Sarcomere Shortening Destabilizes the Ca2+ Control System in Ventricular Myocytes: Implications for Understanding Arrhythmias in Familial Hypertrophic Cardiomyopathy

Abstract

Familial hypertrophic cardiomyopathy (FHC) results from mutations of contractile proteins. Certain forms of FHC are linked with a surprisingly high incidence of sudden cardiac death. It is a long-standing conundrum how mutations in motor proteins give rise to electrical arrhythmias. Quantitative modeling studies using large-scale simulations reveal an intimate link between the contractile system and the Ca2+ control system. This insight may help resolve this conundrum. Our simulations show that a small decrease in sarcomere length (SL) can destabilize the Ca2+ control system and increase the probability of spontaneous Ca2+ waves. FHC mutations on cardiac troponin T (cTnT) increase myofilament Ca2+ sensitivity, which may account for the shortened SL in cardiomyocytes from mice harboring the cTnT mutations. To test the model predictions we conducted experiments using the myofilament Ca2+ sensitizer EMD 57033 (Merck) to reduce the resting SL length. EMD in the range of 1-3 μM reduced the resting SL from 1.9 to 1.5 μm without altering sarcoplasmic reticulum Ca2+ load, systolic, or diastolic Ca2+ levels. Upon cessation of pacing (1 Hz), control myocytes (0 EMD) were quiescent but EMD treated myocytes exhibited spontaneous contractions and Ca2+ release. These results are consistent with the model predictions lending support to the idea that FHC mutations destabilize the Ca2+ control system, which in turn, become a substrate for arrhythmias.