Return of calcium: manipulating intracellular calcium to prevent cardiac pathologies.

H eart failure resulting from ischemia reperfusion and other forms of injury is characterized by a variety of pathological manifestations, including cellular hypertrophy, contractile dysfunction, and electrical instability. Abnormal calcium signaling leading to cytoplasmic calcium overload is thought to be a critical and perhaps common mechanism underlying these abnormalities. Since the 1980s, it has been known that inhibition of cardiac metabolism leads to increased intracellular calcium (1), and that pharmacologic therapies aimed at blocking calcium entry into cells not only reduce cellular injury (2), but also decrease the frequency of ventricular arrhythmias (3). More recently, studies using targeted genetic approaches have demonstrated that manipulating cardiomyocyte calcium handling can prevent or reduce the progression of hypertrophy and cardiac dysfunction associated with aging, ischemia, reperfusion, and pressure overload [see Sobie et al. (4) for review] but have also raised concerns about the potential for worsening heart failure (5, 6). In a recent issue of PNAS, del Monte et al. (7) use a genetic strategy to modify cellular calcium handling during ischemia by overexpressing sarcoplasmic reticulum ATPase via an adenovirus vector. Similar to pharmacologic strategies for reducing cytosolic free calcium, such as calcium channel blockers and beta-blockers, SERCA overexpression not only reduces infarct size and preserves cardiac function, but also reduces arrhythmia frequency. The success of this approach once again supports the long-held notion that calcium cycling is an important therapeutic target to prevent the deleterious consequences of ischemia reperfusion injury.