Reperfusion Injury

Although immediate restoration of blood flow and oxygen to ischemic tissue is ultimately a beneficial and important therapy, it should be noted that additional myocardial damage can occur on myocardial reperfusion. In what has been termed the oxygen paradox, the resupply of oxygen to a hypoxic cell simultaneously activates two intracellular processes of particular interest: the membrane-bound calcium pumps and the contractile apparatus. Resumption of contractile activity in the presence of oscillating and increasing intracellular Ca2+ levels can force the heart into a state of hypercontracture and cause intracellular edema. Collectively, these etiologies may ultimately result in membrane disruption and cell death.

Reperfusion injury can present or be associated with one or more of the following pathologies: (1) reperfusion arrhythmias, (2) microvascular damage and no reflow, (3) accelerated cell death, (4) myocardial stunning, or (5) postpump syndrome in procedures requiring cardiopulmonary bypass (Fig. 5). Reperfusion injury may cause immediate myocardial necrosis in severely damaged cells and delayed necrosis in cells adjacent to the ischemic region, or conversely, complete recovery of myocardial function may occur despite an ischemic episode. Of importance, necrosis occurring during the ischemic episode must be differentiated from that which may occur following reperfusion, especially when discussing therapies targeted at attenuating reperfusion injury.

Assessment of reperfusion injury following ischemia is often difficult to perform, especially in the postsurgical patient. Yet, the determination of the presence or extent of injury can be

Fig. 5. Aspects of reperfusion injury. Although reperfusion is still the most beneficial therapy for ischemia, any combination of the stunning, accelerated cell death, arrhythmias, microvascular damage, or postpump syndrome could occur, thus leading to postischemic dysfunction or necrosis.

indirectly accomplished by hemodynamic monitoring (pressures, cardiac outputs, echocardiography) and examining blood levels of cardiac enzymes (creatine kinase-MB fraction [CK-MB], troponin I, lactate dehydrogenase [LDH], and/or aspartate transferase [AST]). Ideally, left ventricular end-diastolic pressure-volume measurements would provide functional and quantitative information relative to the degree of reperfusion injury; however, clinically such data are difficult and rarely feasible to obtain. On the other hand, myocardial viability can be assessed with inotropic stimulation as the postischemic stunned or the potentially reversibly injured myocardium will display an increased heart rate and contractility; the irreversibly injured (necrotic) myocardium exhibits little to no response to the inotrope (e.g., by dopamine stress echocardiography). Note that, by definition, myocardial stunning is reversible; therefore, within days, a depressed cardiac function caused by stunning should recover (Figs. 2 and 3). This phenomenon is observed clinically when patients following coronary artery bypass grafting require 24-48 h of inotropic support.

5.1. Aspects of Reperfusion Injury 5.1.1. Myocardial Stunning

As discussed in Section 4.1., the presence of intracellular oxygen free radicals and increased intracellular calcium during reperfusion leads to a reversible hypocontractile state of variable, yet normally brief duration.

5.1.2. Accelerated Cell Death

Accelerated cell death on reperfusion mostly refers to cells that have been irreversibly damaged during the prior ischemic episode and are destined to die despite reperfusion. However, irreversible damage is not a prerequisite for cell death; on reperfusion, detrimental ischemia-induced intracellular alterations may also occur in viable cells. During reperfusion, the development of increased sarcolemmal permeability caused by ischemia allows for the uncontrolled influx of calcium, resulting in hypercontracture, decreased energy production, or cell death. In addition, it should be noted that there is a paradoxical finding that apoptosis-related cell death in postischemic viable myocardium is lessened by early reperfusion and is accelerated in irreversibly ischemic-damaged cells (24).

5.1.3. Arrhythmias

Similar to myocardial stunning, increased episodes of arrhythmias on reperfusion may be in part caused by the presence of free radicals during ischemia or intracellular calcium oscillations at reflow. The restoration of flow enables the cell to resynthesize ATP. This abundance of energy and increased intracellular calcium at reperfusion may lead to excess cycling, which in turn may cause delayed after-depolarizations and ventricular automaticity (25). Interestingly, a Gaussian (bell-shaped) relationship has been described between duration of ischemia and severity of reperfusion arrhythmias, with the peak occurring with reperfusion after 5-20 min of ischemia (3). This is presumably because of the finding that, in severe ischemic episodes, the production of ATP during reperfusion is limited because of increased cellular necrosis, and consequently energy-dependent calcium oscillations are reduced (26).

The timing and speed of reperfusion are also considered to influence the occurrences and severity of induced arrhythmias. It has been speculated that sudden reperfusion is associated with a higher incidence of arrhythmias than is a gradual reperfusion. Whether this phenomenon occurs in humans is controversial because a study comparing revascularization, with either thrombolysis (a relatively slow reperfusion) or percutaneous transluminal coronary angioplasty (rapid reperfusion), of patients diagnosed with acute myocardial infarction revealed no differences in the occurrence of arrhythmias upon reperfusion (27).

5.1.4. Microvascular Damage and No Reflow

The "no-reflow" phenomenon is defined to occur when an attempt to reperfuse an ischemic area, by removing an occlusion regionally or reestablishing coronary flow globally, does not result in reflow to the area at risk. In fact, a study of patients diagnosed with acute myocardial infarction and treated with thrombolytic therapy revealed that approximately one-third of this study group showed impaired regional coronary flow 5 d after treatment (28).

There are two proposed mechanisms to explain this immediate or delayed no reflow: (1) endothelial damage induced by free radicals causes edema development and inhibits the release of vasodilatory agents into the coronary circulation; or (2) ischemic contracture of the myocardium mechanically constricts flow through the coronary system (3). In addition, activated neutrophils reintroduced at reperfusion can adhere to damaged endothelium and, in severe cases, cause platelet aggregation and restenosis (29). Importantly, cardioplegia-induced global myocardial ischemia can cause regional no flow, and infarctions will develop as a consequence of this phenomenon.

5.1.5. Postpump Syndrome

When blood comes in contact with foreign nontissue surfaces, such as during cardiopulmonary bypass, a circulatory inflammatory response may be triggered. A host of cell types is typically activated during such a foreign body response, including mono-cytes, macrophages, endothelial cells, T cells, and eventually neutrophils. In a process collectively referred to as neutrophil trafficking, these cells accumulate and adhere to the damaged endothelial layer (3). They then migrate into the vascular interstitial space, which results in liberation of free radicals and leukotrienes (3). This in turn may promote not only postsurgical myocardial damage, but also widespread systemic damage or multiorgan dysfunction (30). For example, it has been reported that cases of cerebral edema can develop after cardiopulmon-ary bypass; this is considered to be mediated by bypass-related inflammation and endothelial cell activation (31).

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