Mechanisms of Myocardial Cell Injury during Ischemia and Reperfusion

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Abstract
Ischemia in myocardial tissue results in impaired high energy phosphate production and diminished perfusion of the interstitial space. Reduction in the supply of ATP to the sarcolemmal and sarcoplasmic reticulum Na+ and Ca2+ pumps results in a rise in intracellular (Ca2+), which can exceed normal systolic levels within 10 to 15 minutes. Elevated (Ca2+)i can cause activation of proteases and phospholipases, which can damage the sarcolemma and release toxic metabolites, such as lysophospholipids. Oxygen free radicals can be produced by breakdown of nucleosides and accumulate in the interstitial space. Accumulation of metabolites intracellularly can cause cell swelling, which in addition to rigor due to ATP depletion, can stress the weakened sarcolemma, producing cell rupture and death. With reperfusion, additional injury to the myocyte may occur. Resupply of oxygen can result in a burst of oxygen free radical production. Resynthesis of ATP may sensitize the myofilaments to Ca2+, resulting in a hypercontracture that can further promote cell rupture. Resupply of ATP and washout of H+ may cause activation of Na/Ca2+ exchange, thus intensifying Ca2+ overload. Washout of the hypertonic interstitial space fluid may aggravate cell swelling and produce sarcolemmal rupture. Prevention or alteration of ischemic and reperfusion injury in myocardial cells is important clinically. Strategies currently being explored include reducing the rise in (Ca2+)i, which occurs during ischemia and reperfusion; inhibiting the actions of phospholipase on the cell membrane; decreasing free radical effects; and reducing stress on the sarcolemmal by prevention of cell swelling and hypercontracture.