Arrhythmogenic Remodeling in Murine Models of Deoxycorticosterone Acetate-Salt-Induced and 5/6-Subtotal Nephrectomy-Salt-Induced Cardiorenal Disease

Abstract

Background: Renal failure is associated with adverse cardiac remodeling and sudden cardiac death. The mechanism leading to enhanced arrhythmogenicity in the cardiorenal syndrome is unclear. The aim of this study was to characterize electrophysiological and tissue alterations correlated with enhanced arrhythmogenicity in two distinct mouse models of renal failure. Methods: Thirty-week-old 129Sv mice received a high-salt diet and deoxycorticosterone acetate (DOCA) for 8 weeks, followed by an additional period of high-salt diet for 27 weeks (DOCA-salt aged model). Adult CD-1 mice were submitted to 5/6-subtotal nephrectomy (SNx) and treated for 11 weeks with a high-salt diet (SNx-salt adult model). Vulnerability to arrhythmia as well as conduction velocities (CVs) of the hearts were determined ex vivo with epicardial mapping. Subsequently, the hearts were characterized for connexin 43 (Cx43) and fibrosis. Results: DOCA-salt and SNx-salt mice developed renal dysfunction characterized by albuminuria. Heart, lung and kidney weights were increased in DOCA-salt mice. Both DOCA-salt and SNx-salt mice were highly susceptible to ventricular arrhythmias. DOCA-salt mice had a significant decrease in both longitudinal and transversal CV in the left ventricle. Histological analysis revealed a significant reduction in Cx43 expression as well as an increase in interstitial fibrosis in both DOCA-salt and SNx-salt mice. Conclusion: DOCA-salt and SNx-salt treatment induced renal dysfunction, which resulted in structural and electrical cardiac remodeling and enhanced arrhythmogenicity. The reduced Cx43 expression and increased fibrosis levels in these hearts are likely candidates for the formation of the arrhythmogenic substrate.

Refining the Mouse Subtotal Nephrectomy in Male 129S2/SV Mice for Consistent Modeling of Progressive Kidney Disease With Renal Inflammation and Cardiac Dysfunction

“…In our 129S2/SV mice no cardiac fibrosis was detected per se but on the gene expression level Collagen III was increased by 10-weeks post-surgery. Using the CD1 strain of mice, cardiac fibrosis can be induced with the added insult of additional dietary salt (Fontes et al, 2015) which may be required in this model too. In a pilot study in this genetic background, the refined STNx model resulted in significant renal fibrosis and increased pro-fibrotic gene expression in the kidney which matches that previously observed (Ma and Fogo, 2003).…”

Uremia increases QRS duration afterβ-adrenergic stimulation in mice

“…The authors further challenge the NX mice with a high‐salt diet, which increases urine albumin content; however, this does not significantly alter arrhythmia burden (Fontes et al. ).…”

“…Thus, it appears that isolated hearts from mice (Fontes et al. ) or rats (Hsueh et al. ) with CKD are prone to ventricular pacing‐induced arrhythmias, and the proposed mechanisms are diverse and may be influenced by model, strain, and species differences.…”

Uremic toxins in chronic kidney disease highlight a fundamental gap in understanding their detrimental effects on cardiac electrophysiology and arrhythmogenesis

“…Interestingly, mechanistic investigations always indicate a hampered calcium handling, fibrosis formation, and a decreased Cx43 expression as the main potentiators of the pro-arrhythmic paramete rs. [93][94][95][97][98][99]102,103 Perfusion of a single toxin is an alternative method to specifically investigate its effects, which in case of the non-toxin FGF23 revealed to lead to increased arrhythmogenicity, via disturbed calcium handling. 94,104 Unfortunately, the main drawback of these studies is that there are no data available on specific culprits for the electrophysiological changes and the mechanisms behind the effects have rarely been investigated.…”