Abstract 18677: Disease Progression in Human Heart Failure is Associated With Leptin Deficiency and Ketosis

Abstract

Introduction: Dysregulation of the adipocyte hormone leptin has been implicated in insulin resistance and metabolic syndromes of excess non-esterified free-fatty acids (NEFAs). We have recently identified a reliance on ketones in the human end-stage failing heart, and described a metabolic signature of decreased myocardial acylcarnitines, disrupted Krebs cycling, and increased circulating NEFAs. We hypothesize that the progression to end-stage heart failure is marked by loss of circulating leptin, as cachexia and increased lipolysis deplete the adipocyte mass sustaining the utilization of peripheral ketones by the heart. Methods: Leptin was measured for 1159 subjects in the Penn Heart Failure Study (R&D Systems ELISA). Circulating β-hydroxybutyrate (β-HB) was assayed utilizing a commercially available colorimetric assay (Caymen) in 16 lean, non-diabetic patients with end-stage heart failure at the time of cardiac transplantation and 18 non-failing, non-diabetic donors as controls. Results: Over a median follow-up time of 4.2 years, there were 337 events: 218 deaths, 92 transplants, and 27 LVAD placements. The figure below presents Kaplan-Meier curves for survival free from transplant or LVAD implantation by leptin tertiles (Logrank p=0.0003). After adjustment for covariates including BMI lower leptin levels remained associated with worsening survival (third versus first tertile of leptin: HR 0.73, p=0.04). In the patients with end-stage heart failure we found a significant increase in circulating β-HB (mean 145 μM versus 19 μM in non-failing, p=0.02) and NEFAs (mean 1.03mM versus 0.56mM in non-failing, p=0.01) Conclusion: Decreased circulating leptin is associated with worsening survival in human heart failure, while serum β-hydroxybutyrate is increased in advanced heart disease. Future studies will explore the mechanistic link between ketogenesis and dysregulated leptin in the emerging metabolic syndrome of heart failure.