Sustained reduction in myocardial reperfusion injury with an adenosine receptor antagonist: possible role of the neutrophil chemoattractant response.

Recent studies have demonstrated that three membrane-permeant A(1) receptor antagonists reduced infarct size in a model of ischemia followed by brief reperfusion. However, it was not determined whether cardioprotection was mediated by nonspecific intracellular effects of these highly lipophilic drugs and whether the antagonists only delayed myocardial necrosis without affecting the ultimate infarct size. In the present study, closed-chest dogs were subjected to 90 min of left anterior descending coronary artery occlusion and 72 h of reperfusion and received either a nonmembrane-permeant adenosine receptor blocker that is devoid of direct intracellular effects and is 6-fold selective for the A(1) receptor [1, 3-dipropyl-8-p-sulfophenylxanthine (DPSPX); n = 11] or vehicle (n = 12). DPSPX was administered as three 200-mg boluses 60 min before and 30 and 120 min after reperfusion. The area of necrosis was determined histologically and expressed as a percentage of the area at risk. Baseline predictors of infarct size were similar in the two groups. The ratio of the area of necrosis to the area at risk was less in the DPSPX group (17.8 +/- 4.3% versus 35.0 +/- 1.9%; P =. 012), and DPSPX improved regional ventricular function. Under both basal and stimulated (formyl-Met-Leu-Phe) conditions, suspensions of human neutrophils generated extracellular adenosine levels (approximately 50 nM) sufficient to activate A(1) receptors. Moreover, both DPSPX and 1,3-dipropyl-8-cyclopentylxanthine, a selective A(1) receptor antagonist, significantly reduced the chemoattractant response of neutrophils to formyl-Met-Leu-Phe. We conclude that blockade of A(1) adenosine receptors attenuates myocardial ischemic/reperfusion injury, possibly in part by decreasing the chemoattractant response of neutrophils.

Reperfusion enhances the local release of endothelin after regional myocardial ischemia.

The role of endothelin, a potent long-acting vasoconstrictor peptide, in the pathogenesis of the "no-reflow" phenomenon was investigated in nine closed-chest mongrel dogs undergoing 90 minutes of proximal left anterior descending artery occlusion and 3.5 hours of reperfusion. Endothelin levels were measured serially from the coronary sinus (CS) and aorta (Ao) by radioimmunoassay and correlated with regional myocardial blood perfusion. Prolonged anesthesia, surgery, and vascular instrumentation did not change endothelin levels in four sham animals. A progressive and parallel increase in CS and Ao endothelin levels occurred during coronary occlusion. A further increase in CS levels was observed during the reperfusion period, resulting in significantly higher values of the peptide at 30 and 60 minutes (30 minutes: CS 22.1 +/- 3.5 vs Ao 15.1 +/- 5.1 pg/ml; 60 minutes: CS 21.1 +/- 4.5 vs Ao 15.0 +/- 3.6 pg/ml; p < 0.05 by analysis of variance). Microvascular perfusion determined semiquantitatively with fluorescent beads was significantly reduced in the central ischemic zone (CIZ) compared with that in the nonischemic zone (NIZ) (CIZ endocardium 1.14 +/- 0.4 beads/m2, CIZ midmyocardium 1.19 +/- 0.3 beads/m2, NIZ 3.8 +/- 0.6 beads/m2; p < 0.05). A significant correlation was noted between mean reperfusion levels of endothelin in the CS and endocardial flow in the CIZ (r = -0.88; p = 0.009). This study demonstrates that reperfusion per se enhanced the spillover of endothelin from the cardiac interstitium. Local release of endothelin may contribute to the progressive decrease in microvascular flow in the reperfused bed.

Intravenous adenosine suppresses cardiac release of endothelin after myocardial ischaemia and reperfusion.

