Novel insights in the pathomechanism of Brugada syndrome and fever‐related type 1 ECG changes in a preclinical study using human‐induced pluripotent stem cell‐derived cardiomyocytes

Abstract

Background Brugada syndrome (BrS) is causing sudden cardiac death (SCD) mainly at young age. Studying the underlying mechanisms associated with BrS type I electrocardiogram (ECG) changes in the presence of fever and roles of autophagy for BrS remains lacking. Objectives We sought to study the pathogenic role of an SCN5A gene variant for BrS with fever‐induced type 1 ECG phenotype. In addition, we studied the role of inflammation and autophagy in the pathomechanism of BrS. Methods Human‐induced pluripotent stem cell (hiPSC) lines from a BrS patient harboring a pathogenic variant (c.3148G>A/p. Ala1050Thr) in SCN5A and two healthy donors (non‐BrS) and a CRISPR/Cas9 site‐corrected cell line (BrS‐corr) were differentiated into cardiomyocytes (hiPSC‐CMs) for the study. Results Reductions of Na v 1.5 expression, peak sodium channel current (I Na ) and upstroke velocity (V max ) of action potentials with an increase in arrhythmic events were detected in BrS compared to non‐BrS and BrS‐corr cells. Increasing the cell culture temperature from 37 to 40°C (fever‐like state) exacerbated the phenotypic changes in BrS cells. The fever‐effects were enhanced by protein kinase A (PKA) inhibitor but reversed by PKA activator. Lipopolysaccharides (LPS) but not increased temperature up to 40°C enhanced the autophagy level in BrS‐hiPSC‐CMs by increasing reactive oxidative species and inhibiting PI3K/AKT signalling, and hence exacerbated the phenotypic changes. LPS enhanced high temperature‐related effect on peak I Na shown in BrS hiPSC‐CMs. Effects of LPS and high temperature were not detected in non‐BrS cells. Conclusions The study demonstrated that the SCN5A variant (c.3148G>A/p.Ala1050Thr) caused loss‐of‐function of sodium channels and increased the channel sensitivity to high temperature and LPS challenge in hiPSC‐CMs from a BrS cell line with this variant but not in two non‐BrS hiPSC‐CM lines. The results suggest that LPS may exacerbate BrS phenotype via enhancing autophagy, whereas fever may exacerbate BrS phenotype via inhibiting PKA‐signalling in BrS cardiomyocytes with but probably not limited to this variant.

Can Hyperthermia Unveil Brugada Pattern?

“…Recent literature supports a polygenic mode of inheritance with common and rare genetic variants to exhibit the BrS phenotype [ 4 ]. Premature inactivation/blockade of the Na v 1.5 sodium channel at higher temperatures is associated with a high risk of ST-segment elevation and an increased risk of VF and SCD [ 9 , 10 ]. In patients with BrS, cardiac structural changes involving the right ventricular outflow tract (RVOT) are also noted [ 1 ].…”

“…Certain environmental factors that can influence the type 1 EKG phenotype include temperature, medications (sodium channel blockers (SCB)), electrolyte disturbances (hypokalemia, hyperkalemia, and metabolic acidosis), infections, and illicit drug use like cocaine [ 7 , 9 , 12 ]. In particular, hyperthermia can trigger VF and cause cardiac arrest in patients with a diagnosis of BrS; it can also induce a Brugada type 1 EKG pattern in patients without a prior diagnosis of BrS [ 13 ].…”

Noncoding RNAs and Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Cardiac Arrhythmic Brugada Syndrome

“…They reported increased channel sensitivity to high temperature and lipopolysaccharide challenge in hiPSC-CMs from a BrS cell line with this variant but not in two non-BrS hiPSC-CM lines. They also suggested that lipopolysaccharides may exacerbate the BrS phenotype by enhancing autophagy, whereas fever may exacerbate the BrS phenotype by inhibiting PKA signaling in BrS cardiomyocytes [149]. SCN5A-1795insD leads to an overlap syndrome, in which patients present with both features of BrS and cardiac conduction disease (decreased I Na ) and long QT syndrome type 3 (increased late I Na ).…”