A preferred reperfusion strategy for acute myocardial infarction.
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Abciximab↗
Biomedical subjects
Eric J Topol
Publications and source records attributed to Eric J Topol.
The rudimentary phase of personalised medicine: coronary risk scores.
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Adult↗
Mutation of MEF2A in an inherited disorder with features of coronary artery disease.
The early genetic pathway(s) triggering the pathogenesis of coronary artery disease (CAD) and myocardial infarction (MI) remain largely unknown. Here, we describe an autosomal dominant form of CAD/MI (adCAD1) that is caused by the deletion of seven amino acids in transcription factor MEF2A. The deletion disrupts nuclear localization of MEF2A, reduces MEF2A-mediated transcription activation, and abolishes synergistic activation by MEF2A and by the transcription factor GATA-1 through a dominant-negative mechanism. The MEF2A protein demonstrates strong expression in the endothelium of coronary arteries. These results identify a pathogenic gene for a familial vascular disease with features of CAD and implicate the MEF2A signaling pathway in the pathogenesis of CAD/MI.
Aged↗
In-hospital initiation of lipid-lowering therapy after coronary intervention as a predictor of long-term utilization: a propensity analysis.
BACKGROUND: Despite multiple randomized trials demonstrating their efficacy for the secondary prevention of coronary disease, lipid-lowering agents remain underused. Few studies have examined the relationship between predischarge initiation of lipid-lowering therapy and long-term use. METHODS: Using data from patients at 69 centers from the United States and Canada enrolled in the Evaluation in PTCA to Improve Long-term Outcome With Abciximab GP IIb/IIIa Blockade (EPILOG) trial, we performed a retrospective propensity-analyzed cohort study. Patients underwent percutaneous coronary intervention for stable or recently unstable coronary disease and were older than 21 years, were not taking lipid-lowering therapy at the time of admission, and survived to hospital discharge; 175 were discharged taking lipid-lowering therapy and 1951 were not. RESULTS: After 6 months, 77% of patients who started taking lipid-lowering agents before hospital discharge continued taking therapy, compared with only 25% of those discharged without these agents (relative risk, 3.17; 95% confidence interval, 2.88-3.41; P<.001). After restricting the analysis to propensity-matched patients (n = 477) and adjusting for other potential confounders, initiation of a lipid-lowering agent during hospitalization was the strongest independent predictor of use at 6 months (relative risk, 2.50; 95% confidence interval, 2.29-2.65; P<.001). CONCLUSIONS: Inpatient initiation of lipid-lowering therapy is a strong and independent positive predictor of subsequent use, with patients who start taking lipid-lowering therapy before hospital discharge nearly 3 times as likely to be taking these agents 6 months later. Inpatient initiation of lipid-lowering therapy appears to be an effective strategy for bridging the gap between current medical knowledge and practice.
Abciximab↗
Prognostic value of myeloperoxidase in patients with chest pain.
BACKGROUND: Inflammation is linked to adverse outcomes in acute coronary syndromes. Myeloperoxidase, an abundant leukocyte enzyme, is elevated in culprit lesions that have fissured or ruptured in patients with sudden death from cardiac causes. Numerous lines of evidence suggest mechanistic links between myeloperoxidase and both inflammation and cardiovascular disease. METHODS: We assessed the value of plasma levels of myeloperoxidase as a predictor of the risk of cardiovascular events in 604 sequential patients presenting to the emergency department with chest pain. RESULTS: Initial plasma myeloperoxidase levels predicted the risk of myocardial infarction, even in patients who are negative for troponin T (<0.1 ng per milliliter) at base line (P<0.001). Myeloperoxidase levels at presentation also predicted the risk of major adverse cardiac events (myocardial infarction, the need for revascularization, or death) within 30 days and 6 months after presentation (P<0.001). In patients without evidence of myocardial necrosis (defined as those who were negative for troponin T), the base-line myeloperoxidase levels independently predicted the risk of major adverse coronary events at 30 days (unadjusted 2nd, 3rd, and 4th quartile odds ratios, 2.2 [95 percent confidence interval, 1.1 to 4.6], 4.2 [95 percent confidence interval, 2.1 to 8.4], and 4.1 [95 percent confidence interval, 2.0 to 8.4], respectively) and at 6 months. CONCLUSIONS: A single initial measurement of plasma myeloperoxidase independently predicts the early risk of myocardial infarction, as well as the risk of major adverse cardiac events in the ensuing 30-day and 6-month periods. Myeloperoxidase levels, in contrast to troponin T, creatine kinase MB isoform, and C-reactive protein levels, identified patients at risk for cardiac events in the absence of myocardial necrosis, highlighting its potential usefulness for risk stratification among patients who present with chest pain.
