Showing papers by "Eugene Braunwald published in 1982"

The stunned myocardium: prolonged, postischemic ventricular dysfunction.

Abstract: Myocardial ischemia has, for many decades, been viewed as an all-or-none process that causes myocardial necrosis when prolonged and severe, but whose effects are transient when it is brief or mild. In view of the evidence that the ischemic process may "hit, run and stun," perhaps our thinking about the consequences of myocardial ischemia should be expanded. According to this formulation, an ischemic insult not of sufficient severity of duration to produce myocardial necrosis may acutely affect myocardial repolarization and cause angina (hit); but these changes wane rapidly (run), when the balance between myocardial oxygen supply and demand has been reestablished. However, the ischemia may interfere with normal myocardial function, biochemical processes and ultrastructure for prolonged periods (stun). The severity and duration of these postischemic changes depend on the length and intensity of the ischemia, as well as on the condition of the myocardium at the onset of the ischemic episode. Furthermore, it is likely that when the myocardium is repeatedly stunned, it may exhibit chronic postischemic left ventricular dysfunction, an ill-defined condition. If prolonged, chronic postischemic left ventricular dysfunction can progress to myocardial scarring and ischemic cardiomyopathy, it may be important to determine how often it can be ameliorated by permanent improvement of myocardial perfusion by surgical treatment.

Mechanism of Action of Calcium-Channel-Blocking Agents

Abstract: Calcium ions (Ca++) are vital in many biologic processes, including a variety of enzymatic reactions, activation of excitable cells, coupling of electrical activation to cellular secretion, hemostasis, and the metabolism of bone. The development of drugs that interfere with the entry of Ca++ into cells — variously termed Ca++-channel blockers, Ca++-entry blockers, Ca++ antagonists, and slow-channel blockers — has provided the basic scientist with powerful new tools for the study of the role of this ion in normal as well as pathologic states and has provided the clinician with several important new therapeutic agents for use in . . .

Limitation of experimental infarct size by an angiotensin-converting enzyme inhibitor.

Abstract: The effects of angiotensin-converting enzyme inhibitor (CEI) SQ14225 on infarct size and regional myocardial blood flow were studied in 21 anesthetized dogs subjected to 6 hours of coronary occlusion. An area of myocardium at risk of necrosis was determined in vivo after 15 minutes of coronary occlusion but before CEI treatment (AR1) using an autoradiographic technique and after treatment after 6 hours of coronary occlusion (AR2) using a fluorescent dye technique. An in vitro area at risk (AR8), which measures coronary bed size, was determined by injecting Monastral dye postmortem. Infarct size was determined by planimetry of unstained myocardium after incubating heart slices in triphenyltetrazolium chloride. Regional myocardial blood flow (RMBF) was measured by injecting tracer microspheres simultaneously with measurements of AR1 and AR2. In 11 saline-treated control dogs (group A), infarct size averaged 93 ± 8% of AR1, 96 i 2% of AR2 and 75 ± 6% of AR9, respectively. In 10 dogs treated with CEI (0.25 mg/kg/hour) between 30 minutes and 6 hours after coronary occlusion (group B), infarct size was smaller and averaged 68 ± 5% of AR1 (p < 0.01), 79 ± 5% of AR2 (p < 0.005), and 57 ± 7% of AR3 (p < 0.05). RMBF in the ischemic zone remained constant in group A but increased by 62 ± 26% in group B (p < 0.025). In group B, mean arterial pressure decreased from 115 ± 6 to 103 ± 7 mm Hg (p < 0.025) between 30 minutes and 6 hours after coronary occlusion and left atrial pressure decreased from 9.0 ± 1.8 to 5.7 ± 0.8 mm Hg (p < 0.0025). These measurements did not change in group A. Thus, CEI is potent in reducing infarct size in the dog after coronary occlusion. It may act by increasing collateral flow to the ischemic zone and reducing afterload.

Regression of left ventricular hypertrophy and prevention of left ventricular dysfunction by captopril in the spontaneously hypertensive rat

Abstract: To determine whether chronic antihypertensive therapy prevents the progression of cardiac hypertrophy and the deterioration in cardiac performance observed in spontaneously hypertensive rats (SHR) with long-term hypertension, 14-month-old female SHR and normotensive American Wistar rats (NWR) were treated for 10 months with an inhibitor of angiotensin I-converting enzyme, captopril (2 g/liter of drinking water). Captopril reduced the marked left ventricular hypertrophy of 24-month-old SHR (untreated, 4.37 +/- 0.2 mg/g of body weight; treated, 3.01 +/- 0.1 mg/g; P less than 0.02) to levels observed in 6-month-old SHR. Treatment prevented the reductions in baseline and maximal aortic blood flows that occurred in SHR between ages 12 and 24 months yet had no effect on the blood flows of NWR. The diminished maximal stroke volume of untreated SHR was ejected from a significantly increased left ventricular end-diastolic volume, so that the ejection-fraction index was markedly reduced (24-month-old untreated NWR, 84 +/- 3%; untreated SHR, 56 +/- 5%; P less than 0.001). Therapy restores this index in SHR to normal (77 +/- 4%). The relationship between ejection-fraction index, and afterload was also normal in treated SHR. Thus, chronic therapy with captopril produced a marked regression of cardiac hypertrophy and prevented the deterioration of cardiac performance in SHR with long-standing hypertension.

