The mechanical and metabolic effects of 3 min of complete global ischemia and 25 min of reperfusion were studied in the isolated rat heart. The decrease in contracile function was biphasic; a rapid 50% decline occurred in the first 10 s of ischemia, after which contractile function transiently stabilized and then fell at a slower rate. During reperfusion, recovery of relaxation was impaired relative to recovery of contractile function. A second period of ischemia and reflow produced changes in contractility, relaxation, and lactate production virtually identical to the initial one. In the absence of glycolytic blockade, tissue lactate accumulation developed, no contracture occurred, the pacing threshold did not increase, and reperfusion after 3 min of ischemia resulted in complete recovery of contractile function. Glycolytic blockade with 0.1 mM iodoacetate (IAA) prevented ischemic lactate production, accelerated the fall in contractility, caused irreversible contracture after 30 s of ischemia, an irreversible increase in pacing threshold within 3 min of ischemia, and poor recovery of contractile function with reperfusion. Thus during the first 3 min of severe ischemia, glycolysis exerted a net beneficial effect on myocardial function despite significant tissue lactate accumulation.
The effect of global ischemia of different degrees of severity and reperfusion was studied in the isolated working rat heart. Four degrees of ischemia were induced by reducing the control total coronary flow of 8 ml/min to 0, 0.04, 0.4, or 0.8 ml/min for 30 minutes, after which the coronary flow was returned to the control level. After severe ischemia (0 and 0.04 ml/min ischemic coronary flow groups), recovery of contractility was to less than 30% of the control, pre-ischemic value of ventricular developed pressure and dP/dt, and irreversible cardiac contracture and an increased pacing threshold occurred. After moderate ischemia (0.4 and 0.8 ml/min ischemic coronary flow groups), contractile function recovered completely, ischemic contracture was rapidly reversible and the pacing threshold did not increase. The moderately ischemic groups were able to function at a stable, low level of contractility for the 30 minute ischemic period, whereas the severely ischemic groups had no contractile activity. The amount of calculated tissue lactate accumulation correlated with the occurrence of irreversible ischemic injury; the severely ischemic groups which failed to recover with reperfusion accumulated 3-5 times as much lactate as the moderately ischemic groups which recovered completely. The results suggest that relatively small differences in the severity of the ischemic condition can markedly affect the degree of tissue injury.
To study metabolic factors in the genesis of coronary heart disease in previously healthy young adults, 24 men (aged 23 to 49 years) who had recovered from proven myocardial infarction were compared with an age-matched series of 20 healthy subjects-10 business and professional men and 10 prisoners. Both series averaged 10% above ideal body weight. The patients were shorter, were heavier smokers, and had a high familial incidence (70%) of coronary heart disease. The controls had more familial diabetes. Oral glucose tolerance tests without and with cortisone showed higher peak blood sugar levels and delayed return in the patients. Four patients were found to have fasting serum triglycerides above 300 mg% and were placed in a separate category of essential hyperlipidemia. In the remaining 20 patients, serum cholesterol and triglycerides in combination were higher than in the controls, together with elevation of pre-β-lipoproteins. α 1 -Lipoprotein was decreased. Mean postheparin lipolytic activity was slightly less in the patients-in the lower part of the normal range. In the combined series of patients and control subjects, the relative body weight showed significant correlations-directly with the 1-hour blood sugar level in the glucose tolerance test and with the fasting serum triglyceride level, and inversely with the α 1 -lipoprotein. The relative body weight did not show a significant correlation with the serum cholesterol level. A set of 10 characteristics and biochemical variables, referred to in preceding paragraphs, was found to discriminate well between the patients and their controls. The total incidence of abnormal findings was high among the patients (mean, 4.9 per man) and low among the controls (mean, 1.9 per man), but the positive items were grouped in many different ways in individuals. Analysis of the data suggests that over-nutrition and heavy smoking interact with hereditary factors in certain individuals to accelerate the progress of coronary atherosclerosis. Since individuals who exhibit many of the criteria indicative of increased risk are not uncommon in our population, their identification as candidates for coronary heart disease early in life is a significant public health problem.
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