Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure

Background: Accumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and increasing cardiac delivery ameliorates dysfunction. As an initial step development therapies, we investigated effect chronic oral ester (KE) supplementation as a prevention or treatment strategy in rodent failure models. Methods: Two independent models were used for studies: transverse aortic constriction/myocardial infarction (MI) mice post-MI remodeling rats. Seventy-five underwent with KE comprised hexanoyl-hexyl-3-hydroxybutyrate (KE-1) diet, 77 rats treated either regimen using commercially available ?-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet. Results: The KE-1 diet elevated ?-hydroxybutyrate levels during nocturnal feeding, whereas KE-2 induced ketonemia throughout 24-hour period. preventive attenuated left ventricular dysfunction post-transverse constriction/MI (left ejection fraction±SD, 36±8 vehicle versus 45±11 KE-1; P =0.016). therapeutic approach also fraction, 41±11 MI-vehicle 61±7 MI-KE-2; <0.001). In addition, weight, cardiomyocyte cross-sectional area, expression ANP (atrial natriuretic peptide) significantly KE-2–treated MI group. However, did not influence fibrosis post-MI. myocardial transporter 2 ketolytic enzymes was fed along normalization ATP to sham values. Conclusions: Chronic effective both preclinical animal our results indicate reprogrammed genes involved body normalized production following MI, consistent provision auxiliary fuel. These findings provide rationale assessment KEs patients failure.