I

Myocardial Salvage i

Little or No Recovery of Contractile Function

Infarcted Myocardium t

Lower Infarct Area i

Fig. 2. Consequences of myocardial ischemia. The stunned myocardium usually results from a transient coronary occlusion followed by prompt reperfusion; however, it may also occur following prolonged ischemia in the preconditioned heart. Preconditioning may lessen the infarct area following a sustained coronary occlusion; however, the relationship between preconditioning and the maimed myocardium is unknown. Modified from ref. 15. © 1995, with permission from Elsevier.

(Figs. 3 and 4). Patients with electrocardiogram changes of ischemia and contractile failure who lack chest pain may be experiencing silent ischemia. It has been proposed that these patients are either less sensitive to painful stimuli or their ischemia is somewhat milder (3).

4.1. Myocardial Stunning

There are two general theories for explaining the patho-mechanism underlying myocardial stunning, and they are not mutually exclusive. The formation of free-radical reactive species or alterations in intracellular calcium, both with a detrimental effect on the myocardium, have been speculated as the principal causes of postischemic stunning (5). Intracellular acidosis during ischemia can potentially generate intracellular calcium oscillations and calcium overload on reperfusion via activation of the sarcolemmal Na+/H+ exchanger (Fig. 4) (6).

Experimental studies have shown that the calcium sensitivity of the contractile apparatus is decreased in the stunned myocardium, thereby resulting in lower maximal force generation even at higher than normal transient calcium levels (7,8). Furthermore, decreased myofilament sensitivity to calcium is considered primarily responsible for systolic dysfunction; for example, the stunned myocardium is still responsive to inotropic stimulation. Of additional interest are the findings that cardiac troponin I (cTnI) degradation products were discovered in the human myocardium during aortic cross-clamping with bypass, and that serum levels of cTnI increased during reperfusion, peaking approx 24 h following cross-clamp removal (9). This preliminary evidence further suggests that cTnI degradation products may potentially be utilized as biomarkers for stunning.

During the early stage of stunning, it is considered beneficial to prevent calcium oscillations and thus attenuate significant injury caused by reperfusion. This has been accomplished experimentally by utilizing Ca2+ antagonists, inorganic blockers, ryanodine, low-calcium reperfusion buffers, or Na+/H+ exchange (NHE) blockers (10). Conversely, when contractility is suppressed, as in the late stage of stunning, therapies should include those that increase the amplitudes of intracellular calcium transients, inducing inotropic responses. Included in this subset are high-calcium buffers, Ca2+ agonists, catecholamines, and phosphodiesterase inhibitors. Importantly, many of these therapies are specific to the stage or degree of stunning, and hence the timing of their use is critical so they do not become a detrimental therapy.

Fig. 3. New ischemic syndromes that do not fall within the realm of classic acute reversible and irreversible myocardial ischemia. (A) The stunned myocardium is characterized by a decrease in function following an ischemic event in which there is a complete absence of necrosis from ischemia or reperfusion and a complete functional recovery hours to days later. (B) The hibernating myocardium is characterized by chronic depressed myocardial function because of sublethal ischemia lasting for weeks to months, and revascularization may result in complete recovery of function. (C) The maimed myocardium has permanent damage resulting from a preceding prolonged ischemic episode and has some functional recovery that does not return to preischemic levels. (D) Ischemic preconditioning exists when short ischemic episodes followed by reperfusion confer myocardial protection during a subsequent prolonged ischemic event. However, two areas of uncertainty exist in the preconditioning phenomenon: (1) Functional recovery following the preceding short ischemic events may not return to preischemic levels; and (2) although it is known that ischemic preconditioning lessens infarct size, it is uncertain whether long-term functional recovery following the prolonged ischemic episode is significantly improved (via decreased myocardial stunning). Only delayed ischemic preconditioning has been shown to attenuate myocardial stunning. Modified from ref. 15. © 1995, with permission from Elsevier.

Fig. 3. New ischemic syndromes that do not fall within the realm of classic acute reversible and irreversible myocardial ischemia. (A) The stunned myocardium is characterized by a decrease in function following an ischemic event in which there is a complete absence of necrosis from ischemia or reperfusion and a complete functional recovery hours to days later. (B) The hibernating myocardium is characterized by chronic depressed myocardial function because of sublethal ischemia lasting for weeks to months, and revascularization may result in complete recovery of function. (C) The maimed myocardium has permanent damage resulting from a preceding prolonged ischemic episode and has some functional recovery that does not return to preischemic levels. (D) Ischemic preconditioning exists when short ischemic episodes followed by reperfusion confer myocardial protection during a subsequent prolonged ischemic event. However, two areas of uncertainty exist in the preconditioning phenomenon: (1) Functional recovery following the preceding short ischemic events may not return to preischemic levels; and (2) although it is known that ischemic preconditioning lessens infarct size, it is uncertain whether long-term functional recovery following the prolonged ischemic episode is significantly improved (via decreased myocardial stunning). Only delayed ischemic preconditioning has been shown to attenuate myocardial stunning. Modified from ref. 15. © 1995, with permission from Elsevier.

For instance, hypocalcemia during and following cardiopulmonary bypass is a common occurrence mainly attributed to the utilization of priming fluids, citrated blood, and large doses of heparin during bypass (11). Normally, hypocalcemia is successfully corrected with the administration of calcium chloride; however, calcium levels may return to preoperative levels prior to removal from cardiopulmonary bypass without supplemental calcium (12). Therefore, the risk of stunning and myocardial damage may actually be increased with generalized calcium chloride administration; there exists a lack of specific therapeutic guidelines for calcium administration during and following bypass.

