Reduced Na ⁺ and higher K ⁺ channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice

Abstract

Brugada syndrome (BrS) is associated with ventricular tachycardia originating particularly in the right ventricle (RV). We explore electrophysiological features predisposing to such arrhythmic tendency and their possible RV localization in a heterozygotic Scn5a+/− murine model. Nav1.5 mRNA and protein expression were lower in Scn5a+/− than wild-type (WT), with a further reduction in the RV compared with the left ventricle (LV). RVs showed higher expression levels of Kv4.2, Kv4.3 and KChIP2 in both Scn5a+/− and WT. Action potential upstroke velocity and maximum Na+ current (INa) density were correspondingly decreased in Scn5a+/−, with a further reduction in the RV. The voltage dependence of inactivation was shifted to more negative values in Scn5a+/−. These findings are predictive of a localized depolarization abnormality leading to slowed conduction. Persistent Na+ current (IpNa) density was decreased in a similar pattern to INa. RV transient outward current (Ito) density was greater than LV in both WT and Scn5a+/−, and had larger time constants of inactivation. These findings were also consistent with the observation that AP durations were smallest in the RV of Scn5a+/−, fulfilling predictions of an increased heterogeneity of repolarization as an additional possible electrophysiological mechanism for arrhythmogenesis in BrS.

Patient-Specific and Genome-Edited Induced Pluripotent Stem Cell–Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Brugada Syndrome

“…We subsequently compared our BrS gene expression profile with published reports of human cardiac tissue gene expression and noted commonalities. We observed a relative reduction in SCN5A gene expression in BrS iPSC-CMs compared to controls, which has been documented in both human and mouse tissue gene expressions studies (31,40). Furthermore, we noted a marked reduction in thlevels of KCND3 , which is congruent with human tissue studies from BrS patients that demonstrated marked down regulation of the Kv4.3 associated gene (31).…”

Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis

“…28,29 Finally, some studies have suggested that I Na might be smaller in RV than LV. 23,35 At the cellular level, APs showed deeper notches, shorter APDs at 50 % and 95 % of repolarisation and less APD prolongation on slowing of the pacing rate in RV than LV, 27,24,29 consistent with the larger I to and I Ks . Similarly, duration of monophasic APs in vivo was shorter in RV than in LV.…”

“…A mouse model with heterozygous knock-out of SCN5A has also suggested that the RV might be particularly sensitive to loss of functional Na + channels, with a larger reduction in I Na in RV compared with LV. 23 Similarly, Veeraraghavan and Poelzing 35 showed that heterogeneity in Na v 1.5 expression in guinea pig may become a significant determinant of conduction heterogeneities under conditions where I Na is functionally reduced. However, this study also highlights that conduction heterogeneities can be further modulated by interventricular differences in other ion channels, including I K1 .…”

“…6 Potential ionic differences between basal LV and RV cellular electrophysiology have been identified at the mRNA, protein and functional levels (see Table 1). In most species and experimental models, the RV myocardium shows a relative overexpression of K v 4.2, K v 4.3 and KChIP2, 23,24 molecular components of I to , as well as greater KCNQ1 expression, 25,26 part of the I Ks macromolecular complex. In agreement, a number of studies observed larger I Ks and I to in RV compared with LV.…”

European Perspectives

“…5 She finally demonstrated the molecular mechanism for these right ventricular changes using reverse transcription polymerase chain reaction, Western blots, and functional ionic current analysis through a specific reduction in right ventricular expression of Na + compared to K + channels in the Scn5a +/-hearts producing both slowed conduction and repolarisation heterogeneity. 6 Dr Martin's prize-winning research was carried out in the Physiological Lab, University of Cambridge, Cambridge, England, where she worked in the group of Professor Christopher Huang, MD, PhD, alongside the group of Andrew Grace, FRCP, PhD, in the Biochemistry Department. She also collaborated with several other centres: Cesare Terracciano, MD, PhD, and his group, Heart Science Centre, Imperial College London, London, on cardiac myocyte isolation and patch-clamp experiments; Professor Ming Lei, DPhil, and his group, Institute of Cardiovascular Sciences, University of Manchester, Manchester, England, on multielectrode mapping experiments; Cristina Rada, PhD, and her group, Medical Research Council Lab of Molecular Biology, Cambridge, on Western blot experiments; and Nicola Brice, PhD, and her group at Takeda Cambridge Limited on reverse transcription polymerase chain reaction experiments.…”