Robert A. Kloner

The stunned myocardium: prolonged, postischemic ventricular dysfunction.

Myocardial ischemia has, for many decades, been viewed as an all‐or‐none process that causes myocardial necrosis when prolonged and severe, but whose effects are transient when it is brief or mild. In view of the evidence that the ischemic process may hit, run and stun, perhaps our thinking about the consequences of myocardial ischemia should be expanded. According to this formulation, an ischemic insult not of sufficient severity or duration to produce myocardial necrosis may acutely affect myocardial repolarization and cause angina (hit); but these changes wane rapidly (run), when the balance between myocardial oxygen supply and demand has been reestablished. However, the ischemia may interfere with normal myocardial function, biochemical processes and ultrastructure for prolonged periods (stun). The severity and duration of these postischemic changes depend on the length and intensity of the ischemia, as well as on the condition of the myocardium at the onset of the ischemic episode. Furthermore, it is likely that when the myocardium is repeatedly stunned, it may exhibit chronic postischemic left ventricular dysfunction, an ill-defined condition. If prolonged, chronic postischemic left ventricular dysfunction can progress to myocardial scarring and ischemic cardiomyopathy, it may be important to determine how often it can be ameliorated by permanent improvement of myocardial perfusion by surgical treatment.

Deleterious effects of oxygen radicals in ischemia/reperfusion. Resolved and unresolved issues.

Oxygen free radicals are known to be generated during periods of ischemia followed by reperfusion. There is still some controversy, however, concerning the use of electron paramagnetic resonance spectroscopy to accurately detect and identify the free radical species that are formed. There is no doubt that oxygen radicals are deleterious to the myocardium; free radicals cause left ventricular dysfunction and structural damage to myocytes and endothelial cells in both in vitro and in vivo preparations. Potential sources of these cytotoxic oxygen species include the xanthine oxidase pathway, activated neutrophils, mitochondria, and arachidonate metabolism, yet the crucial source of free radicals in the setting of ischemia and reperfusion is unresolved. There is little doubt that oxygen radicals play a role in the phenomenon of stunned myocardium induced by brief periods of ischemia followed by reperfusion; numerous studies have consistently observed that pretreatment with free radical scavengers and antioxidants enhances contractile function of stunned, postischemic tissue. Whether oxygen free radical scavengers administered only during reperfusion enhance recovery of stunned myocardium in models of brief ischemia remains to be determined. In models of prolonged ischemia (2 hours) followed by reperfusion, we have not observed a beneficial effect of scavengers on stunned myocardium. The issue of whether oxygen free radical scavengers are capable of reducing so-called irreversible or lethal reperfusion injury remains, in our opinion, unresolved. Although some studies have observed that agents such as superoxide dismutase and catalase reduce infarct size in ischemia and reperfusion models, many others have reported negative results. Additional studies will be needed to resolve this ongoing controversy. Oxygen free radicals may also contribute to reperfusion-induced arrhythmias in rodent heart preparations; however, less data are available in other animal models. The concept of reperfusion injury should not be considered a deterrent to reperfusion for the treatment of acute myocardial infarcts in the clinical setting. Thrombolytic therapy reduces myocardial infarct size, enhances recovery of left ventricular function, and improves survival. Whether incremental beneficial effects on these parameters will be obtained when oxygen radical-scavenging agents are used as adjuvant therapy to thrombolysis in patients remains to be determined.

Evaluation of nonradioactive, colored microspheres for measurement of regional myocardial blood flow in dogs.

Measurement of regional myocardial blood flow (RMBF) is crucial in experimental studies of myocardial ischemia and reperfusion in dogs. The standard measurement technique uses radioactive microspheres; however, not all institutions are able to dispose of radioactive waste and therefore cannot make use of this method. We tested a new, nonradioactive microsphere, labeled with colors instead of nuclides. Simultaneous blood flow measurements with two nuclide-labeled and two colored microspheres were performed after coronary occlusion in dogs. Both techniques show a within-method correlation of r greater than 0.98. Duplicate variability for paired RMBF values in 80 samples was 8.7 +/- 0.1% when computed with radioactive microspheres and 13.2 +/- 1.8% when computed with colored microspheres. There was a good correlation in the measurement of RMBF between the radioactive- and colored-microsphere methods (r = 0.98). The best-fitting linear regression line was expressed by the formula: Colored-microsphere RMBF = 1.11 (radioactive-microsphere RMBF)-0.02. When measured by colored microspheres, RMBF was approximately 8% higher than when computed with radioactive microspheres for blood flow values of 0-2 ml/min/g. When blood flow was increased pharmacologically to levels of 2-7.5 ml/min/g, colored microspheres yielded blood flow values 39% higher than the values computed by radioactive microspheres. We conclude that the nonradioactive, colored-microsphere method correlates with the radioactive technique, but at high flows, it yields values greater than those obtained with radioactive microspheres.