OBJECTIVE: Intravenous adenosine decreases infarct size in experimental models of myocardial ischaemia/reperfusion. Ischaemia/reperfusion is associated with a significant increase in cardiac release of endothelin. The effect of cardioprotective doses of adenosine on endothelin release was explored in dogs undergoing 90 min coronary occlusion and 210 min reperfusion. METHODS: Dogs were assigned to intravenous adenosine in a dose of 0.15 mg.kg-1.min-1 (n = 12) or control (n = 11) during the first 150 min reperfusion. Serial endothelin levels were obtained from the coronary sinus and aortic blood and measured by radioimmunoassay. RESULTS: Adenosine significantly reduced infarct size expressed as a percent of the risk region (28.8 6% v 14.4 2%; p = 0.03). A similar increase in aortic and coronary sinus blood endothelin was observed in both groups during temporary occlusion. A significant transcardiac increase in endothelin levels was present in the control group 60 min after reperfusion whereas no increase occurred in the adenosine treated group [control 5.6(SEM 1.9) v adenosine -0.2(1.4) pg.ml-1; p = 0.02]. Similarly, intravenous adenosine tended to prevent the increase in myocardial endothelin production seen in control animals during the early reperfusion period [control 280(146) v adenosine -57(55) pg.min-1; p = 0.05]. Endocardial blood flow in the ischaemic zone 210 min after reperfusion was significantly higher in the adenosine group, at 0.60(0.02) v 0.38(0.02) ml.min-1.g-1; p < 0.05. A significant correlation between endothelin levels, endocardial flow and infarct size was observed in the control group 3 h after reperfusion: r = 0.73, p = 0.02; r = 0.62, p = 0.03 respectively. This relationship was absent in animals treated with adenosine. CONCLUSIONS: Intravenous adenosine suppresses the release of endothelin from the previously ischaemic myocardium during the early reperfusion period. This effect may in part contribute to the improvement by adenosine in postischaemic microcirculatory flow resulting in attenuation of the "no reflow" phenomenon.

The effects of intravenous infusions of selective adenosine A1-receptor and A2-receptor agonists on myocardial reperfusion injury.

To determine the efficacy of very low doses of adenosine on myocardial reperfusion injury and whether its effect is receptor mediated, 78 rabbits underwent 30 minutes of left circumflex artery occlusion and 48 hours of reperfusion. Animals were randomly assigned to receive one of three doses of adenosine, cyclopentyladenosine (a selective A1-receptor agonist), or CGS 21680C (a selective A2-receptor agonist). The drugs were infused for 65 minutes beginning 5 minutes before reperfusion. A significant reduction in histologically determined infarct size was noted with all three doses of adenosine, intermediate and low doses of the A1-receptor agonist (cyclopentyladenosine), and high and intermediate doses of the A2-receptor agonist (CGS 21680C). Furthermore, all three adenosine receptor agonists afforded similar degrees of protection. Results of this study demonstrate that intravenous infusions of very low doses of adenosine significantly enhance myocardial salvage and this protection is receptor mediated. Furthermore, the administration of the A1-receptor agonist would be clinically appealing, since it would avoid the potential side effects associated with activation of A2 receptors.

Reperfusion injury in the ischemic myocardium.

Myocardial reperfusion injury is defined as the conversion of reversibly injured myocytes to irreversibly injured cells following temporary coronary artery occlusion. Although not universally accepted, the concept of lethal reperfusion injury is strongly supported by studies that temporally link an interventional therapy administered in the perireperfusion period to myocardial salvage. Myocardial reperfusion may be due to the deleterious consequences of cellular edema, calcium overload, free-radical generation, neutrophil infiltration, and microvascular damage. Current studies suggest that perfluorochemicals and adenosine (agents that preserve endothelium and attenuate neutrophil chemotaxis) are the most promising compounds that reduce infarct size in experimental animal models and may warrant clinical trials in man.

Myocardial reperfusion injury in the canine model after 40 minutes of ischemia: effect of intracoronary adenosine.

To explore the contribution of reperfusion injury to final infarct size after a short duration of ischemia, closed-chest dogs underwent 40 minutes of proximal left anterior descending artery occlusion followed by 3 days of reperfusion. Animals randomly received intracoronary adenosine (n = 8) at 3.75 mg/min during the first hour of reperfusion or no therapy (control, n = 9). Infarct size was measured histologically. Regional ventricular function was determined with contrast ventriculography. The risk region was similar and collateral blood flow in the inner two thirds of the ischemic zone was markedly reduced in both groups (adenosine: 0.05 +/- 0.07 ml/min/gm; control: 0.02 +/- 0.07 ml/min/gm; p = NS). Infarct size as a percent of the area at risk was significantly reduced in the adenosine group (5.0 +/- 1.3% versus 13.5 +/- 3.2%; p = 0.03), associated with a trend for improved recovery of regional ventricular function. Relative endothelial preservation was seen in the adenosine group. These results suggest that reperfusion injury contributes to final myocardial cell necrosis in the closed-chest canine model subjected to 40 minutes of regional ischemia.

