Abstract 4362812: Metabolic interventions modulate arrhythmogenic cardiomyopathy phenotype and severity in knock-in mice carrying Tmem43 S358L mutation.

Abstract

Background: The TMEM43 S358L mutation causal for arrhythmogenic cardiomyopathy (ACM), a sex-influenced disease, affects cardiac, small intestine, and metabolic homeostasis in vivo . However, roles of the gut and microbiome in the pathogenesis of ACM remains understudied. Objectives: This study investigated the mechanisms underlying sex-based responses to metabolic interventions in knock-in Tmem43 S358L mice. Methods: Eight-week-old control wildtype (Tmem43 WT ) and mutant (Tmem43 S358L ) mice were divided into groups (N≥5/sex): 1) chow, high- and low-fat diets (CD, HFD and LFD); or 2) receiving either vertical sleeve gastrectomy (VSG) to induce weight loss or SHAM surgery and antibiotics (ABX) or vehicle. Body weight (BW) was monitored daily. Serial EchoMRI, echocardiogram (ECHO), and electrocardiogram (ECG) data were collected at baseline and at 6 weeks post-HFD/LFD and at 12-weeks post-VSG. Serum lipid, cardiac histology, transcriptome, and microbiome analysis were followed. Results: At baseline, mice from all groups displayed normal cardiac function. Frequency of premature atrial contractions (PACs) was higher in Tmem43 S358L vs Tmem43 WT group. Post-HFD, a significant gain in BW was observed in all groups, while body fat (%) and serum LDL decreased in post-VSG mice compared to that in the baseline. Male and female Tmem43 S358L mice on CD, LFD, or post-SHAM demonstrated significant reduction in EF%. Female mice on CD and LFD had significantly higher left ventricular (LV) volumes compared to HFD. ECG tracings revealed a slight increase in PACs in female mutant mice on HFD and LFD. In contrast, Tmem43 S358L mutants (male and female) displayed preserved ejection fraction post-VSG (EF%: 58.3±4.7% vs 54.5±5.5% at baseline) and LV end-systolic volumes, while PACs were decreased in those mutants. There was no difference in ECHO or ECG parameters from baseline to ABX in control or mutant cohorts. There was also no difference between groups in grip-test, confirming that cardiac function changes were not related to skeletal muscle function. Conclusions: Mutant Tmem43 S358L mice demonstrated systolic dysfunction, LV dilation and increase in PACs on CD, LFD, and post-SHAM, resembling ARVC5 in humans. Cardiac function was preserved, and PACs were reduced in mutants on HFD and post-VSG, suggesting beneficial effects of 6-week-HFD and VSG on ACM phenotype in vivo . Currently, we are in a process of identifying associations between cardiac transcriptomes and gut microbiota.