Altered myocardial states: The stunned and hibernating myocardium

There are several potential outcomes of myocardial ischemia. When ischemia is severe and prolonged, myocyte cell death occurs and there is no recovery of contractile function of these cells. When myocardial ischemia is less severe but still prolonged, myocytes may remain viable but exhibit depressed contractile function, which may be a protective mechanism whereby these cells attempt to reduce their oxygen demand in the setting of reduced oxygen supply. The resultant chronic left ventricular dysfunction has been termed hibernating myocardium. Finally, myocardial ischemia may be reversed with coronary artery reperfusion resulting in salvage of the myocytes. However, the viable myocardium may demonstrate relatively prolonged but transient postischemic contractile dysfunction, the situation termed stunned myocardium. The concepts of stunned myocardium are reviewed as they apply to both coronary reperfusion during evolving acute myocardial infarction, as well as brief periods of ischemia that may occur during angina pectoris, or coronary vasospasm, or both. The concept of hibernating myocardium is reviewed as it applies to left ventricular function prior to and after coronary artery bypass surgery.

Effect of verapamil on postischemic “stunned” myocardium: Importance of the timing of treatment☆

Timely administration of verapamil has been shown to reduce indexes of ischemic injury in experimental models of prolonged coronary artery occlusion, yet its effect on contractile function of reversibly injured (that is, stunned) myocardium remains unknown. The objective of the present study was to determine whether verapamil--administered either 30 min before coronary artery occlusion, at the time of reperfusion or 30 min after reperfusion--could attenuate the regional contractile dysfunction and alterations in high energy phosphate metabolism produced by 15 min of transient coronary artery occlusion in anesthetized, open chest dogs. All treatment groups exhibited passive systolic bulging during occlusion. In the control dogs receiving saline solution, segment shortening in the previously ischemic tissue averaged only 31 +/- 8% of normal baseline values after 3 h of reperfusion. In addition, endocardial adenosine triphosphate (ATP) stores were depleted by -8.7 +/- 0.8 nmol/mg cardiac protein to 26.5 +/- 1.1 nmol/mg protein, and endocardial creatine phosphate content increased by 9.6 +/- 4.3 nmol/mg cardiac protein over normal values. Pretreatment with verapamil essentially ablated the phenomenon of postischemic stunning: segment shortening was restored to 115 +/- 8% of normal after 3 h of reflow (p less than 0.01 versus control), endocardial ATP stores were partially preserved (30.6 +/- 1.2 nmol/mg protein; p less than 0.05 versus control) and creatine phosphate overshoot was blunted (endocardial creatine phosphate content decreased by -5.6 +/- 2.9 nmol/mg protein; p less than 0.05 versus control). Verapamil administered at or after reperfusion also attenuated postischemic contractile dysfunction: segment shortening for both groups recovered to 65 +/- 9% of baseline at 3 h after reperfusion (p less than 0.05 versus control). Verapamil given at or after reperfusion had no beneficial effect, however, on high energy phosphate stores. Thus, even when treatment was delayed, that is, initiated at or after reperfusion, administration of verapamil significantly increased contractile function of the postischemic stunned myocardium.

Postischemic Myocardial Stunning: A Clinically Relevant Phenomenon

Excerpt Coronary artery reperfusion by means of thrombolytic therapy is rapidly emerging as a fundamental strategy in the management of patients with acute myocardial infarction. Although successfu...

Early treatment with deferoxamine limits myocardial ischemic/reperfusion injury

Oxygen-derived free radicals (the superoxide anion O2- and hydroxyl radical.OH) have been implicated in myocardial injury associated with coronary artery occlusion followed by reperfusion. Transition metals (such as iron or copper) are needed to catalyze the formation of the .OH radical and subsequent .OH-mediated lipid peroxidation, yet the role of these transition metals in the pathogenesis of myocyte necrosis remains undefined. To address this issue, 21 dogs underwent 2 h of coronary artery occlusion and 4 h of reperfusion. Each animal was randomly assigned into 1 of 3 treatment groups: 7 received the iron chelator deferoxamine beginning 30 min preocclusion, 7 received deferoxamine beginning 5 min prior to reperfusion, while 7 dogs served as saline controls. Deferoxamine effectively chelated free iron in both treatment groups (total urine iron content averaged 42 +/- 16, 662 +/- 177 and 803 +/- 2.5 micrograms in control, pretreated, and deferoxamine at reperfusion groups respectively; p less than 0.05), but had no significant effect on in vivo area at risk (AR), hemodynamic parameters, collateral blood flow during occlusion, or myocardial blood flow following reperfusion. Area of necrosis (AN) in dogs pretreated with deferoxamine (34.6 +/- 3.7% of the AR; p less than 0.05) was significantly smaller than that observed in the saline control group (55.4 +/- 4.7% of the AR). Deferoxamine administered at the time of reperfusion, however, had no significant effect on infarct size (AN/AR = 54.3 +/- 8.7%, p = NS vs. controls). Thus, early treatment with the iron chelator deferoxamine acutely reduced the extent of myocyte necrosis produced by 2 h of transient coronary artery occlusion in the canine model.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of calcium antagonists on infarcting myocardium

