Lack of involvement of thromboxane A2 in postischemic recovery of stunned canine myocardium

Modification of the thromboxane: prostacyclin ratio alters the severity of reperfusion arrhythmias and postischemic damage in long-term, irreversibly injured myocardium. In this study, the effects of the thromboxane synthetase inhibitor dazmegrel and the thromboxane receptor antagonist BM 13.505 on myocardial postischemic functional recovery and preservation of tissue adenine nucleotides was examined after a 15-minute episode of ischemia followed by 3 hours of reperfusion (myocardial stunning). Dazmegrel (3 or 8 mg/kg) or BM 13.505 (10 mg/kg) was given 15 minutes before coronary occlusion and compared with a control group in barbital-anesthetized dogs. Regional segment shortening (percent segment shortening, sonomicrometry), regional myocardial blood flow (microspheres), and coronary venous eicosanoid and high-energy phosphate levels (biopsies after 3 hours of reperfusion) were measured. Areas at risk, regional myocardial blood flow, and regional segment shortening during coronary occlusion were similar in all groups. Dazmegrel (3 mg/kg) attenuated the decrease in endocardial and midmyocardial adenosine 5'-triphosphate, and both doses significantly improved regional segment shortening during reperfusion. Coronary venous thromboxane levels were significantly decreased throughout the experiment in both dazmegrel-treated groups, and thromboxane levels were significantly elevated in the control group 3 hours after reperfusion. Prostacyclin, measured in the form of its main metabolite, 6-keto-prostaglandin F1 alpha, did not change significantly in the control group throughout the experiment, but it was markedly increased in dazmegrel groups throughout reperfusion, particularly in the dazmegrel group receiving 3 mg/kg. BM 13.505 exerted no beneficial effects on postischemic function or metabolism. In conclusion, after a reversible ischemic insult, postischemic recovery of function and metabolic status was not enhanced by preocclusion treatment with a thromboxane receptor blocker, and thus, the beneficial effects of thromboxane synthesis inhibition on postischemic abnormalities was not due to a reduction in thromboxane but was the result of endoperoxide shunting and a subsequent increase in prostacyclin. Therefore, thromboxane does not appear to be an important mediator of reversible ischemia-reperfusion damage.     

Beneficial effects of iloprost in the stunned canine myocardium

The effect of the prostacyclin-mimetic, iloprost, on the reversibly damaged ("stunned") myocardium was studied in barbital-anesthetized, open-chest dogs subjected to 15 minutes of coronary artery occlusion and 3 hours of reperfusion. Regional myocardial segment shortening (%SS) was measured in the subendocardium of nonischemic and ischemic-reperfused areas by sonomicrometry. Iloprost was infused for 30 minutes beginning 15 minutes prior to occlusion (0.05 microgram/kg/min, ILO-LOW, or 0.1 microgram/kg/min, ILO-HIGH) or immediately prior to reperfusion (0.1 microgram/kg/min, ILO-REP). %SS in the ischemic-reperfused region recovered to 3% of pretreatment values in the control (saline-treated) group by 3 hours of reperfusion. In contrast, %SS in the iloprost-treated groups was significantly enhanced versus the control group at all times of reperfusion. At 3 hours of reperfusion, %SS recovered to 43% (ILO-LOW), 58% (ILO-HIGH), and 35% (ILO-REP) of pretreatment values. The beneficial effect on functional recovery was significantly greater when iloprost was administered before occlusion versus immediately prior to reperfusion. Thus, part of the salutory effects of iloprost appear to occur prior to and/or during ischemia. Iloprost did not improve collateral blood flow to the ischemic region or myocardial high energy phosphate content at 3 hours of reperfusion. While iloprost significantly decreased mean arterial pressure during ischemia and early reperfusion, the hypotensive action did not appear to play a role in the amelioration of postischemic dysfunction, as preocclusion treatment with an equihypotensive dose of sodium nitroprusside produced no significant effect on postischemic recovery beyond 5 minutes of reperfusion. Results of in vitro experiments indicated that iloprost had no effect on the xanthine oxidase free-radical generating system including lipid peroxidation. However, iloprost decreased the neutrophil-derived superoxide burst after chemotactic stimulation. This beneficial action may, in part, explain the efficacy of iloprost in enhancing postischemic function of the stunned myocardium.     

