Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 300, Issue 1, Pages H279-H287Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00079.2010
Keywords
cardiac myocyte; dynamic clamp; action potential; excitation-contraction coupling
Funding
- National Heart, Lung, and Blood Institute at the National Institutes of Health [HL084539]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R21HL084539] Funding Source: NIH RePORTER
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Dong M, Niklewski PJ, Wang HS. Ionic mechanisms of cellular electrical and mechanical abnormalities in Brugada syndrome. Am J Physiol Heart Circ Physiol 300: H279-H287, 2011. First published October 8, 2010; doi: 10.1152/ajpheart.00079.2010.-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 Ca2+ influx and sarcoplasmic reticulum load, resulting in marked attenuation of myocyte contraction and Ca2+ 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.
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