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Biomedical subjects

Eric J Topol

Publications and source records attributed to Eric J Topol.

At least 163 records · Page 9Linked to original sources
PubMed2003

Frequency of stent thrombosis after acute coronary syndromes (from the SYMPHONY and 2nd SYMPHONY trials).

We studied stent thrombosis in 4,607 patients with acute coronary syndromes who received a coronary stent as part of routine care during 2 trials of aspirin versus sibrafiban for secondary prevention. In these patients, stent thrombosis occurred more often than in previous patients who underwent elective percutaneous coronary intervention. These patients and their outcomes may be more representative of patients with typical acute coronary syndromes undergoing stenting in clinical practice.

Acute Disease↗
PubMed2003

Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease.

BACKGROUND: This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients. METHODS AND RESULTS: Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban. CONCLUSIONS: Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.

Administration, Oral↗
PubMed2003

Effect of abciximab versus tirofiban on activated clotting time during percutaneous intervention and its relation to clinical outcomes--observations from the TARGET trial.

Previous evidence suggests that the monoclonal antibody abciximab may have a more potent anticoagulant effect than small-molecule glycoprotein (GP) IIb/IIIa inhibitors. We prospectively reviewed collected heparin dose, activated clotting time (ACT), and corresponding clinical outcome data from The Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial (TARGET), a direct comparison of tirofiban versus abciximab in patients who underwent percutaneous intervention. Of the 4,809 patients enrolled in the trial, 3,739 patients (78%) had an ACT measured after the administration of GP IIb/IIIa and heparin (peak procedural ACT); this formed the population for the present study. Mean total heparin dose was 75 +/- 32 and 76 +/- 31 U/kg in the tirofiban and abciximab groups, respectively. The resultant mean peak ACTs were 296 +/- 91 and 299 +/- 89 seconds (p = 0.09). In a subset of patients with both baseline ACT (before any heparin or GP IIb/IIIa therapy) and peak procedural ACT measurements, the difference in ACT between these time points was 80 +/- 97 vs 82 +/- 101 seconds (p = 0.44) for the tirofiban and abciximab groups, respectively. After adjusting for patients' weight, weight-adjusted heparin dose, and method of ACT measurement in a multiple linear regression analysis, the type of GP IIb/IIIa inhibitor was not predictive of the peak ACT (p = 0.24). When stratified by ACT quartile, no statistically significant difference in bleeding or ischemic end points between the tirofiban and abciximab cohorts was observed. In this large contemporary percutaneous coronary intervention trial, there was no observed difference in the anticoagulant effect of tirofiban and abciximab, as measured by the ACT, or in the incidence of bleeding or ischemic complications in each ACT quartile.

Abciximab↗
PubMed2003

Effect of revascularization on mortality associated with an elevated white blood cell count in acute coronary syndromes.

Inflammation is increasingly recognized as having an important role in patients with acute coronary syndromes. We sought to determine whether an elevated white blood cell (WBC) count would predict subsequent mortality and whether revascularization would have a protective effect. We analyzed data from 10,480 patients with acute coronary syndromes enrolled in the PURSUIT trial who had a WBC count measured on admission. WBC count values were stratified by quartiles, and death rates at 6 months were examined in univariate and multivariate analyses. Propensity analysis was performed to assess the effect of revascularization on the relation between WBC count and mortality. In the lowest quartile of WBC count, mortality was 4.0%; it was 5.8% in the second quartile, 6.7% in the third quartile, and 8.0% in the fourth quartile (p <0.001). In a multivariable model incorporating baseline demographic and clinical variables, an increasing WBC count was a significant predictor of death, with a hazard ratio of 1.07 per 1,000/microl increment in WBC count (p <0.001). Furthermore, the interaction term between mortality due to an elevated WBC count and benefit of in-hospital revascularization was significant (hazard ratio 0.94, p = 0.032), suggesting that the excess risk due to an elevated WBC count was attenuated by revascularization. An elevated WBC count at hospital admission, although only a crude index of inflammation, nevertheless is an independent predictor of death at 6 months in patients with acute coronary syndromes. This finding supports a pivotal role for inflammation in acute coronary syndromes. Importantly, this study suggests that in-hospital revascularization may mitigate some of the excess risk due to inflammation.