Effect of intravenous adenosine on myocardial reperfusion injury in a model with low myocardial collateral blood flow.

The purpose of this study was to investigate the effects of various doses of adenosine administered intravenously on myocardial reperfusion injury in a model with poor collateral blood flow. New Zealand White rabbits were subjected to 30 minutes of occlusion of the obtuse marginal branch of the left circumflex artery and to 48 hours of reperfusion. Animals were randomized to receive intravenous adenosine in doses of 0.1 mg/min (low), 0.3 mg/min (intermediate), or 0.55 mg/min (high), or an equivalent volume of saline (control) commencing 5 minutes prior to reperfusion and continuing through the first 60 minutes of reperfusion. The area at risk was determined in vivo with Monastral blue dye and the area of necrosis was histologically examined with Masson's trichrome stain. Both the intermediate and high doses of adenosine, but not the low dose, significantly (p less than 0.05) decreased mean blood pressure. However, all three doses of adenosine produced a significant (p less than 0.05) and comparable decrease in infarct size expressed as a percent of area at risk (control, 52.0 +/- 4.6%; low, 35.3 +/- 4.1%; intermediate, 31.7 +/- 4.6%; high, 31.3 +/- 4.6%). Regional myocardial blood flow was significantly increased and coronary vascular resistance decreased by all three doses of adenosine in a subset of animals that did not undergo coronary occlusion (p less than 0.05). This study demonstrates that intravenous administration of nonhypotensive doses of adenosine given during the early reperfusion period attenuates reperfusion injury in a model with poor collateral blood flow.

Role of adenosine in the treatment of myocardial stunning.

Adenosine is an endogenous nucleoside produced from the breakdown of adenosine triphosphate (ATP) that possesses a number of complex cellular and metabolic effects that could ameliorate postischemic contractile dysfunction (myocardial stunning). Potential mechanisms include the repletion of high-energy phosphate stores, reduced myocardial oxygen consumption, a decrease in oxygen-derived free radicals, restoration of calcium homeostasis, and an increase in regional myocardial blood flow. Experimental studies have shown that adenosine can reduce myocardial stunning with or without a concomitant increase in the total myocardial ATP stores. Adenosine may be a useful pharmacologic strategy in the prevention and treatment of ventricular dysfunction following episodes of regional or global ischemia, although further studies are needed to clarify the precise cellular mechanisms involved.

Reduction of myocardial reperfusion injury by intravenous adenosine administered during the early reperfusion period.

Adenosine influences the function of several cell types thought to be involved in the pathogenesis of myocardial reperfusion injury. We have previously demonstrated that intracoronary administration of adenosine enhances myocardial salvage 24 hours after reperfusion. To determine if these beneficial effects could be obtained during a prolonged period of reperfusion using an intravenous route of administration, 22 closed-chest dogs were subjected to 90 minutes of proximal left anterior descending coronary artery occlusion and 72 hours of reperfusion. Animals randomly received either intravenous adenosine (0.15 mg/kg/min) or an equal volume of Ringer's lactate during the first 150 minutes of reperfusion. The area at risk was defined in vivo with Monastral blue, and infarct size was measured histologically with Mallory's trichrome stain. Serial global and regional ventricular function were determined with contrast ventriculography and analyzed using a computerized radial shortening method. Biopsies were obtained from the central ischemic zone to assess endothelial ultrastructure and capillary obstruction. No significant effects in heart rate or blood pressure were noted during adenosine infusion. Transmural collateral blood flow during ischemia was similar in the groups. Infarct size expressed as a percentage of the anatomical area at risk was significantly less in the adenosine-treated group (35.3 +/- 4.3% in controls versus 17.1 +/- 4.3% in treated animals, p less than 0.01). A progressive decrease in transmural blood flow was noted in control animals during reperfusion, resulting in a significant reduction at 3 hours compared with the preocclusion value (0.69 +/- 0.11 ml/min/g [at baseline versus 0.45 +/- 0.10 ml/min/g at 3 hours, p less than 0.05]). In contrast, flow in adenosine animals at 3 hours was similar to baseline values (0.91 +/- 0.15 ml/min/g at baseline versus 0.98 +/- 0.14 ml/min/g at 3 hours, p = NS) and was significantly higher (p less than 0.05) than the control group. Radial shortening in the ischemic zone was significantly improved at 3 (-2.6 +/- 2.8% in controls versus 11.6 +/- 3.3% in treated animals, p less than 0.01) and 72 hours (5.5 +/- 2.0% in controls versus 17.3 +/- 3.5% in treated animals, p less than 0.01) after reperfusion in treated animals. Electron microscopy showed reduced neutrophil and erythrocyte plugging of capillaries with relative preservation of endothelial cell structure in the adenosine group.(ABSTRACT TRUNCATED AT 400 WORDS)

