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Eric J Topol

Publications and source records attributed to Eric J Topol.

At least 55 records · Page 3Linked to original sources
PubMed2005

Polymorphisms A387P in thrombospondin-4 and N700S in thrombospondin-1 perturb calcium binding sites.

Recent genetic studies have associated members of the thrombospondin (TSP) gene family with premature cardiovascular disease. The disease-associated polymorphisms lead to single amino acid changes in TSP-4 (A387P) and TSP-1 (N700S). These substitutions reside in adjacent domains of these highly homologous proteins. Secondary structural predictive programs and the homology of the domains harboring these amino acid substitutions to those in other proteins pointed to potential alterations of putative Ca2+ binding sites that reside in close proximity to the polymorphic amino acids. Since Ca2+ binding is critical for the structure and function of TSP family members, direct evidence for differences in Ca2+ binding by the polymorphic forms was sought. Using synthetic peptides and purified recombinant variant fragments bearing the amino acid substitutions, we measured differences in Tb3+ luminescence as an index of Ca2+ binding. The Tb3+ binding constants placed the TSP-1 region affected by N700S polymorphism among other high-affinity Ca2+ binding sites. The affinity of Ca2+ binding was lower for peptides (3.5-fold) and recombinant fragments (10-fold) containing the S700 vs. the N700 form. In TSP-4, the P387 form acquired an additional Ca2+ binding site absent in the A387 form. The results of our study suggest that both substitutions (A387P in TSP-4 and N700S in TSP-1) alter Ca2+ binding properties. Since these substitutions exert the opposite effects on Ca2+ binding, a decrease in TSP-1 and an increase in TSP-4, the two TSP variants are likely to influence cardiovascular functions in distinct but yet pathogenic ways.

Amino Acid Sequence↗
PubMed2005

Identification of four gene variants associated with myocardial infarction.

Family history is a major risk factor for myocardial infarction (MI). However, known gene variants associated with MI cannot fully explain the genetic component of MI risk. We hypothesized that a gene-centric association study that was not limited to candidate genes could identify novel genetic associations with MI. We studied 11,053 single-nucleotide polymorphisms (SNPs) in 6,891 genes, focusing on SNPs that could influence gene function to increase the likelihood of identifying disease-causing gene variants. To minimize false-positive associations generated by multiple testing, two studies were used to identify a limited number of nominally associated SNPs; a third study tested the hypotheses that these SNPs are associated with MI. In the initial study (of 340 cases and 346 controls), 637 SNPs were associated with MI (P<.05); these were evaluated in a second study (of 445 cases and 606 controls), and 31 of the 637 SNPs were associated with MI (P<.05) and had the same risk allele as in the first study. For each of these 31 SNPs, we tested the hypothesis that it is associated with MI, using a third study (of 560 cases and 891 controls). We found that four of these gene variants were associated with MI (P<.05; false-discovery rate <10%) and had the same risk allele as in the first two studies. These gene variants encode the cytoskeletal protein palladin (KIAA0992 [odds ratio (OR) 1.40]), a tyrosine kinase (ROS1 [OR 1.75]), and two G protein-coupled receptors (TAS2R50 [OR 1.58] and OR13G1 [OR 1.40]); all ORs are for carriers of two versus zero risk alleles. These findings could lead to a better understanding of MI pathophysiology and improved patient risk assessment.

Aged↗
PubMed2005

Mortality at 1 year for the direct comparison of tirofiban and abciximab during percutaneous coronary revascularization: do tirofiban and ReoPro give similar efficacy outcomes at trial 1-year follow-up.

AIMS: Compared with placebo, abciximab has been associated with mortality reduction at late follow-up. The TARGET trial was performed to test whether tirofiban and abciximab provide similar efficacy outcomes among patients undergoing non-emergent, stent-based percutaneous coronary intervention. We report here the 1-year mortality of the study population. METHODS AND RESULTS: In 18 countries at 149 hospitals, 4,809 patients undergoing elective or urgent stent implantation were randomly assigned a bolus and infusion of tirofiban or abciximab. Ischaemic events were assessed at 30 days and 6 months and mortality was assessed at 1 year. We previously reported that abciximab was superior to tirofiban considering the composite rate of death or myocardial infarction at 30 days among all patients and at 6 months among those with an acute coronary syndrome (ACS). At 1-year follow-up death occurred in 46 (1.9%) patients who received tirofiban and 42 (1.7%) patients who received abciximab (hazard ratio 1.10, 95% CI 0.72-1.67; P=0.660). Mortality rates for patients with ACS were 2.3% with tirofiban vs. 2.2% with abciximab (hazard ratio 1.03, 95% CI 0.64-1.67; P=0.897) and those without ACS were 1.4 vs. 1.0% (hazard ratio 1.32, 95% CI 0.56-3.13; P=0.530). CONCLUSION: At 1 year, tirofiban provided a similar level of survival benefit compared with abciximab.