Left ventricular end-systolic stress-shortening and stress-length relations in human. Normal values and sensitivity to inotropic state.

Abstract: Experimental studies suggest that the extent of left ventricular (LV) fiber shortening is determined by both the wall stress at end-systole and the contractile state. To evaluate the relation between these variables assessed noninvasively, 26 normal subjects were studied by M-mode echocardiography, phonocardiography, and indirect carotid pulse tracings during infusion of methoxamine to alter load (in all 26 subjects) and infusion of dobutamine (in 10 subjects) to increase contractility. End-systolic pressure was estimated from the incisura of a calibrated carotid pulse tracing. LV end-systolic dimension and wall thickness, and percent internal dimension shortening were determined by echocardiography, and end-systolic meridional wall stress was calculated. The relation between end-systolic stress and shortening was inversely linear (r = −0.83) for 130 control points. Dobutamine infusion resulted in a higher percent fractional shortening for any end-systolic stress; all 43 stress-shortening points were more than 2 standard deviations above the mean for the regression line. The relation between stress and dimension for the control points showed wider scatter than between stress and shortening (r = 0.56). However, in individual patients dobutamine always shifted the stress-dimension lines to the right, as compared with the baseline position resulting in a smaller end-systolic dimension for any end-systolic wall stress. Thus, LV end-systolic wall stress and percent fractional shortening are inversely and linearly related and their relation can be accurately assessed by noninvasive methods. The end-systolic stress-shortening relation is highly sensitive, while the end-systolic stress-dimension relation is less sensitive to alterations in LV inotropic state.

Favorable effects of therapy on cardiac performance in spontaneously hypertensive rats.

Abstract: To determine whether chronic antihypertensive therapy reduces cardiac mass and improves performance in spontaneously hypertensive rats (SHR) with marked left ventricular hypertrophy and evidence of cardiac dysfunction, 12-mo-old male and female SHR and age- and sex-matched normotensive rats (NORM) were treated for 6 mo with either tap water or tap water containing hydralazine or guanethidine. Cardiac performance was assessed by the peak stroke volume and cardiac indices attained during volume loading and by the maximum left ventricular pressure developed during an aortic occlusion. Passive diastolic pressure-volume curves were obtained in the potassium-arrested heart. Treatment prevented the progression of left ventricular hypertrophy in SHR and the marked deterioration in peak pumping ability observed in untreated male SHR and the modest impairment observed in female SHR. The peak developed pressure of both the male and female treated SHR was reduced toward that of NORM and was associated with a reduction in the left ventricular mass-to-volume ratio toward that of NORM. Thus chronic therapy with either hydralazine or guanethidine reduced cardiac mass and prevented the deterioration in cardiac pumping performance observed in SHR with sustained hypertension and marked cardiac hypertrophy.

Studies of amiodarone during experimental myocardial infarction: beneficial effects on hemodynamics and infarct size.

Abstract: The effect of amiodarone was investigated in a canine model of myocardial infarction. The left anterior descending coronary artery was occluded in 24 anesthetized dogs. After 15 minutes of coronary artery occlusion, the ischemic myocardium at risk of necrosis was determined by labeling the heart with technetium-99m-labeled human albumin microspheres injected into the systemic circulation through the left atrium, and the dogs were than randomized to either a saline-treated control group (n = 13) or an amiodarone-treated group (n = 11) that received i.v. amiodarone, 10 mg/kg, administered in a single bolus 30 minutes after coronary artery occlusion. Myocardial infarct size was determined directly after 6 hours of coronary occlusion by incubation of sections of myocardium in triphenyltetrazolium chloride, a dehydrogenase stain, and expressed as a percentage of left ventricle below occlusion. Autoradiography of the stained myocardial sections was performed to determine the ischemic myocardium at risk of necrosis, which was similar in the control and amiodarone-treated groups (31.8 +/- 2.8% vs 32.5 +/- 3.3% of the left ventricle, respectively). In the amiodarone-treated group, only 67.1 +/- 8.4% of the myocardium at risk became necrotic; in the control group, 97.5 +/- 7.7% of the myocardium at risk became necrotic (p less than 0.01), representing 21.8 +/- 3.5% vs 31.1 +/- 2.8% of the left ventricle below occlusion, respectively (p less than 0.025). Amiodarone decreased heart rate, contractility and afterload. Its beneficial action on infarct size is related presumably to reduced myocardial oxygen demand.

Effects of hypertension on cardiac performance in rats with myocardial infarction.

