Impaired Right Ventricular Calcium Cycling Is an Early Risk Factor in R14del-Phospholamban Arrhythmias.

Kobra Haghighi,Despina Sanoudou,Fadi G Akar,George Gardner,Phillip Bidwell,Pieter A Doevendans,Roger J Hajjar,Jianyong Ma,Elizabeth Vafiadaki,Deeptankar Demazumder,Mohit Kumar,Francesca Stillitano,Sakthivel Sadayappan,Michael Tranter,Jack Rubinstein,Evangelia G Kranias,Demetrios A Arvanitis,Rutger R Van De Leur ,Lisa C Green ,Sheryl E Koch ,Jeffrey S Crocker ,Hong Sheng Wang

doi:10.3390/jpm11060502

Abstract

The inherited mutation (R14del) in the calcium regulatory protein phospholamban (PLN) is linked to malignant ventricular arrhythmia with poor prognosis starting at adolescence. However, the underlying early mechanisms that may serve as prognostic factors remain elusive. This study generated humanized mice in which the endogenous gene was replaced with either human wild type or R14del-PLN and addressed the early molecular and cellular pathogenic mechanisms. R14del-PLN mice exhibited stress-induced impairment of atrioventricular conduction, and prolongation of both ventricular activation and repolarization times in association with ventricular tachyarrhythmia, originating from the right ventricle (RV). Most of these distinct electrocardiographic features were remarkably similar to those in R14del-PLN patients. Studies in isolated cardiomyocytes revealed RV-specific calcium defects, including prolonged action potential duration, depressed calcium kinetics and contractile parameters, and elevated diastolic Ca-levels. Ca-sparks were also higher although SR Ca-load was reduced. Accordingly, stress conditions induced after contractions, and inclusion of the CaMKII inhibitor KN93 reversed this proarrhythmic parameter. Compensatory responses included altered expression of key genes associated with Ca-cycling. These data suggest that R14del-PLN cardiomyopathy originates with RV-specific impairment of Ca-cycling and point to the urgent need to improve risk stratification in asymptomatic carriers to prevent fatal arrhythmias and delay cardiomyopathy onset.

Highlights

Arrhythmogenic cardiomyopathy (ACM) is a rare disease with a prevalence of about1:1000 to 1:5000
The most prominent ones were thrombospondin-1 (Thbs1), which is a Ca-binding protein that may control ER stress; several heat shock proteins (Hspa1a, Hspa1b, Dnaja1 and Dnajb1), which act as molecular chaperones involved in protein quality control and correct folding; and glutathione specific gamma-glutamylcyclotransferase 1 (Chac1), which is a regulator of the unfolded protein response (UPR) pathway, downstream of Atf3
Since alterations in Ca-cycling may affect cellular pathways involved in disease progression, we examined the expression of ER stress and UPR associated genes that may impact remodeling at an early stage

Summary

Introduction

Arrhythmogenic cardiomyopathy (ACM) is a rare disease with a prevalence of about1:1000 to 1:5000. Characteristics include predisposition to ventricular arrhythmias even in the absence of overt functional or structural abnormalities. ACM is mainly a genetically linked disease and a key etiology of sudden cardiac death in young carriers, usually linked to exercise or adrenergic stimulation [2]. ACM is mainly associated with mutations in desmosomal genes, it is becoming increasingly apparent that non-desmosomal proteins may lead to similar clinical phenotypes [1]. A mutation in PLN, entailing deletion of Arg-14 (R14del), a highly conserved basic amino acid in the coding region, has been receiving interest recently as carriers develop abnormal characteristic electrocardiogram (ECG) with an increased risk for malignant ventricular arrhythmias at an early age [3,5]. The carriers have prompted the formation of the PLN Foundation [8]

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