Abciximab↗
PubMed2005

Mechanism and effect of thrombospondin-4 polymorphisms on neutrophil function.

High-throughput genomic technology identified an association between a single nucleotide polymorphism (SNP), a proline (P387) rather than the predominant alanine (A387) at position 387 in thrombospondin-4 (TSP-4) and premature myocardial infarction. The inflammatory hypothesis of atherosclerosis invokes a prominent role of leukocytes and cytokines in pathogenesis. As the expression of TSP-4 by vascular cells permits its exposure to circulating leukocytes, the interactions of human neutrophils (polymorphonuclear leukocytes [PMNs]) with both TSP-4 variants were investigated. Phorbol 12-myristate 13-acetate (PMA)-stimulated PMNs adhered and migrated well and equally on the TSP-4 variants. Integrin alpha(M)beta2 was identified as the TSP-4 receptor mediating these responses, and the 3 epidermal growth factor (EGF)-like domains of TSP-4 harboring the SNPs interacted with the alpha(M)I-domain. Despite the similarity in these responses, the P387 variant induced more robust tyrosine phosphorylation of the stress-related mitogen-activated protein kinases (MAPKs): p38MAPK and c-Jun NH2-terminal kinase (JNK), as well as signal transducer and activator of transcription-1 (STAT1) and heat shock protein 27 (HSP27) than the A387 variant. Additionally, cells adherent to P387 TSP-4 variant released 4-fold more H2O2 and secreted 2-fold more interleukin 8 (IL-8) as compared with the A387. H2O2 release and p38MAPK activation were totally inhibited by blockade of alpha(M)beta2. Thus, alpha(M)beta2 plays a central role in proinflammatory activities of TSP-4 (P387) and may contribute to the prothrombotic phenotype associated with this variant.

Cell Adhesion↗
PubMed2005

Extent of ST-segment depression and cardiac events in non-ST-segment elevation acute coronary syndromes.

AIMS: We sought to determine whether the extent of myocardial ischaemia on the admission electrocardiogram (ECG) has independent predictive value for short-term risk stratification of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). Although the presence of ischaemic ECG changes on admission has been shown to predict outcome, the relationship between the extent of ECG changes and the risk of cardiac events is still ill defined. METHODS AND RESULTS: We analysed the admission ECGs of 5192 ACS patients enrolled in the GUSTO-IIb trial, without an ECG indication for thrombolysis. ECG tracings showing one or more of the following were eligible: ST-segment depression >0.5 mm, T-wave inversion >1 mm, and ST-segment elevation >0.5 mm but <1 mm. ECG variables associated with unfavourable 30 day outcomes in a univariable analysis were further assessed in a multivariable logistic regression model including independent clinical predictors. In the multivariable clinical, enzymatic, and ECG model, the sum of ST-segment depression (in millimetres) in all leads was a powerful independent predictor of 30 day death (P<0.0001), with a continuous increase in risk with the extent of ST-segment depression. The sum of ST-segment depression (P<0.0001) and the presence of minimal inferior ST-segment elevation (P<0.0001) or anterior ST-segment elevation (P=0.0182) were also independent predictors of the composite of death and myocardial infarction or reinfarction. The extent of ST-segment depression showed a highly significant correlation with the prevalence of three-vessel (P<0.0001) or left main coronary disease (P<0.0001), and also with the peak levels of creatine kinase (P<0.0001) during the index episode of ACS. CONCLUSION: In patients with NSTE ACS, the sum of ST-segment depression in all ECG leads is a powerful predictor of all-cause mortality at 30 days, independent of clinical variables and correlates with the extent and severity of coronary artery disease. The presence of even minimal (<1 mm) ST-segment elevation in anterior or inferior leads is independently associated with adverse outcomes.

Acute Disease↗
PubMed2005

Use of bivalirudin during percutaneous coronary intervention in patients with diabetes mellitus: an analysis from the randomized evaluation in percutaneous coronary intervention linking angiomax to reduced clinical events (REPLACE)-2 trial.

