The presence of a shortened ERP within atrial cardiomyocytes is felt to contribute to the development of a substrate capable of supporting multiple-circuit reentry that may EPZ5676 chemical structure predispose to a form of AF reflective of the multiple wavelet hypothesis.20 The importance of KCNQ1 in the pathogenesis of AF has been further strengthened by additional linkage analyses and reports that have identified KCNQ1 mutations in familial AF cases.21-23 It should be noted that 9 of the 16 individuals from the original family possessing the KCNQ1 Ser140Gly had prolonged QT-intervals on 12-lead electrocardiography Inhibitors,research,lifescience,medical that is inconsistent with a gain-of-function

effect, since an increased IKs would be predicted to Inhibitors,research,lifescience,medical result in a shortened QT-interval. The explanation for this discrepancy remains unclear but may be reflective of different electrical properties in the atria and ventricles or may be secondary to an inability to accurately recapitulate the electrical milieu of the heart with in vitro functional models. Since the original landmark discovery, candidate gene Inhibitors,research,lifescience,medical approaches that screened AF cases for mutations within multiple potassium channel genes has led to further insight into the role of three additional potassium channel genes in AF pathogenesis secondary to gain-of-function mutations, namely KCNE2, KCNJ2, and KCNE5.24-26 An identical mutation within KCNE2, which encodes the

β subunit of the rapid component of the delayed rectifier potassium current (IKr), was discovered in 2 of 28 unrelated

Chinese Inhibitors,research,lifescience,medical kindreds with familial AF.24 The probands within both families were found to carry an Arg27Cys mutation that appeared to segregate with affected members from both kindreds and was absent from 462 healthy controls. It should be noted that there were multiple unaffected members in each family who carried the KCNE2 Arg27Cys mutation. Inhibitors,research,lifescience,medical This apparent discrepancy may be reflective of low penetrance or may potentially reflect the possibility that KCNE2 Arg27Cys is a disease-contributing as opposed to a disease-causing variant. oxyclozanide Ensuing functional work on the mutant form of KCNE2 was suggestive of a gain of function that would result in acceleration of cardiomyocyte repolarization due to enhanced IKs. A KCNJ2 gene mutation was identified in a single AF proband following screening of 30 Chinese AF kindreds for mutations within 10 ion channel or channel-binding related genes (KCNQ1, KCNH2, SCN5A, ANK-B, KCNJ2, KCNE1-5).25 KCNJ2 encodes Kir2.1, which is responsible for the cardiac inward rectifier potassium current IK1. This channel mediates a potassium current that contributes to the resting membrane potential of the cell and influences cardiac excitability and repolarization. It is also the causative gene for congenital long QT syndrome type 7, also referred to as Andersen-Tawil Syndrome.