Effect of Global Cardiac Ischemia on Human Ventricular Fibrillation: Insights from a Multi-scale Mechanistic Model of the Human Heart

Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels from these measurements.Author Summary: Cardiac arrhythmias are an important cause of death in the industrialized world. The most dangerous type of cardiac arrhythmias is ventricular fibrillation. If left untreated, it leads to death within just few minutes. In most of the cases ventricular fibrillation occurs as a result of cardiac ischemia, which is a shortage of blood supply to the heart muscle. Futhermore ventricular fibrillation leads to decreased cardiac output, which in turn results in secondary ischemia. A recent clinical study investigated the effect of secondary ischemia on the organization of ventricular fibrillation in the human heart. However, in the clinical study it was not possible to obtain the whole picture of activation of the heart and to separate the relative roles of different processes induced by ischemia in the alterations to the cardiac electrical activity. In this study we use computer modeling to address these problems and to complement the results of the clinical study. Our results allow us to explain the change of electrical activation pattern in the heart during the first minutes of ischemia and to estimate the relative rates of those ischemia-induced physiological processes. We also present previously unpublished data on individual patient recordings from the clinical study.