Kortney Dunn

Background: Sudden Cardiac Death (SCD) is caused by gene mutations encoding desmosomal proteins in the heart which can lead to heart palpitations, arrhythmias, and heart failure in young people and athletes.^1,2,3 A leading genetic cause predisposing one to SCD is Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), an inherited autosomal dominant cardiac condition.^1,2,3 This condition is characterized by cardiac structural markers of ARVC revealing a pathological fibrofatty infiltration in the right ventricle causing a thinning of the right ventricular wall.^6,8 Current treatment is targeted towards the mutated desmosomal proteins, such as desmoglein-2 (DSG2) and plakophilin-2 (PKP2), which are responsible for the structural integrity and desmosomal adhesiveness of cardiac cells.^2,5,6,7 Treatments such as RyR2 blockers could allow ARVC patients to exercise without as much concern for sudden cardiac death (SCD) by preventing exercise-induced arrhythmias caused by spontaneous calcium release from faulty PKP2 proteins.

Objective: This narrative review investigates the pathological morphologies and mechanisms through which desmosomal protein mutations in DSG2 and PKP2 proteins led to SCD by ARVC.

Search Methods: A search of the PubMed database was performed for the years 2018-2023 using specific keywords: “Arrhythmogenic Right Ventricular Cardiomyopathy”, “Sudden Cardiac Death”, “Plakophilin-2 mutations”, “Desmoglein-2 mutations”.

Results: Studies demonstrated that abnormal incorporation of uncleaved mutant proDSG2 during cellular stress leads to weakened desmosomal adhesiveness.² Furthermore, mutations in the DSG2 propeptide cleavage-site prevented propeptide cleavage which led to decreased interactions between N-terminal extracellular 1 domains and faulty cadherin regulation of DSG2.² Whole genome sequencing investigating blood samples of 2 different families with ARVC showed that the more severe phenotype associated with ARVC involved the compound heterozygous mutations of DSG2 F531C and splicing mutation (217-1G>T) or intronic mutation (524-3C>G).⁵ Both mutations impacted the splicing function and revealed a highly genetic contribution of ARVC pathogenesis suggesting that mutations in DSG2 F531C are the main reason for ARVC. ^2,5 A study analyzed biopsy samples from the right ventricle of ARVC patients with PKP2 mutations and it was shown that deletion of the PKP2 causes a decrease in nuclear envelope integrity, leading to DNA damage and an excessive oxidant production, damaging myocytes.⁴ Another study demonstrated how PKP2 deficient hearts can undergo life-threatening arrhythmias triggered by exercise.³ On a molecular level, an elevated Ca²⁺ spark frequency resulted in irregular calcium release.³ These calcium overloads produce proarrhythmic conditions which result in characteristic arrhythmias seen in ARVC, showing how spontaneous calcium release from defective PKP2 proteins to be a significant mechanism of ARVC.³ Furthermore, PKP2 deficiency leading to calcium dysregulation resulting in proarrhythmogenic effect can be helped through an RyR2 blocker, which would block spontaneous calcium release.³

Conclusions: The highly genetic component of ARVC provides a foundation for future treatment studies targeted towards the DSG2 protein.^2,5 Additionally, drugs targeted towards lowering DNA damage and oxidant production in PKP2 mutations could be an avenue for treating ARVC.⁴ Future studies need to be conducted regarding RyR2 blockers as this would be a significant advancement in ARVC therapy by lowering SCD in young individuals and athletes and allow for them to engage in exercise.^3,4

Works cited:

1. Delgado-Vega AM, Kommata V, Svennblad B, Wisten A, Hagström E, Stattin EL. Family History and Warning Symptoms Precede Sudden Cardiac Death in Arrhythmogenic Right Ventricular Cardiomyopathy (from a Nationwide Study in Sweden). Am J Cardiol. 2022;178:124-130. doi:10.1016/j.amjcard.2022.05.015
2. Vite A, Gandjbakhch E, Hery T, et al. Desmoglein-2 mutations in propeptide cleavage-site causes arrhythmogenic right ventricular cardiomyopathy/dysplasia by impairing extracellular 1-dependent desmosomal interactions upon cellular stress. Europace. 2020;22(2):320-329. doi:10.1093/europace/euz329
3. van Opbergen CJM, Bagwan N, Maurya SR, et al. Exercise Causes Arrhythmogenic Remodeling of Intracellular Calcium Dynamics in Plakophilin-2-Deficient Hearts. Circulation. 2022;145(19):1480-1496. doi:10.1161/CIRCULATIONAHA.121.057757
4. Pérez-Hernández M, van Opbergen CJM, Bagwan N, et al. Loss of Nuclear Envelope Integrity and Increased Oxidant Production Cause DNA Damage in Adult Hearts Deficient in PKP2: A Molecular Substrate of ARVC. Circulation. 2022;146(11):851-867. doi:10.1161/CIRCULATIONAHA.122.060454
5. Lin Y, Huang J, Zhao T, et al. Compound and heterozygous mutations of DSG2 identified by Whole Exome Sequencing in arrhythmogenic right ventricular cardiomyopathy/dysplasia with ventricular tachycardia. J Electrocardiol. 2018;51(5):837-843. doi:10.1016/j.jelectrocard.2018.06.012
6. Finocchiaro G, Westaby J, Sheppard MN, Papadakis M, Sharma S. Sudden Cardiac Death in Young Athletes: JACC State-of-the-Art Review. J Am Coll Cardiol. 2024;83(2):350-370. doi:10.1016/j.jacc.2023.10.032
7. Polovina M, Tschöpe C, Rosano G, et al. Incidence, risk assessment and prevention of sudden cardiac death in cardiomyopathies. Eur J Heart Fail. 2023;25(12):2144-2163. doi:10.1002/ejhf.3076
8. Gandjbakhch E, Redheuil A, Pousset F, Charron P, Frank R. Clinical Diagnosis, Imaging, and Genetics of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: JACC State-of-the-Art Review. J Am Coll Cardiol. 2018;72(7):784-804. doi:10.1016/j.jacc.2018.05.065
9. Delgado-Vega AM, Kommata V, Svennblad B, Wisten A, Hagström E, Stattin EL. Family History and Warning Symptoms Precede Sudden Cardiac Death in Arrhythmogenic Right Ventricular Cardiomyopathy (from a Nationwide Study in Sweden). Am J Cardiol. 2022;178:124-130. doi:10.1016/j.amjcard.2022.05.015