Pathogenesis of arrhythmias in a model of CKD

J Am Soc Nephrol. 2014 Dec;25(12):2812-21. doi: 10.1681/ASN.2013121343. Epub 2014 May 22.

Abstract

Patients with CKD have an increased risk of cardiovascular mortality from arrhythmias and sudden cardiac death. We used a rat model of CKD (Cy/+) to study potential mechanisms of increased ventricular arrhythmias. Rats with CKD showed normal ejection fraction but hypertrophic myocardium. Premature ventricular complexes occurred more frequently in CKD rats than normal rats (42% versus 11%, P=0.18). By optical mapping techniques, action potential duration (APD) at 80% of repolarization was longer in CKD rats (78±4ms) than normal rats (63±3 ms, P<0.05) at a 200-ms pacing cycle length. Calcium transient (CaT) duration was comparable. Pacing cycle length thresholds to induce CaT alternans or APD alternans were longer in CKD rats than normal rats (100±7 versus 80±3 ms and 93±6 versus 76±4 ms for CaT and APD alternans, respectively, P<0.05), suggesting increased vulnerability to ventricular arrhythmia. Ventricular fibrillation was induced in 9 of 12 CKD rats and 2 of 9 normal rats (P<0.05); early afterdepolarization occurred in two CKD rats but not normal rats. The mRNA levels of TGF-β, microRNA-21, and sodium calcium-exchanger type 1 were upregulated, whereas the levels of microRNA-29, L-type calcium channel, sarco/endoplasmic reticulum calcium-ATPase type 2a, Kv1.4, and Kv4.3 were downregulated in CKD rats. Cardiac fibrosis was mild and not different between groups. We conclude that cardiac ion channel and calcium handling are abnormal in CKD rats, leading to increased vulnerability to early afterdepolarization, triggered activity, and ventricular arrhythmias.

Keywords: calcium; cardiovascular; fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Arrhythmias, Cardiac / physiopathology*
  • Calcium / metabolism
  • Calcium Signaling
  • Disease Models, Animal
  • Echocardiography
  • Electrophysiology
  • Fibrosis / pathology
  • Gene Expression Regulation*
  • Heart Rate
  • Male
  • MicroRNAs / metabolism
  • Myocardium / pathology
  • RNA, Messenger / metabolism
  • Rats
  • Renal Insufficiency, Chronic / physiopathology*
  • Transforming Growth Factor beta / metabolism
  • Ventricular Fibrillation / pathology

Substances

  • MIRN29 microRNA, rat
  • MicroRNAs
  • RNA, Messenger
  • Transforming Growth Factor beta
  • mirn21 microRNA, rat
  • Calcium