Ionic mechanisms of cellular electrical and mechanical abnormalities in Brugada syndrome

Abstract

The Brugada syndrome (BrS) is a right ventricular (RV) arrhythmia that is responsible for up to 12% of sudden cardiac deaths. The aims of our study were to determine the cellular mechanisms of the electrical abnormality in BrS and the potential basis of the RV contractile abnormality observed in the syndrome. Tetrodotoxin was used to reduce cardiac Na(+) current (I(Na)) to mimic a BrS-like setting in canine ventricular myocytes. Moderate reduction (<50%) of I(Na) with tetrodotoxin resulted in all-or-none repolarization in a fraction of RV epicardial myocytes. Dynamic clamp and modeling show that reduction of I(Na) shifts the action potential (AP) duration-transient outward current (I(to)) density curve to the left and has a biphasic effect on AP duration. In the presence of a large I(to), I(Na) reduction either prolongs or collapses the AP, depending on the exact density of I(to). These repolarization changes reduce Ca(2+) influx and sarcoplasmic reticulum load, resulting in marked attenuation of myocyte contraction and Ca(2+) transient in RV epicardial myocytes. We conclude that I(Na) reduction alters repolarization by reducing the threshold for I(to)-induced all-or-none repolarization. These cellular electrical changes suppress myocyte excitation-contraction coupling and contraction and may be a contributing factor to the contractile abnormality of the RV wall in BrS.

The HVCN1 voltage‐gated proton channel contributes to pH regulation in canine ventricular myocytes

“…Wedge-shaped left ventricular free wall was dissected and cannulated via a descending branch of the left circumflex artery. Ventricular myocytes were dissociated by perfusion with a Tyrode solution containing 85 unit/ml collagenase (type II, Worthington Biochemical Corp., Lakewood, NJ, USA) at 37°C, as we have previously described (Dong et al 2011). Isolated myocytes were harvested and stored in a standard Tyrode solution containing 0.1 mM Ca 2+ at room temperature or 4°C, for recordings on the same day or the following day.…”

Brugada Syndrome: New Insights From Cardiac Magnetic Resonance and Electroanatomical Imaging

“…Our experience supports prior experimental studies showing that in BrS the changes in RV mechanics as a consequence of myocyte electrical abnormalities are likely to be subtle and undetectable in small areas of the RV, while in larger areas may be able to suppress myocyte excitation-contraction coupling and contraction in the same areas, thus unmasking consistent contractile abnormalities of the RV wall. 43 Structural RV abnormalities and future directions.…”

Effects of human atrial ionic remodelling by β-blocker therapy on mechanisms of atrial fibrillation: a computer simulation

“…Grandi et al 18 and Workman et al 11 helped show that the major ionic currents implicated in the maintenance of AF include some of those central to the present study. Indeed, the involvement of I K1 and I to changes in arrythmogenesis have also been explored in previous mathematical modelling studies for atria and ventricles 17, 19, 36, 37 . Zhang et al 17 used two human atrial cell models to demonstrate that an increase of I K1 reduces cell APD dramatically.…”