Aged↗
Prognostic importance of physical examination for heart failure in non-ST-elevation acute coronary syndromes: the enduring value of Killip classification.
CONTEXT: In acute myocardial infarction, the presence and severity of heart failure at the time of initial presentation have been formally categorized by the Killip classification. Although well studied in ST-elevation myocardial infarction, the prognostic importance of Killip classification in non-ST-elevation acute coronary syndromes is not well established. OBJECTIVES: To determine the prognostic importance of physical examination for heart failure analyzed according to Killip classification in non-ST-elevation acute coronary syndromes and to understand its predictive value relative to other variables. DESIGN, SETTING, AND PATIENTS: From April 2001 to September 2003, We analyzed information from 26 090 patients with non-ST-elevation acute coronary syndromes enrolled in the GUSTO IIb, PURSUIT, PARAGON A, and PARAGON B trials. Demographic information was categorized by Killip class. Killip classes III and IV were combined into 1 category. Multivariate Cox proportional hazard models were developed to determine the prognostic importance of Killip classification in comparison with other variables. MAIN OUTCOME MEASURE: Association between Killip classification and all-cause mortality at 30 days and 6 months. RESULTS: Patients in Killip class II (n = 2513) and III/IV (n = 390) were older than those in Killip class I (n = 23 187), with higher rates of diabetes, prior myocardial infarction, ST depression, and elevated cardiac enzymes (all P<.001). Higher Killip class was associated with higher mortality at 30 days (2.8% in Killip class I vs 8.8% in class II vs 14.4% in class III/IV; P<.001) and 6 months (5.0% vs 14.7% vs 23.0%, respectively; P<.001). Patients with Killip class II, III, or IV constituted 11% of the overall population but accounted for approximately 30% of the deaths at both time points. In multivariate analysis, Killip class III/IV was the most powerful predictor of mortality at 30 days (hazard ratio [HR], 2.35; 95% confidence interval [CI], 1.69-3.26; P<.001) and 6 months (HR, 2.12; 95% CI, 1.63-2.75; P<.001). Killip class II was predictive of mortality at 30 days (HR, 1.73; 95% CI, 1.44-2.09; P<.001) and 6 months (HR, 1.52; 95% CI, 1.31-1.76; P<.001). Five factors-age, Killip classification, heart rate, systolic blood pressure, and ST depression-provided more than 70% of the prognostic information for 30-day and 6-month mortality. CONCLUSIONS: Killip classification is a powerful independent predictor of all-cause mortality in patients with non-ST-elevation acute coronary syndromes. Age, Killip classification, heart rate, systolic blood pressure, and ST depression should receive particular attention in the initial assessment of these patients.
Age Factors↗
Current status and future prospects for acute myocardial infarction therapy.
Considerable new evidence has accumulated in randomized trials of myocardial reperfusion. The trials of catheter-based reperfusion compared with fibrinolytics have shown an advantage for angioplasty and stenting over pharmacologic therapy, even accounting for delays in transporting patients from facilities with intervention capabilities. On the basis of the recent trials, it is recommended that a regional center for infarct intervention be set up akin to regional trauma centers in the United States. Now that we have entered the third decade of myocardial reperfusion therapy, we can expect iterative improvement in all aspects, and ultimately a fused approach of pharmacology and mechanical therapies-to achieve the optimal outcomes and continue to lower the toll of fatality and morbidity of acute myocardial infarction (MI).
Angioplasty, Balloon, Coronary↗
Evidence for substantial effect modification by gender in a large-scale genetic association study of the metabolic syndrome among coronary heart disease patients.
Major genetic determinants of the metabolic syndrome - a clustering of abdominal obesity, high triglycerides, low HDL cholesterol, high blood pressure and high fasting glucose - remain elusive. We surveyed 207 single-nucleotide polymorphisms in 110 candidate genes among coronary artery disease patients, a population enriched for metabolic abnormalities. The number of abnormalities (0-5) was determined in the 214 male and 91 female patients, and the association with each polymorphism evaluated by means of ordinal regression analysis. Polymorphisms in eight genes, including LDLR, GBE1, IL1R1, TGFB1, IL6, COL5A2, SELE and LIPC, were associated with metabolic syndrome in the whole population ( P values ranged from 0.047 to 0.008). Variants in seven additional genes showed significant gene by gender interaction. Among these, separate analyses in men and women revealed a strong association with a silent polymorphism in the low-density lipoprotein receptor-related protein gene, LRPAP1, among females ( P=0.0003), but not males ( P=0.292). Other genes associated only in females included THBS1, ACAT2, ITGB3, F2 and SELP ( P values ranging from 0.032 to 0.002). Only one gene ( PRCP) was significantly associated in men alone ( P=0.039). Our results propose several new candidate genes for the metabolic syndrome and suggest that the genetic basis of this syndrome may be strongly modified by gender.
