Abstract 20396: Chronic Kidney Disease Disrupting Transmural Gradient of Transient Outward Potassium Current via Downregulation of KChIP2 May Promote Susceptibility to Ventricular Tachyarrhythmias
Introduction: Chronic Kidney Disease (CKD) is associated with a higher risk for ventricular tachyarrhythmias and sudden cardiac death. However, the underlying mechanism remains to be elucidated. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and the underlying mechanisms that may increase vulnerability to ventricular arrhythmias in CKD.
Methods and Results: Adult male Sprague-Dawley rats underwent Unx (n=6) or sham (n=6) operations. Eight weeks later, the UNx group had a higher serum blood urea nitrogen (18.83±1.01 vs. 15.33±1.02 mg/dL; P=0.04) level, creatinine (0.37±0.02 vs. 0.28±0.02 mg/dL; P<0.01) level, and electrocardiographic longer QTc (0.060±0.002 vs. 0.037±0.004 sec; P<0.01) interval than the sham group. Patch-clamp study revealed epicardial (EPI)-predominant prolongation of action potential duration (APD) at 50% and 90% repolarization in UNx EPI myocytes compared to sham EPI myocytes (P=0.048 and P=0.008, respectively) with equivalent APD between UNx and sham endocardial (ENDO) myocytes. The differential prolongation of APD was mediated by a significant reduction of transient outward potassium current (Ito) in EPI but not in ENDO myocytes of UNx rats leading to a decreased transmural gradient of Ito compared to sham animals (P=0.023). The reduction of Ito currents in UNx EPI myocytes was secondary to downregulation of KChIP2 with no changes of Kv4.2, Kv4.3, and Kv1.4 protein expression. KChIP2 deficiency was accompanied with a shifting of the voltage dependence of Ito activation to less hyperpolarized potentials and a slower recovery from inactivation. Incubation of plasma electronegative low-density lipoprotein (LDL) (100 μg/mL) from UNx with normal EPI and ENDO myocytes recapitulates the cardiac electrophysiological phenotype of UNx rats.
Conclusions: CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2 in EPI region that may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD.
Author Disclosures: K. Chang: None. A. Lee: None. W. Chen: None. C. Chen: None.
- © 2016 by American Heart Association, Inc.