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This syndrome encompasses several diseases, previously thought to be separate and defined disease states. In this syndrome, unstable angina, non-Q wave myocardial infarctions (NQMI), and myocardial infarctions (MI) are all part of this category. The pathogenesis begins with atherosclerosis which leads to plaque rupture. This rupture activates the coagulation cascade leading to platelet activation and thrombus formation. The thrombus leads to partial or complete coronary artery occlusion leading to various clinical manifestations ranging from angina to a myocardial infarction.

Until recently, the criteria for the diagnosis of a myocardial infarction included 2 of the 3 following changes: chest pain, serum markers, and ECG changes. Today, measurement of serum troponin is now the gold standard for the diagnosis of myocardial infarction. A consensus document authored by a joint committee of the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) has redefined a myocardial infarction (MI) as any amount of myocardial necrosis as indicated by an elevation of troponin in the setting of clinical ischemia. It is a "maximal concentration of troponin T or I exceeding the decision limit (99th percentile of the values for a reference control group) on at least one occasion during the first 24 hours after the index clinical event" (see reference below). The change in diagnostic criteria is the result of numerous studies that have documented the sensitivity and specificity of serum troponin which is the single best marker for myocardial infarction.

J Am Coll Cardiol 2000;36:959-969.

Just as significantly, the risk of significant cardiac events increases with increasing troponin I or T levels. This association provides an opportunity to risk stratification for acutely ill patients with chest pain.


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A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke.

Cipollone F, Toniato E, Martinotti S, Fazia M, Iezzi A, Cuccurullo C, Pini B, Ursi S, Vitullo G, Averna M, Arca M, Montali A, Campagna F, Ucchino S, Spigonardo F, Taddei S, Virdis A, Ciabattoni G, Notarbartolo A, Cuccurullo F, Mezzetti A; Identification of New Elements of Plaque Stability (INES) Study Group.

G. d'Annunzio University of Chieti and G. d'Annunzio University Foundation, Chieti, Italy
JAMA. 2004 May 12;291(18):2221-8. Abstract quote  

CONTEXT: Myocardial infarction (MI) and ischemic stroke are thought to be caused by matrix digestion by metalloproteinases (MMPs) leading to rupture of atherosclerotic plaques. Production of macrophage MMP-2 and MMP-9 is induced by cyclooxygenase 2 (COX-2) and prostaglandin E(2) synthesis. Although COX-2 expression may be genetically determined, the relation between COX-2 polymorphisms and the risk of MI and stroke is unclear.

OBJECTIVE: To investigate the relationship between the -765G-->C polymorphism of the COX-2 gene and clinically evident plaque rupture.

DESIGN, SETTING, AND PARTICIPANTS: Prospective, matched case-control study conducted between March 2002 and October 2003 among 864 patients with first MI or atherothrombotic ischemic stroke and 864 hospitalized controls. The groups were matched for age, sex, body mass index, smoking, hypertension, hypercholesterolemia, and diabetes. The -765G-->C variant of the COX-2 gene was genotyped by restriction endonuclease digestion of polymerase chain reaction products.

MAIN OUTCOME MEASURES: Presence of the -765G-->C polymorphism of the COX-2 gene; COX-2, MMP-2, and MMP-9 expression and activity in plaques and in peripheral monocytes; urinary 6-keto PGF1alpha (marker of endothelial prostacyclin); and endothelium-dependent and -independent forearm blood flow vasodilation.

RESULTS: The prevalence of -765GC was 2.41 times higher among controls than among cases (43.3% vs 17.9%; P<.001). The prevalence of -765CC homozygosity was 5.81 times higher (6.4% vs 1.1%; P =.04). Among participants carrying the -765GC and -765CC genotypes, the prevalence ratios for MI or stroke were 0.48 (95% CI, 0.36-0.68) and 0.33 (95% CI, 0.24-0.55), respectively. Expression of COX-2 and MMPs was significantly lower in atherosclerotic plaques from participants carrying the -765C allele, while the -765G-->C polymorphism did not affect endothelial prostacyclin biosynthesis or endothelium-dependent vasodilation in vivo. In subgroup analyses (n = 224 cases), serum high-sensitivity C-reactive protein was significantly lower in patients carrying the -765C allele (mean [SD], 0.78 [0.1] vs 2.56 [0.4] mg/L; P =.04).

