The circulatory system, consisting of the heart and arterial, venous, and capillary blood vessels, delivers oxygen and nutrients to all organs and transports metabolites to sites of further metabolization and excretion. To execute this central role, the heart continuously pumps the blood through the vasculature. Although the heart is a single organ, in terms of function, it represents two pumps working in series. Whereas the left heart generates high pressure (basal level 120 mm Hg) to supply all organs (except the lung) with oxygenated blood, the right heart enables blood flow through the pulmonary vasculature by generating a low-pressure gradient (basal level 20 mm Hg). In order to perform life-long under conditions of varying workload, the heart critically depends on oxidative phosphorylation to generate sufficient amounts of ATP, making it vulnerable to episodes of ischemia. A pronounced metabolic flexibility, i.e. the ability to utilise different substrates (glucose, fatty acids, ketone bodies, lactate) for energy production, is an important ability of the heart to cover the high energy demand even with a changing supply.