Molecular basis of contractility in failing heart. There is increasing evidence that disturbances in calcium handling play a central role in the disturbed contractile function in myocardial failure. The sarcoplasmic reticulum calcium ATPase (SERCA) is depressed both in function, as well as in expression. At the same time the sarcolemmal sodium-calcium (Na+/Ca2+) exchanger is increased both in function and in expression. The result is a characteristic change in calcium homeostasis with decreased diastolic uptake of calcium into the sarcoplasmic reticulum with subsequently reduced calcium release during the next systole, resulting in reduced contractile performance. At the same time increased capacity of the sodium-calcium exchanger extrudes intracellular calcium ions to the extra-cellular space, thereby rendering these ions unavailable for the contractile cycle. Intracellular Ca2+ handling is abnormal in heart failure and cause systolic and diastolic dysfunction. The mRNA and protein levels of the Na+/Ca2+ exchanger are increased in myocites from heart failure patients and correlates inversely with the SERCA mRNA levels. The augmentation in Na+/Ca2+ exchange activity is a compensatory response to the reduction in Ca2+ reuptake caused by a decrease in SERCA2. But enhanced Na+/Ca2+ exchange instead of SRCa2+ reuptake is an energy-wasting process: ATP consumption to extrude cytosolic Ca2+ from the myocyte is almost doubled with respect to the normal SRCa2+ reuptake.