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Eric J Topol

Publications and source records attributed to Eric J Topol.

At least 127 records · Page 7Linked to original sources
PubMed2004

Triple antiplatelet therapy does not increase femoral access bleeding with vascular closure devices.

BACKGROUND: The use of arteriotomy closure devices (CDs) to achieve hemostasis after femoral artery access in percutaneous coronary intervention is steadily increasing. However, the safety information with these devices in the era of triple antiplatelet therapy is limited. METHODS: We reviewed prospectively collected data from the Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial (TARGET), where all patients received aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitor therapy. At the treating physician's discretion, manual compression (MC) or a vascular hemostasis device was selected following femoral angiography. Patients receiving MC were to have sheaths removed 2 to 6 hours postprocedure when the activated clotting time was < or = 175 seconds. RESULTS: Of 4809 patients, 4736 had femoral access, and 985 of these had a CD (Perclose 47%, Angio-Seal 43%, VasoSeal 5%, and other 5%). The MC and CD groups were similar regarding most demographic characteristics, including age, systolic blood pressure, and weight, but those with MC were more often female, diabetic, and had history of peripheral vascular disease. Patients with a CD had a lower ischemic event rate suggesting they were a lower risk cohort overall. There were no differences in major bleeding at the access site (0.4% vs 0.5%, P =.588), minor bleeding at the access site (1.9% vs. 3.1%, P =.142) or transfusions (0.8% vs 1.0%, P =.513) between the MC and CD groups, respectively. CONCLUSIONS: In contemporary percutaneous coronary intervention practice, with appropriate patient selection, a CD can be safely utilized despite aggressive polypharmacy for procedural anticoagulation.

Angioplasty, Balloon, Coronary↗
PubMed2004

Association of diabetes mellitus and glycemic control strategies with clinical outcomes after acute coronary syndromes.

BACKGROUND: Diabetes is associated with an increased risk for coronary artery disease (CAD) and its complications. The relative effect of glucose-lowering strategies of "insulin provision" versus "insulin sensitization" among patients with CAD remains unclear. METHODS: To evaluate the associations of diabetes and hypoglycemic strategies with clinical outcomes after acute coronary syndromes, we analyzed data from 15,800 patients enrolled in the SYMPHONY and 2nd SYMPHONY trials. RESULTS: Compared with nondiabetic patients, patients with diabetes (n = 3101; 19.6%) were older, more often female, more often had prior CAD, hypertension, and hyperlipidemia, and less often were current smokers. The diabetic cohort had higher 90-day unadjusted risk of the composite of death/myocardial infarction (MI)/severe recurrent ischemia (SRI), death/MI, and death alone, as well as a near doubling of 1-year mortality rates. At 1 year, diabetes was associated with significantly higher adjusted risks of death/MI/SRI (OR, 1.3 [95% confidence interval, 1.1, 1.5]) and death/MI (OR, 1.2 [1.0, 1.4]). Hypoglycemic therapy including only insulin and/or sulfonylurea (insulin-providing; n = 1473) was associated with higher 90-day death/MI/SRI compared with therapy that included only biguanide and/or thiazolidinedione therapy (insulin-sensitizing; n = 100) (12.0% vs 5.0%); (adjusted OR, 2.1 [1.2, 3.7]). CONCLUSIONS: Diabetic patients with acute coronary syndromes had worse clinical outcomes. Although the findings regarding the influence of glycemic-control strategies should be interpreted with caution because of the exploratory nature of the analyses and the relatively small sample size of the insulin-sensitizing group, the improved risk-adjusted outcomes associated with insulin-sensitizing therapy underscore the need to further evaluate treatment strategies for patients with diabetes and CAD.

Aged↗
PubMed2004

Replication of the association between the thrombospondin-4 A387P polymorphism and myocardial infarction.