Acute Disease↗
PubMed2003

N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy.

BACKGROUND: Biochemical markers are useful for prediction of cardiac events in patients with non-ST-segment-elevation acute coronary syndrome (ACS). The associations between N-terminal pro-brain natriuretic peptide (NT-proBNP) and other biochemical and clinical risk indicators, as well as their prognostic value concerning the individual end points of death and myocardial infarction (MI), were elucidated in a large cohort of ACS patients. METHODS AND RESULTS: NT-proBNP, troponin T, and C-reactive protein (CRP) were analyzed in blood samples obtained at a median of 9.5 hours from symptom onset in 6809 of 7800 ACS patients in the Global Utilization of Strategies To Open occluded arteries-IV (GUSTO-IV) trial. Levels of NT-proBNP were correlated independently with age, female gender, low body weight, diabetes, renal dysfunction, history of MI, heart failure, heart rate, ongoing myocardial damage, and time since onset of ischemia. Increasing quartiles of NT-proBNP were related to short- and long-term mortality that reached 1.8%, 3.9%, 7.7%, and 19.2%, (P<0.001), respectively, at 1 year. Levels of troponin T, CRP, heart rate, and creatinine clearance, in addition to ST-segment depression, were also correlated independently with 1-year mortality, but NT-proBNP was the marker with the strongest relation. In contrast, only troponin T, creatinine clearance, and ST-segment depression were independently related to future MI. The combination of NT-proBNP and creatinine clearance provided the best prediction, with a 1-year mortality of 25.7% with both markers in the top quartile vs 0.3% with both markers in the bottom quartile. CONCLUSIONS: The use of NT-proBNP appears to add critical prognostic insight to the assessment of patients with ACS.

Abciximab↗
PubMed2003

Increased expression of thrombospondin-1 in vessel wall of diabetic Zucker rat.

BACKGROUND: Thrombospondin-1 (TSP-1) expression in the vascular wall has been related to the development of atherosclerotic lesions and restenosis. TSP-1 promotes the development of neointima and has recently been associated with atherogenesis at a genetic level. Because TSP-1 expression is responsive to glucose stimulation in mesangial cells, we hypothesized that glucose may stimulate its production by vascular cells. Thus, TSP-1 expression in the blood vessel wall may increase, providing a molecular link between diabetes and accelerated vascular lesion development. METHODS AND RESULTS: To determine whether the expression level of TSP-1 in vessel wall is increased in diabetes, aorta and carotid arteries of Zucker rats were used for immunostaining, Western blotting, and in situ RNA hybridization. A significant increase in TSP-1 expression was found in the adventitia of blood vessels from diabetic rats. Consistent with the well-known antiangiogenic effect of TSP-1, the number of vasa vasorum was reduced in aortas from diabetic rats. In cultured endothelial cells, vascular smooth muscle cells, and fibroblasts, TSP-1 expression increased in response to glucose stimulation (>30-fold). After balloon catheter injury to carotid arteries, expression of TSP-1 protein and mRNA was higher at all time points in the vessels of diabetic rats. CONCLUSIONS: Increased expression of TSP-1 in blood vessels in diabetes may represent a new link between diabetes, atherogenesis, and accelerated restenosis. This increase in TSP-1 production may be a direct response of vascular cells to glucose.

Animals↗
PubMed2003

Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials.

INTRODUCTION: Oxidised LDL is thought to play an important part in the pathogenesis of atherosclerosis. Observational studies have associated alpha tocopherol (vitamin E), beta carotene, or both, with reductions in cardiovascular events, but not clinical trials. We did a meta-analysis to assess the effect of these compounds on long-term cardiovascular mortality and morbidity. METHODS: We analysed seven randomised trials of vitamin E treatment and, separately, eight of beta carotene treatment; all trials included 1000 or more patients. The dose range for vitamin E was 50-800 IU, and for beta carotene was 15-50 mg. Follow-up ranged from 1.4 to 12.0 years. FINDINGS: The vitamin E trials involved a total of 81788 patients and the beta carotene trials 138113 in the all-cause mortality analyses. Vitamin E did not provide benefit in mortality compared with control treatment (11.3 vs 11.1%, odds ratio 1.02 [95% CI 0.98-1.06] p=0.42) or significantly decrease risk of cardiovascular death (6.0 vs 6.0%, p=0.86) or cerebrovascular accident (3.6 vs 3.5%, p=0.31). Beta carotene led to a small but significant increase in all-cause mortality (7.4 vs 7.0%, 1.07 [1.02-1.11] p=0.003) and with a slight increase in cardiovascular death (3.4 vs 3.1%, 1.1 [1.03-1.17] p=0.003). No significant heterogeneity was noted for any analysis. INTERPRETATION: The lack of a salutary effect was seen consistently for various doses of vitamins in diverse populations. Our results, combined with the lack of mechanistic data for efficacy of vitamin E, do not support the routine use of vitamin E.

