Showing papers by "Eugene Braunwald published in 1985"

Influence of chronic captopril therapy on the infarcted left ventricle of the rat.

Abstract: To determine whether the relationship between infarct size and ventricular performance, volume, and compliance could be altered favorably, captopril was administered to rats for 3 months following coronary artery ligation. Baseline left and right ventricular and systemic arterial pressures and aortic blood flow, and maximal stroke volume and cardiac indices attained during a volume loading, were measured. Passive pressure-volume relations of the left ventricle were determined, and the slopes of segments of this relation were analyzed to characterize ventricular chamber stiffness. In untreated rats, left ventricular end-diastolic pressure progressively rose (from 5-28 mm Hg) as a function of infarct size, whereas, in captopril-treated rats, filling pressure remained within normal limits (5 +/- 1 mm Hg) in all but those with extensive infarcts. Chronic captopril therapy reduced baseline mean arterial pressure and total peripheral resistance, yet maintained cardiac and stroke outputs in rats both with and without infarcts. In untreated rats, maximal pumping ability progressively declined with increasing infarct size, whereas, in captopril-treated rats, peak stroke volume index remained within normal limits in all but those with extensive infarcts. The in vitro left ventricular volumes of captopril-treated rats were significantly less than those of untreated rats. The maintenance of forward output from a lesser dilated left ventricle yielded an index of ejection fraction for treated rats with moderate and large infarcts that was significantly elevated compared with that of untreated rats with infarcts of comparable size. Left ventricular chamber stiffness, which fell as infarct size increased in untreated rats, was normalized by chronic captopril therapy. Thus, captopril attenuated the left ventricular remodeling (dilation) and deterioration in performance that were observed in rats with chronic myocardial infarction.

Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside.

Abstract: Milrinone is a potent positive inotropic and vascular smooth muscle-relaxing agent in vitro, and therefore, it is not known to what extent each of these actions contributes to the drug's hemodynamic effects in patients with heart failure. In 11 patients with New York Heart Association class III or IV congestive heart failure, incremental intravenous doses of milrinone were administered to determine the dose-response relationships for heart rate, systemic vascular resistance, and inotropic state, the latter measured by peak positive left ventricular derivative of pressure with respect to time (dP/dt). To clarify further the role of a positive inotropic action, the relative effects of milrinone and nitroprusside on left ventricular stroke work and dP/dt were compared in each patient at doses matched to cause equivalent reductions in mean arterial pressure or systemic vascular resistance, indices of left ventricular afterload. Milrinone caused heart rate, stroke volume, and dP/dt to increase, and systemic vascular resistance to decrease in a concentration-related manner. At the two lowest milrinone doses resulting in serum concentrations of 63 +/- 4 and 156 +/- 5 ng/ml, respectively, milrinone caused significant increases in stroke volume and dP/dt, but no changes in systemic vascular resistance or heart rate. At the maximum milrinone dose administered (mean serum concentration, 427 +/- 11 ng/ml), heart rate increased from 92 +/- 4 to 99 +/- 4 bpm (P less than 0.01), mean aortic pressure fell from 82 +/- 3 to 71 +/- 3 mmHg (P less than 0.01), right atrial pressure fell from 15 +/- 2 to 7 +/- 1 mmHg (P less than 0.005), left ventricular end-diastolic pressure fell from 26 +/- 3 to 18 +/- 3 (P less than 0.005), stroke volume index increased from 20 +/- 2 to 30 +/- 2 ml/m2 (P less than 0.005), stroke work index increased from 14 +/- 2 to 21 +/- 2 g X m/m2 (P less than 0.01), and dP/dt increased from 858 +/- 54 to 1,130 +/- 108 mmHg/s (P less than 0.005). When compared with nitroprusside for a matched reduction in mean aortic pressure or systemic vascular resistance, milrinone caused a significantly greater increase in stroke work index at the same or lower left ventricular end-diastolic pressure. Milrinone caused a concentration-related increase in dP/dt (32% increase at maximum milrinone dose), whereas nitroprusside had no effect. These data in patients with severe heart failure indicate that in addition to a vasodilating effect, milrinone exerts a concentration-related positive inotropic action that contributes significantly to the drug's overall hemodynamic effects. The positive inotropic action occurs at drug levels that do not exert significant chronotropic or vasodilator effects.