BACKGROUND: The purpose of our study was to replicate an association between the A387P polymorphism in the thrombospondin-4 (THBS4) gene and myocardial infarction (MI), as previously reported by our group while taking confounding into account, and to assess whether ascertainment by age of onset would affect this association. METHODS: We performed a case-control study of 474 white patients with MI (not selected on the basis of age of onset nor family history) and 472 white control subjects. We then applied our findings to our original population of 184 white patients with premature, familial MI and 406 white control subjects. RESULTS: In the replication population, no significant association was found between THBS4 genotype and MI (P =.41) with univariate analysis. However, after adjusting for age, sex, first-degree family history, and waist-to-hip ratio, an association was apparent in the replication population (P =.032), and the original association became much stronger (P =.00008). Both studies showed a 2.5- to 3-fold increased odds of MI in individuals with the P allele. Furthermore, several variables appeared to modify the effect of THBS4 on MI, including waist-to-hip ratio, diabetes mellitus, and hypertension. When we stratified our cases by age of onset (< or =45 years in men, < or =50 years in women), there were no significant differences in genotype frequencies when comparing premature cases with late-onset cases or premature cases with control subjects in either unadjusted or adjusted analyses (all P values >.25). CONCLUSIONS: Our findings suggest that the A387P variant of the THBS4 gene may be an important determinant in the development of MI at any age. Careful assessment of clinical covariates helped to unmask a significant association and therefore may be an important reason for why studies do not replicate.

Adult↗
PubMed2004

Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.

BACKGROUND: Clopidogrel is a more potent antiplatelet agent than aspirin, resulting in greater clinical efficacy in patients with atherothrombotic disease. Furthermore, the combination of clopidogrel plus aspirin has been demonstrated to be superior to aspirin alone in the treatment of patients with acute coronary syndromes and after coronary stenting. Whether dual antiplatelet therapy is superior to aspirin monotherapy for high-risk primary prevention and secondary prevention is unknown. METHODS AND RESULTS: The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study was designed to evaluate the efficacy and safety of clopidogrel plus aspirin versus placebo plus aspirin in patients with established coronary, cerebral, or peripheral arterial disease or in patients with multiple risk factors for atherothrombosis who have not yet sustained an ischemic event. This randomized, international, multicenter, double-blinded, placebo-controlled study has finished enrolling patients worldwide. A total of 15,603 patients will be followed long term. The primary end point will be the composite of vascular death, myocardial infarction, or stroke. Rates of severe bleeding will also be compared between the two arms of the study. CONCLUSIONS: This large-scale trial of patients at high risk for atherothrombotic events will allow determination of the value of a strategy of adding clopidogrel to the current standard of care, including low-dose aspirin, for a wide spectrum of patients with atherothrombosis.

Arteriosclerosis↗
PubMed2004

Impact of female sex on outcome after percutaneous coronary intervention.

BACKGROUND: Prior reports have suggested that women have increased mortality compared to men following percutaneous coronary intervention (PCI). It remains unclear if this difference is secondary to sex or other confounding variables. METHODS: We sought to examine the characteristics and outcomes of 18039 consecutive women and men undergoing PCI at The Cleveland Clinic Foundation from 1992-2002. RESULTS: Procedural success rates were similar in both sexes, but the female cohort had a greater incidence of access site hematoma (5% vs. 2%, P < .0001) and blood product transfusion (12% vs. 4%, P < .0001) following PCI. The rate of myocardial infarction (MI) at 1 year was slightly higher among females (10% vs. 9%, P = .004), but revascularization rates were not significantly different between sexes. One-year mortality was also higher in the female cohort (7% vs. 5%, P < .0001). After adjustment in a multivariate model, the Cox proportional hazard ratio for mortality in females was 1.01 (95% CI 0.93-1.11, P = .78). The hazard ratio for the combined endpoint of death or MI was 1.05 (95% CI 0.97-1.13, P = .23). CONCLUSIONS: After adjustment for differences in comorbidities, the risk for long-term mortality is not significantly different between sexes following PCI. However, there is a greater incidence of post-procedural bleeding complications among women.

