Calcium-mediated cell death during myocardial reperfusion

Reperfusion may induce additional cell death in patients with acute myocardial infarction receiving primary angioplasty or thrombolysis. Altered intracellular Ca-2 handling was initially considered an essential mechanism of reperfusion-induced cardiomyocyte death. However, more recent studies have demonstrated the importance of Ca-2-independent mechanisms that converge on mitochondrial permeability transition (MPT) and are shared by cardiomyocytes and other cell types. This article analyses the importance of Ca-2-dependent cell death in light of these new observations. Altered Ca-2 handling includes increased cytosolic Ca-2 levels, leading to activation of calpain-mediated proteolysis and sarcoplasmic reticulum-driven oscillations; this can induce hypercontracture, but also MPT due to the privileged Ca-2 transfer between sarcoplasmic reticulum and mitochondria through cytosolic Ca-2 microdomains. In the opposite direction, permeability transition can worsen altered Ca-2 handling and favour hypercontracture. Ca-2 appears to play an important role in cell death during the initial minutes of reperfusion, particularly after brief periods of ischaemia. Developing effective and safe treatments to prevent Ca-2-mediated cardiomyocyte death in patients with transient ischaemia, by targeting Ca-2 influx, intracellular Ca-2 handling, or Ca-2-induced cell death effectors, is an unmet challenge with important therapeutic implications and large potential clinical impact.