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

Abstract

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 In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels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.

Electrophysiology of Hypokalemia and Hyperkalemia

“…Further experimental studies are needed to better clarify the specific mechanisms of tachyarrhythmia initiation by systemic hyperkalemia. In simulated ventricles, once reentry has been initiated, hyperkalemia tends to stabilize spiral/scroll wave reentry by flattening APD restitution slope 44 . The shorter APD increases the dominant frequency until CV slowing becomes prominent.…”

“…6 48 ). Interstitial hyperkalemia during acute ischemia has all of the electrophysiological actions described for systemic hyperkalemia, complicated by additional changes related to hypoxia, acidosis and other ischemic components 44, 48 . In particular, APD shortening is accelerated by activation of sarcolemmal ATP-sensitive K (K ATP ) channels due the ischemic fall in the cytoplasmic ATP/ADP ratio.…”

Phase Entrainment of Induced Ventricular Fibrillation: A Human Feasibility and Proof of Concept Study.

“…which range between 5-20 (mean~11) [31] . During VF there are thin, moving, sheet-like volumes of tissue that have recovered excitability, and are ahead of and about to be invaded by the propagating wavefront surfaces.…”

Image-Based Biophysical Simulation of Intracardiac Abnormal Ventricular Electrograms

“…These models have evolved in the last decades to better represent physiological phenomena [16], e.g. some have been used to study VT or other arrhythmia episodes [17], [18], [19], [20].…”