Deeksha Sarda

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%^[3]. 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^[4]. This results in functionally-divergent behavior which triggers arrhythmia and structural cardiac remodeling^[4]. 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^[4]. 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^[4]. 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^[5]. 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^[6]. 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^[6]. 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^[6].

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.

Works Cited:

1. Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 12th ed. Philadelphia, PA: Elsevier; 2018.
2. Lilly LS. Pathophysiology of Heart Disease. 7th ed. Philadelphia, PA: Wolters Kluwer; 2020.
3. American Heart Association. CVD: A Costly Burden for America – Projections Through 2035. Dallas, TX: American Heart Association; 2017.
4. Alvarado FJ, Bos JM, Yuchi Z, et al. Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2. JCI Insight. 2019;5(7):e126544. Published 2019 Mar 5. doi:10.1172/jci.insight.126544
5. Søndergaard MT, Liu Y, Guo W, et al. Role of cardiac ryanodine receptor calmodulin-binding domains in mediating the action of arrhythmogenic calmodulin N-domain mutation N54I. FEBS J. 2020;287(11):2256-2280. doi:10.1111/febs.15147
6. Stevens TL, Manring HR, Wallace MJ, et al. Humanized Dsp ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes. Cells. 2022;11(19):3049. Published 2022 Sep 29. doi:10.3390/cells11193049