In vivo adenoviral gene transfer of Kir2.1 shortened the QTc interval by 7.7%, while dominant-negative suppression of Kir2.1 prolonged the QTc interval by 16.7% in guinea pigs.
Does in vivo manipulation of Kir2.1 expression alter inward rectifier current (IK1), action potential duration, and QTc interval in guinea pig ventricular myocytes?
In vivo manipulation of Kir2.1 demonstrates that IK1 is essential for rapid terminal repolarization and maintaining a stable resting membrane potential, providing direct evidence that Kir2 channel suppression causes the long-QT phenotype seen in Andersen syndrome.
p-value: p=<0.005
Kir2.1 subunits, encoded by the KCNJ2 gene, assemble to form tetrameric inward rectifier potassium channels in many cell types, including cardiac myocytes.Thus, Kir2.1 is essential in the generation of the cardiac inward rectifier current (I K1 ).I K1 is considered to contribute significant repolarizing current during the terminal phase of the action potential (AP) and serves as the primary conductance controlling the resting membrane potential (RMP) in ventricular myocytes (1).Near RMP, the ventricular I K1 conductance is much larger than that of any other current, with the exception of the ATP-sensitive potassium current, which is normally not active.It is thus likely that physiological modulation of this current will have a significant effect on excitability.Clinically, I K1 is downregulated in human heart failure (2).Furthermore, mutations in Kir2.1 have been reported to cause Andersen syndrome with accompanying periodic paralysis and QT prolongation with ventricular arrhythmias (3,4).The ventricular arrhythmias presented in Andersen syndrome are predominately complex ventricular ectopy and polymorphic ventricular tachycardia (3, 4).Less frequently, the arrhythmias degenerate into torsades de pointes or ventricular fibrillation (4).The cardiac manifestations exhibited in Andersen syndrome illustrate the important role that I K1 plays in the heart.Unfortunately, lack of I K1 -specific pharmacologic tools, and thus an inability to manipulate I K1 experimentally, have been a significant impediment to further advancements in the study of I K1 in cardiac excitability.These facts prompted us to investigate the role of I K1 by manipulating Kir2.1 expression using gene transfer.We previously described the effect of extreme I K1 suppression to liberate endogenous pacemaker activity in the ventricle (5).In this study, we sought to clarify more broadly the roles of I K1 in ventricular repolarization and in maintaining a polarized diastolic resting potential.We pursued a quantitative approach using in vivo adenoviral gene transfer to achieve I K1 enhancement and suppression.For the former, we overexpressed Kir2.1; for the latter, we used a Kir2.1-AAAdominantnegative construct to suppress the endogenous I K1 .
Miake et al. (Thu,) conducted a other in Normal cardiac electrophysiology (Andersen syndrome model). Kir2.1 overexpression and dominant-negative suppression (Kir2.1AAA) vs. GFP control group (AdEGI) or baseline was evaluated on Heart rate-corrected QT interval (QTc) at 72 hours (p=<0.005). In vivo adenoviral gene transfer of Kir2.1 shortened the QTc interval by 7.7%, while dominant-negative suppression of Kir2.1 prolonged the QTc interval by 16.7% in guinea pigs.