Qutuba KarwiAssistant Professor of Cardiovascular Sciences I BSc in Pharmacy (Hon), MSc in Pharmaceutical Sciences, PhD in Pharmacology (Cardiff University, Cardiff, Wales, United Kingdom)
BioMedical Sciences Cardiovascular and Renal Science
The heart has a very high energy demand and must continuously produce large amounts of ATP to sustain contractile function. If not replaced, the heart would run out of ATP in 2-10 seconds, resulting in contractile failure. As a result, the continuous production of ATP must occur to maintain cardiac function. The heart normally achieves this by metabolizing a variety of fuels, primarily by mitochondrial oxidative phosphorylation, a process requiring large amounts of oxygen. Disruptions in the metabolic pathways that produce ATP can have catastrophic consequences on heart function. As a result, compromised cardiac energy production is an important contributor to most forms of heart disease.
Mitochondrial oxidative phosphorylation normally contributes ~95% of myocardial ATP requirements, with glycolysis providing the remaining 5%. The healthy heart is also “metabolically flexible” and can readily shift between different energy substrates to maintain ATP production. The main fuels of the heart are fatty acids, glucose, ketones, lactate, and amino acids. The majority of mitochondrial ATP production, ~40-60%, is derived from the oxidation of fatty acids. The remainder originates from pyruvate oxidation (from glucose and lactate), ketone bodies and amino acids. The majority of the oxygen consumed by the heart is used for mitochondrial oxidative phosphorylation by the electron transport chain (ETC), while the synthesis of ATP derived from glycolysis does not require oxygen.
Heart failure is a debilitating disease with a major clinical and economic impact on the world’s population. The inability of the heart to adequately pump enough blood to meet the body’s needs for nutrients and oxygen results in heart failure patients having significant disabilities and a high mortality rate. The failing heart loses its metabolic flexibility and can become energy-deficient due to decreased ability to produce ATP. It can have up to 30% less ATP content than a healthy heart. This energy deficit is likely primarily due to a reduced mitochondrial oxidative capacity in heart failure. Impaired mitochondrial function in the failing heart can occur due to a number of reasons, including 1) increased reactive oxygen species (ROS) production and dysregulation of mitochondrial Ca2+ homeostasis, 2) impairments in mitochondrial dynamics, that include sustained mitophagy and increased autophagic cell death of cardiomyocytes, and 3) alterations in transcriptional regulation of mitochondrial proteins and increases in post-translational protein modifications. Therefore, understanding the metabolic alterations in the failing heart and how these alterations affect the contractile function and cardiac structure will help develop targeted therapeutics to treat patients with heart failure.
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