Aged↗
PubMed2004

Coronary artery disease and the thrombospondin single nucleotide polymorphisms.

GeneQuest was a high throughput, large-scale analysis of single nucleotide polymorphisms (SNPs) to identify gene associated with familial, premature coronary artery disease and myocardial infarction. The three SNPs showing the highest and most significant associations with disease were all members of the thrombospondin gene family, thrombospondin-1, thrombospondin-2 and thrombospondin-4. These unanticipated associations have kindled efforts to understand how the three SNPs influence the structures and functions of the thrombospondins. The SNP in thrombospondin-1 and thrombospondin-4 reside in their coding regions and result in single amino acid changes: in thrombospondin-1, the predominant asparagine at position 700 is changed to a serine while, in thrombospondin-4, it is a change of an alanine to a proline at position 387. The SNP in thrombospondin-2 is a base change in the 3'-untranslated region of the mRNA. At this early stage of investigation, predictive analyses suggest that the substitutions in thrombospondin-2 and thrombospondin-4 should alter structure, and there is direct evidence to indicate that the thrombospondin-1 SNP alters conformational stability. In addition, profound differences in the function of the thrombospondin-4 SNP variants have been identified with respect to their capacity to support endothelial cell adhesion and proliferation. While substantial additional information is needed to understand if and how the polymorphic forms of the thrombospondins affect coronary artery disease, the data assembled to date suggest marked effects of these SNPs on the structures and functions of the thrombospondins, which are consistent with induction of a proatherogenic and prothrombotic phenotype.

Binding Sites↗
PubMed2004

Percutaneous coronary intervention in diabetic patients with non-ST-segment elevation acute coronary syndromes.

Key pathophysiologic mechanisms of diabetes-related coronary disease include inflammation and a prothrombotic state. In the setting of non-ST-segment elevation acute coronary syndromes diabetic patients are at high risk for subsequent cardiovascular events. At the same time, they derive greater benefit than non-diabetic counterparts from aggressive antithrombotic therapy, early coronary angiography, and stent-based percutaneous coronary intervention. The mainstays of antithrombotic therapy for diabetic patients undergoing percutaneous revascularization include aspirin, clopidogrel, platelet glycoprotein IIb/IIIa receptor antagonists, and heparin or low-molecular-weight heparin. Despite dramatic reduction in restenosis conferred by drug-eluting stents, diabetic patients remain at increased risk for repeat revascularization. More efforts are needed both in terms of local drug elution as well as systemic pharmacologic therapies to further contain the excessive neointimal proliferation that characterizes the diabetic response to vascular injury.

Angioplasty, Balloon, Coronary↗
PubMed2004

Role of stem cell homing in myocardial regeneration.

Recent studies have demonstrated the potential for myocardial regeneration at the time of myocardial infarction. Our lab focuses on understanding how stem cells home to injured tissue. We believe that a detailed analysis of the biological responses to tissue injury not only gives us insight into how damage occurs, but can also yield insight into how the body attempts to repair itself. In the case of the heart, we have shown that these "healing pathways" are only expressed for a short time following injury, and this may be why myocardial damage is usually irreversible. Furthermore, work suggests that deciphering these "healing pathways" and re-establishing their expression at time remote from injury offers an avenue for developing novel therapeutics that ultimately may allow us to orchestrate and exaggerate the healing process at time remote from tissue injury.

Animals↗
PubMed2004

An ensemble method for gene discovery based on DNA microarray data.

The advent of DNA microarray technology has offered the promise of casting new insights onto deciphering secrets of life by monitoring activities of thousands of genes simultaneously. Current analyses of microarray data focus on precise classification of biological types, for example, tumor versus normal tissues. A further scientific challenging task is to extract disease-relevant genes from the bewildering amounts of raw data, which is one of the most critical themes in the post-genomic era, but it is generally ignored due to lack of an efficient approach. In this paper, we present a novel ensemble method for gene extraction that can be tailored to fulfill multiple biological tasks including (i) precise classification of biological types; (ii) disease gene mining; and (iii) target-driven gene networking. We also give a numerical application for (i) and (ii) using a public microarrary data set and set aside a separate paper to address (iii).

