A Heart for Diversity: Simulating Variability in Cardiac Arrhythmia Research

In cardiac electrophysiology, there exist many sources of inter- and intra-personal variability. These include variability in conditions and environment, and genotypic and molecular diversity, including differences in expression and behavior of ion channels and transporters, which lead to phenotypic diversity (e.g., variable integrated responses at the cell, tissue, and organ levels). These variabilities play an important role in progression of heart disease and arrhythmia syndromes and outcomes of therapeutic interventions. Yet, the traditional in silico framework for investigating cardiac arrhythmias is built upon a parameter/property-averaging approach that typically overlooks the physiological diversity. Inspired by work done in genetics and neuroscience, new modeling frameworks of cardiac electrophysiology have been recently developed that take advantage of modern computational capabilities and approaches, and account for the variance in the biological data they are intended to illuminate. In this review, we outline the recent advances in statistical and computational techniques that take into account physiological variability, and move beyond the traditional cardiac model-building scheme that involves averaging over samples from many individuals in the construction of a highly tuned composite model. We discuss how these advanced methods have harnessed the power of big (simulated) data to study the mechanisms of cardiac arrhythmias, with a special emphasis on atrial fibrillation, and improve the assessment of proarrhythmic risk and drug response. The challenges of using in silico approaches with variability are also addressed and future directions are proposed.