OBJECTIVES: The objective of this study was to confirm that the efficacy and safety of percutaneous coronary intervention (PCI) in diabetic patients are not compromised by a bivalirudin-based antithrombotic strategy. BACKGROUND: Previous studies have shown a survival benefit with use of platelet glycoprotein (GP) IIb/IIIa inhibitors in diabetic patients undergoing PCI. The Randomized Evaluation in Percutaneous Coronary Intervention Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial showed the non-inferiority of a strategy of bivalirudin with provisional GP IIb/IIIa inhibition compared with routine GP IIb/IIIa inhibition. The relative efficacy of these two strategies in diabetic patients has not been studied. METHODS: We evaluated the diabetic patients enrolled in the REPLACE-2 trial to assess the impact of these antithrombotic strategies on the short- and long-term outcome after PCI. RESULTS: The REPLACE-2 trial enrolled 1,624 diabetic patients and 4,368 non-diabetic patients. Compared with non-diabetic patients, diabetic patients had similar short-term outcome but higher mortality at 1 year (3.06% vs. 1.85%, p = 0.004). There was no difference in short-term or long-term ischemic events among the diabetic patients randomized to the two arms. Specifically, the 1-year mortality rate was non-significantly lower in the bivalirudin arm, suggesting no differential survival impact of the two strategies (2.3% vs. 3.9%). There was less minor bleeding in the bivalirudin arm in diabetic patients (12.6% vs. 24.4%, p < 0.001), whereas no difference was seen in the incidence of major bleeding (3.0% vs. 3.3%, p = 0.69). CONCLUSIONS: Compared with routine GP IIb/IIIa inhibition, the use of bivalirudin with provisional GP IIb/IIIa inhibitors in diabetic patients is associated with no differences in clinical outcomes at 30 days, a trend toward lesser mortality at 1 year, and a reduction in minor bleeding.

Aged↗
PubMed2005

Characterization of myocardial infarction as an end point in two large trials of acute coronary syndromes.

Myocardial infarction (MI) is a key component of composite end points in trials that evaluate new therapies in non-ST-segment elevation acute coronary syndromes. Types of MI events in these trials have not been well characterized. A similar clinical-events classification process adjudicated all suspected MI end points in the PURSUIT and PARAGON B trials. All MI end points were classified as nonprocedural, related to percutaneous coronary intervention, or related to coronary artery bypass grafting. A total of 16,173 patients was enrolled in the 2 trials, and 1,802 MI end points occurred during a 30-day follow-up. Nearly 66% of MI end points were not related to percutaneous coronary intervention or coronary artery bypass grafting. Patients who had MI compared with those who did not had higher 30-day mortality rates (13.6% vs 2.3%, p <0.001) and 6-month mortality rates (18.4% vs 4.4%, p <0.001). Patients who had been randomized to glycoprotein IIb/IIIa inhibition showed trends toward fewer MI events regardless of type. Two-thirds of MI end points in 2 large trials of acute coronary syndrome were not related to procedure. All MI types were associated with worse short- and long-term outcomes. Characterization of the type of MI provides an opportunity for more informed interpretation of clinical trial results and improved planning for future trials.

Angioplasty, Balloon, Coronary↗
PubMed2005

Platelet, not endothelial, P-selectin is required for neointimal formation after vascular injury.

BACKGROUND: P-selectin blockade significantly inhibits inflammation and neointimal formation after arterial injury; however, the independent roles of platelet and endothelial P-selectins in this process are unknown. In atherosclerosis, both platelet and endothelial cell P-selectins are important. This study was designed to determine whether P-selectin expression on platelet, endothelial, or both surfaces is critical to the inflammatory response and neointimal formation after arterial injury. METHODS AND RESULTS: Using wild-type (WT) and P-selectin-knockout (Psel(-/-)) mice, we performed bone marrow transplantation to generate chimeric mice that expressed either platelet P-selectin (Plt-Psel) or endothelial P-selectin (EC-Psel). Double injury of the carotid artery was performed in these mice as well as in WT and Psel(-/-) mice. Animals were euthanized 4 or 21 days after arterial injury. Morphometric data showed that there was more neointimal formation in the WT mouse group when compared with the Psel(-/-) mouse group (0.015+/-0.004 vs 0.004+/-0.004 mm2, P<0.001). Further comparison showed significantly less neointimal area in EC-Psel mice (0.006+/-0.004 mm2) compared with Plt-Psel mice (0.011+/-0.005 mm2, P=0.026) and WT mice (0.015+/-0.004 mm2, P=0.001). No significant differences were observed between WT and Plt-Psel mice or between Psel(-/-) and EC-Psel mice. Decreased neointimal formation was accompanied by a reduced inflammatory response, as evidenced by immunostaining of RANTES and MCP-1 4 days after injury. CONCLUSIONS: Platelet P-selectin expression, but not endothelial P-selectin, plays a crucial role in the development of neointimal formation after arterial injury, and therapeutic strategies targeting leukocyte-platelet interactions could be effective in inhibiting restenosis.