Base Sequence↗
Anticoagulation with prosthetic cardiac valves.
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Anticoagulants↗
Triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year survival: results from the Do Tirofiban and ReoProGive Similar Efficacy Outcome Trial (TARGET).
OBJECTIVE: We sought to examine if clopidogrel treatment initiated before coronary stenting improved clinical outcomes among patients receiving aspirin and a glycoprotein (GP) IIb/IIIa inhibitor. BACKGROUND: Antiplatelet therapy plays a pivotal role in contemporary percutaneous coronary interventions (PCI). METHODS: Outcomes among 4,809 patients randomized to tirofiban or abciximab during PCI with stent placement were compared according to whether they received 300 mg of clopidogrel before PCI (93.1%) versus immediately after the procedure. RESULTS: The 30-day primary composite end point (death, myocardial infarction [MI], or urgent target vessel revascularization [TVR]) was lower among clopidogrel-pretreated patients (6.6% vs. 10.4%, p = 0.009), mainly because of reduction of MI (6.0% vs. 9.5%, p = 0.012). The benefit of clopidogrel pretreatment was sustained at six months (death, MI, any TVR: 14.6% vs. 19.8%, HR = 0.71, p = 0.010), and this was due mainly to lowering of death and MI (7.8% vs. 13.0%, p = 0.001). At one year, clopidogrel pretreatment was associated with a lower mortality rate (1.7% vs. 3.6%, p = 0.011). Because clopidogrel pretreatment was not randomized, multivariable and propensity analyses were performed. After adjusting for baseline heterogeneity, clopidogrel pretreatment was an independent predictor for death or MI at 30 days (HR = 0.63, p = 0.012) and at six months (HR = 0.61, p = 0.003), and survival at one year (HR = 0.53, p = 0.044). No excess in 30-day bleeding events was noted with clopidogrel pretreatment. CONCLUSIONS: Among patients undergoing coronary stent placement with aspirin and a GP IIb/IIIa inhibitor, clopidogrel pretreatment is associated with a reduction of death and MI irrespective of the type of GP IIb/IIIa inhibitor used.
Abciximab↗
Identification of new genes differentially expressed in coronary artery disease by expression profiling.
Genetic factors increase the risk to coronary artery disease (CAD). To date, a limited number of genes that potentially contribute to development of CAD have been identified. In this study, we have performed large-scale gene expression analysis of approximately 12,000 human genes in nine severely atherosclerotic and six nonatherosclerotic human coronary arteries using oligonucleotide microarrays. Fifty-six genes showed differential expression in atherosclerotic coronary artery tissues; expression of 55 genes was increased in atherosclerotic coronary arteries, whereas only one gene, GST, encoding a reducing agent, showed downregulated expression. The expression data of selected genes were validated by quantitative RT-PCR analysis as well as immunostaining. The associations of 49 genes with CAD appear to be novel, and they include genes encoding ICAM-2, PIM-2, ECGF1, fusin, B cell activator (BL34, GOS8), Rho GTPase activating protein-4, retinoic acid receptor responder, beta2-arrestin, membrane aminopeptidase, cathepsins K and H, MIR-7, TNF-alpha-induced protein 2 (B94), and flavocytochrome 558. In conclusion, we have identified 56 genes whose expression is associated with CAD, and 49 of them may represent new genes linked to CAD.
Apoptosis↗
Angiographic variables predict increased risk for adverse ischemic events after coronary stenting with glycoprotein IIb/IIIa inhibition: results from the TARGET trial.