4.2. Hibernating Myocardium

As discussed in this section, myocardial stunning and hibernation are related in terms of a depressed state of contractility and in the potential for dysfunctional myocardium to return to normal. However, it must be restated that, although stunning can be attributed to the reperfusion following a brief bout of ischemia, the hibernating myocardium is in a chronic hypo-contractile state because of a decreased oxygen supply and thus may only recover full function with revascularization. In addition, many of the underlying mechanisms of stunning are considered directly related to the detrimental effects of reperfusion injury (discussed in Section 5) (13). Although there is an absence of necrosis with myocardial hibernation, morphological changes to the myocardial architecture, such as loss of myofibrils and increased interstitial fibrosis, may occur if this state persists (14).

4.3. Maimed Myocardium

The maimed myocardium closely resembles a classic myo-cardial infarction in that ischemia-induced necrosis leads to loss of contractile performance. Unlike myocardial stunning, the duration of ischemia is long enough to result in necrosis; however, there can be partial recovery of function to this ischemic region following reperfusion (15). An example of the maimed myocardium syndrome would be seen in patients who exhibit an incomplete recovery of myocardial function following drug-induced or mechanical (angioplasty) reperfusion of an occluded coronary artery and then demonstrate regions of viable myocardium in the ischemic area.

NCE NHE Na+-K+ATPase

NCE NHE Na+-K+ATPase

Ca2+ Overload Ischemia

Fig. 4. Reperfusion injury via the Na+-H+ exchanger (NHE). Reperfusion injury-induced calcium overload can be explained in part by activation of the NHE. (1) Intracellular acidosis from a prior ischemic episode activates the NHE on reperfusion, thereby decreasing intracellular acidosis and increasing Na+ influx. (2) Intracellular sodium is primarily removed from the cell via the Na+-K+ATPase (adenosine triphosphatase) during normal myocardial function. However, after ischemia (i.e., during the early stages of reperfusion), the lack of abundance of ATP (adenosine triphosphate) does not allow for normal operation of the pump and intracellular Na+ increase. (3) Consequently, the Na+-Ca2+ exchanger (NCE), which normally operates by extruding Ca2+ from the cytoplasm, is the primary mechanism for intracellular Na+ removal operating in a reverse mode. (4) Intracellular Ca2+ overload results from NCE activation, possibly causing arrhythmias, stunning, and necrosis.

Ca2+ Overload Ischemia

Fig. 4. Reperfusion injury via the Na+-H+ exchanger (NHE). Reperfusion injury-induced calcium overload can be explained in part by activation of the NHE. (1) Intracellular acidosis from a prior ischemic episode activates the NHE on reperfusion, thereby decreasing intracellular acidosis and increasing Na+ influx. (2) Intracellular sodium is primarily removed from the cell via the Na+-K+ATPase (adenosine triphosphatase) during normal myocardial function. However, after ischemia (i.e., during the early stages of reperfusion), the lack of abundance of ATP (adenosine triphosphate) does not allow for normal operation of the pump and intracellular Na+ increase. (3) Consequently, the Na+-Ca2+ exchanger (NCE), which normally operates by extruding Ca2+ from the cytoplasm, is the primary mechanism for intracellular Na+ removal operating in a reverse mode. (4) Intracellular Ca2+ overload results from NCE activation, possibly causing arrhythmias, stunning, and necrosis.

4.4. Ischemic Preconditioning

Ischemic preconditioning is a biological phenomenon by which brief ischemic episodes, followed by reperfusion, protect tissue from a subsequent prolonged ischemic event (16). In the myocardium, ischemic preconditioning has been shown to be potentially infarct limiting (16) as well as antiarrhythmic

(17), although the latter of these effects has been disputed. It is also well established that endogenous opioid receptor activation participates in myocardial ischemic preconditioning

(18), and that preischemic administration of synthetic opioid agonists can mimic the benefits of ischemic preconditioning

(19). Although ischemic and opioid preconditioning have been convincingly shown to delay cell death in various experimental animal models, the clinical applicability of these aforementioned observations may be limited to situations in which the ischemic event can be anticipated (e.g., on- or off-bypass cardiac surgery, percutaneous transluminal coronary angio-plasty, or stenting procedures) (20). For a more comprehensive review of ischemic and opioid preconditioning, see ref. 21 (ischemic preconditioning) or 22 (opioid preconditioning).

4.5. Silent Ischemia

Silent ischemia refers to single or multiple asymptomatic episodes of transient ischemia. In some cases, silent ischemia can occur in the weeks following an acute myocardial infarction in patients with a history of coronary artery disease. In other scenarios a seemingly normal healthy individuals may experience episodes of silent ischemia that go relatively unnoticed. Detection of silent ischemia primarily relies on electrocardi-graphic monitoring, either in the form of 24-h Holter monitoring (ambulatory) or an exercise- or stress-induced assessment session. In both cases, ischemia is detected by asymptomatic ST elevations (23). Silent ischemia is postulated to be related to a lack of oxygen supply rather than an increase in oxygen demand; however, controversy remains concerning the mechanism by which silent ischemia can proceed unnoticed.

4.6. How Can the Heart

Be Protected From Ischemia?

As shown in Fig. 1, there are several means of decreasing myocardial oxygen demand when the oxygen supply is compromised. These include hypothermia, pharmacologically decreasing the heart rate, or controlled cardiac arrest. In addition, as mentioned in Section 4.4., ischemic or pharmacological preconditioning of the heart are other means of protecting the heart from an ischemic episode (cardioprotection). However, these aforementioned therapies require anticipation of the ische-mic event, such that the therapies can be administered prior to or early during the ischemia. When anticipation of ischemia is not possible, for example, in acute myocardial infarction, interventions that reestablish blood flow and oxygen to the ischemic zone (reperfusion) are the primary therapies.

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Essentials of Human Physiology

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