Improvement in functional recovery of stunned canine myocardium by long-term pretreatment with oral propranolol

We investigated the effect of long-term oral pretreatment with the beta-adrenergic antagonist, propranolol (Inderal LA, 160 mg daily for 8 days) on the functional recovery of myocardium after 15-minute coronary artery occlusion followed by 3 hours of reperfusion in barbital-anesthetized dogs. Propranolol-pretreated dogs (N = 9) displayed a significantly lower left ventricular peak-positive rise in ventricular pressure (dP/dt), heart rate, and rate-pressure product throughout the experiment compared with the control group (N = 15). Subendocardial percent segment shortening as measured by sonomicrometry recovered to 65.4 +/- 7.2% of the preocclusion level after pretreatment with propranolol, whereas the control group recovered to only 11.1% +/- 10.2% after 3 hours of reperfusion. To ascertain the beneficial role of a lower heart rate on the recovery of regional contractile function, a third group of dogs (N = 6) was pretreated with propranolol, but heart rate was maintained at control levels by atrial pacing. The beneficial effects of pretreatment with propranolol were abolished in this group. There were no differences between groups in myocardial perfusion in the normal region as measured by the radioactive microsphere technique. However, in postischemic, reperfused myocardium, there was a significantly higher blood flow to subepicardium, mid-myocardium, and subendocardium after reperfusion in the propranolol-pretreated, unpaced group. Thus long-term oral pretreatment with propranolol enhances the contractile recovery of postischemic, reperfused myocardium. This protective effect of beta-adrenergic blockade is primarily related to the reduction in heart rate and enhanced perfusion in the postischemic region.     

犬顿抑心肌31P磁共振波谱

目的 :观察顿抑心肌状态时心肌能量代谢变化规律。方法 :8条健康犬以麻醉开胸结扎冠状动脉左前降支 30min后再灌注 ,建立顿抑心肌动物模型 ,定期用 3 1 P磁共振波谱 （MRS）检查高能磷酸盐代谢变化。结果 :顿抑心肌再灌注后 2 h,Pcr/ β- ATP和 p H下降 ,Pi/ Pcr上升 ,Pcr/ β- ATP在再灌注 4h后可恢复至正常 ,而 Pi/ Pcr上升持续到再灌注后 3d,12 d恢复正常水平。结论 :13 1 P MR波谱方法能非侵入性测定心肌能量代谢 ;2 Pi/ Pcr变化较 Pcr/β- ATP和 p H的变化显著 ;3顿抑心肌能量代谢逐渐恢复后 ,持续性的心肌力学障碍与心肌细胞 ATP含量无明显关系     

What factors predict recovery of contractile function in the canine model of the stunned myocardium?

Recovery of contractile function of myocardium stunned by a brief, transient period of regional ischemia is highly variable. In our experience, segment shortening (an index of regional systolic contractile function) assessed during the initial hours after a 15-minute period of coronary artery occlusion in anesthetized open-chest dogs ranged from -84 to +99% of normal preocclusion values. In this retrospective study, regression analysis was used to assess the effects of various parameters on segment shortening 2 hours after reperfusion. Parameters assessed included regional myocardial blood flow both during occlusion and after reperfusion, high-energy phosphate content of previously ischemic tissue, systemic hemodynamic parameters (heart rate, mean arterial pressure and double product), occluded bed size and segment shortening measured during coronary artery occlusion. Recovery of systolic contractile function was not influenced by the degree of ischemia during coronary artery occlusion, myocardial blood flow after reperfusion, high-energy phosphate content, hemodynamic parameters or occluded bed size (correlation coefficients, r, ranged from 0.001 to 0.37 [p = not significant]). Only the degree of dyskinesia/hypokinesia exhibited during coronary occlusion significantly and reliably predicted recovery of segment shortening measured 2 hours after reflow (r = 0.70, p less than 0.001). Thus, recovery of systolic contractile function in the anesthetized canine model of the stunned myocardium is determined primarily by the degree of dysfunction exhibited during the preceding period of ischemia.     

