Role In Acute Myocardial Infarction Research Articles

The endothelin system and its role in acute myocardial infarction.

Immediately after an acute myocardial infarction (AMI) or in models of ischemia-reperfusion injury, cardiac endothelin (ET) system is markedly activated, and plasma levels of ET are increased. In the heart, expression of the main components of the ET system (ET-1 peptide, both receptor subtypes ETA and ETB, though not endothelin converting enzyme) are increased both at the gene level and protein level, in the viable myocardium, and--even more substantially--in the necrotic area. Despite these conspicuous abnormalities, the role of ET in this setting remains unclear. In the absence of human data, most short-term studies in animals (in terms of hours to up to 8 days post-AMI) and in the reperfused ischemic heart, have found beneficial effects of ET receptor blockade on survival rate, incidence of arrhythmias, cardiac function, and morphology. In contrast, many studies in which a long-term ET inhibition was started immediately post-infarction and the late effects were examined in animals with ensuing chronic heart failure (14-100 days postinfarction), adverse effects were also observed, such as scar thinning, further ventricular dilation, or even a worse survival rate. It appears that the ET system plays a dual role during the early post-AMI period. At present, it is not clear whether the short-term beneficial effects or long-term adverse effects of ET receptor blockade would prevail. Acute use of short-acting ET receptor antagonists in patients with AMI complicated by an acute heart failure is an attractive possibility that also remains to be investigated.

Variation in the alpha2B-adrenoceptorgene as a risk factor for prehospitalfatal myocardial infarction and sudden cardiac death

ObjectivesOur aim was to corroborate the observed association between the deletion/deletion (DD) genotype of the insertion/deletion polymorphism in the alpha2B-adrenoceptor (AR) and increased risk for acute myocardial infarction (AMI), and to study whether this genotype also confers an increased risk for sudden cardiac death (SCD). BackgroundVasospasm has been suggested to play a role in AMI. Alpha2-AR mediate coronary vasoconstriction in humans, and studies on mice suggest the involvement of the alpha2-AR subtype B in vasoconstriction. A deletion variant of the human alpha2B-AR has been associated with impaired receptor desensitization in vitro. In a population-based prospective study of 912 middle-aged men, the DD genotype of the alpha2B-AR conferred an increased risk for AMI. MethodsA series of 700 unselected sudden out-of-hospital deaths of middle-aged white men subjected to medico-legal autopsy was analyzed. ResultsGenotype information was obtained for 683 men (DD = 22%, insertion/deletion = 51%, insertion/insertion = 27%). Carriers of the DD genotype had an increased risk for SCD (n = 278, odds ratio [OR] = 2.0, p = 0.01) and fatal AMI (n = 84, OR = 2.1, p = 0.04) compared with the other two genotypes combined. The risks for SCD and fatal AMI were higher in carriers of the DD genotype who died before the age of 55 years (OR = 4.5 and 5.0, p < 0.001 for both). ConclusionsMiddle-aged white men carrying the DD genotype of the alpha2B-AR have a significantly increased risk for SCD and AMI, especially before the age of 55 years.

Inhibition of mitochondrial calcium-independent phospholipase A2 (iPLA2) attenuates mitochondrial phospholipid loss and is cardioprotective.

Calcium-independent phospholipase A(2) (iPLA(2)) is the predominant phospholipase A(2) present in myocardium, and its pathophysiological role in acute myocardial infarction has been suggested by the rapid increase in membrane-associated iPLA(2) activity during myocardial ischaemia and reperfusion (I/R). We therefore examined iPLA(2) in mitochondrial fractions prepared from Langendorff-perfused adult rabbit hearts. Our studies indicate that iPLA(2)beta is present in rabbit heart mitochondrial inner membranes with no apparent translocation during ischaemia, I/R or preconditioning. Mitochondrion-associated iPLA(2) was catalytically competent and exhibited 2-, 3- and 2.5-fold increases in measured iPLA(2) activity following ischaemia, I/R and preconditioning, respectively, when compared with the activity of iPLA(2) measured in mitochondria from control hearts. Mitochondrial phospholipids are essential for maintaining the ordered structure and function of the organelle. I/R resulted in a rapid overall decrease in phosphatidylcholine and phosphatidylethanolamine glycerophospholipid species, as determined by electrospray ionization MS, that was partially alleviated by pretreatment of hearts with the iPLA(2)-specific inhibitor, bromoenol lactone (BEL). Pretreatment of I/R hearts with 10 microM BEL significantly reduced the infarct size almost to that of continuously perfused hearts and was cardioprotective only when administered prior to ischaemia. Cardioprotection by BEL was reversed by the simultaneous perfusion of 100 microM 5-hydroxydecanoate, implicating the mitochondrial K(ATP) channel in BEL-mediated protection from I/R. Preconditioning also significantly reduced the infarct size in response to I/R but protection was lost by concurrent perfusion of 10 microM arachidonic acid. Taken together, these data strongly implicate mitochondria-associated iPLA(2) in the signal transduction of myocardial I/R injury.