Effect of intracoronary verapamil on infarct size in the ischemic, reperfused canine heart: Critical importance of the timing of treatment☆

Abstract: In an effort to determine whether the beneficial effect of calcium blocking drugs occurs only during ischemia or during reperfusion as well, anesthetized dogs were subjected to 3 hours of occlusion of the left anterior descending coronary artery followed by 3 hours of reperfusion. In protocol A, intracoronary verapamil (0.01 mg/kg/min) was begun 90 minutes after coronary occlusion and continued for 1 hour into the reperfusion phase (n = 6) while a control group received an infusion of saline solution (n = 6). In vivo area at risk determined by dye injection was 29 ± 3% of the left ventricle (± standard error of the mean) in the control group and 30 ± 3% in the verapamil group (difference not significant [NS]), whereas the area of necrosis determined by triphenyltetrazolium staining and expressed as a percent of area at risk was smaller in the verapamil group (29 ± 8%) than in the control group (57 ± 8%, p

Use of an ultra short-acting beta-blocker in patients with acute myocardial ischemia.

Abstract: Esmolol is a new ultra short-acting (half-life [t1/2] beta 9 min) beta 1-adrenergic-receptor antagonist reported to have no intrinsic sympathomimetic activity. The safety and efficacy of esmolol in lowering the ventricular rate and rate-pressure product in patients with acute myocardial infarction (n = 5), postmyocardial infarction angina (n = 10), or acute unstable angina (n = 4), and without cardiogenic shock were studied. After a 30 min observation period, esmolol was titrated to a maximum dose of 300 micrograms/kg/min and infused for up to 420 min. The ventricular rate fell from 92 +/- 11 (mean +/- SD) to 77 +/- 13 beats/min (p less than .01) and the systolic arterial pressure decreased from 120 +/- 13 to 97 +/- 11 mm Hg (p less than .01) during the initial 30 min titration period. There was no significant change during the maintenance phase, and both the ventricular rate and arterial pressure returned rapidly toward baseline values within 30 min of termination of the infusion. The cardiac index fell from 2.8 +/- 0.6 to 2.2 +/- 0.6 liters/min/m2 (p less than .01) during the same period, and also returned to the baseline level 30 min after termination of the infusion. There was no significant change in the pulmonary capillary wedge pressure, respiratory rate, or PR interval. Five patients required termination of infusion because of hypotension and all recovered uneventfully within 30 min of stopping the esmolol. One patient required a brief infusion of dopamine to restore hemodynamic stability.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiologic assessment of the inotropic, vasodilator and afterload reducing effects of milrinone in subjects without cardiac disease.

Abstract: Milrinone increases left ventricular (LV) shortening. Whether these changes result from vasodilation alone or from a combination of vasodilation and a positive inotropic action is controversial. Load-independent end-systolic indexes of LV contractility were measured over a wide range of aortic pressures generated by methoxamine infusion before and during milrinone administration. Sixteen studies were performed using echocardiography and calibrated carotid pulse tracings in 11 normal subjects. Milrinone loading doses of 30, 45 or 60 μg/kg were given intravenously over 10 minutes, followed by a maintenance infusion to achieve steady-state drug levels. Milrinone induced a dose-dependent decrease in baseline (i.e., before methoxamine) total systemic resistance (p

Electrocardiographic, enzymatic and scintigraphic criteria of acute myocardial infarction as determined from study of 726 patients (a MILIS study)

