Ventricular tachyarrhythmias associated with acute myocardial ischemia or the relief of ischemia are a major cause of sudden cardiac death. Considerable efforts have been made to understand the mechanisms of these arrhythmias in order to develop more effective therapeutic and preventive approaches. Potassium has long been recognized as a major mediator of electrophysiological alterations and an important factor in arrhythmogenesis in the ischemic ventricle. Furthermore, recent clinical trials have implicated abnormal K+ gradients in the increased propensity of hypokalemic patients to lethal ventricular arrhythmias. Recent studies have also suggested that attenuation of K+ fluxes may be involved in the cardioprotective and antiarrhythmic actions of beta adrenoceptor blocking drugs. However, due to previous methodological limitations, the precise relationship between K+ gradients and ischemic ventricular arrhythmogenesis has not been subjected to quantitative analysis. The specific scientific aim is to determine quantitatively the causal role of potassium in ischemic ventricular arrhythmogenesis. Our scientific hypothesis is that ventricular tachyarrhythmias resulting from acute myocardial ischemia or the relief of ischemia correlate with the magnitude, rate of change, extent and heterogeneity of regional K+ gradients. To test this hypothesis, innovative and sophisticated techniques will be used in several experimental canine models, and rigorous methods of analysis applied. Intramyocardial electrograms as well as extracellular K+ activity will be recorded continuously and simultaneously in close proximity at 32 to 64 sites within the ischemic and normal zones of the heart using custom-designed multipolar bifunctional intramyocardial electrodes. Coronary blood flow and collateral blood flow will be measured in the normal and ischemic zones using radioactive tracers. The comparative effects of both graded and abrupt ischemia and reperfusion, infusion of K+ into a coronary artery, acute ischemia superimposed on chronic myocardial infarction and acute ischemia superimposed on chronic hypokalemia will be evaluated as well as the effects of beta adrenoceptor blockade in these models. The ability to correlate changes in regional electrical and extracellular K+ activities with blood flow in the ischemic and reperfused heart will provide a quantum increase in our understanding of the genesis of lethal ventricular arrhythmias. This should lead to more effective and innovative therapeutic approaches to the prevention of lethal arrhythmias in patients with coronary heart disease.
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