Ventricular arrhythmias in mouse models of diabetic kidney disease

Kenneth R Laurita,Robert Gaivin,Ji-Dong Fu,Vincent Li,Shenaz Khan,Adrienne T Dennis,Tracy Mcmahon,Hima Sapa,Jeffrey R Schelling

doi:10.1038/s41598-021-99891-9

Abstract

Chronic kidney disease (CKD) affects more than 20 million people in the US, and it is associated with a significantly increased risk of sudden cardiac death (SCD). Despite the significance, the mechanistic relationship between SCD and CKD is not clear and there are few effective therapies. Using optical mapping techniques, we tested the hypothesis that mouse models of progressive diabetic kidney disease (DKD) exhibit enhanced ventricular arrhythmia incidence and underlying arrhythmia substrates. Compared to wild-type mice, both Leprdb/db eNOS−/− (2KO) and high fat diet plus low dose streptozotocin (HFD + STZ) mouse models of DKD experienced sudden death and greater arrhythmia inducibility, which was more common with isoproterenol than programmed electrical stimulation. 2KO mice demonstrated slowed conduction velocity, prolonged action potential duration (APD), and myocardial fibrosis; both 2KO and HFD + STZ mice exhibited arrhythmias and calcium dysregulation with isoproterenol challenge. Finally, circulating concentrations of the uremic toxin asymmetric dimethylarginine (ADMA) were elevated in 2KO mice. Incubation of human cardiac myocytes with ADMA prolonged APD, as also observed in 2KO mice hearts ex vivo. The present study elucidates an arrhythmia-associated mechanism of sudden death associated with DKD, which may lead to more effective treatments in the vulnerable DKD patient population.

Highlights

Chronic kidney disease (CKD) affects more than 20 million people in the US, and it is associated with a significantly increased risk of sudden cardiac death (SCD)
We previously demonstrated that glomerular filtration rate (GFR) values were reduced by 56% in 2KO and 36% in high fat diet (HFD) + STZ m ice[19], which suggests that end stage kidney disease is not the cause of death
SCD due to VT is a major cause of mortality in CKD and end stage renal disease (ESRD), and the electrophysiologic mechanisms may be unique in these patient populations

Summary

Introduction

Chronic kidney disease (CKD) affects more than 20 million people in the US, and it is associated with a significantly increased risk of sudden cardiac death (SCD). CKD and ESRD are established risks for SCD, most clinical cardiology trials exclude patients with estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m210 It is unclear whether findings from landmark studies are applicable to this vulnerable population. Meta-analyses that have addressed ICD prophylaxis of SCD in CKD patients are conflicting[11,12], and the only randomized trial to evaluate ICD effectiveness in ESRD demonstrated no b enefit[7] These findings raise important questions about whether the pathophysiology of SCD is unique in the context of CKD, and whether circulating factors, which are not efficiently cleared by diseased kidneys, may be toxic to the heart. Despite the validated DKD phenotype in Leprdb/db eNOS−/− (2KO) mice, electrophysiological and arrhythmia characterization has never been evaluated in this model

Methods

Results

Conclusion