Abstract Body: Introduction: The pathogenesis of heart failure with preserved ejection fraction (HFpEF) is poorly understood and therapies are limited. We previously found that impaired mitochondrial quality control contributed to HFpEF development, which could be rescued by enhancing cardiac fatty acid oxidation via deletion of acetyl-CoA carboxylase 2 in cardiomyocytes (ACC2-cKO). Here we evaluated whether pharmacological ACC2 inhibition could recapitulate the benefit of genetic ACC2 loss in HFpEF and to explore mechanisms.
Methods: HFpEF was induced in 12-wk-old male mice by high-fat diet and LNAME for 14 wks. A small molecule selective ACC2 inhibitor TLC-3595 (TLC) or vehicle (Veh) were administered (in diet) during the last 6 wks. Food intake, fat mass, glucose tolerance, and HFpEF phenotypes were assessed at the end of treatment. Inducible ACC2-cKO mice carrying cardiac mitochondria-tagged Dendra2 were used to track the fate of cardiac mitochondria in HFpEF.
Results: TLC did not alter food intake or blood pressure in all mice and had no effect on cardiac function in chow-fed mice. In HFpEF mice, TLC (n=5) compared to Veh (n=4) reduced inguinal fat mass (66 ± 46mg vs 114 ± 36mg, p=0.06) and improved insulin sensitivity (AUC for glucose tolerance test: 23 ± 6 vs 38 ± 15, p=0.06). Exercise capacity (distance run) was higher in TLC-HFpEF compared to Veh-HFpEF (166 ± 14m vs 108 ± 63m, p=0.06). TLC did not impact systolic function but improved diastolic function in HFpEF mice (E/e’: 34 ± 3.4 vs 45 ± 5.8, p=0.04). Parallel studies showed improved exercise capacity (173 ± 47m vs 97 ± 39m, p=0.005) and reduced E/e′ (36 ± 5.5 vs 49 ± 4.6, p=0.003) in ACC2-cKO HFpEF (n=9) compared to control HFpEF mice (n=6) without altering insulin sensitivity or obesity. Isolation of extracellular vesicles (EV) in the heart showed a greater abundance of large EV and Dendra2+ EV in HFpEF mice, suggesting that impaired mitochondrial quality control resulted in release of mito-EV. ACC2-cKO reduced large EV (fold over Chow: 1.1 ± 0.3 vs 1.5 ± 0.2, p=0.02) and mito-EV (fold over Chow: 1.2 ± 0.3 vs 1.7 ± 0.6, p=0.03) in HFpEF hearts.
Conclusion: Pharmacological ACC2 inhibition improved HFpEF similar to observations with ACC2-cKO. Further studies will evaluate peripheral vs. cardiac mechanisms for these benefits.