OBJECTIVES: We sought to assess whether pre-procedural angiographic characteristics are associated with adverse clinical outcomes after coronary stenting with glycoprotein IIb/IIIa inhibition. BACKGROUND: Ischemic complications after balloon angioplasty are associated with pre- and post-procedural angiographic variables. However, in the current era of stenting with IIb/IIIa inhibition, it is unknown whether angiographic features assessed before intervention confer an increased risk of adverse procedural and subsequent clinical outcomes. METHODS: In the Do Tirofiban and ReoPro Give Similar Efficacy Outcomes? Trial (TARGET), 4,809 patients undergoing planned stenting were randomized to tirofiban or abciximab. Baseline demographic, clinical, and angiographic variables were obtained. Clinical end points were recorded at 30 days and six months. The relationship between angiographic variables and adverse clinical outcomes was assessed. RESULTS: Patients with the combination of thrombus, lesion eccentricity, and lesion length >20 mm had a 21.4% composite incidence of death, myocardial infarction, or urgent target vessel revascularization (TVR) at 30 days, compared with 4.2% in those patients without these high-risk features (hazard ratio [HR] 3.24, p < 0.001). After adjustment, the risk was independently associated with thrombus (HR 1.40, p = 0.034), eccentricity (HR 1.67, p < 0.001), and lesion length >20 mm (HR 1.89, p < 0.001). The risk of six-month TVR was independently associated with left anterior descending coronary artery lesions (HR 1.46, p < 0.001), restenotic lesions at baseline (HR 1.58, p = 0.006), and lesion length (HR 1.19, p = 0.03). CONCLUSIONS: Patients with thrombus, eccentric lesions, or lesion length >20 mm are at high risk for ischemic outcomes after coronary stenting, despite IIb/IIIa inhibition. Further research into novel anti-thrombotic therapies or procedural strategies is necessary for these patients.
Abciximab↗
Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions.
We performed a cumulative meta-analysis of available studies to evaluate the effect of intravenous platelet glycoprotein (GP) IIb/IIIa antagonists on survival at 30 days and 6 months after percutaneous coronary intervention (PCI). Compounds that block the GP IIb/IIIa receptor substantially reduce myocardial infarctions (MIs) and repeat revascularization. We included 12 trials, which enrolled 20,186 patients in all, in the analysis. Overall, 30-day mortality was significantly reduced with GP IIb/IIIa inhibition (odds ratio 0.73, 95% confidence interval 0.55 to 0.96, p = 0.024). Although 10 of the 12 trials showed a beneficial effect of GP IIb/IIIa inhibitor treatment on mortality, no individual trial detected a statistically significant mortality benefit. The 30-day mortality benefit became significant at the p <0.05 level with addition of the ADMIRAL trial and was further enhanced by the CADILLAC trial. No significant heterogeneity was detected in the collection of trials. At 6 months, the odds ratio was 0.84 (95% confidence interval 0.69 to 1.03, p = 0.087). This survival benefit amounts to preventing approximately 1 of every 3 deaths that occur within 30 days after PCI, saving 2.8 lives/1,000 patients treated (number needed to treat, 357). Thus, patients who undergo PCI can expect significantly lower 30-day mortality, in addition to known reductions in nonfatal MI and repeat procedures, with GP IIb/IIa inhibition. There also is increasing evidence that mortality reductions are preserved at 6 months.
Angioplasty, Balloon, Coronary↗
Thrombospondin-4 and its variants: expression and differential effects on endothelial cells.
BACKGROUND: In a recent large-scale genetic association study, a single nucleotide polymorphism in the thrombospondin-4 (TSP-4) gene, resulting in a proline-for-alanine substitution at position 387, was associated with a significantly increased risk for premature atherosclerosis. TSP-4 had not previously been implicated in vascular pathology, and very little information is available on its expression and functions. METHODS AND RESULTS: The goal of this study was to assess TSP-4 expression in vessel wall and to identify differences in functions of TSP-4 variants that could account for the proatherogenic effects of the (P387)TSP-4 variant. TSP-4 expression was demonstrated in human endothelial cells (ECs) and vascular smooth muscle cells from brain blood vessels and coronary arteries. (P387)TSP-4 and its fragment (residues 326 to 722), but not the A(387) forms, suppressed EC adhesion and proliferation. The (P387)TSP-4 was more active in inducing the phosphorylation of focal adhesion kinase, consistent with inhibition of proliferation. Both variant fragments increased the proliferation of human aortic smooth muscle cells. CONCLUSIONS: TSP-4 is expressed by vascular cells and influences the vessel wall by modulating the proliferation of ECs and smooth muscle cells. The A387P substitution is a "gain-of-function" mutation, favoring a form of TSP-4 that interferes with EC adhesion and proliferation and may thereby be proatherogenic.
Arteriosclerosis↗
Peripheral vascular disease and one-year mortality following percutaneous coronary revascularization.
The association between peripheral vascular disease and outcomes after percutaneous coronary intervention was examined in the Do Tirofiban and Reopro Give Similar Efficacy Outcome Trial (TARGET). After adjustments in a multivariate model, a history of peripheral vascular disease was found to be associated with a two- to threefold increase in mortality at 1 year after coronary stent placement.