Inhibition of mitochondrial calcium-independent phospholipase A2 (iPLA2) attenuates mitochondrial phospholipid loss and is cardioprotective

Calcium-independent phospholipase A2 (iPLA2) is the predominant phospholipase A2 present in myocardium, and its pathophysiological role in acute myocardial infarction has been suggested by the rapid increase in membrane-associated iPLA2 activity during myocardial ischaemia and reperfusion (I/R). We therefore examined iPLA2 in mitochondrial fractions prepared from Langendorff-perfused adult rabbit hearts. Our studies indicate that iPLA2β is present in rabbit heart mitochondrial inner membranes with no apparent translocation during ischaemia, I/R or preconditioning. Mitochondrion-associated iPLA2 was catalytically competent and exhibited 2-, 3- and 2.5-fold increases in measured iPLA2 activity following ischaemia, I/R and preconditioning, respectively, when compared with the activity of iPLA2 measured in mitochondria from control hearts. Mitochondrial phospholipids are essential for maintaining the ordered structure and function of the organelle. I/R resulted in a rapid overall decrease in phosphatidylcholine and phosphatidylethanolamine glycerophospholipid species, as determined by electrospray ionization MS, that was partially alleviated by pretreatment of hearts with the iPLA2-specific inhibitor, bromoenol lactone (BEL). Pretreatment of I/R hearts with 10μM BEL significantly reduced the infarct size almost to that of continuously perfused hearts and was cardioprotective only when administered prior to ischaemia. Cardioprotection by BEL was reversed by the simultaneous perfusion of 100μM 5-hydroxydecanoate, implicating the mitochondrial KATP channel in BEL-mediated protection from I/R. Preconditioning also significantly reduced the infarct size in response to I/R but protection was lost by concurrent perfusion of 10μM arachidonic acid. Taken together, these data strongly implicate mitochondria-associated iPLA2 in the signal transduction of myocardial I/R injury.

Increased plasma levels of the soluble form of fas ligand in patients with acute myocardial infarction and unstable angina pectoris

ObjectivesTo examine whether the Fas/Fas ligand system is involved in the pathogenesis of acute myocardial infarction (AMI), we measured the levels of the soluble form of the Fas ligand (sFasL) in the plasma of patients with AMI and stable or unstable angina pectoris (AP). BackgroundThe Fas ligand (FasL) is rapidly cleaved off by a metalloproteinase from the cell membrane to become a soluble form as a cytokine. Fas is expressed in most cells, including cardiomyocytes, whereas FasL is mainly expressed in inflammatory cells such as macrophages, which are greatly accumulated in unstable plaque. MethodsThirty patients with AMI, 10 patients with unstable AP, 10 patients with stable AP and 30 control subjects were enrolled in the present study. ResultsPlasma sFasL levels were significantly elevated on hospital admission in patients with AMI and unstable AP, compared with control subjects. Time-course studies revealed that plasma sFasL levels rapidly decreased within 3 h and then increased again after percutaneous transluminal coronary angioplasty in patients with AMI, but not in patients with stable AP. Importantly, the sFasL levels were higher in the coronary sinus than in the circulation. In addition, in vitro studies showed that the expression of FasL messenger ribonucleic acid was upregulated in mononuclear cells isolated from patients with AMI and that hypoxia stimulated the release of sFasL from isolated mononuclear cells. ConclusionsThis demonstration of elevated levels of sFasL in patients with AMI and unstable AP suggests that activation of the Fas/FasL system may play a pathogenic role in AMI and acute coronary syndromes.

