The myocardial metabolism of free fatty acids, glucose and catecholamines is reviewed in relation to current trends in the therapy of experimental myocardial infarction. Major modifications in the metabolism of free fatty acids, glucose and catecholamines have already been found after acute myocardial infarction in man, and animal experimental data suggest that such metabolic changes might play a role in the modification of infarct size and sometimes in the development of arrhythmias. However, animal experiments often represent extreme situations and the therapeutic use in man of agents to modify the metabolism of free fatty acids, glucose or catecholamines after myocardial infarction needs intensive investigation before general application. The sum total of the evidence from animal experiments suggests that increased circulating concentrations of free fatty acids and catecholamines, if sufficiently high, may be harmful rather than helpful to the outcome of acute myocardial infarction, and that increased provision of glucose (as glucose, insulin and potassium) may be beneficial. Reservations to these conclusions are that the concentrations used appear to be important factors in catecholamine and free fatty acid effects, and that the mechanism of action of glucose-insulin-potassium is more complex than originally thought.

Metabolism of free fatty acids, glucose and catecholamines in acute myocardial infarction. Relation to myocardial ischemia and infarct size.

Coronary blood flow in man

To determine the sequence of changes in segmental myocardial function, regional lactate metabolism and global left ventricular function induced by mild regional ischemia, blood flow in the left anterior descending coronary artery of 10 dogs was reduced by 10 percent decrements with use of a screw clamp. At each level of flow, segmental mechanical function and regional metabolism were assessed, the former with use of a mercury-in-Silastic length gauge and the latter with transmyocardial lactate balance measurements obtained with sampling from the anterior interventricular vein. Coronary arterial flow at the onset of regional lactate production was 48 ± 4 percent (mean ± standard error of the mean) of the control value. The onset of segmental mechanical dysfunction coincided with the onset of lactate production. Epicardial S-T segment abnormalities over the ischemic zone usually could not be detected until coronary flow was further reduced. After the onset of regional ischemia there was a linear correlation between coronary arterial flow and regional lactate production. At the onset of mild regional ischemia, defined as the onset of regional lactate production, no significant or directionally consistent changes were noted in standard measurements of global left ventricular performance, including heart rate, mean aortic pressure, left ventricular end-diastolic pressure, cardiac output, stroke volume, stroke work and peak positive dP/dt (maximal rate of rise of pressure). However, peak negative dP/dt (maximal rate of pressure decrease) decreased from 99 ± 2 to 89 ± 3 percent of the control value ( P

Early changes in regional and global left ventricular function induced by graded reductions in regional coronary perfusion

Responses of the ischemic myocardium to allopurinol

Extraction and clearance kinetics of [1-11C]acetate were examined in 65 experiments in 30 open-chest dogs. Twenty-nine studies were performed at control, 13 during ischemia, eight after reperfusion, 13 during dipyridamole-induced hyperemia, and two during alteration of cardiac workload. [1-11C]Acetate was injected directly into the left anterior descending coronary artery, and myocardial tissue-time activity curves were recorded with a gamma probe. The single-pass extraction fraction averaged 64.2 +/- 9.7% in control, 65.3 +/- 9.1% in ischemia, 70.0 +/- 4.4% in reperfusion, and 46.5 +/- 7.4% in dipyridamole-induced hyperemia groups. 11C clearance was biexponential in all cases. The rate constant k1 for the first rapid clearance phase correlated closely with myocardial oxygen consumption (r = 0.94) in control, ischemia, reperfusion, and dipyridamole-induced hyperemia groups. Monoexponential fitting of only the first linear part of the clearance curve yielded the rate constant kmono, which also correlated with myocardial oxygen consumption (r = 0.96). Arterial lactate concentrations and the amount of free fatty acid oxygen equivalents consumed by the myocardium were shown to have a small but statistically significant impact on the relation between [1-11C]acetate clearance rate constants and myocardial oxygen consumption. The fraction of 14CO2 activity contributing to overall 14C activity leaving the myocardium after simultaneous injection of [1-14C]acetate (n = 24) was relatively high in all cases (97.4 +/- 2.5% in control, 89 +/- 2.6% in ischemia, 94.1 +/- 3.5% in reperfusion, and greater than 99% in dipyridamole groups), indicating that externally measured 11C clearance corresponds to CO2 production and thus to tricarboxylic acid cycle activity. In conclusion, the results validate the use of [1-11C]acetate as a tracer of oxidative myocardial metabolism for use with positron emission tomography.

Validation of [1-11C]acetate as a tracer for noninvasive assessment of oxidative metabolism with positron emission tomography in normal, ischemic, postischemic, and hyperemic canine myocardium.

A technique for the study of local metabolic changes in coronary venous blood draining from a small area of ischemic myocardium is described. Overt left ventricular failure, ventricular arrhythmias and possible secondary effects on local metabolic changes were avoided. Metabolic changes in local coronary venous blood and in coronary sinus blood were compared. Gross changes detected by local coronary venous sampling were not observed in coronary sinus blood samples. The possible relevance of this observation to clinical studies was noted. The small ischemic lesion usually involved less than 10 percent of the heart volume and was characterized by acute S-T segment elevation in the epicardial electrocardiogram and by positive changes in values for local coronary venous blood lactate, pyruvate, lactate/ pyruvate ratio, glucose, potassium and phosphate. Free fatty acids and beta hydroxybutyrate and acetoacetate levels were also studied. The technique and its results are compared with other methods of study of the metabolism of ischemic heart tissue.

Val Young

Papers

Comparison between metabolic changes in local venous and coronary sinus blood after acute experimental coronary arterial occlusion