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- W37340968 abstract "Although sudden cardiac death is a common feature in hypertrophic cardiomyopathy (HCM), the underlying mechanisms are unclear. We recently reported that some but not all mice expressing troponin mutations associated with HCM display increased myofilament calcium sensitivity. Here, we used these mice as well as acute challenge with the Ca 2+ sensitizing agent EMD57033 (EMD) in isolated mouse and rabbit hearts to test the hypothesis that myofilament sensitization leads directly to arrhythmia susceptibility. HCM mice with Ca 2+ sensitizing troponin mutations displayed significantly higher rate of ventricular ectopy (TnT-I79N 10±3, TnT-F110I 11±5, ssTnI 15±4 PVC/h) than mice expressing non-sensitizing troponins (TnT-R278C 1±1, TnT-WT 1±1, non-Tg 2±1 PVC/h, n=5–14 per group, p<0.01). Myofilament sensitization by troponin mutations or EMD shortened the effective refractory period and the ventricular action potential of isolated perfused mouse and rabbit hearts, and caused early afterdepolarizations and triggered beats after fast pacing trains. The action potential shortening was attributable to increased cytosolic Ca 2+ buffering by the Ca 2+ sensitized myofilaments, which resulted in decreased systolic and increased end-diastolic Ca 2+ during fast pacing. Optical mapping demonstrated that Ca 2+ sensitization slowed the ventricular conduction velocity and increased the size of the vulnerable window for ventricular tachycardia both in mouse and rabbit hearts, resulting in a significantly higher incidence of sustained ventricular tachycardia in Ca 2+ sensitized compared with control hearts (5/6 vs 0/6, p<0.05). Conclusion: Myofilament Ca 2+ sensitization alters Ca 2+ buffering to render hearts susceptible to ventricular arrhythmias by creating both an arrhythmogenic substrate and trigger. These results identify a novel mechanism linking sarcomeric mutations to susceptibility to ventricular arrhythmias and raise the prospect of a molecular approach to stratifying arrhythmia risk in HCM." @default.
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- W37340968 date "2007-10-16" @default.
- W37340968 modified "2023-10-02" @default.
- W37340968 title "Abstract 1238: Myofilament Calcium Sensitization Creates Arrhythmia Susceptibility in Familial Hypertrophic Cardiomyopathy" @default.
- W37340968 doi "https://doi.org/10.1161/circ.116.suppl_16.ii_252" @default.
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