Augmented Connexin 43 Expression in an Arrhythmogenic Rat Model of Heart Failure with Preserved Ejection Fraction

Abstract

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterised by near-normal systolic function coincident with diastolic dysfunction. While the extent of hypertrophy is a key diagnostic indicator in HFpEF, the underlying cellular aetiology of this disease is poorly understood. We previously reported a newly derived model of HFpEF: the hypertrophic heart rat (HHR). Exhibiting in vivo diastolic dysfunction with maintained systolic parameters, the HHR was shown to have an increased vulnerability to ventricular arrhythmias. The aim of this study was to assess the cellular mechanisms underlying the arrhythmogenic component of the HHR HFpEF phenotype. Ventricles from adult male HHR and normal heart rate (NHR) were isolated and processed for protein quantification (immunoblotting) and fibrosis (picrosirius red staining). In vivo occurrence of prominent arrhythmic episodes in HHR (but not NHR) was confirmed by externa- lead electrocardiogram, with significant prolongation of mean HHR QRS interval consistent with ventricular abnormality. Total expression of the gap junction protein connexin 43 was increased in HHR (arb units; 1.65 ± 0.31 vs 0.86 ± 0.09, HHR vs NHR, n = 7–9; p < 0.05), with no difference in relative phosphorylation status observed. This was associated with greater total fibrosis in HHR, primarily due to prominent dispersed fibrotic foci. Augmented connexin 43 expression suggests a change in conduction patterns, which together with focal areas of interstitial fibrosis may lead to conduction heterogeneities and arrhythmias. Further studies are required to gain a greater understanding of site-specific connexin 43 phosphorylation and the extent to which this is associated with sarcolemmal laterilisation.