Myocardial ischemia, also referred to as cardiac ischemia, is defined as the deprivation of nutrients and oxygen to the heart. This event happens during myocardial infarction, wherein an occlusive thrombus in a coronary artery blocks the blood supply to the myocardium. It can also happen during cardiac surgery because of pharmacological intervention to temporarily stop the heart. Reperfusion reinstates blood supply to ischemic tissue, although this can paradoxically lead to further tissue damage.
Effects of Ischemia
Under ischemic conditions, the deficiency of oxygenated blood supply to the myocardium makes the energy requirements of the heart impossible to satisfy. Several metabolic alterations derive from cardiac ischemia and, if it is prolonged, ischemia can lead to irreversible injury. Hypoxic-ischemic conditions and the rapid drop in oxygen availability inhibits ATP generation via oxidative phosphorylation, engendering lowered heart contractility. An extended reduction in contractility can itself lead to ventricular dysfunction.
During anaerobic metabolism, glycogen, glutamate, and glucose break down and alanine, succinate, lactate, and hydrogen ions are built up. A build-up of hydrogen ions reduces the pH of the extracellular and intracellular environment. The acidic environment outside and inside cardiomyocytes slowly impact on ion homeostasis, causing increases in intracellular Na+ concentration. Elevated Na+ concentration engenders a consequent increase in Ca2+ ions in a process referred to as ‘Ca2+ overloading’. Apoptosis and necrosis of cardiomyocytes caused by Ca2+ overloading can lead to irreparable damage to the heart.
Figure 1. Ionic disturbances in I/R injury within a cardiac muscle cell. A rise in intracellular Ca2+ concentration ([Ca2+]i ) is evident in ischemia and early reperfusion. This increase has been shown to precede irreversible cardiac injury. The decrease in ATP production, as a result of ischemia, lowers the intracellular pH. This change results in the increased activity of Na+/H+ and Na+/Ca2+ exchangers, thus increasing [Ca2+]i. ATP, generated by glycolysis, is used by F1F0-ATPase to create a mitochondrial membrane potential (Δψm). This is utilized by the mitochondrial calcium uniporter; an increase in mitochondrial Ca2+ concentration, combined with ROS activity and a normalized pH, prompts the opening of the mitochondrial pore during reperfusion. Abbreviations: ANT – adenine nucleoside translocator; ATP – adenosine triphosphate; Cyp D – Cyclophilin D; MCU – mitochondrial calcium uniporter; MPTP – mitochondrial permeability transition pore; ROS – reactive oxygen species; VDAC – voltage-dependent anion channel.
The reperfusion of ischemic myocardium after a period of ischemia represents a further research focus. Restoring blood supply to the ischemic zone causes tissue damage due to the release of intracellular enzymes, sarcolemmal rupture, Ca2+ influx and cardiomyocyte hypercontracture. Rupture of the sarcolemmal membranes causes the movement of Na+ ions through gap junctions between adjacent cells, as well as the induction of reverse Na+/Ca2+ exchange, which propagates the damage to adjacent myocytes. This mechanism of initial ischemia-related damage followed by additional damage induced by reperfusion is termed ischemia/reperfusion (I/R) injury.
The cell death underlying I/R injury is characterized by properties representative of necrosis, autophagy, and apoptosis. An important regulator of both necrotic and apoptotic cell death is the mitochondrial permeability transition pore (MPTP) (Figure 1). Low pH, generated during ischemia, impedes MPTP opening, and pH only returns to normal upon reperfusion. Increased matrix Ca2+ concentrations and reactive oxygen species (ROS) are the principal activators of the MPTP during I/R. Inhibition of ion exchangers influencing cytosolic Ca2+ levels, including the Na+/Ca2+ exchanger (NCX) and Na+/H+ exchanger (NHE), have been proven to lower I/R injury.
One of these inhibitors – zoniporide – selectively inhibits NHE1 and supplies cardioprotection from ischemic injury in vivo. As well as agents that target the NCX and NHE, inhibitors of MPTP, such as cyclosporin A, offer protection against reperfusion injury. Ischemic preconditioning is another cardioprotective strategy currently being investigated for I/R injury. This methodology’s objective is the reduction of the damage associated with I/R injury through the subjection of the vascular system to short, sublethal periods of ischemia.
One benefit of this approach is that identical protective effects can be achieved even when inducing ischemia in a tissue distinct from the heart, such as the lower or upper limbs. This is referred to as remote preconditioning. The cardioprotective tissue response to ischemic preconditioning is believed to implicate multiple biological targets, such as adenosine receptors. Activation of these receptors before ischemia or during reperfusion has been proven to grant cardioprotection; for instance, the subtype-selective A3 agonist, IB-MECA, displays cardioprotective features in a rat model.
Latest Cardioprotective Targets
More recent cardioprotective targets comprise the mitochondrial calcium uniporter (MCU), which has been linked to the cardioprotective response to ischemic preconditioning; the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA); and GSK-3β, a multifunctional kinase that has also been associated with protection against I/R damage.
Enhancing SERCA activity has been proven to lower infarct size and maintain cardiac function in a rodent model of transient myocardial ischemia. The process of administering interventional drugs at the start of reperfusion is restricted as they need to be administered within ten minutes of initiation. Nevertheless, therapeutic targeting of intracellular mechanisms caused during both ischemia and reperfusion continues to represent an encouraging direction for the limitation and/or prevention of both the extent and the occurrence of I/R injury.
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