Abstract 4142958: Obesity Negatively Impacts Left Ventricular Mitochondrial Electron Transport Chain in End-Stage Heart Failure Patients

Introduction: Obesity is an independent risk factor for heart failure (HF). Metabolic remodeling resulting from myocardial lipid accumulation is implicated in left ventricular (LV) dysfunction in HF patients with obesity. While obesity is shown to be inextricably linked to mitochondrial dysfunction in metabolic disease, its affect on LV mitochondrial function in failing hearts is unknown. Hypothesis: As such, we hypothesized that HF patients with obesity demonstrate reduced LV mitochondrial function in comparison to HF patients without obesity. Methods: In accordance with an approved IRB protocol, LV biopsies were sampled from end-stage HF patients undergoing left ventricular assist device (LVAD) surgery at the University of Mississippi Medical Center. Approximately 20 mg of LV tissue per patient was used to isolate mitochondria using differential centrifugation. The activities of individual electron transport chain (ETC) complexes (I-IV) and citrate synthase (CS; marker of mitochondrial content) were measured using Oxygraph-2K and spectrophotometer. Complex I-IV rates (nmol e - /min) were normalized to CS activity (nmol e - /min). Normality, statistical significance, correlations were tested using the Kolmogorov-Smirnov test, Welch’s t test, and Pearson correlation respectively. The data are presented as mean± standard error where appropriate. A p-value <0.05 was considered statistically significant. Results: The study included 16 HF patients (3 females; age=52±3 years; 58% black, 42% white; 6 obese, BMI=40.9±2.11 kg/m 2 ; 10 non-obese, BMI=25.74±0.71 kg/m 2 ). Obese HF patients showed significant reductions in Complex I (46% lower, n=6-10, p=0.0343), and Complex IV (47% lower, n=5-10, p=0.0162) activities vs. non-obese HF patients. However, Complex II and III activities were unaltered between the groups. Further, CS activity was not different between the groups suggesting that LV mitochondrial mass is preserved in obese HF patients. Further, our correlation analysis revealed that Complex I (R 2 =0.3090, p=0.0254) and Complex IV (R 2 =0.4418, p=0.0069) activities were inversely correlated with BMI of the patients. Conclusions: The ETC complex I and IV activities are reduced by nearly half in obese HF patients highlighting a pronounced impact of obesity on myocardial mitochondrial function in end-stage failing hearts. These preliminary findings encourage further exploration on obesity mediated mitochondrial perturbations in heart failure patients.