Related Experiment Video
Updated: Oct 16, 2025
Modeling and Evaluation of Murine Diabetic Cardiomyopathy Model
Published on: November 29, 2024
Ventricular arrhythmias in mouse models of diabetic kidney disease
Kenneth R Laurita1,2, Shenaz Khan3, Tracy McMahon3
1Department of Medicine, Case Western Reserve University, MetroHealth Campus, 2500 MetroHealth Drive, R654, Cleveland, OH, 44109, USA. Kenneth.Laurita@case.edu.
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.
Insights
Diabetic kidney disease (DKD) increases sudden cardiac death risk. This study found DKD mouse models show increased arrhythmias and altered cardiac function, linked to elevated uremic toxin levels, offering new therapeutic targets.
Area of Science:
- Cardiovascular Research
- Nephrology
- Translational Medicine
Background:
- Chronic kidney disease (CKD), including diabetic kidney disease (DKD), is a major risk factor for sudden cardiac death (SCD).
- The precise mechanisms linking DKD to SCD remain unclear, hindering the development of effective therapies.
- Understanding these mechanisms is crucial for improving outcomes in the growing DKD patient population.
Purpose of the Study:
- To investigate the relationship between progressive diabetic kidney disease (DKD) and the incidence of ventricular arrhythmias.
- To identify underlying electrophysiological and structural substrates that contribute to arrhythmias in DKD.
- To explore the role of specific uremic toxins in mediating cardiac dysfunction in DKD.
Main Methods:
- Utilized optical mapping techniques in mouse models of DKD (Leprdb/db eNOS-/- and HFD+STZ).
- Assessed arrhythmia inducibility using isoproterenol challenge and programmed electrical stimulation.
- Measured electrophysiological parameters (conduction velocity, action potential duration) and cardiac fibrosis.
- Analyzed circulating levels of the uremic toxin asymmetric dimethylarginine (ADMA) and its effect on human cardiac myocytes.
Main Results:
- DKD mouse models exhibited significantly higher incidence of sudden death and arrhythmia inducibility compared to wild-type controls.
- DKD hearts showed slowed conduction velocity, prolonged action potential duration (APD), and increased myocardial fibrosis.
- Arrhythmias and calcium dysregulation were observed in DKD models upon isoproterenol challenge.
- Elevated ADMA levels in DKD mice correlated with prolonged APD in both ex vivo hearts and human cardiac myocytes.
Conclusions:
- Diabetic kidney disease creates pro-arrhythmic substrates in the heart, increasing the risk of sudden cardiac death.
- The uremic toxin ADMA plays a significant role in mediating cardiac electrical instability in DKD.
- These findings elucidate a key mechanism of SCD in DKD and suggest potential therapeutic strategies targeting ADMA or related pathways.
