145 - The effects of gastric sleeve surgery induced weight loss in knock-in mutant Tmem43-S358L mice, models of arrhythmogenic cardiomyopathy.

Publication Number: 145.6869

Buyan-Ochir Orgil, University of Tennessee Health Science Center College of Medicine, Memphis, TN, United States; Nathaniel B. Willis, University of Wisconsin-Madison, Madison, WI, United States; Jason N.. Johnson, Le Bonheur Children's Hospital, Memphis, TN, United States; Undral Munkhsaikhan, University of Tennessee Health Science Center College of Medicine, Knoxville, TN, United States; Ning Li, University of Tennessee Health Science Center College of Medicine, Harbin, Heilongjiang, China (People's Republic); Neely Alberson, University of Tennessee Health Science Center College of Medicine, Memphis, TN, United States; Dennis Black, University of Tennessee Health Science Center College of Medicine, Memphis, TN, United States; Jeffrey A. Towbin, Le Bonheur Children’s Hospital, Memphis, TN, United States; joseph F. Pierre, University of Wisconsin-Madison, Madison, WI, United States; Enkhsaikhan Purevjav, University of Tennessee Health Science Center (UTH, Memphis, TN, United States

Background: The gut and microbiome have emerged as therapeutic targets in heart failure, yet their role in the pathogenesis of cardiomyopathy remains understudied. The TMEM43-S358L, a causal mutation of arrhythmogenic cardiomyopathy (ACM) affects cardiac, small intestine, and metabolic homeostasis.

Objective: This study tested whether vertical sleeve gastrectomy (VSG) attenuates cardiac pathology and dysfunction in knock-in Tmem43-S358L mouse models.

Design/Methods: Eight-week-old control (Tmem43WT) and mutant (Tmem43S358L) mice were divided into groups (N=6) receiving either vertical sleeve gastrectomy (VSG) or Sham surgery and antibiotics (ABX) or vehicle. Serial echocardiogram (ECHO), electrocardiogram (ECG), grip, and EchoMRI tests were performed at baseline, during and 12-weeks post-procedure, followed by serum lipid, cardiac transcriptome, and microbiome analysis.

Results: At baseline, mice from all groups displayed normal cardiac function, while the frequency of premature atrial contractions (PACs) per 1000-heartbeats (hb) was higher in Tmem43S358L (1.929±0.905) vs Tmem43WT (0.377±0.077) group. Following VSG, body fat (Fat%) and serum LDL decreased, while lean mass (LM%) was increased in mice from all groups. Running distance significantly increased in Tmem43S358L (274 vs 314 m) compared to Tmem43WT (341 vs 351 m) controls. Post-VSG, Tmem43S358L mutants demonstrated preserved ejection fraction (EF%: 58.3±4.7% vs 54.5±5.5% at baseline) and left ventricular end-systolic volumes. However, Tmem43S358L post-Sham cohort demonstrated cardiac dysfunction (EF%: 45.6±8.4%, P=0.05). Post-VSG, decrease in PACs frequency was recorded in the Tmem43S358L mutants (0.141±0.257/1000 hb) only, while Tmem43WT and Sham cohorts had minimal changes. In contrast, ABX treatment significantly increased Fat% (9.90% to 12.51%), but decreased LM% (87.28% to 83.77%) in Tmem43WT controls, while Tmem43S358L mice had no changes in body composition, suggesting altered microbiota in mutants prior to ABX. 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.

Conclusion(s): Study results demonstrated improved cardiac function and reduced PAC frequency in Tmem43S358L mice post-VSG, indicating VSG-induced beneficial effects on ACM phenotype in vivo. Further analysis will identify associations between cardiac transcriptomes and gut microbiota.