Pathogenesis of arrhythmias in a model of CKD.
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.
Krannert Institute of Cardiology and Division of Cardiology.
Chia-Hsiang
CH
Hsueh
Division of Nephrology, Department of Medicine, and.
Neal X
NX
Chen
Krannert Institute of Cardiology and Division of Cardiology.
Shien-Fong
SF
Lin
Krannert Institute of Cardiology and Division of Cardiology.
Peng-Sheng
PS
Chen
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana;
Vincent H
VH
Gattone
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana;
Matthew R
MR
Allen
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; and.
Michael C
MC
Fishbein
Division of Nephrology, Department of Medicine, and Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana; Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana smoe@iu.edu.
Sharon M
SM
Moe
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D004195:Disease Models, Animal; D004452:Echocardiography; D004594:Electrophysiology; D005355:Fibrosis / Q000473:pathology; D005786:Gene Expression Regulation; D006339:Heart Rate; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000473:pathology
C526366:MIRN29 microRNA, rat; D035683:MicroRNAs; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C546082:mirn21 microRNA, rat; D002118:Calcium
calcium; cardiovascular; fibrosis