Myofilament protein dynamics modulate EAD formation in human hypertrophic cardiomyopathy.

Patients with hypertrophic cardiomyopathy (HCM), a disease associated with sarcomeric protein mutations, often suffer from sudden cardiac death (SCD) resulting from arrhythmia. In order to advance SCD prevention strategies, our understanding of how sarcomeric mutations in HCM patients contribute to enhanced arrhythmogenesis needs to be improved. Early afterdepolarizations (EADs) are an important mechanism underlying arrhythmias associated with HCM-SCD. Although the ionic mechanisms underlying EADs have been studied in general, whether myofilament protein dynamics mechanisms also underlie EADs remains unknown. Thus, our goals were to investigate if myofilament protein dynamics mechanisms underlie EADs and to uncover how those mechanisms are affected by pacing rate, sarcomere length (SL), and different levels of HCM-induced myofilament remodeling. To achieve this, a mechanistically-based bidirectionally coupled human electrophysiology-force myocyte model under the conditions of HCM was constructed. HCM ionic remodeling included a reduced repolarization reserve, while HCM myofilament modeling involved altered thin filament activation. We found that the mechanoelectric feedback (MEF) on calcium dynamics in the bidirectionally coupled model, via Troponin C buffering of cytoplasmic Ca2+, was the myofilament mechanism underlying EADs. Incorporating MEF diminished the degree of repolarization reserve reduction necessary for EADs to emerge and increased the frequency of EAD occurrence, especially at faster pacing rates. Longer SLs and enhanced thin filament activation diminished the effects of MEF on EADs. Together these findings demonstrate that myofilament protein dynamics mechanisms play an important role in EAD formation.