Intracoronary adenosine administration during reperfusion following 3 hours of ischemia: effects on infarct size, ventricular function, and regional myocardial blood flow.

Previous studies have demonstrated that adenosine significantly enhances myocardial salvage after 90 minutes of regional ischemia. To determine its effect after prolonged ischemia, closed-chest dogs underwent 3 hours of left anterior descending artery occlusion followed by 72 hours of reperfusion. Intracoronary adenosine (3.75 mg/min; at 1.5 ml/min:total volume = 90 ml; n = 10) or an equivalent volume of saline (1.5 ml/min: total volume = 90 ml; n = 9) was infused into the left main coronary artery during the first 60 minutes of reperfusion. Regional myocardial blood flow was assessed serially with microspheres and regional ventricular function was assessed by contrast ventriculography. Infarct size was determined histologically. Light and electron microscopy were utilized to assess neutrophil infiltration and microvascular injury. Adenosine failed to reduce infarct size expressed as a percentage of the area at risk (38.0 +/- 4.9% versus 34.8 +/- 4.6%; p = NS) or to improve regional ventricular function as measured by the radial shortening method (3.2 +/- 1.8% versus 2.2 +/- 3.1%; p = NS) at 72 hours after reperfusion. Vasodilatory effects were not observed in the endo- and midmyocardial regions of the ischemic zone during adenosine administration. This was associated with a similar extent of capillary endothelial changes and neutrophil infiltration in both adenosine-treated and saline control groups. These results suggest that severe functional abnormalities are present in the vasculature after 3 hours of ischemia and that adenosine therapy is ineffective in enhancing myocardial salvage.

Effect of coronary angioplasty on electrocardiographic changes in patients with unstable angina secondary to left anterior descending coronary artery disease.

The effect of semiemergent percutaneous transluminal coronary angioplasty on clinical and electrocardiographic (ECG) variables was assessed in 76 patients with unstable angina secondary to an isolated severe proximal left anterior descending coronary artery stenosis. All patients manifested symmetric T wave inversion in two or more anterior ECG leads. Wall motion abnormalities were present in 37 patients on ventriculography before dilation. Angioplasty was successful in 70 patients (92%), resulting in a reduction in luminal diameter stenosis from 91 +/- 8% to 21 +/- 6%, with no major acute procedure-related complications observed. The other six patients underwent semiurgent (less than 48 h) coronary artery bypass surgery and three patients experienced a myocardial infarction (before bypass surgery in two). Serial ECGs revealed complete resolution of ST-T wave changes in 51% of patients at 14 weeks and in 90% at 28 weeks. In contrast, prolongation of the corrected QT interval, which was present in 16 patients (8%), normalized within 48 h of successful angioplasty. Twelve of these 16 patients with a prolonged QT interval had nonocclusive thrombus formation and poor collateral circulation on angiography. Patients were followed up for 6 to 43 months (mean 23 +/- 10). Angiographic evidence of restenosis was present in 34% of patients, all of whom underwent a successful second or third procedure. One death occurred at 8 months after successful angioplasty. Wall motion abnormalities had completely resolved in 13 of 15 patients who underwent repeat ventriculography, at which time 10 had a normal ECG. This study demonstrates that ECG changes may persist for up to 7 months in patients who undergo successful angioplasty for severe left anterior descending coronary artery disease and unstable angina. Semiemergent angioplasty was associated with a high initial success rate and excellent long-term outcome.