Oxygen-derived free radicals and postischemic myocardial dysfunction ("stunned myocardium")

Experimental studies have demonstrated that myocardium reperfused after reversible ischemia exhibits prolonged depression of contractile function ("stunning"), which is associated with various ultrastructural, biochemical, vascular and other functional abnormalities. Clinical observations suggest that stunning occurs in many situations (for example, rest and exercise-induced angina, myocardial infarction with early reperfusion, open heart surgery, transplantation) and thus may contribute significantly to morbidity among patients with coronary artery disease. In recent years an increasing number of studies have provided indirect evidence that postischemic myocardial dysfunction may be mediated in part by the generation of reactive oxygen species, such as superoxide radical (.O2-), hydrogen peroxide (H2O2) and hydroxyl radical (.OH). Thus, it has been shown that the recovery of the stunned myocardium is enhanced by agents that either scavenge oxygen metabolites, such as superoxide dismutase and catalase, N-2-mercaptopropionylglycine and dimethylthiourea, or prevent their generation, such as allopurinol, oxypurinol and desferrioxamine. More recent experiments utilizing electron paramagnetic resonance spectroscopy have directly demonstrated that reperfusion after a reversible ischemic episode is associated with a burst of free radical production. At present, the evidence supporting the free radical hypothesis is suggestive but not conclusive. Definitive demonstration of the role of oxy-radicals will require careful studies measuring the production of these species in conscious animal models of postischemic dysfunction. If confirmed, the free radical hypothesis will provide not only new important insights into the pathophysiology of ischemic injury, but also a rationale for developing clinically applicable interventions.     

Thallium 201 kinetics in stunned myocardium characterized by severe postischemic systolic dysfunction

The hypothesis tested in this study was that despite the presence of severe postischemic myocardial dysfunction ("stunning"), the extraction and subsequent intracellular washout of thallium 201 should be preserved as long as irreversible sarcolemmal membrane injury was avoided. To produce myocardial stunning, 19 open-chested dogs with a critical left anterior descending coronary artery (LAD) stenosis underwent 10 5-minute periods of total LAD occlusion, each interspersed by 10 minutes of reperfusion by reflow through the critical stenosis. In another 12 control dogs observed for the same time period, no LAD occlusions were performed after placement of the critical stenosis. Hemodynamics, regional myocardial thickening by quantitative two-dimensional echocardiography, and microsphere-determined regional blood flows were serially measured. In 18 stunned dogs, systolic thickening in the LAD zone was markedly reduced to 0.4 +/- 2.4% at 40 minutes after the 10th reperfusion period compared with 32.5 +/- 2.2% thickening (p less than 0.001) in 12 control dogs at a matched time. The 201Tl first-pass extraction fraction determined by a double-isotope method using intracoronary 201Tl administration was comparable after the 10th reflow in a subgroup of 13 stunned (0.78) and six control (0.79) dogs. The T1/2 for the intracellular washout rate was also not significantly different in another group of six stunned (60 +/- 13 minutes) and six control (53 +/- 14 minutes) dogs, nor was the percentage of the 201Tl dose initially distributed in the interstitial compartment (11 +/- 3% vs. 7 +/- 2%). Systemic hemodynamics and regional flows were comparable in the two groups at 40 minutes after the 10th reflow. No dog had evidence of myocardial necrosis by triphenyl tetrazolium chloride staining. Thus, normal myocardial 201Tl extraction and washout kinetics are observed in a canine model of severe postischemic dysfunction (stunning) produced by repetitive brief LAD occlusions. These findings might have important clinical implications concerning the application of rest 201Tl scintigraphy for evaluation of perfusion and viability in patients with coronary artery disease and regional myocardial asynergy that is ultimately reversible.     

