Pathogenesis of Arrhythmias in a Model of CKD

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 (7864ms) than normal rats (6363 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 (10067 versus 8063 ms and 9366 versus 7664 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-b, 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. CKD affects more than 26 million individuals; 15% of American adults have some degree of CKD. 1 Cardiovascular events account for 40% of deaths in CKD patients. In patients on dialysis, 25% of cardiovascular deaths are caused by sudden cardiac death, a 100-fold rate compared with the general population. 2,3 Although the increased frequency in dialysis patients has often been attributed to electrolyte imbalances induced by the dialysis procedure in patients with underlying cardiac disease, recent data have highlighted the increased risk with CKD in patients not yet on dialysis, indicating that other factors in these patients with CKD may lead to sudden cardiac death. 4 The Multicenter Automatic Defibrillator Implantation Trial-II showed that the risk for sudden cardiac death was 17% higher for every 10 ml/min per 1.73 m 2 decrease in eGFR. 5 The result was comparable even when patients considered low risk for sudden cardiac death were analyzed. 6 The pathogenesis by which CKD predisposes to sudden cardiac death remains unknown. Our rat model of CKD, the Cy/+ rat, accurately represents many of the changes associated with human CKD, including hypertension, left ventricular hypertrophy, and CKD-mineral bone disorder. Furthermore, we have occasionally

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“…It seems therefore that conduction slowing is not a prerequisite for arrhythmias in this model. Triggered activity as an arrhythmia mechanism was shown earlier in a chronic kidney disease rat model [27]. This is well supported by the high-resolution epicardial activation mapping in our study, which did not show evident signs of reentry, making a triggered activity a very likely mechanism for the arrhythmias.…”

Do Implantable Cardioverter Defibrillators Reduce Mortality in Patients With Chronic Kidney Disease at All Stages?

“…At the cellular level, the cardiac sodium channel, the potassium channel, and calcium handling are abnormal in CKD rats, leading to increased vulnerability to early after depolarization and ventricular arrhythmias. 30) Inherited factors are also considered to be a risk factor for SCD among CKD patients. 31) Based on the reasons explained above, we were not surprised to obtain this result in stage 3 CKD patients.…”

Subcutaneous nerve activity and mechanisms of sudden death in a rat model of chronic kidney disease

“…Our previous study 8 found abnormal ion channel function and calcium handling in the CKD rats. These changes may play a role in producing sinus bradycardia and AV block.…”

“…Cardiac ion channel and calcium handling are abnormal in these CKD rats. 8 These abnormalities may increase ventricular arrhythmogenesis and result in SCD. However, the terminal arrhythmia causing SCD remains unclear.…”