Myocardial reperfusion injury. Histopathological effects of perfluorochemical.

Regional myocardial ischemic injury progresses as a "wave-front" phenomenon from the endocardium to the epicardium. Myocyte damage can be reversible or irreversible and is dependent on the duration of ischemia. Endothelial cell injury lags behind myocyte injury. Reperfusion of ischemic myocardium can result in the acceleration of endothelial injury with resultant conversion of surrounding reversibly injured myocytes to irreversible damage; this has been termed the "no-reflow" phenomenon. This process can be accelerated by the presence of neutrophils. Agents such as perfluorochemicals and adenosine, which attenuate endothelial injury and inhibit neutrophil infiltration, also reduce infarct size in animal models. Infarct size reduction with perfluorochemical was observed with both intracoronary and intravenous infusion. Infarct healing was not adversely affected except for the persistence of perfluorochemical-laden macrophages. These studies suggest that perfluorochemicals and adenosine might be beneficial adjuvants to thrombolytic therapy in the reduction of reperfusion injury.

Mechanisms and therapy of myocardial reperfusion injury.

Recent advances in thrombolytic therapy and balloon angioplasty have resulted in reperfusion therapy as a logical maneuver in the treatment of evolving myocardial infarction. The introduction of electrolytes, oxygen, and cellular elements, especially neutrophils, however, into the previously ischemic bed may initiate cellular and biochemical changes that limit the amount of potentially salvageable myocardium (reperfusion injury). Experimental studies have demonstrated that microvascular damage may play an important role in the pathogenesis of this phenomenon. Reperfusion enhances the infiltration of activated neutrophils into the ischemic bed, and neutrophil plugging of capillary lumens in association with extensive disruption of endothelial cells results in a progressive decrease in blood flow (the "no-reflow" phenomenon). Activated neutrophils may potentiate the inflammatory response, produce cellular damage, and reduce capillary blood flow by producing chemoattractants, proteolytic enzymes and reactive oxygen species, and arachidonate products, respectively. Therapeutic strategies that modify the interaction between neutrophils and endothelium have shown promising results in experimental preparations for reperfusion. The administration of both perfluorochemical (Fluosol, Alpha Therapeutic Corp., Los Angeles, California) and adenosine after reperfusion has resulted in enhanced myocardial salvage after 90 minutes of ischemia in the canine model. Histological studies have shown reduced neutrophil infiltration and relative preservation of endothelial cells without neutrophil plugging with both agents. Both adenosine and perfluorochemical have been shown to reduce neutrophil adherence and cytotoxicity to endothelial cell cultures. These findings suggest that suppression of neutrophil activation, especially chemotaxis, might be an ideal step to reduce this component from the inflammatory response in the ischemic myocardium after reperfusion. Clinical trials seem warranted to determine the role of reperfusion injury in limiting myocardial salvage in patients undergoing reperfusion within the first few hours of a thrombotic event.

Intracoronary adenosine administered after reperfusion limits vascular injury after prolonged ischemia in the canine model.

