Targeting Mechanisms Implicated in Irregular Calcium Handling as a Root-Cause Intervention for Ventricular Arrhythmias
Background: Ventricular arrhythmias include ventricular fibrillation (VF) and ventricular tachycardia (VT) and cause up to 80% of all cases of sudden cardiac death in the United States. VT describes a two-year mortality reported to be as high as 30%. In studying molecular mechanisms for arrhythmogenic phenotypes, there is a crucial role of Ca2+ in regulating cardiac contractility. Abnormalities in Ca2+ handling lead to increased and prolonged Ca2+ transients which cause arrhythmias including VT, and various novel mechanisms are responsible for the irregular Ca2+ handling causing this arrhythmia.
Objectives: This review explores the underlying mechanisms of abnormal calcium handling that result in ventricular arrhythmias, investigating their potential as treatment targets for this condition.
Search Methods: Online searches were performed within the PubMed database from 2018 to 2023 using the keywords “ventricular arrhythmias”, “calcium handling”, “genetic arrhythmias”, and “cardiac mechanisms” to identify relevant literature.
Results: The RyR2-P1124L mutation induces significant conformational changes in the SPRY2 domain of a calcium release channel, ryanodine receptor 2, RyR2. This results in functionally-divergent behavior which triggers arrhythmia and structural cardiac remodeling. The mutation results in a cytosolic Ca2+ activation loss of function and a luminal Ca2+ activation gain of function. This is accompanied by the overexpression of calmodulin (CaM) which disinhibits RyR2, causing an increase in cell voltage and triggering a higher frequency of action potentials, leading to VT. In animal models, P1124L mice showed a nonsignificant tendency to develop more premature ventricular beats than the wildtype, which coalesced into significantly more arrhythmogenic episodes, including bidirectional ventricular tachycardia (BDVT) in homozygous mice. The increase in sustained arrhythmias and BDVT was not statistically significant for heterozygous mice. Additionally, there exists a single N-domain mutation, N54I, of CaM, which results in a diminished inhibition of RyR2, leading to increased RyR2 opening and subsequent Ca2+ release from the sarcoplasmic reticulum, triggering a downstream cascade that ultimately causes catecholaminergic polymorphic VT. There is a methodology where a CRISPR/Cas9 system guided by single-stranded oligodeoxynucleotides was used to introduce the R464G variant into the endogenous desmoplakin (DSP) of C57BL/6J mice. R464G variants have been shown to affect the localization and stability of DSP, leading to abnormal desmosomal structure and function and a reduction of desmosomal proteins at the intercalated discs. In animal models, R451G mice do not display spontaneous arrhythmias at baseline, but do show trends toward a baseline prolonged corrected QT intervals and prolonged T-peak to T-end, indicating potential defects in repolarization more likely to present with VT. These mice display significantly higher rates of prolonged and severe arrhythmogenic events due to catecholaminergic stimulation, including VT and bigeminy when compared to the wildtype.
Conclusion: There are many mechanisms that contribute to an arrhythmogenic phenotype, including VT; as VT is a major constituent of sudden cardiac death, understanding and enhancing its intervention is imperative. The literature concludes that the novel molecular mechanisms RyR2P1124L, CaMN54I, and DSPR464G, can be directly targeted to mediate the abnormal Ca2+ handling occurring in VT.
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