Algorithms↗
PubMed2004

Adjunctive therapy for percutaneous revascularization in acute myocardial infarction.

Primary PCI is an effective reperfusion strategy for acute MI patients, which has evolved significantly in the last decade. While many adjunctive therapies have contributed to its success, substantial obstacles remain before optimal reperfusion can be achieved. Anti-platelet therapy with aspirin, clopidogrel and GP IIb/IIIa inhibitors reduces early ischemic complications, improves microvascular function and, potentially, affects the inflammatory response to ischemic injury. Current anti-thrombin therapy with UFH can be improved with LMWH, and, possibly with direct thrombin inhibitors. A number of important aspects of this strategy, though, need still to be elucidated. We need to optimize microvascular protection before and during PCI in order to capitalize on the myocardial sparing effects of reperfusion therapy. This will be probably achieved with a combination of pharmacological interventions and mechanical emboli protection devices. Improved and more targeted anti-inflammatory therapy should decrease the effects of neutrophil-related reperfusion injury, while a variety of metabolic interventions might preserve myocardial function during ischemia and after reperfusion.

Angioplasty, Balloon, Coronary↗
PubMed2004

The combination of enoxaparin, glycoprotein IIb/IIIa inhibitors and an early invasive approach among acute coronary syndrome patients.

OBJECTIVES: This study was designed to assess the feasibility and safety of enoxaparin in combination with glycoprotein (GP) IIb/IIIa inhibitors during percutaneous coronary intervention (PCI) as part of an early invasive strategy in patients presenting with acute coronary syndromes (ACS). BACKGROUND: Trials in patients with ACS have evaluated the utility of enoxaparin, adjuvant GP IIb/IIIa inhibitors with PCI, and an early invasive approach. Information about the combination of all three of these approaches, however, is limited. METHODS: Forty-nine patients with ACS underwent cardiac catheterization, of whom 23 underwent PCI with enoxaparin and GP IIb/IIIa inhibitors. RESULTS: The primary endpoint of the study, a composite of death, myocardial infarction or urgent revascularization at 30 days, occurred in 8% of patients undergoing PCI. There were no deaths. One patient received a blood transfusion. No other adverse events occurred. These event rates were comparable to those from the pooled EPILOG/EPISTENT database, in which intravenous unfractionated heparin was used in conjunction with GP IIb/IIIa receptor blockade. The mean anti-Xa level in patients undergoing PCI was 0.74 0.48 U/ml. The majority of patients who underwent PCI within eight hours of their last dose of enoxaparin had therapeutic anti-Xa levels. CONCLUSION: In patients with ACS, enoxaparin in combination with GP IIb/IIIa inhibitors and an early invasive approach resulted in comparable clinical complication and bleeding rates versus historical references utilizing unfractionated heparin.

Acute Disease↗
PubMed2004

Pathobiology of atherosclerosis: are there racial and ethnic differences?

Ethnic differences in the prevalence of complex diseases such as atherosclerosis are undoubtedly multifactorial. It is clear that there are social, environmental, biologic, genetic, and other determinants leading to disparities in the rate of coronary heart disease among different ethnic and racial groups. Many epidemiologic studies have characterized the social and environmental factors leading to these differences, but there has been relatively limited investigation of the potential biologic and genetic factors involved. In this review, we will summarize currently available data on ethnic differences in cardiac risk factors, vascular biology, and genetic determinants of atherosclerosis.

Black People↗
PubMed2003

Genetic linkage analysis of longitudinal hypertension phenotypes using three summary measures.