Numerous studies have been conducted over the past 10 years on the effects of calcium antagonists on regional myocardial ischemia and infarct size. Verapamil, for example, reduced the degree of adenosine triphosphate degradation during 15 minutes of coronary occlusion followed by reperfusion in an anesthetized canine preparation. It also preserved the ultrastructural appearance of mitochondria in myocardium subjected to 1 hour of ischemia. Using an 8-hour permanent coronary artery occlusion model in which risk zone was assessed with radioactive microspheres and infarct size determined by tetrazolium staining, verapamil, administered 1 hour after occlusion, resulted in a modest decrease in infarct size. In a reperfusion model in which anesthetized dogs were subjected to 3 hours of coronary artery occlusion followed by 3 hours of reperfusion, verapamil decreased infarct size when it was administered during the period of ischemia, but failed to decrease infarct size when administered only during the reperfusion phase, i.e., after 3 hours of ischemia. Although verapamil is known to have negative inotropic effects, the newer calcium antagonist agent nisoldipine is less negatively inotropic, and might therefore be preferable in the situation of compromised hemodynamics. In a 6-hour permanent coronary artery occlusion model, nisoldipine decreased infarct size without decreasing left ventricular contractility. Most published reports support the concept that calcium antagonists decrease infarct size in models of experimental infarction. Of 4 major clinical studies, only 1 has shown that calcium antagonists are capable of reducing infarct size in man. However, in most of these studies, drug therapy commenced relatively late--4 or more hours after symptoms. In order for these drugs to demonstrate beneficial effects, the risk zone may have to be small and the degree of collateral flow adequate, the drug may have to be given very early or even before coronary occlusion (in a prophylactic fashion) and administration of the drug may have to be coupled to early coronary reperfusion.

Left ventricular topographic alterations in the completely healed rat infarct caused by early and late coronary artery reperfusion

Topographic changes in the completely healed (6 weeks) left ventricle of the rat, caused by early (30 minutes) and delayed (90 minutes) coronary artery reperfusion, were examined. With early reperfusion the extent of the scar, as a percentage of left ventricular (LV) circumference, was reduced compared to the extent of the scar in rats with permanent occlusion (27 +/- 3% vs 42 +/- 2%, p less than 0.01). Early reperfusion also preserved LV topography by preventing dilation of the LV cavity and thinning of the healed free wall. Late reperfusion (90 minutes) did not reduce the extent of the scar (35 +/- 3% vs 42 +/- 2% of LV circumference, p = NS) or prevent dilation of the LV cavity compared with permanent occlusion. However, the healed free wall/noninfarcted septum ratio was significantly greater in rats with late reperfusion than in those with permanent occlusion (0.98 +/- 0.06 vs 0.73 +/- 0.07, p less than 0.05). Thus early reperfusion completely inhibited scar thinning and dilation of the LV cavity, maintaining normal LV topography. Late reperfusion, too late to reduce infarct size, still contributed to improved healing of the myocardium by resulting in a thicker scar.

Preservation of high-energy phosphates by verapamil in reperfused myocardium.

To determine whether verapamil prevents depletion of adenine nucleotides during and after severe myocardial ischemia, dogs were subjected to 15 min occlusions of the left anterior descending coronary artery followed by 240 min of reperfusion. One hour before occlusion, dogs were randomly assigned to a treatment group (n = 10) to which an infusion of intravenous verapamil was given until the onset of reperfusion or to an untreated saline group (n = 9). Verapamil reduced mean aortic pressure and heart rate. After 15 min of ischemia, endocardial adenosine triphosphate (ATP) level, determined by needle biopsy, decreased in the untreated group from 34.7 +/- 2.0 to 24.4 +/- 2.7 nmol X mg protein-1 (p less than .005 vs preocclusion) and in the verapamil group from 32.8 +/- 1.5 to 30.3 +/- 1.5 nmol X mg protein-1 (NS vs preocclusion). Dogs receiving verapamil had significantly higher ATP levels than untreated animals after 90 and 240 min of reperfusion. In untreated animals the sum of inosine and hypoxanthine levels increased during occlusion from very low levels to 4.6 +/- 1.1 nmol X mg protein-1 in the epicardium and to 6.8 +/- 1.5 nmol X mg protein-1 in the endocardium (p less than .05 compared with preocclusion values). In verapamil-treated dogs inosine and hypoxanthine levels increased to only 1.2 +/- 0.3 (epicardium) and 1.9 +/- 0.6 nmol X mg protein-1 (endocardium) (both NS compared with preocclusion values). After 90 min of reperfusion the sum of ATP, adenosine diphosphate, adenosine monophosphate, inosine, and hypoxanthine levels was decreased in the endocardium by 10.2 nmol X mg protein-1 in the untreated group, but no change was observed in verapamil-treated animals. We conclude that breakdown of ATP to inosine and hypoxanthine during severe ischemia is reduced by verapamil, resulting in higher ATP concentrations during occlusion and reperfusion and decreased washout of the diffusible purines inosine and hypoxanthine during reperfusion.