Increased myofilament Ca2+-sensitivity and arrhythmia susceptibility

Abstract

Increased myofilament Ca(2+) sensitivity is a common attribute of many inherited and acquired cardiomyopathies that are associated with cardiac arrhythmias. Accumulating evidence supports the concept that increased myofilament Ca(2+) sensitivity is an independent risk factor for arrhythmias. This review describes and discusses potential underlying molecular and cellular mechanisms how myofilament Ca(2+) sensitivity affects cardiac excitation and leads to the generation of arrhythmias. Emphasized are downstream effects of increased myofilament Ca(2+) sensitivity: altered Ca(2+) buffering/handling, impaired energy metabolism and increased mechanical stretch, and how they may contribute to arrhythmogenesis.

Fig. 1

The effect of myofilament Ca²⁺ sensitization on myocyte Ca²⁺ handling. Panel (A) shows the effect of three TnT mutations on myofilament Ca²⁺ sensitivity measured in skinned fibers of transgenic mice [78]. Panel (B) shows the effect myofilament Ca²⁺ sensitization on apparent Ca²⁺ buffering. The change in total Ca²⁺ was measured by the Na/Ca exchanger integral (bottom, shaded area) simultaneously with the change in [Ca²⁺]_free (top panel) in voltage clamped fluo-4 loaded myocytes [90, 92]. Note that the peak [Ca²⁺] is lower in TnT-I79N despite a similar change in total Ca²⁺, consistent with increased Ca²⁺ buffering. (C)+(D) Ca²⁺ transients simulated with LabHEART 5.0 [176] containing a newly integrated force response [177]. Ionic current conductances were adjusted to reproduce a typical mouse action potential. The myofilament Ca²⁺ sensitivity curves in (A) were reproduced by changing the TnC Ca²⁺ on/off rates and Ca²⁺ binding cooperativity. Ca²⁺ transients are simulated at 1 Hz (C) and 5 Hz (D) pacing frequency. Note that peak [Ca²⁺] is lower and Ca²⁺ transients are prolonged in Ca²⁺ sensitized mutants, while the diastolic [Ca²⁺] is additionally increased in TnT-I79N at 5 Hz. Panel (C)+(D) were kindly provided by Dr. J. Puglisi, UC Davis.

Fig. 2

Mechanism of arrhythmogenesis caused by myofilament Ca²⁺ sensitization. The cartoon illustrates components likely involved in the signaling pathway from myofilament Ca²⁺ sensitization to sudden cardiac death. On the molecular level increased mechanical stress [166], increased Ca²⁺ buffering (published in abstract form [92]) and/or an energetic deficit (reduced free energy from ATP hydrolysis (ΔG_ATP)) [83] may contribute to the observed cellular changes in Ca²⁺ handling [84] and AP repolarization and effective refractory period (ERP)[78, 84]. On the organ level this results in stress-induced contractile dysfunction [49, 166]and abnormalities in propagation of excitation (increased conduction velocity (CV) dispersion [78]), possibly supported by abnormal cell-to-cell coupling (published in abstract form [178]). Together, these factors contribute to ventricular tachyarrhythmias and sudden death.