Superiority of Enoxaparin Over Heparin in Combination With a GPIIb/IIIa Receptor Antagonist During Coronary Thrombolysis in Dogs

It is known that a low-molecular-weight heparin (LMWH) is more effective than unfractionated heparin in unstable angina/non-Q-wave myocardial infarction (UA/NQMI) and the platelet GPIIb/IIIa receptors play an important role in acute myocardial infarction (AMI). Therefore, enoxaparin might have a similar advantage over heparin when used with a GPIIb/IIIa antagonist (RPR109891) in coronary thrombolysis. After induction of coronary thrombosis in anesthetized dogs, infusion of saline, enoxaparin, heparin, RPR109891, enoxaparin+RPR109891, or heparin+RPR109891 was initiated followed 15 min later by recombinant tissue plasminogen activator (rt-PA). The incidence of reperfusion in the enoxaparin+RPR109891- and the heparin+RPR109891-treated groups was similar, but time to reperfusion tended to be shorter for enoxaparin versus heparin. Only 43% of the vessels reoccluded in the enoxaparin+RPR109891 group, compared to 100% vessels in the heparin+RPR109891 group. Enoxaparin+RPR109891 maintained flow for a significantly longer time compared to saline, enoxaparin, heparin, and heparin+RPR109891. Enoxaparin+RPR109891 and heparin+RPR109891 increased the template bleeding time by 2- and 3-fold and activated partial thromboplastin time (APTT) by 1.3- and 3-fold, respectively. These data suggest that enoxaparin is more effective and potentially safer than heparin when combined with a GPIIb/IIIa receptor antagonist during rt-PA-induced coronary thrombolysis.

Kinetics of tumor necrosis factor α in plasma and the cardioprotective effect of a monoclonal antibody to tumor necrosis factor α in acute myocardial infarction

Background Inflammation plays a critical role in acute myocardial infarction (AMI) and tumor necrosis factor alpha (TNF-α) is a potent inflammatory trigger. This study was designed to examine the kinetics of TNF-α in plasma in patients with AMI and the potential benefit of inhibition of TNF-α monoclonal antibody in AMI. Methods And Results TNF-α levels in plasma were measured in 42 patients with AMI. TNF-α levels were elevated at 4 hours after onset of chest pain and declined to control values at 48 hours. TNF-α levels were higher in patients with Killip III and IV than in those with Killip I and II ( P < .01). To examine the pathogenic role of TNF-α, New Zealand White rabbits were treated with buffer or a TNF-α monoclonal antibody before left anterior descending artery (LAD) ligation. Treatment with the TNF-α monoclonal antibody decreased area of necrosis, number of circulating endothelial cells, and lipid peroxidation product malonaldehyde bis(dimethyl acetal). There was a significant correlation of TNF-α levels with peak CK-MB in AMI patients, and area of necrosis, MDA, and circulating endothelial cells in rabbits (all P < .05). Conclusions TNF-α release early in the course of AMI contributes to myocardial injury and dysfunction. Treatment with the monoclonal antibody against TNF-α can be cardioprotective, particularly in the setting of heart failure in patients with AMI. (Am Heart J 1999;137:1145-52).

Platelet and Thrombin Inhibitors as Adjuncts to Thrombolytic Therapy and Percutaneous Coronary Interventions: A Review

A large body of evidence supports the critical role of thrombus formation in the pathogenesis of acute MI as well as the early ischemic complications after percutaneous coronary interventions. Both platelets and the plasma proteins involved in fibrin formation are intimately involved in the thrombotic process. Recently, pharmacological agents that hinder fibrin formation and platelet activation or aggregation have been developed. These drugs are being tested in patients with acute MI, in conjunction with thrombolytic agents, and in patients undergoing percutaneous coronary interventions. So far, the antiplatelet agents appear very promising in the area of percutaneous coronary intervention. Information on their role in acute myocardial infarction is still too preliminary to draw conclusions. Results with antithrombin agents have been less promising. This article will briefly describe the mechanisms of thrombus formation, detail the mechanism of action of available antithrombotic pharmacological agents, and review recent clinical trials of these agents.

Calcium-channel blockers in ischemic heart disease.

Recent reports add to a growing body of evidence that short-acting calcium-channel blockers, whether used for hypertension, unstable angina, or acute myocardial infarction, may have unfavorable effects. Short-acting nifedipine has no role in acute myocardial infarction, and the United States Food and Drug Administration has recently issued a warning discouraging its use in hypertension and unstable angina. Other short-acting calcium antagonists such as diltiazem and verapamil may have associated adverse effects as well, although the evidence is not as definitive. What effect sustained-release preparations and newer calcium antagonists have on the clinical endpoints of myocardial infarction and death is not known, and large prospective randomized clinical trials with these medications, some of which are underway, are needed to address these issues. Until that time, only medications with clearly documented efficacy and safety should be used for first-line therapy for hypertension, unstable angina, and acute myocardial infarction.

Magnesium sulfate reduces myocardial infarct size when administered before but not after coronary reperfusion in a canine model.

