1. Date of download: 7/16/2016 Copyright © The American College of Cardiology. All rights reserved. From: Metabolic Impairment in Heart Failure: The Myocardial and Systemic Perspective J Am Coll Cardiol. 2014;64(13):1388-1400. doi:10.1016/j.jacc.2014.04.083 Evolving Paradigm of HF Pathophysiology Advancing complexity of heart failure (HF) pathophysiology from a mere hemodynamic disorder to an increasingly systemic involvement of neurohormonal, immune, and metabolic pathways. Current therapeutic concepts focus exclusively on hemodynamic failure and neuroendocrine activation (left column). Novel therapies are warranted to target crucial components of HF pathophysiology, such as metabolic failure and inflammatory activation. ACE = angiotensin-converting enzyme; AT Rec = angiotensin receptor; CRT = cardiac resynchronization therapy; H-ISDN = hydralazine and isosorbide dinitrate; ICD = implantable cardioverter-defibrillator; LVAD = left ventricular assist device; MR = mineralocorticoid receptor; TNF = tumor necrosis factor; Tx = therapy; XO = xanthine oxidase. Figure Legend:

2. Date of download: 7/16/2016 Copyright © The American College of Cardiology. All rights reserved. From: Metabolic Impairment in Heart Failure: The Myocardial and Systemic Perspective J Am Coll Cardiol. 2014;64(13):1388-1400. doi:10.1016/j.jacc.2014.04.083 Myocardial Energy Metabolism Cellular energy metabolism from substrate utilization to oxidative phosphorylation to energy transfer for energy-requiring processes. Current therapeutic concepts to improve energetic efficiency (purple arrows) predominantly target proportional substrate use by decreasing fatty acid metabolism and increasing glucose oxidation. ADP = adenosine diphosphate; ATP = adenosine triphosphate; CPT = carnitine palmitoyltransferase; Cr = free creatine; FA = fatty acid; FFA = free fatty acids; G6P = glucose-6-phosphate; GLUT4 = glucose transporter 4; HK = hexokinase; LPL = lipoproteinlipase; MCD = malonyl-CoA decarboxylase; PCr = phosphocreatine; PDH = pyruvate dehydrogenase; ROS = reactive oxygen species; TCA = tricarboxylic acid cycle (Krebs cycle); TG = triglycerides; UCP = uncoupling protein; ß-ox = beta oxidation. Figure Legend:

3. Date of download: 7/16/2016 Copyright © The American College of Cardiology. All rights reserved. From: Metabolic Impairment in Heart Failure: The Myocardial and Systemic Perspective J Am Coll Cardiol. 2014;64(13):1388-1400. doi:10.1016/j.jacc.2014.04.083 Insulin Resistance: Intrinsic Feature in HF Pathophysiology The vicious cycle of insulin resistance as an intrinsic component of heart failure (HF) pathophysiology. Several features of HF trigger insulin resistance (right section in red). In turn, insulin resistance induces a range of signals responsible for HF progression. Accordingly, insulin resistance is a major underlying mechanism of the reciprocal interaction between congestive HF and diabetes mellitus, with hyperglycemia only exerting additive effects in overt DM. AGE = advanced glycation end products; PARP = poly(ADP- ribose) polymerase; PKC = protein kinase C; SNS = sympathetic nervous system; TNF = tumor necrosis factor; other abbreviations as in Figure 1. Figure Legend:

4. Date of download: 7/16/2016 Copyright © The American College of Cardiology. All rights reserved. From: Metabolic Impairment in Heart Failure: The Myocardial and Systemic Perspective J Am Coll Cardiol. 2014;64(13):1388-1400. doi:10.1016/j.jacc.2014.04.083 Independent Lipolysis Pathways in CHF Independent signaling pathways of increased lipolytic activity in heart failure. All 3 pathways are activated in congestive heart failure (CHF). ANP = A-type natriuretic peptide; AR = adrenergic receptor; BNP =B-type natriuretic peptide; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; c-Jun = N-terminal kinases; CNP = C-type natriuretic peptide; FFA = free fatty acids; JNK = c-Jun N-terminal kinase; MAPK = mitogen activated protein kinase; NP rec = natriuretic peptide receptor; PKA = protein kinase A; PKG = protein kinase G; TG = triglyceride; TNF = tumor necrosis factor. Figure Legend: