Fueling the heart.

An invitation from Eduardo Marbán, on the occasion of the 50th anniversary of Circulation Research, provides an opportunity to reflect on my understanding of the most important advance in regulation of cardiac metabolism. By the early 1950s, the major findings were the observation by Locke and Rosenheim in 1907 that glucose is used as a fuel by the isolated perfused heart and the observation by Bing and coworkers in 1954 that normally beating human hearts prefer fatty acid to any other substrate for oxidation. Bing’s in situ experiments involved measurements of the myocardial extraction of various substrates and oxygen and of coronary flow. Although there is no substitute for studying metabolism of the heart working in a normal environment, these studies do not allow for the exploration of individual enzymatic reactions. The most important advance in understanding the regulation of cardiac metabolism was the discovery, in the post– World War II era, of the pathways of glycolysis and fatty acid metabolism including the role of membrane transport in glucose uptake. Although heart muscle slices and homogenates were used for studies of glycolysis, some or all of the cardiac muscle cells were disrupted and prevented rigorous studies of membrane permeability.