Gerrymandering in the heart: How tissue heterogeneities promote premature ventricular contractions

Premature ventricular contractions (PVCs) are abnormal heartbeats that can trigger life-threatening arrhythmias. One mechanism responsible for PVCs is triggered activity. In this process, spontaneous calcium (Ca2+) release from the sarcoplasmic reticulum, and subsequent Ca2+ waves at the subcellular level promote transient inward currents that lead to delayed afterdepolarizations at the cellular level. In uniform, healthy tissue, such events are often benign because the surrounding healthy cells act as an electrical sink, suppressing the abnormal signals from a few pathological source cells. This phenomenon is known as "source-sink mismatch." In this study, using computational modeling, we show how structural and functional tissue heterogeneities can overcome this protective mechanism. Regions of weak electrical coupling or specific cellular arrangements can electrically isolate small clusters of pathological cells. Within such isolated regions, the number of abnormal cells can more easily reach the "critical mass" required to overcome the source-sink mismatch and initiate a PVC. This principle, where the spatial arrangement of a minority group enables it to determine a local outcome of the whole group, is analogous to the political concept of gerrymandering. Our findings provide a novel mechanistic framework for understanding arrhythmia initiation and highlight the critical role of tissue heterogeneity.