Myocardial salvage after reperfusion may be limited by deleterious vascular changes in the previously ischemic microcirculatory bed. This could result in a progressive decrease in blood flow in the capillary bed to potentially viable myocytes (no-reflow phenomenon). The effect of intracoronary adenosine on these changes was assessed in 15 closed-chest dogs subjected to 2 hours of proximal left anterior descending artery (LAD) occlusion followed by 3 hours of reperfusion. Animals randomly received adenosine (n = 8) 3.75 mg/min into the proximal LAD or an equivalent volume of saline (control) (n = 7) for 1 hour after reperfusion. Endothelial-dependent and independent coronary vasodilator reserve was determined using a chronically implanted volume-flowmeter on the mid-LAD at baseline and 1 and 3 hours after reperfusion with acetylcholine and papaverine infusions, respectively, into the proximal vessel. Regional myocardial blood flow was measured serially with radioactive microspheres and regional contractile function with contrast ventriculography. Both agonists produced a significant increase in LAD flow before occlusion. Endothelial-dependent and independent vasodilatory reserve was significantly reduced (p less than 0.05) at 1 and 3 hours after reperfusion in control animals compared with adenosine treatment. A progressive decrease in mid-LAD flow and increase in coronary vascular resistance after reperfusion was observed in control animals (p less than 0.05). The treated group manifested improved regional myocardial blood flow in endocardial regions from the central (0.73 +/- 0.15 versus 0.24 +/- 0.11 ml/g/min; p less than 0.02) and lateral ischemic zones (0.80 +/- 0.15 versus 0.34 +/- 0.12 ml/g/min; p less than 0.05) 3 hours after reperfusion. A significant reduction (p less than 0.05) in endocardial and midmyocardial flow compared with baseline was seen in control animals at 3 hours. Intravascular and interstitial neutrophil infiltration was reduced in adenosine animals and this was associated with relative ultrastructural preservation of endothelial cells. Regional ventricular function in the ischemic zone was improved in the adenosine group 3 hours after reperfusion (13.4 +/- 3.9% versus -5.3 +/- 1.6%; p less than 0.001). This study demonstrates that selective administration of adenosine after reperfusion significantly attenuates functional and structural abnormalities in the microvasculature after prolonged (2 hours) regional ischemia in the canine model. Prevention of microvascular injury and the non-reflow phenomenon by adenosine may preserve reversibly injured myocytes following restoration of blood flow to previously ischemic myocardium.

Emergent coronary angioplasty in the treatment of acute ischemic mitral regurgitation: long-term results in five cases.

Severe mitral regurgitation in the setting of an evolving myocardial infarction is associated with a high operative mortality rate. Five patients with acute severe mitral regurgitation secondary to ischemic posterior papillary muscle dysfunction underwent emergent percutaneous transluminal coronary angioplasty. Two patients were in cardiogenic shock and required intraaortic balloon counterpulsation. Angioplasty resulted in rapid improvement in hemodynamic variables, and all patients were discharged at a mean of 10 days after the procedure. Long-term follow-up study (mean 35 +/- 6 months) revealed normal mitral valve function angiographically and by Doppler echocardiography in four patients. Repeat angioplasty was required in one patient, and another underwent coronary artery bypass surgery without valve replacement for restenosis. One patient developed progressive mitral regurgitation and required elective mitral valve replacement 12 months after angioplasty. These preliminary findings suggest that emergent coronary angioplasty is a useful therapeutic intervention in the treatment of ischemic mitral regurgitation and is associated with a favorable long-term outcome.

Myocardial protection by perfluorochemical infusion during transient ischemia produced by balloon coronary occlusion.

To assess the efficacy of the perfluorochemical Fluosol-DA 20% for myocardial protection during repeated periods of balloon occlusion of the left circumflex coronary artery, 25 anesthetized dogs were randomized to receive either oxygenated perfluorochemical, (Fluosol-DA [F]; n = 10) or oxygenated Ringer's lactate (R; n = 6), at the rate of 30 ml/min, during inflation of the balloon. A control group (C; n = 9) received no infusion. A total of eight inflations were performed, each lasting 90 seconds, followed by an equivalent deflation time. Hemodynamics, ECGs, regional myocardial function, and biochemical parameters were studied. Significant differences were noted in ST segment elevation at 90 seconds of inflation in the F (1.5 mm +/- 0.6), C (3.7 mm +/- 0.75), and R (2.9 mm +/- 0.75) groups (F vs C or R p less than 0.05). This was associated with significant improvement in radial shortening in the jeopardized zone at 45 seconds into occlusion in the F group compared to the C and R groups (F = 21.1% +/- 5.1 vs C = 3.5% +/- 4.5 or R = 1.1% +/- 3.2; p less than 0.05). Results of electron microscopy showed reversible changes of ischemia within the mitochondria, and these were most marked in the C and R groups compared to the F group. Endothelial swelling was mild and was present only focally in the R and C groups. Thus perfluorochemicals may enhance the safety and efficacy of balloon angioplasty.

The pathology of mitral valve prolapse.

