Conduction slowing by the gap junctional uncoupler carbenoxolone

Background: Cellular electrical coupling is essential for normal propagation of the cardiac action potential, whereas reduced electrical coupling is associated with arrhythrmas. Known cellular uncoupling agents have severe side effects on membrane ionic currents. We investigated the effect of carbenoxolone on cellular electrical coupling, membrane ionic currents, and atrial and ventricular conduction. Methods and Results: In isolated rabbit left ventricular and right atrial myocytes, carbenoxolone (50 mumol/l) had no effect on action potential characteristics. Calcium, potassium, and sodium currents remained unchanged. Dual current clamp experiments on poorly coupled cell pairs revealed a 21 +/- 3% decrease in coupling conductance by carbenoxolone (mean +/- S.E.M., n = 4, p <0.05). High-density activation mapping was performed in intact rabbit atrium and ventricle during Langendorff perfusion of the heart. The amplitude of the Laplacian of the electrograms, a measure of coupling current in intact hearts, decreased from 1.45 +/- 0.66 to 0.75 +/- 0.51 muA/mm(3) (mean +/- SD, n = 32, p <0.05) after 15 min of carbenoxolone. Carbenoxolone reversibly decreased longitudinal and transversal conduction velocity from 66 +/- 15 to 49 +/- 16 cm/s and from 50 +/- 14 to 35 +/- 15 cm/s in ventricle, respectively (mean SD, n = 5, both p <0.05). In atrium, longitudinal and transversal conduction, velocity decreased from 80 +/- 29 to 60 +/-16 cm/s and from 49 +/- 10 to 38 +/- 10 cm/s (mean SD, n = 8, both p <0.05). Conclusions: Carbenoxolone-induced uncoupling causes atrial and ventricular conduction slowing without affecting cardiac membrane currents. Activation delay is larger in poorly coupled cells. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved

In silico investigations on functional and haplotype tag SNPs associated with congenital long QT syndromes (LQTSs)

Single-nucleotide polymorphisms (SNPs) play a major role in the understanding of the genetic basis of many complex human diseases. It is still a major challenge to identify the functional SNPs in disease-related genes. In this review, the genetic variation that can alter the expression and the function of the genes, namely KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2, with the potential role for the development of congenital long QT syndrome (LQTS) was analyzed. Of the total of 3,309 SNPs in all five genes, 27 non-synonymous SNPs (nsSNPs) in the coding region and 44 SNPs in the 5′ and 3′ un-translated regions (UTR) were identified as functionally significant. SIFT and PolyPhen programs were used to analyze the nsSNPs and FastSNP; UTR scan programs were used to compute SNPs in the 5′ and 3′ untranslated regions. Of the five selected genes, KCNQ1 has the highest number of 26 haplotype blocks and 6 tag SNPs with a complete linkage disequilibrium value. The gene SCN5A has ten haplotype blocks and four tag SNPs. Both KCNE1 and KCNE2 genes have only one haplotype block and four tag SNPs. Four haplotype blocks and two tag SNPs were obtained for KCNH2 gene. Also, this review reports the copy number variations (CNVs), expressed sequence tags (ESTs) and genome survey sequences (GSS) of the selected genes. These computational methods are in good agreement with experimental works reported earlier concerning LQTS

Cardiac Sodium Channel (Dys)Function and Inherited Arrhythmia Syndromes

Normal cardiac sodium channel function is essential for ensuring excitability of myocardial cells and proper conduction of the electrical impulse within the heart. Cardiac sodium channel dysfunction is associated with an increased risk of arrhythmias and sudden cardiac death. Over the last 20 years, (combined) genetic, electrophysiological, and molecular studies have provided insight into the (dys)function and (dys)regulation of the cardiac sodium channel under physiological circumstances and in the setting of SCN5A mutations identified in patients with inherited arrhythmia syndromes. Although our understanding of these sodium channelopathies has increased substantially, important issues remain incompletely understood. It has become increasingly clear that sodium channel distribution, function, and regulation are more complicated than traditionally assumed. Moreover, recent evidence suggests that the sodium channel may play additional, as of yet unrecognized, roles in cardiomyocyte function, which in turn may ultimately also impact on arrhythmogenesis. In this chapter, an overview is provided of the structure and function of the cardiac sodium channel and the clinical and biophysical characteristics of inherited sodium channel dysfunction. In addition, more recent insights into the electrophysiological and molecular aspects of sodium channel dysregulation and dysfunction in the setting of SCN5A mutations are discussed