Abstract: Methods for detecting acute myocardial infarction (AMI) were compared in a prospective study of 726 patients with pain presumed to be caused by ischemia that lasted 30 minutes or longer and was associated with electrocardiographic changes (ST-segment deviation greater than or equal to 0.1 mV and/or new Q waves or left bundle branch block). Using MB-CK values of more than 12 IU/liter as the standard criterion for detection of AMI, 639 patients (88%) were judged to have AMI. Total plasma CK values, technetium-99m stannous pyrophosphate images 48 to 72 hours after admission, and serial 12-lead electrocardiograms over 10 days were analyzed by investigators blinded to other clinical and laboratory data. For detection of AMI, total CK, electrocardiograms (ECGs) and pyrophosphate imaging were all highly accurate and sensitive (total CK accuracy 97%, ECG 92%, pyrophosphate 88%; total CK sensitivity 98%, ECG 96% and pyrophosphate 91%). However, both pyrophosphate and ECG were less specific than total CK (p less than 0.01) (total CK specificity 89%, pyrophosphate 64% and ECG 59%). The sensitivity (p less than 0.05) and accuracy (p less than 0.01) of total CK and pyrophosphate for those patients with Q-wave development were slightly greater than for those in whom Q waves did not evolve. The ECG was less accurate (p less than 0.02) and pyrophosphate was less specific (p less than 0.04) in patients with prior MI compared with those with initial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental and clinical observations on the efficacy of esmolol in myocardial ischemia

Abstract: Beta blockers reduce myocardial oxygen demand and are therefore useful in ischemic states. They reduce angina pectoris and reduce the risk of death when administered long-term after acute myocardial infarction. Some studies suggest that when administered early after coronary occlusion they can reduce myocardial infarct size. Relative contraindications to beta blockers, such as a history of congestive heart failure, chronic obstructive lung disease, atrioventricular conduction defects and low blood pressure, limit their use. Conventional beta blockers have a relatively long duration of action and are either contraindicated or must be used with particular caution in patients with these contraindications. Esmolol is an ultrashort-acting beta blocker with a biologic half-life of 9 minutes. Therefore, such an agent may be useful in patients with ischemic heart disease in whom reducing heart rate would be beneficial but in whom there is concern that beta blockers might not be tolerated. Esmolol reduced myocardial infarct size in 2 experimental studies of coronary occlusion followed by reperfusion, and improved the recovery of the stunned myocardium when administered during experimental myocardial ischemia. Esmolol's brief duration of action may make it safer than conventional beta blockers for the management of patients with unstable angina or myocardial infarction.

Effects of transient increased afterload during experimentally induced acute myocardial infarction in dogs.

Abstract: Alterations in afterload may occur during acute myocardial infarction (AMI), but it is unknown whether such alterations cause long-term changes in the left ventricular topography or alter healing of the AMI. AMI was produced by ligation of the left anterior descending coronary artery in open-chest dogs. Eight dogs were randomized to a methoxamine group with an infusion dose of 30 μg/kg/min starting 1 hour after ligation for 4 hours to increase systemic systolic pressure by 40 to 50 mm Hg, and 8 were randomized to a saline control group (n = 8). Seven days later the dogs were killed and the hearts examined. The ratio of infarct wall thickness to noninfarct wall thickness was 1.13 ± 0.03 (mean ± standard error of the mean) in control dogs and was 0.98 ± 0.03 in the dogs treated with methoxamine (p

End-systolic pressure-volume and stress-length relations in the assessment of ventricular function in man.

Abstract: ‘The systolic size of the heart varies directly with the arterial resistance. The diastolic volume depends on the diastolic filling of the heart. The arterial pressure remaining constant, the output depends solely on the diastolic filling, the systolic volume being independent within wide limits of the diastolic filling.’ Kozawa, 1915 [1].

Current Status of Interventions Designed to Limit Infarct Size

Abstract: Coronary artery disease remains the most serious public health problem in the Western world. In the United States alone, each year there are 1,250,000 myocardial infarctions (MI) and 650,000 patients die as a result of their acute MI. The loss of viable myocardium in those patients who survive acute infarction also leads to major morbidity from heart failure and cardiac arrhythmias. Coronary care units, which were developed in the late 1960s and early 1970s, have been able to provide close observation and electrocardiographic monitoring of patients with acute MI and have reduced the number of deaths due to arrhythmias and conduction disturbances. In recent years, however, in-hospital deaths from acute infarction have not changed significantly [1] despite the many advances in cardiovascular therapy and technology. Most in-hospital deaths related to acute MI now are due to pump failure.