Reversal of dysfunction in postischemic stunned myocardium by epinephrine and postextrasystolic potentiation

After brief coronary occlusions, myocardium may become "stunned," exhibiting prolonged depression of function despite the absence of necrosis. Because of the accompanying decline in adenosine triphosphate and adenine nucleotide precursors, a deficiency of energy supply has been proposed as the basis for postischemic dysfunction. This study examined whether sufficient functional and metabolic reserve exists in stunned myocardium to sustain a prolonged, maximal inotropic response to epinephrine and postextrasystolic potentiation. In 11 open chest dogs, the left anterior descending coronary artery was occluded for 5 minutes, followed by 10 minutes of reflow, repeated 12 times, with a final 1 hour recovery period. Regional myocardial function was measured using pairs of ultrasonic dimension crystals implanted in ischemic and nonischemic zones. During repetitive reflows a progressive decrease in mean systolic segment shortening occurred: baseline 21.8%, 1st reflow 15.2%, 12th reflow 4.3%, 1 hour recovery 7.9%. Intravenous epinephrine, titrated to produce a maximal inotropic response, caused segment shortening to increase to 21.6% after 10 minutes and to 24.8% after 1 hour of infusion, despite a 20 mm Hg increase in systolic pressure. The same dose of epinephrine given before ischemia increased segment shortening to 30.5%. In six of the dogs, postextrasystolic potentiation before ischemia increased segment shortening from 21.8 to 31.1%, and after 1 hour of recovery from ischemia, from 7.9 to 24.8%. Lesser increases in segment shortening were also seen in nonischemic segments. The results indicate that stunned myocardium possesses considerable functional reserve. Deficient energy stores are therefore not likely to be the basis for depressed function seen at rest in stunned myocardium.     

Alterations in cardiac sarcoplasmic reticulum calcium transport in the postischemic "stunned" myocardium

This study examined the possibility that the postischemic mechanical depression observed in the "stunned" myocardium is a result of an alteration in the control of intracellular calcium. Regional myocardial stunning was produced in five open-chest dogs by eight to twelve 5-minute occlusions of the left anterior descending coronary artery, alternated with 10-minute reflow periods and followed by a final 60-minute period of reperfusion. Systolic segment shortening in the postischemic zone, measured by sonomicrometry, fell from 14.9% at baseline to -1.1% at the end of reperfusion. Sarcoplasmic reticulum isolated from stunned myocardium demonstrated a 17% reduction in oxalate-supported 45Ca2+ transport compared with sarcoplasmic reticulum from normal myocardium (0.93 vs. 1.12 mumol Ca2+/mg protein/min, p less than 0.005). There was also a 20% decrease in the maximal activation by Ca2+ of the sarcoplasmic reticulum Ca2+, Mg2+-ATPase (2.46 vs. 1.96 mumol Pi/mg protein/min, p less than 0.005), and a downward shift in the Ca2+-activation curve of the Ca2+, Mg2+-ATPase. These results indicate that myocardial stunning is associated with damage to the calcium-transport system of the sarcoplasmic reticulum. Altered intracellular control may contribute to the inability of the stunned heart to maintain normal mechanical function.     

Beneficial effects of oxypurinol pretreatment in stunned, reperfused canine myocardium

