Abstract 18828: Comprehensive Lipidomic Analysis of Myocardial and Circulating Acylcarnitine Levels in Patients With Advanced Heart Failure Before and After Mechanical Unloading and Controls

Abstract

Background: Advanced heart failure (HF) is associated with myocardial metabolic derangements and insulin resistance. Acylcarnitine (AC) accumulation has been suggested to be a marker of abnormal fatty acid metabolism and mitochondrial dysfunction. We hypothesized that ACs accumulate in the failing myocardium and blood of patients with HF compared to controls. Methods: Myocardial and plasma samples were obtained from HF patients during ventricular assist device (VAD) placement and explantation. Control (CON) samples were obtained from hearts not used for heart transplantation. CON plasma was collected from healthy donors. After methanol extraction of total lipids, ACs were measured by LC/MS/MS (MS ACQUITY UPLC). Results: Our study included 11 patients with HF (age 61±8 yrs, EF 17±5%, BMI 28±4 kg/m2) before and after LVAD placement and 6 CON (age 41 ±2 yrs, EF>60%, BMI 26±5 kg/m2). Free carnitine levels decreased in failing myocardium compared to CON (15.7±11.8 vs 16.2±93.0 ng/mg, p<0.001) without plasma changes. Total ACs decreased in failing myocardium compared to CON (45.9±35.9 vs 132.2±94.0 ng/mg, p<0.01). Of note, the cardiac AC/carnitine ratio was higher in HF compared to CON (387% of con, p<0.001) and remained unchanged post-VAD. Circulating total AC levels were higher in HF compared to CON (7.7±2.8 vs 4.7±2.7 ng/ml, p<0.05) with a decrease post-VAD (5.7±1.6 ng/ml, p<0.05 vs pre-VAD). Short chain (C2+C3), medium chain (C4-C12) and long chain ACs (C14-C18) were found increased in HF plasma (+162%, +158% and +174% vs CON, respectively; all p<0.05) with subsequent decrease post-VAD (-73%, -66% and -81% vs pre-VAD, respectively; all p<0.05). The circulating total AC/free carnitine ratio trended to be higher in HF (1.0±0.3 vs 0.7±0.4 in CON, p=0.1) without changes post-VAD. Conclusion: Metabolic derangements in HF include changes in circulating and cardiac ACs with a distinct response to mechanical unloading. An increased ACs/carnitine ratio suggests impaired fatty acid metabolism and mitochondrial dysfunction leading to accumulation of ACs in the failing myocardium. These novel findings implicate abnormal AC metabolism in the metabolic abnormalities and insulin resistance of patients with advanced HF.