Mechanisms of Myocardial Cell Injury during Ischemia and Reperfusion

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.

Targeting the Innate Immune Response to Improve Cardiac Graft Recovery after Heart Transplantation: Implications for the Donation after Cardiac Death

“…Ischemia represents one of the challenges of the organ procurement and storage protocols [ 41 , 44 , 46 , 47 ]. Ischemia hinders ATP production and the cellular homeostasis, leading to uncontrolled fluid re-distribution and cellular edema [ 44 , 53 , 54 ]. Simultaneously, there is an increase in the extracellular pH and fluid stasis in the capillaries.…”

“…This produces capillary damage and decreases the perfusion capacity of the capillaries [ 55 , 56 ]. In addition, reperfusion injury occurs at time of the actual transplantation [ 54 , 55 , 56 ]. Reperfusion injury is intrinsic to the reperfusion and reoxygenation process [ 57 ].…”

Differences in ischemia-reperfusion-induced endothelial changes in hearts perfused at constant flow and constant pressure

“…In fact, reperfusion of the ischemic heart has been shown to produce changes in subcellular organelles such as the sarcolemma (SL) (9,10,26,27), sarcoplasmic reticulum (SR) (10,35,42), myofibrils (10,13) and mitochondria (24). A wide variety of mechanisms (3,28), including the occurrence of oxidative stress (4,10,39), development of intracellular Ca 2ϩ overload (4,10,32), and activation of proteases (36,46), have been suggested to explain cardiac dysfunction and subcellular alterations as a consequence of I/R injury. Although endothelial function with respect to the production of nitric oxide (NO) is defective in the ischemic heart disease (1,2,7,30), the functional status of endothelium in hearts subjected to I/R injury is poorly defined.…”

Late Sodium Current Inhibition Alone with Ranolazine Is Sufficient to Reduce Ischemia- and Cardiac Glycoside-Induced Calcium Overload and Contractile Dysfunction Mediated by Reverse-Mode Sodium/Calcium Exchange

“…Intracellular calcium (Ca 2ϩ i ) overload is a key contributor to the mechanical and electrical dysfunction observed in cardiac ischemia-reperfusion (IR) injury and cardiac glycoside toxicity (Barry, 1987;Tani, 1990;Ferrari et al, 1993;Silverman and Stern, 1994;Piper et al, 2003;Ruch et al, 2003). Excessive Ca 2ϩ influx mediated by reverse mode (RM) operation of the cardiac Na ϩ -Ca 2ϩ exchanger 1.1 (NCX1.1) is thought be the major mediator of the observed Ca 2ϩ i overload.…”