CONCLUSIONS: We found that the -765G-->C polymorphism of the COX-2 gene is associated with a decreased risk of MI and stroke. Detection of this genotype may be useful for predicting genetic risk of MI and stroke.
Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction.

Schuit SC, Oei HH, Witteman JC, Geurts van Kessel CH, van Meurs JB, Nijhuis RL, van Leeuwen JP, de Jong FH, Zillikens MC, Hofman A, Pols HA, Uitterlinden AG.

Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
JAMA. 2004 Jun 23;291(24):2969-77. Abstract quote

CONTEXT: The role of estrogens in ischemic heart disease (IHD) is uncertain. Evidence suggests that genetic variations in the estrogen receptor alpha (ESR1) gene may influence IHD risk, but the role of common sequence variations in the ESR1 gene is unclear.

OBJECTIVE: To determine whether the ESR1 haplotype created by the c.454-397T>C (PvuII) and c.454-351A>G (XbaI) polymorphisms is associated with myocardial infarction (MI) and IHD risk.

DESIGN, SETTING, AND PARTICIPANTS: In 2617 men and 3791 postmenopausal women from The Rotterdam Study (enrollment between 1989-1993 and follow-up to January 2000), a population-based, prospective cohort study of participants aged 55 years and older, ESR1 c.454-397T>C and c.454-351A>G haplotypes were determined. Detailed interviews and physical examinations were performed, blood samples were obtained, and cardiovascular risk factors were assessed.

MAIN OUTCOME MEASURE: The primary outcome was MI and IHD defined as MIs, revascularization procedures, and IHD mortality.

RESULTS: Approximately 29% of women and 28.2% of men were homozygous carriers of the ESR1 haplotype 1 (-397 T and -351 A) allele, 49% of women and 50% of men were heterozygous carriers, and 22% of women and 21.4% of men were noncarriers. During a mean follow-up of 7.0 years, 285 participants (115 women; 170 men) had MI, and 440 (168 women; 272 men) had an IHD event, of which 97 were fatal. After adjustment for known cardiovascular risk factors, female heterozygous carriers of haplotype 1 had an increased risk of MI (event rate, 2.8%; relative risk [RR], 2.23; 95% confidence interval [CI], 1.13-4.43) compared with noncarriers (event rate, 1.3%), whereas homozygous carriers had an increased risk (event rate, 3.2%; RR, 2.48; 95% CI, 1.22-5.03). For IHD events, we observed a similar association. In women, the effect of haplotype 1 on fatal IHD was larger than on nonfatal IHD. In men, the ESR1 haplotypes were not associated with an increased risk of MI (event rate, 5.7%; RR, 0.93; 95% CI, 0.59-1.46 for heterozygous carriers; and event rate, 5.1%; RR, 0.82; 95% CI, 0.49-1.38 for homozygous carriers) compared with noncarriers (event rate, 5.8%) and were not associated with an increased risk of IHD.

CONCLUSIONS: In this population-based, prospective cohort study, postmenopausal women who carry ESR1 haplotype 1 (c.454-397 T allele and c.454-351 A allele) have an increased risk of MI and IHD, independent of known cardiovascular risk factors. In men, no association was observed.




Diagnostic and prognostic value of cardiac troponin I assays in patients admitted with symptoms suggestive of acute coronary syndrome.

Apple FS, Quist HE, Murakami MM.

Department of Laboratory Medicine and Pathology, Hennepin County Medical Center, University of Minnesota School of Medicine, Minneapolis 55415, USA.
Arch Pathol Lab Med. 2004 Apr;128(4):430-4. Abstract quote

CONTEXT: Increasing numbers of patients are presenting to emergency departments with symptoms suggestive of an acute myocardial infarction.

OBJECTIVE: To demonstrate the comparative performance of the Ortho Vitros Troponin I and Beckman Access AccuTnI assays used to detect myocardial infarction and to develop risk stratification schemes for all-cause death in patients who presented with myocardial ischemia symptoms that were suggestive of acute coronary syndrome (ACS).

