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Biomedical subjects

E Braunwald

Publications and source records attributed to E Braunwald.

At least 379 records · Page 21Linked to original sources

Observations on experimental myocardial ischaemia.

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.

Adenosine Triphosphate↗

Effects of amrinone on myocardial energy metabolism and hemodynamics in patients with severe congestive heart failure due to coronary artery disease.

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.

Aged↗

Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion: which comes first?

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.

Animals↗

Increased plasma norepinephrine levels during prazosin therapy for severe congestive heart failure.

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.

Heart Failure↗

Calcium channel blocking agents in the treatment of cardiovascular disorders. Part I: Basic and clinical electrophysiologic effects.

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.

Action Potentials↗

Calcium channel blocking agents in the treatment of cardiovascular disorders. Part II: Hemodynamic effects and clinical applications.

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.

Benzazepines↗

Cardio-selective beta adrenergic stimulation with prenalterol in the conscious dog.

The effects of cardioselective beta-1 adrenergic agonist, 1-(4-hydroxyphenoxy)-isopropylamino-2-propanol), i.e., prenalterol, were examined on direct and continuous measurements of left ventricular (LV) pressure, diameter, dP/dt, velocity of shortening, arterial pressure, iliac blood flow and heart rate in 10 conscious dogs. Prenalterol was infused on 3 separate days in doses of 1, 2 and 4 micrograms/kg/min for 15 min. The largest dose of the drug increased LV/dP/dt by 70 +/- 7% from 3581 +/- 130, velocity of LV shortening by 27 +/- 4% from 86 +/- 7 mm/sec, heart rate by 51 +/- 9% from 80 +/- 5 beats/min and iliac blood flow by 40 +/- 4% from 134 +/- 15 ml/min and decreased LV end-diastolic diameter by 8 +/- 2% from 35 +/- 2 mm and LV end-systolic diameter by 15 +/- 2% from 24 +/- 2 mm. All these responses were significant, P < .01. Mean arterial pressure did not change. The positive inotropic effects persisted for 1 hr. The lowest dose of the drug studied increased LV dP/dt and velocity but not heart rate. Practolol, a beta-1 adrenergic receptor blocker, prevented the positive inotropic effects and the increases in iliac blood flow indicating that prenalterol exerts its cardiovascular actions primarily by stimulation of beta-1 adrenergic receptors.

Adrenergic beta-Agonists↗

Intramural PCO2: a reliable index of the severity of myocardial ischemic injury.

The present study was performed to evaluate the usefulness of changes in intramural oxygen (PmO2) and carbon dioxide (PmCO2) tensions shortly after coronary artery occlusion as indices of the severity of myocardial ischemic injury. In 14 open-chest, anesthetized dogs, a 60-min coronary artery occlusion was performed, during which PmO2 and PMCO2 were measured continuously with a mass spectrometer. Regional myocardial blood flow (RMBF) adjacent to the mass spectrometer probes was measured by the xenon-127 washout technique both before and 30 min after coronary artery occlusion. At the end of 60 min of occlusion, the dogs were killed, and biopsies for histological examination of 1-micron-thick sections were obtained from the tissue surrounding each mass spectometer probe. The decline in PmO2 during the 60-min occlusion bore no relationship either to the severity of ischemic injury as assessed by histological examination, or to the reduction of RMBF. In contrast, the magnitude of rise in PmCO2 during the 60 min of occlusion corresponded closely to both the severity of injury assessed histologically and the reduction of RMBF.

Animals↗

Myocardial infarct size and ventricular function in rats.

