Normal interventricular differences in tissue architecture underlie right ventricular susceptibility to conduction abnormalities in a mouse model of Brugada syndrome

Abstract

AimsLoss-of-function of the cardiac sodium channel NaV1.5 is a common feature of Brugada syndrome. Arrhythmias arise preferentially from the right ventricle (RV) despite equivalent NaV1.5 downregulation in the left ventricle (LV). The reasons for increased RV sensitivity to NaV1.5 loss-of-function mutations remain unclear. Because ventricular electrical activation occurs predominantly in the transmural axis, we compare RV and LV transmural electrophysiology to determine the underlying cause of the asymmetrical conduction abnormalities in Scn5a haploinsufficient mice (Scn5a+/−).Methods and resultsOptical mapping and two-photon microscopy in isolated-perfused mouse hearts demonstrated equivalent depression of transmural conduction velocity (CV) in the LV and RV of Scn5a+/− vs. wild-type littermates. Only RV transmural conduction was further impaired when challenged with increased pacing frequencies. Epicardial dispersion of activation and beat-to-beat variation in activation time were increased only in the RV of Scn5a+/− hearts. Analysis of confocal and histological images revealed larger intramural clefts between cardiomyocyte layers in the RV vs. LV, independent of genotype. Acute sodium current inhibition in wild type hearts using tetrodotoxin reproduced beat-to-beat activation variability and frequency-dependent CV slowing in the RV only, with the LV unaffected. The influence of clefts on conduction was examined using a two-dimensional monodomain computational model. When peak sodium channel conductance was reduced to 50% of normal the presence of clefts between cardiomyocyte layers reproduced the activation variability and conduction phenotype observed experimentally.ConclusionsNormal structural heterogeneities present in the RV are responsible for increased vulnerability to conduction slowing in the presence of reduced sodium channel function. Heterogeneous conduction slowing seen in the RV will predispose to functional block and the initiation of re-entrant ventricular arrhythmias.

Interventricular differences in sodium current and its potential role in Brugada syndrome

“…The authors suggested that normal structural heterogeneities present in the RV are responsible for increased vulnerability to conduction slowing in the presence of reduced sodium channel function (Kelly et al. ). Alternatively, other studies have shown lower Na + channel expression in the RVOT compared to the RV and have implicated the RVOT as the main origin of arrhythmias in BrS (Boukens et al.…”

Mechanisms of Arrhythmias in the Brugada Syndrome

“…Using histology and two-photon microscopy, the RV wall of the mouse heart was previously found to be occupied by a higher number of non-vascular clefts, also of a bigger size, compared with the mouse LV wall [ 32 ]. This difference in tissue architecture was not accompanied by a significant difference in fibrosis levels [ 32 ].…”

“…Using histology and two-photon microscopy, the RV wall of the mouse heart was previously found to be occupied by a higher number of non-vascular clefts, also of a bigger size, compared with the mouse LV wall [ 32 ]. This difference in tissue architecture was not accompanied by a significant difference in fibrosis levels [ 32 ]. Although the number and size of intramural clefts may affect the normal pathway of conduction in the RV and thereby cause a delay in transmural activation or conduction block, several key questions remain unanswered.…”

Calcium in Brugada Syndrome: Questions for Future Research

“…Indeed, a murine heterozygous SCN5A+/− model was generated for BrS in vivo studies ( Papadatos et al, 2002 ). This model has been used by several groups to mimic BrS, demonstrating how the SCN5A haploinsufficiency was responsible for the onset of a complex range of phenotypes, including a 50% reduction of sodium conductance, a delayed intramyocardial conduction, a sinus node dysfunction, and ventricular arrhythmogenesis, which are hallmarks of BrS patients ( Zhang et al, 2014 ; Tse et al, 2017 ; Kelly et al, 2018 ). However, caution must be made when translating the results of action potential studies in murine models to the situation in humans, as many differences exist between the species ( Milani-Nejad and Janssen, 2014 ).…”