Inhibition of neutrophil adhesion reduces myocardial infarct size

Neutrophil accumulation and activation within the myocardium during ischemia and reperfusion has been shown to play a prominent role in the development of myocardial stunning and infarction. To determine if a simple inhibitor of neutrophil adhesion could reduce myocardial infarct size, we administered NPC 15669 (a new antiinflammatory agent that inhibits neutrophil adhesion) to 12 pigs (6 controls, 6 NPC-treated) in a porcine model of ischemia and reperfusion injury. Each animal received a continuous infusion of either NPC (10 mg/kg intravenous bolus followed by 6 mg.kg-1 x h-1 intravenous infusion) or an equal volume of normal saline solution during 1 hour of left anterior descending artery occlusion and 2 hours of reperfusion. There were no significant differences in the pre-ischemia, mid-ischemia, or postischemia rate-pressure product between control and experimental groups. The regions at risk were similar in both groups. However, the mean myocardial infarct size was reduced by 51% with administration of NPC 15669 (30.7% +/- 6.8%) compared with controls (62.3% +/- 5.4%; p < 0.01). These data indicate that NPC 15669, an inhibitor of neutrophil adhesion, substantially reduces myocardial infarct size after transient left anterior descending artery occlusion and that adhesion of the white cell to vascular endothelium may be an important element of the pathogenesis of myocardial infarction.     

Reduction of myocardial infarct size in vivo by carbohydrate-based glycomimetics

One of the foremost mechanisms involved in the pathogenesis of myocardial reperfusion injury is the adhesion of neutrophils within the myocardium. The initial neutrophil-endothelial cell interactions are mediated by the selectin family of adhesion molecules. Blockade of this group of adhesion molecules, through the use of synthetic carbohydrate analogs to the selectin ligand sialyl Lewisx and glycomimetics, has been beneficial in reducing neutrophil influx and infarct size. In the present study, glycyrrhizin (GM1292), a natural structural glycomimetic, was analyzed for the ability to decrease myocardial infarct size after regional myocardial ischemia/reperfusion. To determine the structural requirements for optimal cardioprotective activity, two additional compounds related to glycyrrhizin, GM3290 and GM1658 (glycyrrhetinic acid), were studied. The molecular structures of the latter two compounds differ in the number of glucuronic acid residues in their respective molecules. Open-chest, anesthetized rabbits were subjected to 30 min occlusion of the left coronary artery followed by 5 hr of reperfusion. Vehicle or glycomimetic (10 mg/kg/hr) was administered intravenously immediately before the onset of reperfusion and every hour during the reperfusion period. Myocardial infarct size in rabbits treated with GM1292 (two glucuronic acid residues) and GM3290 (one glucuronic acid residue) was reduced significantly when compared with vehicle-treated animals (P < .05). GM1658, which lacks glucuronic acid residues, did not provide a protective effect in vivo. The data suggest that GM1292 and GM3290, which contain carbohydrate moieties, are effective in reducing the degree of myocardial injury after an acute period of ischemia/reperfusion.     

Clinical and metabolic aspects of juvenile myocardial infarct

A clinical and metabolic study of 61 patients with myoocardial infarct before the age of 40 yr showed a high frequency of familial involvement, particularly in subjects with type IIA and IIB hyperbetalipoproteinaemia. Excess weight and arterial hypertension were rare, while premonitory angina was absent in 59%. Four subjects were diabetic. Oral glucose tolerance was normal in 14 and of diabetic type in 26 of 40 patients examined; the insulin response pointed to insulin-resistance. Dyslipidaemia was noted in 45%, including type IIA and IIB hyperbetalipoproteinaemia in 27%. Distribution of the frequency of infarct in function of cholesterolaemia classes gave a bimodal curve indicative of distinct normo- and hypercholesterolaemic groups within the series. Reduced glucose tolerance was more frequent in patients with low blood cholesterol. This suggests that reduced tolerance and high blood cholesterol are independent risk factors in coronary disease. No relation between the clinical and metabolic data could be ascertained.     

Clinical prediction of the early prognosis in acute myocardial infarct

Several clinical factors can influence the pathophysiology, clinical course and prognosis of acute myocardial by different means. Some of them may be easily detected through the history, physical examination or ECG in an early phase. The knowledge of these factors may help the therapeutic decision making of patients with myocardial infarction. The influence for the main clinical factors (age, sex, risk factors, cardiologic antecedents and evolutive findings) on the short-term prognosis of acute myocardial infarction is reviewed. An analysis of the likely mechanisms of the influence of these factors on infarct prognosis is also performed.     

