Sarcoplasmic reticulum Ca-ATPase and heart failure 20 years later.

T his article reflects on the impact of a classic paper identifying the effects of loss of sarcoplasmic reticu-lum Ca-ATPase activity in heart failure. Understanding the effects of heart failure on contraction and Ca signaling in the heart has long been a priority. By the late 1980s, many studies on animal models had shown that heart failure resulted in a slowing of the decay of the systolic Ca transient 1 because of a decrease in the expression of the sar-coplasmic reticulum (SR) Ca-ATPase (SERCA). 2 Work using human tissue found similar changes. 3,4 In 1994, Hasenfuss et al 5 published a now classic article in Circulation Research entitled " Relation between myocardial function and expression of sarcoplasmic reticulum Ca-ATPase in failing and non-failing human myocardium. " Previous work had shown that SERCA expression and activity were decreased in heart failure. Other work had shown that the increase of force seen on increasing the frequency of stimulation (the positive force– frequency curve) disappeared in heart failure. Hasenfuss et al 5 showed that the degree of change in the force–frequency relationship correlated with the loss of SERCA. Hearts with low levels of SERCA developed maximum force at lower frequencies than those with higher levels. In addition, and suggested as causative of the reduced force–frequency responses, the failing hearts had reduced SERCA-mediated Ca uptake. The work in this article has influenced 2 areas of research: changes of SR function in heart failure and restoration of SERCA as a therapeutic strategy. We consider these in turn. Twenty years later, the role of changes of SERCA expression in heart failure is well-established. The majority of studies of heart failure in either humans or experimental animals show that SERCA activity is decreased in heart failure. This decrease of SERCA has 2 immediate effects on Ca signaling. First, it slows the rate of decay of the systolic Ca transient, thereby impairing relaxation. Second, as a consequence of decreasing SR Ca content , it will decrease the amplitude of the systolic Ca transient and thus contraction. However, subsequent work has shown that changes of SERCA are part of a group of changes of Ca signal-ing that occur in heart failure. As highlighted in Figure, 2 other factors will also decrease the SR Ca content. First, there is an increase of NCX expression or activity. 6–8 This adaptation has the benefit of making up for the reduced SERCA, thereby …