The mechanism of reperfusion induced injury in acutely ischaemic myocardium is controversial but may be connected with oxygen free radical generation. However, chronic allopurinol treatment has beneficial effects in ischaemic myocardium which are not due to its inhibition of xanthine oxidase induced oxygen free radical production. Allopurinol is rapidly metabolised to oxypurinol, so we have examined the effects of this compound on nutrient blood flow and contractility in a canine model of stunned, reperfused myocardium. Twenty anaesthetised dogs underwent 15 min of total circumflex artery occlusion followed by 15 min restricted reflow and 2 h full reflow. Posterior wall thickening was determined by sonomicrometry and expressed as % control function. Regional myocardial blood flow was measured by microsphere technique and expressed in ml.min-1.g-1. Dogs in the treatment group (n = 10) received 25 mg.kg-1 oxypurinol as a 5 min left atrial infusion, 15 min prior to circumflex occlusion. Controls (n = 10) received a saline infusion. During occlusion mean circumflex pressure (17.6 v 18.2 mm Hg), endocardial flow [0.02(SEM 0.01) v 0.03(0.01) ml.min-1g-1], and area at risk [31.4(1.2%) v 34.6(2.4%)] were similar for both groups (control v treated respectively). Endocardial blood flow increased following acute administration of oxypurinol: 1.57(0.15) v 0.92(0.15) ml.min-1g-1 in control (vehicle) group, p less than 0.05. This effect persisted for the duration of the experiment, with a significant increase during early reflow: 1.83(0.32) v 0.74(.21), p = 0.03. There was also a marked increase in posterior wall function in the treated group, at 54.6(5.5)% v 5.1(8.4)% in the control group (p = 0.0003). These results show that pretreatment with oxypurinol protects acutely ischaemic myocardium, producing enhanced myocardial blood flow, diminished systolic bulge during occlusion, and markedly enhanced function recovery following reperfusion.     

Nifedipine administered after reperfusion ablates systolic contractile dysfunction of postischemic "stunned" myocardium

Recent evidence suggests that postischemic contractile dysfunction of viable myocardium salvaged by reperfusion ("stunned myocardium") may be a consequence of abnormal calcium flux within the previously ischemic cells. Calcium channel blocking agents have been shown to enhance contractile function of stunned postischemic tissue, but it is not certain whether these improvements in function are due to the profound hemodynamic and vasodilator effects of these agents or to a direct effect on calcium flux within the stunned myocytes. Therefore, the effects of 1) high doses of nifedipine, given intravenously at 30 min after reperfusion, and 2) minute doses of nifedipine, infused directly into the coronary circulation at 30 min after reflow, were assessed and compared in anesthetized open chest dogs subjected to 15 min of transient coronary artery occlusion. As anticipated, intravenous nifedipine significantly reduced arterial pressure and increased regional myocardial blood flow. In addition, intravenous nifedipine restored systolic contractile function of the stunned, previously ischemic tissue to essentially normal preocclusion values: segment shortening averaged 102 +/- 8% versus 26 +/- 11% of baseline at 2 h after treatment in treated versus control dogs, respectively (p less than 0.003). Low dose intracoronary infusion of nifedipine did not alter hemodynamic variables or myocardial blood flow, but did improve segment shortening (90 +/- 9% versus 37 +/- 10% of preocclusion values at 1 h after treatment versus 25 min after reperfusion [that is, pretreatment], respectively; p less than 0.03). These data indicate that the calcium channel blocking agent nifedipine, given 30 min after reperfusion, enhances systolic contractile function of postischemic stunned myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reversibly injured, postischemic canine myocardium retains normal contractile reserve

Transient coronary occlusion (15 minutes) does not result in irreversible myocardial injury but is associated with a depression of contractile function sustained for several hours to days ("stunned myocardium"). The defect in the contractile process responsible for this phenomenon has been suggested to be causally related to a reduced energetic state, altered excitation or excitation-contraction coupling, or damaged contractile filaments. The purpose of this study was to attempt to exclude one or more of these hypotheses by evaluating the contractile reserve of reperfused myocardium. Regional subendocardial segment function was measured (sonomicrometry) in a control region and in an area (treatment region) perfused by a carotid artery to anterior descending coronary artery bypass in 13 chloralose-anesthetized dogs. Dose-response curves were constructed from changes in segment shortening (%SS) in response to intracoronary calcium infusion before ischemia and following 5 or 15 minutes of occlusion and reperfusion (30 minutes). Calcium infusion before ischemia resulted in dose-dependent increases in %SS in the treatment area to a maximum value of 36.6% from a preinfusion value of 25.5% (p less than 0.01), in the absence of changes in control region shortening (23.7%). After 15 minutes of occlusion and reperfusion, treatment area %SS had fallen to a depressed but stable level (46% of preischemic values; p less than 0.01). Subsequent calcium infusion at the same doses as in the preischemic trial produced increases in treatment segment function with return of shortening to control levels at an intermediate dose. At the highest dose, %SS was 35.4%, which was not different from the maximal value found in the preischemic trial. Alterations in heart rate and left ventricular systolic and diastolic pressures during calcium infusion were minor and similar before and after ischemia. Calcium-induced increases in regional segment shortening above control levels (113% of control) in reperfused myocardium were sustained with continuous infusion (30 minutes) without deleterious effects on subsequent function. These results demonstrate that stunned myocardium in this model retains a normal contractile reserve in response to calcium, suggesting that the mechanism responsible for postischemic contractile dysfunction involves calcium.     