Modification of infarct size

The persistent high mortality from power failure resulting from myocardial infarction has stimulated an intensive search for methods of reducing infarct size, which has been shown to relate directly to the occurrence of power failure. By analyzing the time course of myocardial injury during ischemia, the reversibility of lesions with reperfusion, and the characteristics of reversibly injured tissues along the border zone of ischemic areas, concepts have been formulated regarding the possibility of salvaging marginally injured cells. Measures designed to diminish myocardial oxygen consumption, to increase blood flow or oxygen supply to ischemic areas, to increase substrate availability, or to change the degree of swelling and autolysis of injured cells have all been tested in experimental animals with some success. These methods are just beginning to be tested in the clinical setting, and, if successful, will no doubt usher in a new era in medical therapy for acute myocardial infarction.     

Cyclosporine A limits myocardial infarct size even when administered after onset of ischemia

OBJECTIVE: The role of the immunosuppressant cyclosporine A as a preconditioning-mimetic in the rabbit heart was examined. METHODS: Cyclosporine A, a potent protein 2B or calcium/calmodulin-dependent phosphatase (PP) inhibitor, was administered isolated rabbit hearts starting either 15 min prior to or 10 or 20 min after the onset of a 30 min period of regional ischemia and continuing until the onset of reperfusion. The effect of pretreatment with a second PP2B antagonist, FK-506, was also examined. In an additional protocol L-NAME was perfused for 50 min starting 5 min before the 45-min infusion of cyclosporine A. After 2 h of reperfusion infarct size was measured with triphenyltetrazolium chloride. In a second study left ventricular biopsies of isolated rabbit hearts were obtained to measure the effect of cyclosporine A on dephosphorylation of [32P] phosphorylase kinase by calcium/calmodulin-dependent phosphatases. RESULTS: Pretreatment with cyclosporine A resulted in only 10.0%, infarction of the risk zone, significantly less than that in untreated control hearts (28.7%, p < 0.001) but comparable to the extent of infarction in ischemically preconditioned hearts (10.0% p < 0.001 vs. control). Equivalent protection was also observed in hearts with treatment delayed for 10 min following the onset of ischemia (10.4% infarction, p < 0.001 vs. control). However, protection waned when cyclosporine A was administered only during the last 10 min of the 30-min ischemic period (25.5% infarction, p = n.s. vs. control). Pretreatment with FK-506 also resulted in myocardial salvage (10.4% infarction, p < 0.001 vs. control). When hearts were exposed to a co-infusion of L-NAME and cyclosporine A, protection was still evident (18.1% infarction, p < 0.05 vs. L-NAME), although not as robust as that seen with the PP2B blocker alone. In hearts pretreated with cyclosporine A dephosphorylation of [32P] phosphorylase kinase by calcium/calmodulin-dependent phosphatases was inhibited by 67%. CONCLUSIONS: Cyclosporine A and FK-506, potent PP2B inhibitors, can protect the ischemic rabbit heart, and at least cyclosporine A continues to be effective when infusion is delayed until after the onset of ischemia. The mechanism of this protection may be related to inhibition of phosphatases and prolongation of the phosphorylation state of ischemic cells.     

Influence of an early adrenergic blockade on thrombotic infarct size and myocardial metabolism

To evaluate the extent to which the protective effect of metoprolol was accompanied by changes in myocardial oxygen consumption and metabolism, thrombotic occlusion of coronary artery followed by infusion of metoprolol or placebo was performed in twenty four German Shepherds. To restore a coronary blood flow rt-PA was administered. Plasma levels of oxygen, glucose, lactic acid, non esterified fatty acids, triacylglyceride and adenosine breakdown products were measured before and at the end of the occlusion and in the early and late reperfusion periods. Regional myocardial blood flow was measured by means of radioactive tracer microspheres. Infarct size was estimated after perfusion and staining of excised hearts with Evans blue. Plasma levels of metoprolol were determinated before the end of occlusion and during reperfusion and therapeutic concentrations were confirmed. The infarct size was smaller in dogs receiving metoprolol (21.6 +/- 20.7 vs 43.0 +/- 17.3% p. < 0.02). Coronary collateral blood flow was greater in metoprolol than in placebo dogs (18.68 +/- 7.58 vs 11.05 +/- 6.10 ml/min/100g, p. < 0.01). As a consequence of myocardial ischemia a shift toward carbohydrate utilization, the myocardial lactate release and the accompanying symptoms of diminished myocardial lipid uptake were observed. A washout of adenosine degradation products during early reperfusion was also noticed. In beta 1 blocked animals the reduction of myocardial oxygen consumption and preserved myocardial uptake of lactate and non esterified fatty acids were documented.     

