart. Eight dogs underwent serial 15 min coronary artery occlusion (CAO) with intervening periods of coronary reperfusion. Saline was infused during the control CAO and amrinone or isoprenaline was infused intravenously at rates necessary to raise left ventricular dP/dt (LV dP/dt) by equivalent amounts in the latter two CAOs. Summed epicardial ST segment elevation (ΣST) was 42.9 ± 14.9 mV in the control CAO, but increased significantly to 76.1 ± 14.4 mV during CAO with amrinone infusion and to 68.6 ± 16.4 mV during CAO with isoprenaline infusion (P<0.001). Acute ischaemic injury was further assessed by mass spectrometric measurement of intramyocardial P co2 ( P m,co2) during a control CAO (saline infusion) and CAO with amrinone or isoprenaline infused to raise LV dP/dt by equivalent amounts in seven dogs. The magnitude of P m,co2 rise from baseline(Δ P m,co2) was 6.0 ± 0.5 kPa (45.3 ± 3.9 mmHg) for the control CAO, and was significantly higher during CAO with amrinone or isoprenaline infusion (8.7 ± 0.7 and 8.5 ± 1.0 kPa (64.9 ± 5.0 and 63.7 ± 7.2 mmHg), P <0.01 and P <0.05, respectively). Reproducible changes for ΣST and Δ P m,co2 in consecutive CAO's without inotropic stimulation were documented in further studies.
We conclude that amrinone, when infused to produce positive inotropic effects equivalent to those of isoprenaline, is equally detrimental in increasing acute myocardial ischaemic injury in the non-failing canine heart, as manifest by augmentation of epicardial ST segment elevation and intramyocardial Pco 2 with both agents during coronary occlusion.
TL;DR: Arterial pressure of the hypertensive rats was reduced to levels within the normotensive range in animals with moderate and large myocardial infarctions and the peripheral vascular response to methoxamine was similar in rats with and without infarction.
Abstract: 1. Haemodynamic changes during graded methoxamine infusion have been measured in 16 spontaneously hypertensive rats with healed myocardial infarction produced by left coronary artery ligation and in 15 hypertensive rats without infarction. 2. Arterial pressure of the hypertensive rats was reduced to levels within the normotensive range in animals with moderate and large myocardial infarctions. 3. The peripheral vascular response to methoxamine was similar in rats with and without infarction. 4. The reduction in blood pressure resulted from a combination of lower heart rate and inability to maintain stroke volume at hypertensive pressures.