Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice

Abstract

In human cardiomyopathy, anatomical abnormalities such as hypertrophy and fibrosis contribute to the risk of ventricular arrhythmias and sudden death. Here we have shown that increased myofilament Ca 2+ sensitivity, also a common feature in both inherited and acquired human cardiomyopathies, created arrhythmia susceptibility in mice, even in the absence of anatomical abnormalities. In mice expressing troponin T mutants that cause hypertrophic cardiomyopathy in humans, the risk of developing ventricular tachycardia was directly proportional to the degree of Ca 2+ sensitization caused by the troponin T mutation. Arrhythmia susceptibility was reproduced with the Ca 2+ -sensitizing agent EMD 57033 and prevented by myofilament Ca 2+ desensitization with blebbistatin. Ca 2+ sensitization markedly changed the shape of ventricular action potentials, resulting in shorter effective refractory periods, greater beat-to-beat variability of action potential durations, and increased dispersion of ventricular conduction velocities at fast heart rates. Together these effects created an arrhythmogenic substrate. Thus, myofilament Ca 2+ sensitization represents a heretofore unrecognized arrhythmia mechanism. The protective effect of blebbistatin provides what we believe to be the first direct evidence that reduction of Ca 2+ sensitivity in myofilaments is antiarrhythmic and might be beneficial to individuals with hypertrophic cardiomyopathy.

Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse

“…In troponin T mutant transgenic mice with increased myofibrillar Ca 2ϩ sensitivity, the shape of the ventricular action potentials was changed compared with nontransgenic controls, resulting in shorter effective refractory periods, greater beat-to-beat variability of APD, and increased dispersion of ventricular conduction velocities at high heart rates. It was proposed that these changes created an arrhythmogenic substrate (50,51). This is compatible with our finding that early mortality in ACTC E99K mice is twice as frequent in females than males because it is known that female mice have an inherently longer APD that could make the mutation-related alterations in APD worse; moreover, the age of early death corresponds to puberty where the APD lengths of males and females diverge in humans (52,53).…”

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

“…Ca 2+ sensitization causes susceptibility to arrhythmias without remodelling, that is, without fibrosis or hypertrophy 81 . In mouse papillary muscles, myofibril Ca 2+ sensitivity changes the shape of ventricular action potentials, induces greater beat-to-beat variability in action potential durations, and increases dispersion of conduction velocities at fast heart rates, providing an arrhythmogenic substrate 82 . This enhanced arrhythmogenicity was blocked by blebbistatin, a myosin inhibitor that selectively reduces Ca 2+ sensitivity.…”

“…Although its capacity to increase exercise oxygen consumption through a lusitropic effect is the primary end point, an important secondary end point is the effect of this drug on ventricular arrhythmias assessed using a 30-day monitor 82 .…”

Generation and Functional Characterization of Knock-in Mice Harboring the Cardiac Troponin I-R21C Mutation Associated with Hypertrophic Cardiomyopathy

“…The hearts were excised, and the left ventricles were dissected. Cardiac muscle fibers were prepared and mounted following a standard laboratory procedure (32).…”