Prospective identification of myocardial stunning using technetium-99m sestamibi-based measurements of infarct size

OBJECTIVES: We sought to prospectively identify patients with stunning and hyperkinesia at hospital discharge on the basis of mismatches between left ventricular (LV) function and infarct size as assessed by technetium-99m (Tc-99m) sestamibi perfusion tomographic imaging. BACKGROUND: Mechanical indexes of LV function may not accurately reflect myocardial damage after acute myocardial infarction (MI) because of myocardial stunning and compensatory hyperkinesia in noninfarct-related territories. Myocardial perfusion techniques are unaffected by these variables. METHODS: Eighty-four patients with acute MI underwent hospital admission and discharge Tc-99m-sestamibi tomographic imaging. Global LV ejection fraction (LVEF) was measured at hospital discharge and 6 weeks later. The perfusion defect size was quantified and expressed as a percentage of the LV. The discharge perfusion defect, which is a measure of infarct size, was used to predict the 6-week LVEF for each patient based on a previously reported regression equation. Patients were classified into one of three groups depending on whether their LVEF at hospital discharge fell within, above or below one standard error (6.8 LVEF points) of the predicted 6-week LVEF. RESULTS: There were 48 patients classified as having a "match" between function and infarct size; these patients demonstrated no significant change in LVEF at 6 weeks. There were 21 patients (25%) classified as "mismatch stunned" who had discharge LVEFs lower than those predicted by infarct size. These patients demonstrated a significant improvement in mean LVEF at 6 weeks (mean [+/-SD] discharge LVEF 0.41 +/- 0.08, 6-week LVEF 0.47 +/- 0.10; p = 0.003). Fifteen patients (18%) were classified as "mismatch-hyperkinetic." The mean LVEF for these patients significantly declined at 6 weeks (discharge LVEF 0.64 +/- 0.06, 6-week LVEF 0.58 +/- 0.09; p = 0.002). There was a marked increase in LVEF within the infarct zone (8 +/- 15 LVEF points; p = 0.03) for patients predicted to have stunning and a marked decline in LVEF outside the infarct zone (9 +/- 15 LVEF points; p = 0.06) in patients predicted to have hyperkinesia. Both discharge LVEF (p < 0.0001) and group classification (p = 0.005) were independent predictors of LVEF 6 weeks later. CONCLUSIONS: Perfusion imaging with Tc-99m-sestamibi can identify post-MI patients at hospital discharge in whom LV function is discordant with the measured infarct size. Patients with stunning have late increases in LVEF; patients with hyperkinesia have late decreases. This methodology, performed at discharge, is predictive of late changes in LV function.     

Non-invasive methods for evaluating reperfusion in acute myocardial infarct: enzymes and MIBI-SPECT cardiac gammagraphy

INTRODUCTION: Several studies point out the importance of what is called rescue angioplasty or fibrinolysis when thrombolysis has been ineffective in acute myocardial infarction. Therefore, it is necessary to make use of new non-invasive methods to asses reperfusion and to safely establish that such a treatment has not been effective. PATIENTS AND METHOD: We present a work which is based on the assessment of patients with acute myocardial infarction treated with or without fibrinolysis. After determining cardiac enzymatic profiles of creatine kinase and MB isoform (time course, peak, appearance rate constant time-activity: K1). With cardiac imaging gammagraphies 99mTc-isonitrile-single-photon emission computed tomography pre and post treatment after to calculating myocardium at risk, salvage and relationship. RESULTS: In patients treated with fibrinolysis, the salvage myocardium was higher (8.3% vs 3.0%; p < 0.05). Considering that an improvement in perfusion defect (salvaged myocardium/myocardium at risk) higher than 30% can be viewed as an effective reperfusion, we can see that the percentage in the group treated with fibrinolysis being 45.8%, and the percentage in the group under conventional treatment being just 6.7%. Patients with acute myocardial infarction treated with fibrinolysis show much shorter start of rise-peak time and pain-peak time, all this with very significant differences for the creatine kinase (p < 0.0001) as well as for the MB (p < 0.001). Patients with reperfusion show a rapid increase in activity enzymatic, as demonstrated by the pain-peak time variable and the appearance rate constant time-activity (K1), with very significant differences in the latter (p < 0.0001). In relation with gammagraphy, values of K1 higher or equal to 0.19 for the creatine kinase and 0.14 for the MB isoform, achieved a sensibility of 83% and 91%, and a specificity of 85% and 80% respectively, to asses reperfusion. CONCLUSION: We think that cardiac imaging gammagraphy with isonitriles as well as as determination of the appearance rate enzymatic constant time-activity, can be useful in monitoring treatment with fibrinolysis in infarction patients. New studies are needed to assess these same aspects, with a lesser number of enzymatic determinations.     

