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.     

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.     

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.     

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.     

Stress echocardiography in myocardial infarct

For patients with recent myocardial infarction, the main determinants of prognosis are: extent of transmural necrosis, state of the infarct-related artery and the presence and extent of myocardium at risk. The basic principle underlying the use of stress echocardiography states that myocardial ischaemia produces abnormalities of regional wall motion which are by themselves early, sensitive and specific markers of decreased perfusion. Dobutamine infusion allows for evaluation of myocardial contractile reserve by increasing inotropism. In low doses it gives us information on regional viability. In high doses, wall motion under increased oxygen demand, it becomes dependent on the ability of the coronary arteries to increase blood flow. Dipyridamole induces coronary vasodilation. In low doses it produces an increase in the blood flow. In high doses the steal effect deviates blood from the regions dependent on stenosed arteries. Ischaemia and regional wall motion abnormalities ensue. A negative stress echocardiogram, either under dobutamine or dipyridamole, has an excellent negative predictive value while a positive stress echocardiogram is predictive of an increased rate of events in the follow-up.     

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.     

Effect of catecholamine depletion on myocardial infarct size in dogs: role of catecholamines in ischemic preconditioning

OBJECTIVES: Cardioprotective adaptation to brief periods of ischemia and reperfusion is termed ischemic preconditioning (PC). Limitation of infarct size by preconditioning is associated with marked slowing of ischemic metabolism. The cause of metabolic slowing has not been determined but may involve either pro- or anti-adrenergic mechanisms. Hypothetically, adrenergic stimulation could signal the adaptive response. Alternatively, metabolic slowing during the sustained ischemic challenge could occur through a reduction in beta-adrenergic stimulation. This study was designed to test the role of cardiac norepinephrine (NE) in PC. METHODS: The effect of PC on myocardial infarct size was studied in control dogs and dogs depleted of catecholamines by pretreatment with reserpine (RES; 0.25 mg/kg i.v.). PC was induced by four cycles of 5 min of ischemia and 5 min of reperfusion. Infarcts were produced by 60 min of ischemia and 3 h of reperfusion. Cardiac NE depletion was verified by radioimmunoassay of tissue samples and by absence of hemodynamic response to a tyramine bolus (1.4 mg/kg) administered at the end of each experiment. Infarct size, expressed as percent of area at risk, was controlled for variation in collateral blood flow using analysis of covariance (ANCOVA). RESULTS: Adjusted mean infarct size was 25.5 +/- 3.2% in untreated controls vs. 19.1 +/- 3.3% in RES-treated controls (P = NS). PC limited infarct size in untreated dogs (7.4 +/- 1.8 vs. 25.5 +/- 3.2%; PC vs. control; P < 0.01) but not in RES-treated dogs (15.7 +/- 3.0% vs. 19.1 +/- 3.3%; RES + PC vs. RES; P = NS). Infarct size was larger in dogs with RES + PC than with PC alone, even though there was a trend toward a slight beneficial effect with RES alone. CONCLUSION: The cardioprotective effect of ischemic preconditioning cannot be explained entirely as an anti-adrenergic effect. On the contrary, adrenergic receptor stimulation may be required for the full expression of ischemic preconditioning in canine myocardium.     

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.