Is AMPK the savior of the failing heart?

•Heart failure is one of the leading causes of death worldwide. •A decline in cardiac energy metabolism contributes to heart failure pathogenesis. •AMPK has a major role in the regulation of cardiac energy metabolism. •Pharmacological activation of AMPK may be useful in the treatment of heart failure. 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 contributes 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 protein kinase (AMPK), a major regulatory kinase controlling 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. 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 contributes 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 protein kinase (AMPK), a major regulatory kinase controlling 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. an enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. AMPK phosphorylates ACC activity. 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. 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. a small molecule that can inhibit AMPK. 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%. also called β-oxidation; a catabolic process in which fatty acid molecules are broken down in the mitochondria and eventually used to generate ATP. 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. a protein responsible for the transport of glucose into the cell in an insulin-dependent manner. 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%. 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. an enzyme involved in glucose metabolism; it is activated by AMPK through phosphorylation. PFK2 produces fructose 2,6-bisphosphate, a potent stimulator of glycolysis. chemically reactive oxygen-containing molecules, 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. also known as NAD+-dependent deacetylase; is an enzyme involved in the deacetylation of proteins in cellular regulation.