Aged↗
Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy.
BACKGROUND: Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. METHODS: We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. FINDINGS: Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm2, n=4 per group, p<0.02) resulting in greater left-ventricular mass (1.24 [0.29] vs 1.57 [0.27] g) and better cardiac function (shortening fraction 9.2 [4.9] vs 17.2 [4.2]%, n=8 per group, p<0.05). INTERPRETATION: These findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.
Animals↗
Prevalence of conventional risk factors in patients with coronary heart disease.
CONTEXT: It is commonly suggested that more than 50% of patients with coronary heart disease (CHD) lack any of the conventional risk factors (cigarette smoking, diabetes, hyperlipidemia, and hypertension). This claim implies that other factors play a significant role in CHD and has led to considerable interest in nontraditional risk factors and genetic causes of CHD. OBJECTIVE: To determine the prevalence of the 4 conventional risk factors among patients with CHD. DESIGN, SETTING, AND PATIENTS: In 2002-2003, we analyzed data for 122458 patients enrolled in 14 international randomized clinical trials of CHD conducted during the prior decade. Patients included 76716 with ST-elevation myocardial infarction, 35527 with unstable angina/non-ST-elevation myocardial infarction, and 10215 undergoing percutaneous coronary intervention. MAIN OUTCOME MEASURES: Prevalence of each conventional risk factor and number of conventional risk factors present among patients with CHD, compared between men and women and by age at trial entry. RESULTS: Among patients with CHD, at least 1 of the 4 conventional risk factors was present in 84.6% of women and 80.6% of men. In younger patients (men < or =55 years and women < or =65 years) and most patients presenting either with unstable angina or for percutaneous coronary intervention, only 10% to 15% of patients lacked any of the 4 conventional risk factors. This pattern was largely independent of sex, geographic region, trial entry criteria, or prior CHD. Premature CHD was related to cigarette smoking in men and cigarette smoking and diabetes in women. Smoking decreased the age at the time of CHD event (at trial entry) by nearly 1 decade in all risk factor combinations. CONCLUSIONS: In direct contrast with conventional thinking, 80% to 90% of patients with CHD have conventional risk factors. Although research on nontraditional risk factors and genetic causes of heart disease is important, clinical medicine, public health policies, and research efforts should place significant emphasis on the 4 conventional risk factors and the lifestyle behaviors causing them to reduce the epidemic of CHD.
Adult↗
Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial.
BACKGROUND: Statins primarily metabolized by cytochrome P450 3A4 (CYP3A4) reportedly reduce clopidogrel's metabolism to active metabolite, thus attenuating its inhibition of platelet aggregation ex vivo. However, the clinical impact of this interaction has not been evaluated. METHODS AND RESULTS: Clopidogrel for the Reduction of Events During Observation (CREDO) was a double-blind, placebo-controlled, randomized trial comparing pretreatment (300 mg) and 1-year (75 mg/d) clopidogrel therapy (clopidogrel) with no pretreatment and 1-month clopidogrel therapy (75 mg/d) (control) after a planned percutaneous coronary intervention. All patients received aspirin. The 1-year primary end point was a composite of death, myocardial infarction, and stroke. We performed a post hoc analysis to evaluate the clinical efficacy of concomitant clopidogrel and statin administration, categorizing baseline statin use to those predominantly CYP3A4-metabolized (atorvastatin, lovastatin, simvastatin, and cerivastatin) (CYP3A4-MET) or others (pravastatin and fluvastatin) (non-CYP3A4-MET). Of the 2116 patients enrolled, 1001 received a CYP3A4-MET and 158 a non-CYP3A4-MET statin. For the overall study population, the primary end point was significantly reduced in the clopidogrel group (8.5% versus 11.5%, RRR 26.9%; P=0.025). This clopidogrel benefit was similar with statin use, irrespective of treatment with a CYP3A4-MET (7.6% clopidogrel, 11.8% control, RRR 36.4%, 95% CI 3.9 to 57.9; P=0.03) or non-CYP3A4-MET statin (5.4% clopidogrel, 13.6% control, RRR 60.6%, 95% CI -23.9 to 87.4; P=0.11). Patients given atorvastatin or pravastatin had similar 1-year event rates. Additionally, concomitant therapy with statins had no impact on major or minor bleeding rates. CONCLUSIONS: Although ex vivo testing has suggested a potential negative interaction when coadministering a CYP3A4-metabolized statin with clopidogrel, this was not clinically observed statistically in a post hoc analysis of a placebo-controlled study.
Angioplasty, Balloon, Coronary↗