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.     

Profound structural alterations of the extracellular collagen matrix in postischemic dysfunctional ("stunned") but viable myocardium

Ultrastructural studies of the extracellular collagen matrix were made on the "stunned" myocardium using scanning, conventional and high voltage transmission electron microscopy and light microscopy. Regional myocardial dysfunction was produced by 12 sequential 5 minute occlusions of the left anterior descending coronary artery, separated by 10 minute intervals of reperfusion. A final 90 minute reperfusion period documented persistent myocardial dysfunction. At the end of the final reperfusion period, the percent systolic shortening, measured by sonomicrometers, was depressed significantly to 35 +/- 9% of baseline. The heart was then perfusion fixed, and samples were taken from both control and stunned areas. No changes associated with irreversible cellular damage were noted in the stunned region. However, scanning electron microscopy of the stunned area showed that the extracellular collagen matrix underwent profound structural changes. Collagen cables were roughened, uncoiled and discontinuous. Linear grooves on the surface of the myocytes were frequently seen, indicating complete loss of collagen cables. The usual dense collagen weave surrounding myocytes became patchy or absent. Myocyte to myocyte struts were sparse and frequently absent, with remnant nodular or nublike structures indicative of breakage. High voltage electron microscopy of the stunned area showed that the collagen struts were discontinuous and vacuolated with rounded tips. Light microscopy of silver-stained sections of the stunned tissue demonstrated large patchy areas that were devoid of silver, indicating absence of the collagen matrix. There was a progressive increase in percent systolic bulging during each sequential coronary occlusion, suggesting increasing myocardial compliance. These results indicate that the myocardial collagen matrix is severely damaged from reversible ischemic cell injury. The greater myocardial compliance and less effective contractile effort in the stunned myocardium might be explained on a structural basis: disruption of the mechanical coupling function provided by the extracellular collagen matrix.     

Disruption of myofibrillar energy use: dual mechanisms that may contribute to postischemic dysfunction in stunned myocardium

The abnormalities in regional function produced by myocardial ischemia persist after the ischemic episode resolves. Since a close functional coupling exists between myofibrillar creatine kinase and myosin ATPase, a disruption of this coupling could adversely influence myocardial function and might provide a mechanism for the myocardial dysfunction observed. The purpose of the present study was to determine if an alteration in the activity of creatine kinase associated with the myofibril occurs in the postischemic period. Anesthetized open-chest dogs (n = 6) underwent coronary occlusion for 15 minutes, followed by reperfusion for 15 minutes. In reperfused myocardium, adenine nucleotide content was decreased (72 +/- 10% of nonischemic myocardium, p less than 0.05), documenting the presence of previous ischemia. The creatine phosphate content of reperfused myocardium returned to normal, indicating resumption of myocardial energy production. The creatine kinase activity of purified myofibrils isolated from reperfused myocardium was decreased by 17 +/- 7% compared to that of nonischemic myofibrils (p less than 0.03). In addition, the free adenosine diphosphate concentration in reperfused myocardium was calculated to be 96 microM and was less than the Km of adenosine diphosphate determined for myofibrillar creatine kinase (105 microM). The results suggest two putative mechanisms for disruption of energy use in postischemic myocardium: decreased creatine kinase activity associated with the myofibril, and limitation of substrate necessary for maximal creatine kinase activity.     

