Insights from an electro-mechanical heart failure cell model: Role of SERCA enhancement on arrhythmogenesis and myocyte contraction

Background and objective: Structural and electrical remodeling in heart failure predisposes the heart to ventricular arrhythmias. Computer modeling approaches, used to complement experimental results, can provide a more mechanistic knowledge of the biophysical phenomena underlying cardiac pathologies. In- deed, previous in-silico studies have improved the understanding of the electrical correlates of heart fail- ure involved in arrhythmogenesis; however, information on the crosstalk between electrical activity, in- tracellular Ca 2 + and contraction is still incomplete. This study aims to investigate the electro-mechanical behavior of virtual failing human ventricular myocytes to help in the development of therapies, which should ideally target pump failure and arrhythmias at the same time. Methods: We implemented characteristic remodeling of heart failure with reduced ejection fraction by including reported changes in ionic conductances, sarcomere function and cell structure (e.g. T-tubules disarray). Model parametrization was based on published experimental data and the outcome of simula- tions was validated against experimentally observed patterns. We focused on two aspects of myocardial dysfunction central in heart failure: altered force-frequency relationship and susceptibility to arrhythmo- genic early afterdepolarizations. Because biological variability is a major problem in the generalization of in-silico findings based on a unique set of model parameters, we generated and evaluated a population of models. Results: The population-based approach is crucial in robust identification of parameters at the core of abnormalities and in generalizing the outcome of their correction. As compared to non-failing ones, fail- ing myocytes had prolonged repolarization, a higher incidence of early afterdepolarizations, reduced con- traction and a shallower force-frequency relationship, all features peculiar of heart failure. Component analysis applied to the model population identified reduced SERCA function as a relevant contributor to most of these derangements, which were largely reverted or diminished by restoration of SERCA function alone. Conclusions: These simulated results encourage the development of strategies comprising SERCA stimu- lation and highlight the need to evaluate both electrical and mechanical outcomes.