1. Date of download: 7/22/2016 Copyright © The American College of Cardiology. All rights reserved. From: Prognostic Implications of Long-Chain Acylcarnitines in Heart Failure and Reversibility With Mechanical Circulatory Support J Am Coll Cardiol. 2016;67(3):291-299. doi:10.1016/j.jacc.2015.10.079 Primary Outcome: Factor 5 and Time to Event As the adjusted Kaplan-Meier curve demonstrated, patients with heart failure in the highest tertile of long-chain acylcarnitine factor (factor 5) had an increased risk of the primary outcome of all-cause mortality and hospitalizations compared with patients in lower tertiles. Risk increased for all patients over time. Figure Legend:

2. Date of download: 7/22/2016 Copyright © The American College of Cardiology. All rights reserved. From: Prognostic Implications of Long-Chain Acylcarnitines in Heart Failure and Reversibility With Mechanical Circulatory Support J Am Coll Cardiol. 2016;67(3):291-299. doi:10.1016/j.jacc.2015.10.079 Factor 5 and LVAD Support Although levels of the factor 5 metabolites C16, C18:1, and C18:2 were significantly higher at baseline in patients with end-stage heart failure (HF) prior to left ventricular assist device (LVAD) placement, those levels decreased after support. The other major components of factor 5—arginine, C18, and C20:4—did not change significantly with LVAD support. *Metabolite levels differed significantly pre- and post-LVAD implantation. †Metabolite levels differed significantly between patients with chronic HF and those with end-stage HF pre-LVAD. Figure Legend:

3. Date of download: 7/22/2016 Copyright © The American College of Cardiology. All rights reserved. From: Prognostic Implications of Long-Chain Acylcarnitines in Heart Failure and Reversibility With Mechanical Circulatory Support J Am Coll Cardiol. 2016;67(3):291-299. doi:10.1016/j.jacc.2015.10.079 Metabolite Profiles of Systolic Heart Failure: Free Fatty Acid Metabolism The primary energy source for the normally functioning human heart is free fatty acids, which are broken down by β-oxidation and entered into the Krebs cycle for eventual conversion into adenosine triphosphate (ATP). Long-chain fatty acids are converted to their respective acyl-coenzyme A (CoA) ester by the ATP-dependent acyl-CoA synthetases. These acyl-CoA esters are then converted into acylcarnitine and free CoA by carnitine palmitoyltransferase (CPT)-I at the outer mitochondrial membrane. The resulting acylcarnitine is then transported across the inner mitochondrial membrane by the carnitine:acylcarnitine translocase in exchange for free carnitine. Once inside the mitochondrial matrix, the acyl-CoA ester is reformed by CPT-II, and carnitine is released for further exchange by the carnitine:acylcarnitine translocase. In the failing heart, dysfunction in these key enzymes may lead to inadequate substrate utilization, which would be hypothesized to be reflected in serum elevations of long-chain fatty acid intermediate metabolites such as long-chain acylcarnitines. These can contribute to worsening heart failure via promotion of arrhythmias, insulin resistance, adverse remodeling, and decreased energy production. Targeting these pathways might lead to novel therapeutics for heart failure. CACT = carnitine-acylcarnitine translocase; TCA = tricarboxylic acid. Figure Legend: