Increased myofilament Ca2+-sensitivity and arrhythmia susceptibility

Abstract

Increased myofilament Ca 2+ sensitivity, a common attribute of inherited and acquired cardiomyopathies, is often associated with cardiac arrhythmias. Accumulating evidence supports that increased myofilament Ca 2+ sensitivity is an independent risk factor for arrhythmias, but the underlying molecular mechanism remains unclear. This review focuses on potential mechanisms how myofilament Ca 2+ sensitivity may affect cardiac excitation and leads to the generation of arrhythmias. We discuss in detail the downstream effects of increased myofilament Ca 2+ sensitivity, i.e. altered Ca 2+ buffering/handling, impaired energy metabolism and increased mechanical stretch, and how they may contribute to the proarrhythmic effect.Keywords sudden cardiac death; reentry arrhythmias; conduction velocity; Ca2+ handling; energetic deficit; mechanical stretch Regulation of myofilament Ca 2+ sensitivityIn heart muscle, cyclic interactions between thin (actin) filaments and thick (myosin) filaments result in muscle shortening and force production. Initiation of contraction occurs when Ca 2+ binds to troponin C in the troponin complex on the thin filament [1]. The troponin complex is comprised of troponin C (TnC or the Ca 2+ binding subunit), troponin I (TnI, involved in inhibition of actin-myosin interaction in the absence of Ca 2+ ), and troponin T (TnT which binds the troponin complex to tropomyosin, another thin filament protein) in a 1:1:1 stoichiometric ratio [2]. During diastole when cytosolic Ca 2+ levels are low, tropomyosin is positioned such that actin and myosin cannot interact. Once Ca 2+ binds to TnC, tropomyosin shifts and allows actin and myosin to form strong cross-bridges. The thin and thick filaments slide along each other driven by ATP hydrolysis and the heart contracts. Myofilament activation is directly dependent on the amount of activating Ca 2+ , but is also determined by the Ca 2+ dependence of force production (=myofilament Ca 2+ sensitivity), which can be regulated within certain limits. The Ca 2+ sensitivity of the myofilament is usually determined

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).…”

“…In this system, the Ca 2ϩ sensitivity of ACTC E99K mouse heart muscle was again significantly higher than NTG heart muscle (EC 50 NTG muscle/EC 50 ACTC E99K muscle ϭ 1.30 Ϯ 0.03, p ϭ 0.003, see Fig. 4).…”

“…Most directly, in the absence of compensatory changes in the Ca 2ϩ transient, HCM muscle will be hypercontractile with greater force in systole but also impaired relaxation, which could account for diastolic dysfunction. Increased Ca 2ϩ sensitivity will also affect the modulation of Ca 2ϩ sensitivity by PKA phosphorylation of troponin I (29,47,48) (important in the lusitropic response to ␤-adrenergic stimulation), the lengthdependent modulation of Ca 2ϩ sensitivity (responsible for the Frank-Starling effect) (49) and intracellular Ca 2ϩ homeostasis (50).…”

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 .…”

Restrictive cardiomyopathy: A review of literature on clinical status and meta-analysis of diagnosis and clinical management

“…Elevated myofilament calcium sensitivity has been suggested as an independent risk factor inducing fatal ventricular arrhythmias [59,60]. Mutations causing RCM have been linked with elevated myocardial calcium sensitivity, increasing susceptibility of inherited/familial RCM patients to fatal ventricular arrhythmias [61].…”