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.     

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.     

Vasospastic angina: relation to myocardial infarct and electrocardiographic variations

The vasospastic angina can manifest itself electrocardiographically in the classical form with morphasic deformation of the ST-T segment (type A), but also as decrease of the ST segment of subepicardial or subendocardial origin (type B). On the basis of own observations the two forms are compared, it is referred to connections with the myocardial infarction, adequate causes are discussed and attention is paid to particularly endangered patients.     

Pelviureteric obstruction in children: conventional pyeloplasty is superior to endo-urology

BACKGROUND: Hydronephrosis secondary to pelviureteric junction (PUJ) obstruction is common in infancy and childhood. Pyeloplasty has until recently been the accepted method of management, but alternative endo-urological techniques have evolved in the last decade. METHODS: Published results of conventional pyeloplasty for primary PUJ obstruction in children were compared with published results of endo-urological procedures. RESULTS: Sixty-six pyeloplasties were performed in 61 children in a 6-year period. During a similar period, 63 primary endo-urological procedures were reported in the literature. The success rate after pyeloplasty was 95.5% compared with 65% after endo-urology. CONCLUSIONS: Conventional pyeloplasty is superior to endo-urology and should remain the gold standard for the treatment of primary PUJ obstruction in children.     

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.     

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.     

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.     

Early evaluation of results from systemic thrombolysis in acute myocardial infarct: the value of troponin I

STUDY OBJECTIVES: This paper compares the performance of an experimental nasal positive airway pressure device that automatically adjusts the level of applied pressure (APAP) with the performance of a conventional continuous positive airway pressure (CPAP) in a sleep laboratory study. DESIGN: In a randomized sequence, conventional CPAP therapy was applied for 1 night (CPAP night) and APAP therapy the following night (APAP night). SETTING: The study was conducted in an accredited sleep disorders center. PATIENTS OR PARTICIPANTS: Twenty-six men and 5 women between the ages of 35 to 73 (51 +/- 9.6) years with body mass index 35.82 +/- 8.35 (kg/m2) who were diagnosed (using standard nocturnal polysomnography [NPSG] methods) as having OSA syndrome were studied. The subjects were treated with conventional CPAP for approximately 8 (7.79 +/- 3.16) weeks at home prior to their participation in this study. MEASUREMENTS AND RESULTS: All standard polysomnography data and nasal mask pressures were recorded using a computer-based data acquisition system. Sleep and respiratory data were scored by a registered polysomnographer. The mean apnea-hypopnea index (AHI) for subjects for the NPSG night was 55.2 +/- 33.7. It dropped to 4.2 +/- 3.8 for the CPAP night and to 5.4 +/- 5.4 for the APAP night. There was no significant (p = 0.05) difference between mean AHI indices, sleep stages, sleep stage shifts, and snore arousals for CPAP night and APAP night. However, all the measures showed significant (p = 0.05) improvement over NPSG night. The mean of APAP applied pressure (8.4 +/- 3.3 cm H2O) was significantly (p = 0.05) lower than the prescribed pressure (11.5 +/- 3.1 cm H2O), but there was no significant (p = 0.05) difference between the maximum APAP applied pressure (12.8 +/- 4.3 cm H2O) and the prescribed pressure (11.5 +/- 3.1 cm H2O). All mean comparison tests were carried out using two-tailed statistics. CONCLUSIONS: APAP appears to be as effective as CPAP in treating OSA patients. APAP delivers the same level of therapy as CPAP, but it reduces the average airway pressure while providing needed peak pressures.     

Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats

Programmed cell death in the myocardium has been linked to ischemia reperfusion injury as well as to excessive mechanical forces associated with increases in ventricular loading. Moreover, hypoxia activates the suicide program of cardiac myocytes in vitro. Because the supplied portion of the ventricular wall is ischemic and subjected to high levels of systolic and diastolic stresses (acutely after coronary artery occlusion), apoptosis and necrosis may contribute independently to myocyte cell death after infarction. Therefore, myocardial infarction was produced in rats, and, after the determination of ventricular hemodynamics, the contribution of apoptotic and/or necrotic myocyte cell death to infarct size was measured quantitatively from 20 minutes to 7 days after coronary artery occlusion. Programmed cell death was assessed by the terminal deoxynucleotidyl transferase assay and by the electrophoretic detection of DNA laddering. Myocyte necrosis was evaluated by myosin monoclonal Ab labeling. Moreover, the expression of Bcl-2, Bax, and Fas proteins in myocytes was examined by immunocytochemistry. Myocyte cell death by apoptosis and necrosis comprised nearly 3 million myocytes at 2 hours. Apoptotic cell death involved 2.8 million cells and necrotic cell death only 90,000 myocytes. Apoptosis continued to represent the major independent form of myocyte cell death, affecting 6.6 million myocytes at 4.5 hours. Myocyte necrosis peaked at 1 day, including 1.1 million myocytes. DNA electrophoretic analysis confirmed these observations by showing nucleosomal ladders at 2-3 hours, 4.5 hours, 1 day, and 2 days after coronary artery occlusion. Myocytes showing both DNA strand breaks and myosin labeling were a prominent aspect of myocardial damage only after 6 hours. Finally, the expression of Bcl-2 and Fas in myocytes increased 18-fold and 131-fold, respectively. In conclusion, programmed myocyte cell death is the major form of myocardial damage produced by occlusion of a major epicardial coronary artery, whereas necrotic myocyte cell death follows apoptosis and contributes to the progressive loss of cells with time after infarction. The enhanced expression of Fas may be implicated in the activation of apoptosis in spite of the increase in Bcl-2, which tends to preserve cell survival.     

