Is AMPK the savior of the failing heart? Ty T. Kim and Jason R.B. Dyck Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Department of Pediatrics, Faculty of Medicine and Dentistry, 458 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, T6G 2S2, Canada Heart failure (HF) is one of the leading causes of death, affecting more than 20 million people worldwide. A vast array of pathophysiological and molecular events con- tributes to the development and eventual worsening of HF. Of these, defects in myocardial metabolic processes that normally result in proper ATP production necessary to maintain contractile function appear to be a major contributor to HF pathogenesis. A key player involved in regulating myocardial metabolism is AMP-activated pro- tein kinase (AMPK), a major regulatory kinase control- ling numerous metabolic pathways. Here, we review the metabolic changes that occur in HF, what role alterations in energy metabolism has in its progression, and the involvement of AMPK in this context. Understanding heart failure and its global impact Heart failure Cardiovascular disease (CVD) is a leading cause of death and disability in North America [1] and it is predicted that, by 2015, CVD will become the leading cause of death world- wide [2]. While advancements in therapies have improved cardiac mortality, these treatments and/or interventions have ultimately also increased the incidence and prevalence of HF [2]. For example, a substantial portion of patients with ischemic and hypertensive heart disease will eventually develop HF [3,4] and the lifetime risk of developing HF in North American adults by the age of 45 years is 20% [5]. Importantly, the 1-year mortality rate after diagnosis of symptomatic HF is currently 25–40% [6,7], demonstrating the health burden of this syndrome. Although great strides have been made in HF treatment over the past two decades [8], the 1-year mortality rate clearly indicates that there is a need to develop new treatment strategies. Systolic heart failure HF is a clinical syndrome resulting from a progressive decline in the ability of the heart to fill and eject adequate amounts of blood to meet the requirements of the body [9,10]. Patients diagnosed with HF are typically classified via ejection fraction (EF) into one of two groups characterized by either reduced EF (HFrEF) or preserved EF (HFpEF) (see Glossary). HFrEF is associated with specific clinical symp- toms as well as an EF equal to, or below 40% [3], whereas HFpEF is broadly defined as a clinical syndrome in which patients present with symptoms and signs of HF but rela- tively normal EF. However, patients suspected of having HFpEF can also present with or without evidence of abnor- mal diastolic function [11], making the syndrome difficult to diagnose. That said, HFpEF accounts for 30–40% of all HF cases [2,12] and patients with HFpEF have a similar 1-year mortality to that of patients with HFrEF [13]. A vast array of pathophysiological and molecular events contributes to the development and eventual worsening of HF. Some of these changes include impaired cardiomyo- cyte calcium handling [14], cardiomyocyte cell death [15], cardiac structural remodeling, and changes in matrix com- position [16], as well as systemic inflammation [17]. While the list is more exhaustive than that indicated herein, it illustrates the complexity of HF and, thus, the difficulty in Review Glossary Acetyl coenzyme A carboxylase (ACC): an enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. AMPK phosphorylates ACC activity. AMP-activated protein kinase (AMPK): a serine/threonine protein kinase that is activated by a reduction in cellular ATP levels. Activation of AMPK increases energy-generating pathways and reduces energy-consuming pathways to restore energy homeostasis. Carnitine palmitoylCoA transferase (CPT) 1: a mitochondrial enzyme located on the outer mitochondrial membrane. It is part of the carnitine shuttle, which has an essential role in FAO by allowing their transport into the mitochondrial matrix where they can be catabolized. CPT1 is the rate-limiting step of the carnitine palmitoyltransferase system. Compound C: a small molecule that can inhibit AMPK. Ejection fraction (EF): the percentage of blood volume pumped out by a given ventricle during each heartbeat. It is calculated by dividing the stroke volume by the end-diastolic volume of the left ventricle. A healthy heart has an ejection fraction of 55–70%. Fatty acid oxidation (FAO): also called b-oxidation; a catabolic process in which fatty acid molecules are broken down in the mitochondria and eventually used to generate ATP. Fatty acid translocase (FAT/CD36): a plasma membrane-associated protein present in many cell types, including cardiomyocytes, responsible for regulating numerous cellular processes, including the uptake of long-chain fatty acids into the cell. Glucose transporter type 4 (GLUT4): a protein responsible for the transport of glucose into the cell in an insulin-dependent manner. Heart failure with reduced ejection fraction (HFrEF): a clinical syndrome resulting from a progressive decline in the ability of the heart to fill and eject adequate amounts of blood to meet the requirements of the body. HFrEF is characterized by an ejection fraction equal to or below 40%. Metformin: an oral antidiabetic drug that activates AMPK. Metformin lowers plasma glucose levels by increasing insulin sensitivity in several tissues, as well as enhancing glucose utilization. It also activates autophagy in a several cell types. Phosphofructokinase 2 (PFK2): an enzyme involved in glucose metabolism; it is activated by AMPK through phosphorylation. PFK2 produces fructose 2,6- bisphosphate, a potent stimulator of glycolysis. Reactive oxygen species (ROS): chemically reactive oxygen-containing mole- cules, such as oxygen ions and peroxides. Oxidative stress contributes to the production of endogenous ROS, and can cause cellular damage by damaging DNA, impairing mitochondrial function, and inducing apoptosis. Sirtuin 1 (SIRT1): also known as NAD+-dependent deacetylase; is an enzyme involved in the deacetylation of proteins in cellular regulation. 1043-2760/ ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2014.11.001 Corresponding author: Dyck, J.R.B. (jason.dyck@ualberta.ca). Keywords: AMP-activated protein kinase (AMPK); systolic heart failure; cardiac metabolism; myocardial ATP production. 40 Trends in Endocrinology and Metabolism, January 2015, Vol. 26, No. 1