BACKGROUND: Longitudinal data often have multiple (repeated) measures recorded along a time trajectory. For example, the two cohorts from the Framingham Heart Study (GAW13 Problem 1) contain 21 and 5 repeated measures for hypertension phenotypes as well as epidemiological risk factors, respectively. Direct modelling of a large number of serially and biologically correlated traits in the context of linkage analysis can be prohibitively complex. Alternatively, we may consider using univariate transformation for linkage analysis of longitudinal repeated measures. RESULTS: We evaluated the utility of three conventional summary measures (mean, slope, and principal components) for genetic linkage analysis of longitudinal phenotypes by analyzing the chromosome 10 data of the Framingham Heart Study. Except for the temporal slope, all of the summary methods and the multivariate analysis identified the previously reported region, marker GATA64A09, for systolic blood pressure or high blood pressure. Further analysis revealed that this region may harbor gene(s) affecting human blood pressure at multiple stages of life. CONCLUSION: We conclude that mean and principal components are feasible alternatives for genetic linkage analysis of longitudinal phenotypes, but the slope might have a separate genetic basis from that of the original longitudinal phenotypes.

Adult Children↗
PubMed2003

Multivariate sib-pair linkage analysis of longitudinal phenotypes by three step-wise analysis approaches.

BACKGROUND: Current statistical methods for sib-pair linkage analysis of complex diseases include linear models, generalized linear models, and novel data mining techniques. The purpose of this study was to further investigate the utility and properties of a novel pattern recognition technique (step-wise discriminant analysis) using the chromosome 10 linkage data from the Framingham Heart Study and by comparing it with step-wise logistic regression and linear regression. RESULTS: The three step-wise approaches were compared in terms of statistical significance and gene localization. Step-wise discriminant linkage analysis approach performed best; next was step-wise logistic regression; and step-wise linear regression was the least efficient because it ignored the categorical nature of disease phenotypes. Nevertheless, all three methods successfully identified the previously reported chromosomal region linked to human hypertension, marker GATA64A09. We also explored the possibility of using the discriminant analysis to detect gene x gene and gene x environment interactions. There was evidence to suggest the existence of gene x environment interactions between markers GATA64A09 or GATA115E01 and hypertension treatment and gene x gene interactions between markers GATA64A09 and GATA115E01. Finally, we answered the theoretical question "Is a trichotomous phenotype more efficient than a binary?" Unlike logistic regression, discriminant sib-pair linkage analysis might have more power to detect linkage to a binary phenotype than a trichotomous one. CONCLUSION: We confirmed our previous speculation that step-wise discriminant analysis is useful for genetic mapping of complex diseases. This analysis also supported the possibility of the pattern recognition technique for investigating gene x gene or gene x environment interactions.

Adult Children↗
PubMed2003

Risk factors for premature coronary artery disease and determinants of adverse outcomes after revascularization in patients < or =40 years old.

Smoking is an important and modifiable risk factor associated with premature atherosclerosis and the need for coronary revascularization in young adult patients < or =40 years old. Although intermediate and long-term survival is better in young adult patients after percutaneous coronary intervention, co-morbidities such as low ejection fraction, previous myocardial infarction, and previous bypass surgery are important adverse prognostic determinants.

Adult↗
PubMed2003

Revisiting optimal anticoagulation with unfractionated heparin during coronary stent implantation.

Using univariate and multivariate analyses, we evaluated the relation between ischemic and bleeding complications and peak procedural activated clotting time (ACT) in patients undergoing percutaneous coronary intervention whose coronary narrowings were treated with stent implantation. Of the 2,280 patients who qualified for the study, 29% had diabetes mellitus, and 91% received glycoprotein IIb/IIIa inhibitors. The median for ACT was 276 seconds (interquartile range 243 to 317). The incidence of ischemic events by ACT quartiles was 6.3%, 7.5%, 8.1%, and 7.1%, respectively (p=0.71). The incidence of bleeding complications was 6.6%, 5.9%, 6.9%, and 7.3%, respectively (p=0.81). ACT did not independently predict either ischemic or hemorrhagic complications.

Aged↗