(PTFS11-04-24) High-Fat Diet Amplifies Disease Phenotypes in Arrhythmogenic Cardiomyopathy

Objectives: Arrhythmogenic Cardiomyopathy (ACM), an inherited non-ischemic heart disease, causes ventricular dysfunction, arrhythmias, myocardial inflammation, and fibrosis. Disease management relies on antiarrhythmics, cardiac ablations, and implantable cardioverter defibrillators. Patients are advised to limit exercise to delay disease progression and sudden cardiac arrest/death. Other lifestyle choices, such as high fat diet (HFD), are understudied. Unfortunately, Americans consume a diet higher in fat than recommended by the USDA, which increases cholesterol and worsens cardiac function. ACM is considered a disease of the cardiac desmosome, as pathogenic variants in desmosomal genes like desmoglein-2 (DSG2), account for 85-90% of ACM cases. Thus, we investigated the impact of HFD on cardiac function and cholesterol in a well-characterized mouse model of ACM (Dsg2^mut/mut).

Methods: Cohorts (n≥7) were utilized: 1) wild-type (WT) controls and Dsg2^mut/mut mice fed either 2) chow or 3) HFD. Baseline echocardiograms (echos) were performed at 8 weeks, before enrollment in 8-week dietary intervention. At endpoint, echos were collected, and hearts and blood harvested.

Results: Endpoint echos revealed reduced cardiac function in Dsg2^mut/mut mice (e.g. percent left ventricle ejection fraction [%LVEF], a major ACM Task Force Criteria), compared to WT mice. Importantly, HFD further reduced Dsg2^mut/mut %LVEF compared to Dsg2^mut/mut and WT fed chow by 10% and 24%, respectively. This was accompanied by elevations in total (by 34% and 46%) and LDL cholesterol (by 92% and 93%). Pearson’s correlation analysis revealed a positive correlation between %LVEF and HDL and an inverse relationship for %LVEF and LDL. HDL elevation is beneficial due to its ability to remove circulating LDL and VLDL. Pearson’s Correlation Matrix analyses revealed a positive linear correlation (r = 1.0; P=1.08e^-10) between VLDL and total triglycerides; yet a negative linear correlation (r = -0.91; P< 0.01) between VLDL and LDL.

Conclusions: HFD potentiated cardiac dysfunction and increased total, LDL, and HDL in Dsg2^mut/mut mice. Our study highlights a potential diagnostic and/or risk stratification tool in monitoring plasma cholesterol with cardiac function in ACM.

Funding Sources: National Institute of Health ROI (R01HL148348) and a Sponsored Research Agreement from Pfizer, Inc. (1054)