DESIGN: The prospective enrollment of patients with ACS and the measurement of serial plasma samples by 2 commercial cardiac troponin I (cTnI) assays.

SETTING: A metropolitan medical center that admitted patients with ACS during a 2-month period.

PATIENTS: The study population consisted of 200 consecutively admitted patients who presented with symptoms that were suggestive of ACS.

RESULTS: Correlation scatterplots showed no significant bias between cTnI assays based on 659 specimens across the dynamic range of each assay. Only minor differences in slopes and intercepts were observed between assays when correlations were based across selected concentration ranges. The receiver operating characteristic curve areas for the detection of myocardial infarction were not significantly different (Ortho,.991; Beckman,.995). At the 99th percentile (Beckman, 0.04 microg/L; Ortho, 0.08 microg/L), each assay demonstrated 100% sensitivity with 78% and 80% specificity, respectively. Kaplan-Meier survival curves and the log-rank test were used to compare time-to-event data. Patients with increased baseline cTnI values had higher odds ratios of death than did those with normal concentrations. For Ortho, the 99th percentile cutoff was 5.9, and the 10% coefficient of variation cutoff was 10.3; for Beckman, the 99th percentile cutoff was 31.4, and the 10% coefficient of variation cutoff was 15.3.

CONCLUSIONS: Comparable diagnostic and risk stratification abilities were demonstrated in patients with ACS by the Ortho Vitros and Beckman Access cTnI assays, with no significant analytic bias between cTnI assays.



Coronary Angiographic Findings in Patients With Clinical Unstable Angina According to Cardiac Troponin I and T Concentrations in Serum
A Comparative Analysis

Mauro Panteghini, MD, Claudio Cuccia, MD, Franca Pagani, MD, Claudia Turla, MD, Graziella Bonetti, MD, and Elena Bonini, MD

From the Laboratorio Analisi Chimico Cliniche 1 (Drs Panteghini, Pagani, and Bonetti) and the Cattedra and Divisione di Cardiologia (Drs Cuccia, Turla, and Bonini), Azienda Ospedaliera Spedali Civili and Universitá, Brescia, Italy


Arch Pathol Lab Med 2002;Vol. 126, No. 4, pp. 448–451. Abstract quote

Context.—Elevated cardiac troponin levels have been reported to identify unstable angina patients at high risk.

Objective.—To examine the relation of cardiac troponin I (cTnI) and cardiac troponin T (cTnT) levels to findings of coronary angiography in these patients.

Methods.—Samples for troponin estimation were taken every 4 hours throughout the first 48 hours after admission before angiography in 34 patients with primary unstable angina. Patients were considered to be troponin positive if the marker was increased (>0.04 g/L for cTnT and >0.03 g/L for cTnI) in at least one sample collected.

Results.—An increased troponin (I or T) concentration was documented in 14 patients (41.2%). Twelve patients (35.3%) had elevations of both markers, whereas the remaining 2 patients had elevations of cTnI or cTnT alone. Patients with or without increased troponin levels did not differ with respect to degree of coronary disease at angiography. However, patients with elevated troponin concentrations had more complex lesion characteristics. In 69% of patients with increased cTnI levels and in 77% of patients with increased cTnT levels, type B2 or C lesions were documented with presence of ulcerated plaques and thrombus formation. In contrast, only 23% of the patients with elevated cTnI or cTnT levels had type A lesions compared with 71% of patients with negative troponin concentrations.

Conclusions.—Patients with unstable angina who have significant release of cTnI and/or cTnT have evidence of more complex lesions on coronary angiography, supporting the hypothesis that both troponins might be used without distinction as surrogate markers for microembolization from thrombus formation on a disrupted plaque.




Hematopoiesis/Erythropoiesis in Myocardial Infarcts

Bruce I. Goldman, M.D. and John Wurzel, M.D.

Department of Pathology and Laboratory Medicine, Temple University Medical School, Philadelphia, Pennsylvania

Mod Pathol 2001;14:589-594 Abstract quote

Extramedullary hematopoiesis occurring in the myocardium has previously only been reported in a single case of a neonate with cyanotic congenital heart disease. Herein we report the incidental discovery of extramedullary hematopoiesis or pure erythropoiesis in four failing adult hearts with myocardial infarction.

