Reversal of Premature Site-Dependent Ventricular Vulnerability in Simulated Ischemic Tissue

Recent studies demonstrated that the vulnerable window was wider when the premature beat was initiated in the endocardium than in the epicardium. Because acute ischemia causes extensive electrical remodeling to the myocardium, we sought to determine if the same disparity of vulnerability due to the location of premature beat existed in acute ischemia. A numerical model that could reproduce the three cell types (endocardial, epicardial and middle cells) across the ventricular wall was developed by setting different ratios of the maximum conductance for the rapid and slow inward rectifier potassium currents. The model then incorporated the three major conditions of acute ischemia (elevated extracellular K⁺ concentration, acidosis and anoxia) at the level of ionic currents and ionic concentrations, as well as different severity of ischemia across the developed fiber. The results showed that APD dispersion of the whole tissue was enlarged in contrast to the healthier situation. Conduction velocity was much more depressed in the epicardium than that in the endocardium due to ischemia-induced transmural gradient of excitability. Compared with premature beats S2 at endocardial site, the time vulnerable window induced by S2 at epicardial site was found to be much wider (vulnerable window = 59 ms) and much more likely to induce ventricular arrhythmias. Therefore, as opposed to the normal hearts, the acutely ischemic tissue is more vulnerable to premature beats initiated in the epicardium than in the endocardium. Ischemia-induced transmural dispersion of excitability is responsible for such a direct reversal of the location-dependency of vulnerability.