To define the relationship between infarct size and ventricular performance, we performed hemodynamic studies in rats 21 days after left coronary artery occlusion. Ventricular performance was assessed under ether anesthesia by measurements of baseline hemodynamics and stressed performance as determined by the peak cardiac output and stroke volume obtained during intravenous volume loading and by the peak left ventricular developed pressure obtained during occlusion of the ascending aorta. Infarct size was determined by planimetry of the endocardial circumference of each of four histological slices of the left ventricle. Rats with small (4-30%) myocardial infarctions had no discernible impairment in either baseline hemodynamics or peak indices of pumping and pressure-generating ability when compared to the sham-operated, noninfarcted rats. Rats with moderate (31-46%) infarctions had normal baseline hemodynamics but reduced peak flow indices and developed pressure. Rats with infarctions greater than 46% had congestive heart failure, with elevated filling pressures, reduced cardiac output, and a minimal capacity to respond to pre- and after load stresses. The entire spectrum of postinfarction ventricular function was observed, from no detectable impairment to congestive failure. In this model of histologically healed myocardial infarction, the impairment of left ventricular function was directly related to the loss of myocardium.

Animals↗

Assessment of the efficacy of interventions to limit ischemic injury by direct measurement of intramural carbon dioxide tension after coronary artery occlusion in the dog.

Although numerous interventions have been shown to exert a salutary effect on the ischemic myocardium, the severity of ischemia generally has been measured by indirect techniques. In the present investigation the effect of ischemia on intramural carbon dioxide tension (PmCO(2)) was measured directly in the open-chest, anesthetized dog with a mass spectrometer during repetitive 10-min coronary artery occlusions separated by 45-min periods of reflow; simultaneously, regional myocardial blood flow in the ischemic area was measured by (127)Xenon washout. In all dogs the increase in PmCO(2) from before to 10 min after the first occlusion (DeltaPmCO(2)) exceeded that during subsequent occlusions. In those dogs not receiving an intervention (controls), DeltaPmCO(2) during the third occlusion was similar to that during the second occlusion. When propranolol, hyaluronidase, and nitroglycerin were administered to different groups of dogs before the third occlusion, each caused significantly smaller elevations in DeltaPmCO(2) than those occurring during the control second occlusion, and the combination of all three interventions induced the smallest increase in DeltaPmCO(2). Regional myocardial blood flow rose with hyaluronidase and was unchanged with propranolol, nitroglycerin, and the three drugs in combination. In contrast to these beneficial interventions, isoproterenol infused with the third occlusion caused a higher DeltaPmCO(2) than during the control second occlusion. It is concluded, first, that interventions that modify the severity of ischemia can be evaluated by measuring intramural carbon dioxide tension; second, that propranolol, hyaluronidase, and nitroglycerin reduce ischemic injury, whereas isoproterenol increases it; and third, that the combination of propranolol, hyaluronidase, and nitroglycerin exerts an additive beneficial effect on ischemia.

Animals↗

Hemodynamic assessment of amrinone. A new inotropic agent.

Amrinone, a new bipyridine derivative, exerts a positive inotropic action in experimental preparations and is effective when administered orally to dogs. To assess its immediate effects in man, we studied by cardiac catheterization the hemodynamic responses to amrinone (1.85 to 3.5 mg per kilogram given intravenously) in eight patients with congestive heart failure already receiving full doses of digitalis. the following statistically significant (P less than 0.01) effects were noted: cardiac index increased from a mean +/- 1 S.D. of 1.8 +/- 0.3 to 2.6 +/- 0.3 liters per minute per square meter; peak rate of left ventricular pressure rise rose from 849 +/- 233 to 1206 +/- 456 mm Hg per second; left ventricular end-diastolic pressure fell from 25 +/- 9 to 14 +/- 7 mm Hg; pulmonary-capillary pressure fell from 28 +/- 8 to 15 +/- 4 mm Hg; and right atrial pressure fell from 12 +/- 6 to 7 +/- 5 mm Hg. Mean heart rate was unchanged, and aortic mean pressure declined slightly (86 +/- 10 to 80 +/- 7 mm Hg, P less than 0.025). No toxicity was observed. Amrinone, whose mechanism of action has not yet ben defined, warrants further study as a possible treatment for heart failure.

Drug Evaluation↗