Angioplasty, Balloon↗
PubMed2005

Association of height with outcomes in patients with acute myocardial infarction receiving reperfusion therapy.

Data were evaluated for patients with acute ST-elevation myocardial infarction (n = 94,182) enrolled in 6 large clinical trials evaluating the efficacy of various reperfusion strategies. It was found that compared with the tallest quartile, incidences of in-hospital reinfarction, stroke, major bleeding, cardiogenic shock, heart failure, and death in the shortest group were 1.4, 1.7, 1.7, 1.8, 1.9, and 2.4 times greater, respectively. Although a strong inverse association of height was observed with unadjusted 30-day mortality (p <0.001), it was attenuated after adjustment for confounders, including weight, and appeared to be nonlinear, such that for height </=165 cm, the odds ratio [OR] for a 10-cm increment in height was 1.115 (95% confidence interval [CI] 1.014 to 1.223) and for height >165 cm, the OR for a 10-cm increase in height was 0.962 (95% CI 0.896 to 1.033). These data indicate that height-related differences in 30-day mortality are explained in large part by height-related differences in patients' clinical characteristics.

Aged↗
PubMed2005

Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials.

We sought to compare the risk of hemorrhage due to the low (<100 mg), moderate (100 to 200 mg), and high (>200 mg) doses of aspirin (acetylsalicylic acid [ASA]) in 192,036 patients enrolled in 31 clinical trials. Despite substantial differences in the reporting patterns of bleeding complications, low-dose ASA was associated with the lowest risk, and moderate doses caused a relatively high hemorrhagic event rate, especially with regard to minor, gastrointestinal, and total bleeding, and stroke. These findings should be considered when using combination antiplatelets, anticoagulant therapy, or both, with ASA, especially with the daily dose of >100 mg.

Aspirin↗
PubMed2005

Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial.

CONTEXT: Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase-activating protein (FLAP) gene are associated with risk of MI. OBJECTIVE: To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk. DESIGN, SETTING, AND PATIENTS: A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004. INTERVENTIONS: Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks. MAIN OUTCOME MEASURES: Changes in levels of biomarkers associated with risk of MI. RESULTS: In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% CI, -2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events. CONCLUSION: In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.

5-Lipoxygenase-Activating Proteins↗
PubMed2005

Thrombospondin-1 up-regulates expression of cell adhesion molecules and promotes monocyte binding to endothelium.

Expression of cell adhesion molecules (CAM) responsible for leukocyte-endothelium interactions plays a crucial role in inflammation and atherogenesis. Up-regulation of vascular CAM-1 (VCAM-1), intracellular CAM-1 (ICAM-1), and E-selectin expression promotes monocyte recruitment to sites of injury and is considered to be a critical step in atherosclerotic plaque development. Factors that trigger this initial response are not well understood. As platelet activation not only promotes thrombosis but also early stages of atherogenesis, we considered the role of thrombospondin-1 (TSP-1), a matricellular protein released in abundance from activated platelets and accumulated in sites of vascular injury, as a regulator of CAM expression. TSP-1 induced expression of VCAM-1 and ICAM-1 on endothelium of various origins, which in turn, resulted in a significant increase of monocyte attachment. This effect could be mimicked by a peptide derived from the C-terminal domain of TSP-1 and known to interact with CD47 on the cell surface. The essential role of CD47 in the cellular responses to TSP-1 was demonstrated further using inhibitory antibodies and knockdown of CD47 with small interfering RNA. Furthermore, we demonstrated that secretion of endogenous TSP-1 and its interaction with CD47 on the cell surface mediates endothelial response to the major proinflammatory agent, tumor necrosis factor alpha (TNF-alpha). Taken together, this study identifies a novel mechanism regulating CAM expression and subsequent monocyte binding to endothelium, which might influence the development of anti-atherosclerosis therapeutic strategies.

Atherosclerosis↗
PubMed2005

Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials.