Antioxidants↗
PubMed2003

Receptor for AGE (RAGE) mediates neointimal formation in response to arterial injury.

BACKGROUND: Receptor for advanced-glycation end products (RAGE) and its ligands AGEs and S100/calgranulins have been implicated in a range of disorders. However, the role of RAGE/ligand interaction in neointimal hyperplasia after vascular injury remains unclear. METHODS AND RESULTS: We examined the expression of RAGE and its ligands after balloon injury of the carotid artery in both Zucker diabetic and nondiabetic rats. Using a soluble portion of the extracellular domain of RAGE, we determined the effects of suppressing RAGE/ligand interaction on vascular smooth muscle cell (VSMC) proliferation and neointimal formation after arterial injury. We demonstrate a significantly increased accumulation of AGE and immunoreactivities of RAGE and S100/calgranulins in response to balloon injury in diabetic compared with nondiabetic rats. Blockade of RAGE/ligand interaction significantly decreased S100-stimulated VSMC proliferation in vitro and bromodeoxyuridine (BrdU)-labeled proliferating VSMC in vivo, and suppressed neointimal formation and increased luminal area in both Zucker diabetic and nondiabetic rats. CONCLUSIONS: These findings indicate that RAGE/ligand interaction plays a key role in neointimal formation after vascular injury irrespective of diabetes status and suggest a novel target to minimize neointimal hyperplasia.

Angioplasty, Balloon↗
PubMed2003

Relation of inflammation and benefit of statins after percutaneous coronary interventions.

BACKGROUND: Beyond lipid lowering, statins are known to possess antiinflammatory and antithrombotic properties. Recent studies suggested an association between statins and early reduction in death or myocardial infarction (MI) after percutaneous coronary interventions (PCIs). We sought to examine the interrelationship between inflammation, statin use, and PCI outcomes. METHODS AND RESULTS: In the year 2000, 1552 consecutive United States residents underwent elective or urgent PCI at the Cleveland Clinic and were prospectively followed for 1 year. Preprocedural serum high-sensitivity C-reactive protein (hsCRP) levels were routinely measured. Patients who had statins initiated before the procedure (39.6%) had a lower median hsCRP level (0.40 versus 0.50 mg/dL, P=0.012) independent of the baseline cholesterol levels and had less frequent periprocedural MI (defined by CKMB > or =3x upper limit of normal, 5.7% versus 8.1%, P=0.038). At 1 year, statin pretreatment was predictive of survival predominantly among patients within the highest hsCRP quartile (mortality rate with statin pretreatment versus no pretreatment when hsCRP > or =1.11 mg/dL, 5.7% versus 14.8%, P=0.009). Using multivariate analysis, preprocedural hsCRP level remained an independent predictor for 1-year death or MI only in patients without statin therapy (hazard ratio, 1.32/quartile; P=0.001). After adjusting for the propensity of receiving statins, statin pretreatment was an independent predictor for 1-year survival within the highest hsCRP quartile (hazard ratio, 0.44; P=0.039). CONCLUSIONS: Statin therapy before PCI is associated with a marked reduction in mortality among patients with high hsCRP levels. A hsCRP-guided strategy may improve targeting of statin therapy and clinical outcome among patients undergoing PCI.

Aged↗
PubMed2003

Troponin and C-reactive protein have different relations to subsequent mortality and myocardial infarction after acute coronary syndrome: a GUSTO-IV substudy.

