Adenine-induced chronic kidney disease in mice led to significant QT prolongation, bradycardia, and action potential duration prolongation, with female sex acting as a protective factor.
Does chronic kidney disease induce proarrhythmic cardiac remodeling in murine models?
Chronic kidney disease induces proarrhythmic cardiac remodeling via dysregulation of cellular stress response proteins, highlighting potential novel targets for pharmacologic intervention.
BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk of developing cardiac arrhythmogenesis and sudden cardiac death; however, the basis for this association is incompletely known. METHODS: Here, using murine models of CKD, we examined interactions between kidney disease progression and structural, electrophysiological, and molecular cardiac remodeling. RESULTS: C57BL/6 mice with adenine supplemented in their diet developed progressive CKD. Electrocardiographically, CKD mice developed significant QT prolongation and episodes of bradycardia. Optical mapping of isolated-perfused hearts using voltage-sensitive dyes revealed significant prolongation of action potential duration with no change in epicardial conduction velocity. Patch-clamp studies of isolated ventricular cardiomyocytes revealed changes in sodium and potassium currents consistent with action potential duration prolongation. Global transcriptional profiling identified dysregulated expression of cellular stress response proteins RBM3 (RNA-binding motif protein 3) and CIRP (cold-inducible RNA-binding protein) that may underlay the ion channel remodeling. Unexpectedly, we found that female sex is a protective factor in the progression of CKD and its cardiac sequelae. CONCLUSIONS: Our data provide novel insights into the association between CKD and pathologic proarrhythmic cardiac remodeling. Cardiac cellular stress response pathways represent potential targets for pharmacologic intervention for CKD-induced heart rhythm disorders.
King et al. (Sun,) conducted a other in Chronic kidney disease. Adenine-supplemented diet (CKD model) was evaluated on Cardiac structural, electrophysiological, and molecular remodeling. Adenine-induced chronic kidney disease in mice led to significant QT prolongation, bradycardia, and action potential duration prolongation, with female sex acting as a protective factor.
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