Collagen loss in the stunned myocardium.

BACKGROUND. This study was performed to biochemically assess and quantify the previously observed ultrastructural alterations in the collagen matrix of stunned myocardium. METHODS AND RESULTS. The stunned myocardium was produced in 13 mongrel dogs by a series of 12 coronary artery occlusions of 5 minutes followed by 10-minute reperfusion periods, with a final reperfusion period of 90 minutes. Regional systolic function in the stunned myocardium was 17% of control. Relative end-diastolic length in the stunned region increased up to 8%. There was a nonuniform transmural loss of collagen. Hydroxyproline in the stunned endocardium was not different from control. The stunned midwall and epicardium demonstrated 12.5% (p less than 0.05) and 14.6% (p less than 0.005) decreases, respectively. All transmural layers in the stunned myocardium had significant increases in collagenase activity before procollagenase activation, averaging a 73.6% increase (p less than 0.025). Complete activation of all procollagenase forms with aminophenylmercuric acetate revealed no differences in fully activated collagenase between the stunned and normal regions. The lysosomal enzymes, elastase and cathepsin G, were not different between stunned and normal zone tissue. These results would tend to exclude exogenous sources of protease in the stunned myocardium at the 90-minute final reperfusion time frame. Collagen fibers were isolated from the stunned and normal zone tissue and underwent dansyl chloride reaction. Stunned collagen fibers had 9% greater dansyl labeling, suggesting greater numbers of exposed N-terminal amino acid residues on the fiber and compatible with greater enzymatic cleavage activity on the stunned collagen matrix. Tissue water content was consistently greater in the stunned region compared to the normal: a uniform transmural increase of approximately 1.7%. CONCLUSIONS. The stunned myocardium is characterized by both systolic dysfunction and diastolic expansion or dilatation. Endogenous procollagenase is activated by the ischemic process leading to degradation of the extracellular matrix. The underlying mechanisms may be relevant in ischemic enlargement of the heart and cardiomyopathy.     

Coronary vasomotion of the stunned myocardium

The term stunned moycardium describes a dysfunction of the myocardium which may persist for hours, days or even weeks after restoration of coronary blood flow following thrombolysis, percutaneous transluminal coronary angioplasty (PTCA) or aorto-coronary bypass grafting (7, 9). The stunned myocardium is characterized — despite marked dyskinesis — by near, normal levels of myocardial perfusion and normal or even enhanced oxygen consumption (2), probably due to higher oxygen requirements of the contractile elements. Thus, a mismatch between function and flow exists which has been recognized to be a characteristic finding of the stunned myocardium. However, coronary reperfusion may result in an attenuation of the endothelial response to coronary vasodilators such as acetylcholine, bradykinin, etc. (3). It is well established that prolonged myocardial ischemia is associated with irreversible myocardial damage and profound structural and functional derangements of the coronary microvasculature which may persist even if perfusion is restored (1). Local vasoactive substances such as the endotheliumdependent relaxing factor (EDRF) also play an important role in the regulation of myocardial perfusion. EDRF is a potent vasodilator which is released from the coronary endothelium but is reduced in patients with atherosclerotic plaques or hypercholesterolemia (=endothelial dysfunction). Since there are shear-stress dependent flow receptors, EDRF is released proportionally to coronary flow, i.e., the higher the flow the larger the artery and vice versa. However, flow regulation is dependent on several factors such as perfusion pressure, peripheral resistance, sympathetic activation, oxygen saturation, metabolic factors etc. EDRF is synthetized in the endothelial cells and is rapidly broken down during ischemia by superoxide radicals which inactivate EDRF and, thus, decrease flow induced vasodilation (6). Neutrophil aggregation may further contribute to this process by the release of proteolytic enzymes which can convert oxygen to superoxide anions, i.e., oxygen free radicals. These radicals may injure the endothelium when generated in large amounts such as during ischemia (4) and may sensitize the smooth vasculature to contraction by alpha-adrenergic mechanisms (8).