In two cases, extramedullary hematopoiesis or erythropoiesis was identified in cardiectomy specimens removed at orthotopic heart transplantation; in two other cases, erythropoiesis was found in left ventricular tissue removed at the time of implantation of left ventricular assist devices. Myocardial hematopoiesis/erythropoiesis was identified based on characteristic light-microscopic findings in routinely processed tissue and was confirmed by immunhistochemistry using monoclonal antibodies to the erythroid cell marker glycophorin A (positive in all cases), the megakaryocyte marker CD61, and the granulocyte marker neutrophil elastase (the latter two markers positive in one case only). None of the four patients had a myeloproliferative disorder or evidence of a myelophthisic process. No hematopoietic elements were identified in 109 cardiectomy specimens without acute or recent infarcts.

Myocardial hematopoiesis or erythropoiesis could represent heretofore-unrecognized manifestations of altered cytokine expression in patients with heart failure due to myocardial infarction.


Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes.

Rao SV, Jollis JG, Harrington RA, Granger CB, Newby LK, Armstrong PW, Moliterno DJ, Lindblad L, Pieper K, Topol EJ, Stamler JS, Califf RM.

Duke Clinical Research Institute, Durham, NC
JAMA. 2004 Oct 6;292(13):1555-62. Abstract quote  

CONTEXT: It is unclear if blood transfusion in anemic patients with acute coronary syndromes is associated with improved survival.

OBJECTIVE: To determine the association between blood transfusion and mortality among patients with acute coronary syndromes who develop bleeding, anemia, or both during their hospital course.Design, Setting, and

PATIENTS: We analyzed 24 112 enrollees in 3 large international trials of patients with acute coronary syndromes (the GUSTO IIb, PURSUIT, and PARAGON B trials). Patients were grouped according to whether they received a blood transfusion during the hospitalization. The association between transfusion and outcome was assessed using Cox proportional hazards modeling that incorporated transfusion as a time-dependent covariate and the propensity to receive blood, and a landmark analysis.

MAIN OUTCOME MEASURE: Thirty-day mortality.

RESULTS: Of the patients included, 2401 (10.0%) underwent at least 1 blood transfusion during their hospitalization. Patients who underwent transfusion were older and had more comorbid illness at presentation and also had a significantly higher unadjusted rate of 30-day death (8.00% vs 3.08%; P<.001), myocardial infarction (MI) (25.16% vs 8.16%; P<.001), and death/MI (29.24% vs 10.02%; P<.001) compared with patients who did not undergo transfusion. Using Cox proportional hazards modeling that incorporated transfusion as a time-dependent covariate, transfusion was associated with an increased hazard for 30-day death (adjusted hazard ratio [HR], 3.94; 95% confidence interval [CI], 3.26-4.75) and 30-day death/MI (HR, 2.92; 95% CI, 2.55-3.35). In the landmark analysis that included procedures and bleeding events, transfusion was associated with a trend toward increased mortality. The predicted probability of 30-day death was higher with transfusion at nadir hematocrit values above 25%.

CONCLUSIONS: Blood transfusion in the setting of acute coronary syndromes is associated with higher mortality, and this relationship persists after adjustment for other predictive factors and timing of events. Given the limitations of post hoc analysis of clinical trials data, a randomized trial of transfusion strategies is warranted to resolve the disparity in results between our study and other observational studies. We suggest caution regarding the routine use of blood transfusion to maintain arbitrary hematocrit levels in stable patients with ischemic heart disease.


The impact of the National Service Framework for Coronary Artery Disease on treatment and outcome of patients with acute coronary syndromes.

Graham JJ, Timmis AD, Cooper J, Ramdany S, Deaner A, Ranjadayalan K, Knight C.

London Chest Hospital, United Kingdom.

Heart. 2005 May 20; [Epub ahead of print] Abstract quote  

Objective: To evaluate the impact the National Service Framework (NSF) for Coronary Heart Disease (CHD) has had on emergency treatment and outcomes in patients presenting with acute coronary syndromes.

Design: Retrospective cohort study. Setting: Coronary care units of 2 district general hospitals.