The gross criteria for diagnosing prolapsing mitral valve are: 1. interchordal hooding of the involved leaflets, 2. hooding or doming of leaflets towards the left atrium, 3. elongation of the involved leaflets resulting in an increase in valve area, 4. dilatation of the valve annulus in patients with severe mitral regurgitation. The posterior leaflet is most frequently affected. The involved leaflets, in general, are thickened, soft, greyish white and have a smooth atrial surface. Chordae tendineae are described as elongated, tortuous and attenuated or thinned. Deviations from normal chordal insertion have recently been observed which possibly appear to represent the underlying abnormality. Microscopic findings include significant thickening of the spongiosa and the fibrosa, changes in dense collagen fibers in the atrialis layer, occasionally, with fibrin platelet deposits. Histochemical characterization of changes in the spongiosa may also be helpful in the diagnosis. Ultrastructurally, there may be changes in collagen and elastic fibers as well as myxoid areas. On comparison of findings in surgically-removed mitral valves with those of control specimens from autopsy patients with no cardiac abnormalities, the length of the anterior and posterior leaflet as well as the annular ring diameter was larger in the valves with prolapse. Two-dimensional echocardiography accurately assessed leaflet length when compared to morphologic measurements, however, the annular diameter during systole or diastole was smaller. In patients with mitral regurgitation requiring surgery, mitral valve prolapse is the most common cause. Annular ring dilatation and chordae tendineae rupture appear to contribute substantially to incurrence of the mitral regurgitation. The heart weight is increased in the majority of patients with symptomatic mitral valve prolapse but normal, however, in those without symptoms. The most frequent complication of mitral valve prolapse is mitral regurgitation with or without congestive heart failure. Patients with redundant leaflets may be at high risk of sudden death. Young women with abnormal resting ECG, prolonged Q-T interval, family history of sudden death or complex ventricular arrhythmias may also be at a greater risk of sudden death. The incidence of infective endocarditis appears higher in those with redundant than in those with nonredundant valves. The incidence of cerebral ischemic events is low.(ABSTRACT TRUNCATED AT 400 WORDS)

Glutathione redox pathway and reperfusion injury. Effect of N-acetylcysteine on infarct size and ventricular function.

Glutathione peroxidase is an important enzyme in the degradative cascade of reactive oxygen free radicals. N-Acetylcysteine (NAC) is a low molecular weight compound that has been used clinically to replenish glutathione. To assess the role of the glutathione redox pathway on reperfusion injury, 23 animals underwent 90 minutes of proximal left anterior descending coronary artery occlusion followed by 24 hours of reperfusion with the administration of NAC (n = 11) or saline (n = 12) beginning 30 minutes into occlusion and continuing for 3 hours after reperfusion. Regional ventricular function was measured with contrast ventriculography, and regional myocardial blood flow was determined with microspheres. At 24 hours, the area at risk was defined in vivo with Monastral Blue, and the area of necrosis was defined by incubation in triphenyltetrazolium. Biopsies were taken from the ischemic and nonischemic zones to determine levels of total glutathione, superoxide dismutase and glutathione peroxidase activity, and reactivity to thiobarbituric acid, an index of lipid peroxidation. The rate-pressure product and myocardial blood flow were similar in the two groups throughout the study. No significant differences were noted in infarct size expressed as a percentage of the area at risk (28.6 +/- 5.3% vs. 36.6 +/- 6.0%) and of the total left ventricle (14.4 +/- 3.2% vs. 16.5 +/- 3.1%), and no differences were noted between the two groups on examination of the ischemic subendocardium by light and electron microscopy. Both groups exhibited similar degrees of dyskinesis during occlusion; however, treated animals showed significant improvement in regional radial shortening at 3 hours (3.4 +/- 2.4% vs. -2.4 +/- 2.1%, p less than 0.02) and 24 hours (9.2 +/- 2.2% vs. -2.5 +/- 6.3%, p less than 0.001) after reperfusion. No differences were present in total glutathione, thiobarbituric acid reactivity, or superoxide dismutase and glutathione peroxidase activity in the ischemic zones of the two groups. This study suggests that N-acetylcysteine treatment before reperfusion may reduce myocardial stunning but does not limit myocyte death after reperfusion.