Abstract: To determine the effects of hypertension and myocardial infarction on cardiac performance, hemodynamic studies were performed on etheranesthetized, female spontaneously hypertensive rats and on two strains of normotensive rats, Wistar-Kyoto and American Wistar, 26 days after coronary arterial ligation. Baseline measurements of ventricular and arterial pressures and cardiac output (electromagnetic flowmeter) were obtained. Peak cardiac pumping and pressure-generating capacities were determined during a volume load and aortic occlusion, respectively. Infarct size was determined by planimetry. There was a progressive reduction in mean arterial pressure in relation to infarct size in both hypertensive and normotensive rats, but this reduction was twice as great in spontaneously hypertensive rats as in the normotensive rats, such that the arterial pressure of hypertensive rats with a moderate or large infarction decreased to within the “normotensive range.” However, spontaneously hypertensive rats still maintained significantly higher arterial pressures than did normotensive rats at comparable infarct sizes. There was also a progressive reduction in the peak pressure developed during an afterload stress, and this reduction was greater in hypertensive rats than in normotensive rats with a large infarct. Maximal flow-generating capacity was similarly altered in rats with infarction: Peak stroke volume index varied inversely with infarct size and the reduction in this index was significantly greater in spontaneously hypertensive rats than in normotensive rats with a large infarct. Moreover, peak stroke work index was reduced to a greater extent in spontaneously hypertensive rats than in both normotensive strains of rats at any infarct size. Thus, after myocardial infarction, greater reductions in both pressure and flow-generating capacities occurred in hypertensive rats than in normotensive rats.

Extension of myocardial necrosis into normal epicardium following hypotension during experimental coronary occlusion

Abstract: In an effort to determine the manner in which hypotension following experimental coronary occlusion affects myocardial infarct size, the left anterior descending coronary artery was occluded in 22 barbiturate anaesthetised dogs, the chest was closed, and the dogs allowed to recover. Thirty minutes following coronary occlusion, seven dogs were haemorrhaged to a mean arterial pressure of 8.2 ± 0.3 kPa (62±2 mmHg) and maintained at this pressure; no intervention was undertaken in control dogs. Twenty-four hours after coronary occlusion infarct size in control and hypotensive animals was determined. The hypotensive group developed larger percentages of necrosis of the left ventricles distal to the site of occlusion than did the control dogs (37.8 ± 2.3 vs 30.4 ± 1.4 (P<0.01)). Although the percentage of infarcted endocardium did not change significantly, the infarction of epicardium was 45% larger in the hypotensive group (34.4 ± 3.3 % vs 23.7 ± 1.9%, P < 0.01). Regional myocardial blood flow (RMBF) was determined by means of radioactive microspheres in 5 dogs following coronary occlusion before and after hypotension. RMBF following haemorrhage fell by an equal proportion, 61.9 ± 3.3% in normal tissue and 61.2 ± 2.4% in ischaemic zones. In conclusion, hypotension caused infarct extension into the epicardium, ie, into tissue that does not become necrotic under control conditions.

Effects of Aminophylline in the Conscious Dog After Coronary Occlusion

Abstract: The effects of aminophylline were examined in 19 conscious dogs subjected to coronary arterial occlusion. Measurements were made of left ventricular pressure and its first derivative ( dP dt ), segment length and the velocity of segment length shortening in normal and severely ischemic zones. Regional blood flow was measured in these zones using the radioactive microsphere technique. Coronary occlusion increased heart rate, mean arterial pressure and left ventricular end-diastolic pressure but did not change left ventricular systolic pressure or dP dt significantly. It also resulted in increased end-diastolic segment length and reduced segment length shortening (114 ± 6 percent, that is, paradoxical bulging) associated with marked reduction of blood flow to ischemic myocardium. Aminophylline, 1 mg/kg per min for 9 to 15 minutes administered after occlusion, increased heart rate 6 ± 2 beats/min, mean arterial pressure 5 ± 1 mm Hg, left ventricular systolic pressure 9 ± 2 mm Hg and left ventricular dP dt 670 ± 50 mm Hg/s while reducing left ventricular end-diastolic pressure by 3.4 ± 0.3 mm Hg. In severely ischemic zones aminophylline increased transmural blood flow by 21 ± 8.0 percent (p dP dt and heart rate while reducing left ventricular end-diastolic pressure. In severely ischemic myocardium aminophylline appeared to exert a salutary effect and improved both regional perfusion and function.

Symposium “Limiting of Infarct Size”

Abstract: Much has been learned in the past twenty years about the biologic changes occurring in zones of acute myocardial ischemic injury. Almost all of this information has come from studies of regional ischemia in dogs or other experimental animals. In this paper, the changes which occur when myocardium is made acutely and severely ischemic by sudden occlusion of a major branch of a coronary artery in the dog will be reviewed with special attention to those changes which are associated with irreversible (lethal) injury.