62 Gender effects on protein expression profiles related to arrhythmic phenotype in murine ventricles modelling catecholaminergic polymorphic ventricular tachycardia. (17th July 2020)

• Record Type: Journal Article
• Authors: Saadeh, Khalil; Achercouk, Zakaria; Fazmin, Ibrahim; Kumar, Nakulan; Salvage, Samantha; Edling, Charlotte; Huang, Christopher; Jeevaratnam, Kamalan
• Is Part Of: Heart. Volume 106(2020)Supplement 2
• Page Start: A48
• Page End: A49
• Publication Date: 2020-07-17
• Subjects: Catecholaminergic polymorphic ventricular tachycardia -- Arrhythmia -- Conduction velocity; Heart -- Diseases -- Treatment -- Periodicals; Cardiology -- Periodicals; 616.12
• DOI: 10.1136/heartjnl-2020-BCS.62
• Languages: English
• ISSNs: 1355-6037

Abstract

Abstract : Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic condition characterized by stress or exercise induced potentially fatal ventricular arrhythmic episodes. It is attributed to mutations in the cardiac ryanodine receptor (RyR2), calsequestrin (Casq2), and calmodulin (CaM) genes. Clinical symptoms and prognosis were reported more severe in male than female patients. Murine hearts carrying RyR2-P2328S showed a pro-arrhythmic phenotype, disrupted Ca2+ homeostasis and decreased myocardial action potential conduction velocities (CV) in an absence of evidence for tissue fibrosis, implicated in arrhythmic trigger and substrate. Methods: The present studies investigated for independent and interacting effects of sex and homozygotic RyR2-P2328S (RyR2S/S) genotype on expression levels in molecular determinants of both Ca2+ homeostasis (CASQ2, FKBP12, NCX1, SERCA2A, and CaV1.2) and CV (NaV1.5, Cx43, phosphorylated-Cx43, and TGF-β1) in murine ventricles. Thus, ventricular tissue samples were lysed, and proteins extracted were used for western blotting. Relative expression levels were measured semi-quantitatively through densitometry. Two-way ANOVA investigated for independent and interacting effects, and Tukey's honestly significant difference post-hoc tests explored significant pairwise comparisons. Results: Findings demonstrated that phosphorylated Cx43, TGF-β1, CASQ2, FKBP12, NCX1, SERCA2A, and CaV1.2 proteins were not affected by sex or RyR2S/S genotype whether independently or in interaction. However, there were significant interacting effects of sex and genotype on NaV1.5, and significant independent and interacting effects of sex and genotype on Cx43 expression. Further post-hoc testing revealed sex-dependent decrease of NaV1.5 protein to be in the WT only and revealed genotype-dependent decrease of Cx43 to be in the females only. Conclusions: This study excluded participation of accompanying alterations in CASQ2, FKBP12, NCX1, SERCA2A, and CaV1.2 expression thereby implicating abnormal RyR2 function alone in the observed pathological elevation of cytosolic Ca2+ levels and arrhythmic phenotype. Furthermore, the present findings do not implicate altered NaV1.5 expression in the development of slowed CV partly contradicting earlier studies that have reported decreased NaV1.5 expression in CPVT hearts. In contrast, the findings implicate contributions of decreased Cx43 expression in slowed CV though only in female and not male RyR2S/S relative to WT hearts, but not of changes in altered phosphorylated Cx43, and TGF-β1 expression leading to fibrotic change. The CV changes could potentially reflect acute actions of the increased cytosolic Ca2+ on NaV1.5 and Cx43. Conflict of Interest: None