Results: Data from 3371 patients were recorded, 1993 patients in the 27 months prior to NSF and 1378 patients in the 24 months after. Following the introduction of the NSF there was a significant reduction in in-hospital mortality (95 patients [4.8%] versus 43 [3.2%], p=0.02). This was associated with reduction in the development of Q-wave myocardial infarction (40.6% versus 33.3%, p<0.0001) and in the incidence of left ventricular failure (15.9% versus 12.3%, p=0.003). The proportion of patients receiving thrombolysis increased (69.4% versus 84.7%, p<0.0001) with a decrease in the time taken to receive it (proportion thrombolysed within twenty minutes 12.1% versus 26.6%, p<0.0001). There were improvements in the prescription of beta-blockers (51.9% versus 65.8%, p<0.0001), ACE-inhibitors (37% versus 66.4%, p<0.0001) and HMGCoA reductase inhibitors (55.2% versus 72.7%, p<0.0001) and an increase in the proportion of patients referred for invasive investigation (18.3% versus 27.0%, p<0.0001). Trend analysis showed that improvements in mortality and thrombolysis were directly associated with publication of the NSF whereas the improvements seen in prescription of beta blockers and statins were the continuation of pre-existing trends.

Conclusions: In the two years that followed publication of the NSF there were improvements in the initial treatment and outcome of patients presenting with acute coronary syndromes. Some of the improvements can be attributed to the NSF but others are continuations of pre-existing trends.
Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-Segment elevation acute coronary syndromes: a systematic overview.

Petersen JL, Mahaffey KW, Hasselblad V, Antman EM, Cohen M, Goodman SG, Langer A, Blazing MA, Le-Moigne-Amrani A, de Lemos JA, Nessel CC, Harrington RA, Ferguson JJ, Braunwald E, Califf RM.

Duke Clinical Research Institute, Durham, NC 27715, USA.
JAMA. 2004 Jul 7;292(1):89-96. Abstract quote  

CONTEXT: Antithrombin therapy has become a guidelines-recommended standard of care in the treatment of acute coronary syndromes (ACS), but recent trials comparing use of enoxaparin and unfractionated heparin in ACS have yielded less robust efficacy and safety results than have earlier trials of these antithrombin therapies.

OBJECTIVE: To systematically evaluate the end points of all-cause death and nonfatal myocardial infarction (MI), transfusion, and major bleeding observed in the 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in treatment of ACS.

DATA SOURCES: The primary data sets for ESSENCE, A to Z, and SYNERGY were available at the Duke Clinical Research Institute. Baseline characteristics and event frequencies for TIMI 11B, ACUTE II, and INTERACT were provided by the principal investigator of each study.

STUDY SELECTION: All 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in non-ST-segment elevation ACS were selected for analysis.

DATA EXTRACTION: Efficacy and safety end points were extracted from the overall trial populations and the subpopulation receiving no antithrombin therapy prior to randomization.

DATA SYNTHESIS: Systematic evaluation of the outcomes for 21 946 patients was performed using a random-effects empirical Bayes model. No significant difference was found in death at 30 days for enoxaparin vs unfractionated heparin (3.0% vs 3.0%; odds ratio [OR], 1.00; 95% confidence interval [CI], 0.85-1.17). A statistically significant reduction in the combined end point of death or nonfatal MI at 30 days was observed for enoxaparin vs unfractionated heparin in the overall trial populations (10.1% vs 11.0%; OR, 0.91; 95% CI, 0.83-0.99; number needed to treat, 107). A statistically significant reduction in the combined end point of death or MI at 30 days was also observed for enoxaparin in the populations receiving no prerandomization antithrombin therapy (8.0% vs 9.4%; OR, 0.81; 95% CI, 0.70-0.94; number needed to treat, 72). No significant difference was found in blood transfusion (OR, 1.01; 95% CI, 0.89-1.14) or major bleeding (OR, 1.04; 95% CI, 0.83-1.30) at 7 days after randomization in the overall safety population or in the population of patients receiving no prerandomization antithrombin therapy.

CONCLUSION: In a systematic overview of approximately 22 000 patients across the spectrum of ACS, enoxaparin is more effective than unfractionated heparin in preventing the combined end point of death or MI.

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