CONTEXT: The benefits of abciximab in patients with ST-segment elevation myocardial infarction (STEMI) are still a matter of debate. OBJECTIVE: To combine data from all randomized trials conducted with abciximab in STEMI. DATA SOURCES: Formal searches of electronic databases (MEDLINE, PubMed) from from January 1990 to December 2004. STUDY SELECTION: We examined all completed, published, randomized trials of abciximab in STEMI. The following key words were used for study selection: randomized trial, myocardial infarction, reperfusion, primary angioplasty, facilitated angioplasty, stenting, fibrinolysis, IIb-IIIa inhibitors, and abciximab. DATA EXTRACTION: Information on study design, type and dosage of drugs, inclusion and exclusion criteria, number of patients, and clinical outcome was extracted by 2 investigators. Disagreements were resolved by consensus. DATA SYNTHESIS: Eleven trials were analyzed, involving 27115 patients (12,602 [46.5%] in the abciximab group, 14,513 [53.5%] in the control group). When compared with the control group, abciximab was associated with a significant reduction in short-term (30 days) mortality (2.4% vs 3.4%, P = .047) and long-term (6-12 months) mortality (4.4% vs 6.2%, P = .01) in patients undergoing primary angioplasty but not in those treated with fibrinolysis or in all trials combined. Abciximab was associated with a significant reduction in 30-day reinfarction, both in all trials combined (2.1% vs 3.3%, P<.001), in primary angioplasty (1.0% vs 1.9%, P = .03), and in fibrinolysis trials (2.3% vs 3.6%, P<.001). Abciximab did not result in an increased risk of intracranial bleeding (0.61% vs 0.62%, P = .62) but was associated with an increased risk of major bleeding complications when combined with fibrinolysis (5.2% vs 3.1%, P<.001) but not with primary angioplasty (4.7% vs 4.1%, P = .36). CONCLUSIONS: This meta-analysis shows that, when compared with the control group, adjunctive abciximab for STEMI is associated with a significant reduction in 30-day and long-term mortality in patients treated with primary angioplasty but not in those receiving fibrinolysis. The 30-day reinfarction rate is significantly reduced in patients treated with either fibrinolysis or primary angioplasty. A higher risk of major bleeding complications is observed with abciximab in association with fibrinolysis.

Abciximab↗
PubMed2005

Prognostic implication of activated partial thromboplastin time after reteplase or half-dose reteplase plus abciximab: results from the GUSTO-V trial.

AIMS: To evaluate the relationship between activated partial thromboplastin time (aPTT) and clinical outcomes in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-V) trial comparing standard-dose reteplase to half-dose reteplase and abciximab. METHODS AND RESULTS: We analysed data on 11,420 patients receiving unfractionated heparin. Peak aPTT levels recorded during the hospitalization were correlated with clinical outcomes. Multivariable logistic regression models examined the relationship between peak aPTT levels and (i) moderate-to-severe bleeding, (ii) intracerebral haemorrhage, (iii) reinfarction, and (iv) 30-day mortality. Non-linear relationships were explored in the models using cubic spline functions. Higher rates of significant complications were seen in both groups when aPTT levels were <50 s or when levels were >70 s. In the combination therapy group, the relationship between aPTT levels and bleeding appeared accentuated. Reinfarction rates increased gradually as aPTT levels were >70 s in both groups, but the relationships were not statistically significant. Peak aPTT levels <50 s were associated with increased 30-day mortality even after multivariable adjustment. CONCLUSION: Peak aPTT levels <50 s and >70 s are associated with worse clinical outcomes in the modern era of fibrinolytic therapy; these relationships are different in patients receiving standard reteplase vs. combination therapy.

Abciximab↗
PubMed2005

Towards precise classification of cancers based on robust gene functional expression profiles.

BACKGROUND: Development of robust and efficient methods for analyzing and interpreting high dimension gene expression profiles continues to be a focus in computational biology. The accumulated experiment evidence supports the assumption that genes express and perform their functions in modular fashions in cells. Therefore, there is an open space for development of the timely and relevant computational algorithms that use robust functional expression profiles towards precise classification of complex human diseases at the modular level. RESULTS: Inspired by the insight that genes act as a module to carry out a highly integrated cellular function, we thus define a low dimension functional expression profile for data reduction. After annotating each individual gene to functional categories defined in a proper gene function classification system such as Gene Ontology applied in this study, we identify those functional categories enriched with differentially expressed genes. For each functional category or functional module, we compute a summary measure (s) for the raw expression values of the annotated genes to capture the overall activity level of the module. In this way, we can treat the gene expressions within a functional module as an integrative data point to replace the multiple values of individual genes. We compare the classification performance of decision trees based on functional expression profiles with the conventional gene expression profiles using four publicly available datasets, which indicates that precise classification of tumour types and improved interpretation can be achieved with the reduced functional expression profiles. CONCLUSION: This modular approach is demonstrated to be a powerful alternative approach to analyzing high dimension microarray data and is robust to high measurement noise and intrinsic biological variance inherent in microarray data. Furthermore, efficient integration with current biological knowledge has facilitated the interpretation of the underlying molecular mechanisms for complex human diseases at the modular level.

Algorithms↗