Hemodynamic evaluation in acute myocardial infarct. Application to the treatment of contractile insufficiency syndromes of the left ventricle

Even though the coronary care units have reduced to a minimum the mortality due to arrhythmias, the syndromes of left ventricular failure are responsible for the greatest part of hospital deaths in patients with acute myocardial infarction. The poor results depend upon the extensive destruction of left ventricular mass. The management in these cases should be directed to improve the performance of viable muscle as well as to preserve thejeopardized ischemic myocardium that is potentially viable. These goals may be adequately pursued by continuous hemodynamic characterization of left ventricular function. The experience of the Coronary Care Unit of the Instituto Nacional de Cardiología de México in the study of 30 of these patients is presented. Hemodynamic evaluations were performed by means of a Swan-Ganz catheter and cardiac output determinations by the thermodilution technique. The studies may be performed with a minimum of risk. Central venous pressure measurements do not adequately indicate the status of the left ventricle. Its function may be evaluated by the use of end diastolic pulmonary artery pressure which reflects, quite accurately, the left ventricular filling pressure in these patients. Continuous hemodynamic monitorization facilitates the proper manipulation of the determinants of ventricular performance (preload, afterload, cardiac rate and contractility) and permits an attempt to improve the balance between available oxygen and myocardial oxygen requirements. Hemodynamic studies and ventricular function curves are presented in selected patients with acute myocardial infarction. The mortality due to left ventricular failure and cardiogenic shock in patients with acute myocardial infarction remains extremely high. However, it is only through the early recognition by continuous hemodynamic monitorization and the aggressive management of the patient with incipient left ventricular failure that the number of survivors may be increased.     

Serum levels of cardiac troponin I and troponin T in estimating myocardial infarct size soon after reperfusion

BACKGROUND: Cardiac troponin I (TnI) and troponin T (TnT) are highly specific myocardial markers. OBJECTIVE: To determine whether their serum levels can be used to estimate myocardial infarct size soon after reperfusion. METHODS: We measured the serum levels of TnI, TnT, and creatine kinase every 3 h, and the serum cardiac myosin light chain I (MLCI) every 24 h, in 42 patients with acute myocardial infarction in whom reperfusion therapy had successfully been performed. We calculated the severity of regional hypokinesis by analyzing the follow-up ventriculograms with the centerline method. RESULTS: The time from reperfusion to the peak level for TnI was 6.1 +/- 3.5 h, significantly shorter than those for creatine kinase (7.5 +/- 4.1 h) and MLCI (55 +/- 28 h). The time to peak level for TnT (6.8 +/- 4.0 h) differed significantly from that for MLCI but not from that for creatine kinase. There was a significant correlation between the peak levels of TnI and TnT (r = 0.86). The peak TnI and TnT levels were correlated well to the peak creatine kinase level (r = 0.67 and 0.69, respectively), total creatine kinase release (r = 0.66 and 0.66), and the peak MLCI level (r = 0.71 and 0.80). We observed excellent correlations between the peak levels of TnI and TnT, and regional hypokinesis (r = -0.84 and -0.85, respectively). These were comparable to the correlations between regional hypokinesis and the peak creatine kinase level (r = 0.75), total creatine kinase release (r = -0.72), and the peak MLCI level (r = -0.76). CONCLUSIONS: These results suggest that the peak serum levels of TnI and TnT in patients with successful reperfusion are accurate and early indices of infarct size.     

Comparative evaluation of different physical load tests in patients who have had a myocardial infarct

A comparative analysis of the results of exercise tests conducted in 2 groups of patients following myocardial infarction was done on the basis of data from the A.L. Myasnikov Institute of Cardiology, USSR Acad. Med. Sci., and the research group of medical rehabilitation of the Humboldt University, Berlin. Continuous and interrupted step-wisely growing bicycle exercises in sitting position were compared. The duration of each step comprised 5 min with pedalling at 60 rpm. With continuous tests every step increase the workload by 25 W. With stepwise tests in half of the patients the work load was increasing by 25 W every step, in the other half--by 16.7 W, the pause between the steps lasting 10 min. It was found that the main parameters of both types of tests did not differ in the two centers, as shown by statistical processing; an identical threshold capacity of the workload, equal elevations of the arterial pressure and heart contractions rate at the peak of the test were obtained. No differences were revealed in the criteria of test interruption with both types of examinations in the two centers. A slight tendency towards a greater elevation of the heart contractions rate and systolic arterial pressure was noted with continuous tests, in contrast to the step-wise. This results in a greater variance of the workability parameters when comparing the results. Therefore it seems preferable to conduct one type of tests--the continuous one.