The role of magnesium in treating acute myocardial infarction (AMI) has been controversial. Several small clinical trials indicate that magnesium may have a role in treating AMI early, whereas the other results suggest that magnesium is of questionable benefit. We looked at the effect of magnesium on infarct size (IS) when given during a coronary occlusion and after reperfusion. Magnesium sulfate (6-mEq bolus plus 2 mEq/h for 5 hours) was given at 15 or 45 minutes of coronary occlusion or 15 minutes of reperfusion. The left anterior descending coronary artery was occluded for 90 minutes, followed by 300 minutes of reperfusion. IS to area at risk (IS/AR) was measured by planimetry after triphenyltetrazolium chloride staining. Collateral myocardial blood flow was measured with radioactive microspheres. The IS/AR ratio in the control group was 52.3 +/- 19.6% compared with 20.5 +/- 11.7% and 21.3 +/- 6.5% at 15 and 45 minutes of occlusion, respectively (P < .05). There were no significant differences in the reduction in IS at 15 and 45 minutes of occlusion. Although there was a reduction in the IS when magnesium was administered during reperfusion (38.2 +/- 13.4%), it was not statistically significant. There was no significant difference in the AR relative to the total left ventricular weight between the four groups. The data suggest that magnesium infusion during a coronary occlusion has a significant benefit in reducing the IS in this model. Magnesium may have a beneficial clinical role in AMI, especially if administered before reperfusion as a bolus followed by a constant infusion.

Medical therapy of acute myocardial infarction: Part II. The role of adjunctive medical therapy.

The second part of this review summarizes the role of other classes of pharmacological therapy in treatment of acute myocardial infarction (MI). The goals of pharmacological therapy are to alleviate symptoms, to stabilize hemodynamic status, and to prevent arrhythmias. These agents have been utilized primarily because of their ability to limit infarct size. Other beneficial properties may include their effects on neurohormonal activation, hemodynamics, and arrhythmias. In an individual patient, age, associated medical conditions, and hemodynamic status are important considerations in choosing a specific class of drug therapy. The beta-adrenergic blocking agents have modest effects on mortality, and they are useful when used alone and in combination with thrombolytic agents. Calcium antagonists have a limited role in acute MI. Diltiazem reduces the incidence of reinfarction in patients with non-Q MI. Oral nitrate therapy has not been shown to reduce mortality. Data from recent trials suggest that prophylactic administration of antiarrhthymic therapy is also not useful in acute MI. The role of angiotensin-converting enzyme inhibitors when administered in the acute phase of MI needs to be evaluated further. These agents are safe and well tolerated, and they offer greatest benefit when given in patients with left ventricular dysfunction.

Platelet glycoprotein IIb-IIIa and size are increased in acute myocardial infarction.

Platelet aggregation, which plays an important role in acute myocardial infarction (AMI), is mediated by fibrinogen binding to the platelet membrane glycoprotein (GP)IIb-IIIa (CD41). This study measured the relative number of GPIIb-IIIa complexes on platelets from patients immediately following AMI (n = 14) compared with those from controls (n = 14). Flow cytometry was used to demonstrate that there were, on average, 20% more GPIIb-IIIa complexes on platelets after AMI compared with controls. Platelet size was also 7% greater in AMI and it is known that larger platelets are more reactive. Since platelet size and protein content are determined at thrombopoiesis the majority of these platelets must have been circulating prior to AMI. Larger platelets, with more GPIIb-IIIa may, therefore, be causally related to AMI.

Analysis of possible triggers of acute myocardial infarction (the MILIS study)

Recent documentation of a circadian variation in acute myocardial infarction (AMI) suggests that AMI is not a random event, but may frequently result from identifiable triggering activities. The possible triggers reported by 849 patients enrolled in the Multicenter Investigation of Limitation of Infarct Size were analyzed. Possible triggers were identified by 48.5% of the population; the most common were emotional upset (18.4%) and moderate physical activity (14.1%). Multiple possible triggers were reported by 13% of the population. Younger patients, men and those without diabetes mellitus were more likely to report a possible trigger than were older patients, women and those with diabetes. The likelihood of reporting a trigger was not affected by infarct size. This study suggests that potentially identifiable triggers may play an important role in AMI. Because potential triggering activities are common in persons with coronary artery disease, yet infrequently result in AMI, further studies are needed to identify (1) the circumstances in which a potential trigger may cause an event, (2) the specific nature of potential triggering activites, (3) the frequency of such activities in individuals who do not develop AMI and (4) the presence or absence of identifiable triggers in various subgroups of patients with infarction.

Beta-adrenoceptor blockers. An update on their role in acute myocardial infarction.

Beta-adrenoceptor blockers. An update on their role in acute myocardial infarction.