The role of the coronary collateral circulation in limiting myocardial ischemia and infarct size

The role of coronary collateral circulation in limiting ischemia and infarction has been studied prospectively. Transient occlusion of a coronary artery angioplasty has provided evidence that collateral circulation decreases wall motion abnormalities, ST segment changes, and lactate production. Patients who have collateral flow also have a better outcome after coronary artery dissection and acute closure than patients without collateral flow. Collateral circulation also limits infarct size during acute myocardial infarction with and without thrombolysis. Although collateral flow may decrease coronary artery bypass graft patency in certain subgroups of patients, the perioperative infarct rate and mortality is decreased. Growth factors have been identified that increase the development collateral circulation and may improve ventricular function in the setting of myocardial infarction.     

Effect of ethanol on myocardial infarct size in a canine model of coronary artery occlusion-reperfusion

INTRODUCTION: We investigated the effectiveness of Levovist (SHU508A, Schering AG, Berlin, Germany) in the characterization of breast lesions. MATERIAL AND METHODS: June, 1996, to May, 1997, we studied 29 solid lesions in 29 patients (aged 17 to 83 years); our patients were 28 women and 1 man. The 29 solid lesions were 20 carcinomas (15 infiltrating ductal carcinomas, 4 ductal carcinomas in situ, 1 lobular carcinoma in situ), 6 fibroadenomas, 1 suspected postoperative recurrence and 2 apparently benign lesions. We used parameters suitable for the study of slow flows. A single bolus of contrast agent (300 mg/mL) was administered at 1-2 mL/s. Before Levovist injection, we studied the lesion signal intensity and the number of vascular poles. After contrast administration we re-evaluated both these parameters and studied the changes or presence of vessels undetected on the previous images. We also investigated the beginning and duration of enhancement and the presence of vessels inside and outside the lesions. RESULTS: We observed no signal enhancement in 17% of cases, mild enhancement in 7% and strong enhancement in 76% of cases. We found 3 more vascular poles (17%) in 5 lesions and 4 more poles in 3 lesions (10%). Increased vascularization was seen inside the lesion in 17% of cases, inside and outside it in 41% and only outside in 35% of cases. Carcinomas showed a rapid and long-lasting enhancement, while fibroadenomas showed a later and weaker enhancement. CONCLUSIONS: Levovist can be useful in the differential diagnosis of benign from malignant lesions, of recurrences from postoperative fibrosis, as well as in the staging and follow-up of the patients treated with neoadjuvant chemotherapy.     

Secondary prevention of myocardial infarct

Preventive measures are the most powerful measures to treat manifestations of ischemic cardiopathy. Secondary prevention of myocardial infarction involves the following intervention areas: a) Limitation of adverse physiological and emotional consequences of the acute illness; b) Identification of the patients particularly exposed to the risk of new episodes of ischemic cardiopathy or to their consequences, namely reinfarction and sudden death; c) Institution of therapeutic attitudes, surgical or medical, that can prolong life and can oppose functional deterioration and prevent symptoms; d) Institution of measures that can oppose the progression of the initial disease that is, in almost all cases, atherosclerosis. Measures that can oppose the progression of cardiac disease and its consequences after an episode of myocardial infarction, and measures that can oppose the evolution of atherosclerosis are described in this article. The measures that can influence the risk factors after an episode of myocardial infarction are briefly commented: characteristics related to life style and physical exercise; smoking habits; plasmatic lipid levels; high blood pressure; and therapeutic substitution with estrogens after menopause. Pharmacological interventions in secondary prevention of myocardial infarction are described, namely with the following groups of substances: beta-adrenergic blocking agents; platelet active agents; anticoagulants; and angiotensin-converting enzyme inhibitors.     

Morphogenesis of atypical myocardial infarct

Morphology of atypical myocardial infarctions and their morphogenesis were studied in 120 cases. The importance of atherosclerosis as the background process, the secondary development of coronary thrombosis and the leading role of metabolic factors (hypoxy, acidosis, etc) in the origin of atypical myocardial infarctions were established.