OBJECTIVES: We sought to evaluate C-reactive protein (CRP) and troponin T (TnT) as predictors of risk of the individual end points of mortality and myocardial infarction (MI) in a large cohort of patients with acute coronary syndrome (ACS). BACKGROUND: Both CRP and TnT predict risk of future coronary events in patients with ACS. However, the relationships between the levels of the markers and the individual end points are still unclear. METHODS: Baseline levels of CRP and TnT were determined in 7,108 patients with ACS not undergoing early revascularization in the Global Use of Strategies To Open occluded arteries trial IV (GUSTO-IV) trial and related to outcome at 30 days. RESULTS: Quartiles of TnT related to 30-day mortality, which was 1.1%, 3.7%, 3.7%, and 7.4% (p < 0.001) and to the rate of MI: 2.5%, 6.7%, 7.2%, and 5.6% (p < 0.001). Quartiles of CRP also related to 30-day mortality, which was 2.0%, 3.3%, 3.9%, and 6.3% (p < 0.001), whereas there was no relationship to the 30-day rate of MI: 5.6%, 4.7%, 5.2%, and 5.9% (p = 0.48). On multivariable analysis, both TnT and CRP were independent predictors of mortality, but only TnT was a predictor of MI. The combination of CRP and TnT provides an even better risk stratification of mortality, with 0.3% and 9.1% death rates, respectively, when both markers are in the bottom versus top quartiles. CONCLUSIONS: In ACS, baseline levels of TnT and CRP are independently related to 30-day mortality. Any detectable elevation of TnT, but not of CRP, is also associated with an increased risk of subsequent MI. Regarding mortality, the combination of both markers provides a better risk stratification than either one alone.

Acute Disease↗
PubMed2003

A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease.

OBJECTIVES: This study was designed to determine if aspirin resistance is associated with clinical events. BACKGROUND: Aspirin resistance, defined by platelet function testing and presumed clinical unresponsiveness to aspirin, has been previously reported by our group and others. However, little information exists linking the laboratory documentation of aspirin resistance and long-term clinical events. METHODS: We prospectively enrolled 326 stable cardiovascular patients from 1997 to 1999 on aspirin (325 mg/day for > or =7 days) and no other antiplatelet agents. We tested for aspirin sensitivity by optical platelet aggregation using adenosine diphosphate (ADP) and arachidonic acid (AA). The primary outcome was the composite of death, myocardial infarction (MI), or cerebrovascular accident (CVA). Mean follow-up was 679 +/- 185 days. Aspirin resistance was defined as a mean aggregation of > or =70% with 10 microM ADP and > or =20% with 0.5 mg/ml AA. RESULTS: Of the patients studied, 17 (5.2%) were aspirin resistant and 309 (94.8%) were not aspirin resistant. During follow-up, aspirin resistance was associated with an increased risk of death, MI, or CVA compared with patients who were aspirin sensitive (24% vs. 10%, hazard ratio [HR] 3.12, 95% confidence interval [CI] 1.10 to 8.90, p = 0.03). Stratified multivariate analyses identified platelet count, age, heart failure, and aspirin resistance to be independently associated with major adverse long-term outcomes (HR for aspirin resistance 4.14, 95% CI 1.42 to 12.06, p = 0.009). CONCLUSIONS: This study demonstrates the natural history of aspirin resistance in a stable population, documenting a greater than threefold increase in the risk of major adverse events associated with aspirin resistance.

Adult↗
PubMed2003

Proteomic approach to coronary atherosclerosis shows ferritin light chain as a significant marker: evidence consistent with iron hypothesis in atherosclerosis.

Coronary artery disease (CAD) is the leading cause of mortality and morbidity in developed nations. We hypothesized that CAD is associated with distinct patterns of protein expression in the coronary arteries, and we have begun to employ proteomics to identify differentially expressed proteins in diseased coronary arteries. Two-dimensional (2-D) gel electrophoresis of proteins and subsequent mass spectrometric analysis identified the ferritin light chain as differentially expressed between 10 coronary arteries from patients with CAD and 7 coronary arteries from normal individuals. Western blot analysis indicated significantly increased expression of the ferritin light chain in the diseased coronary arteries (1.41 vs. 0.75; P = 0.01). Quantitative real-time PCR analysis showed that expression of ferritin light chain mRNA was decreased in diseased tissues (0.70 vs. 1.17; P = 0.013), suggesting that increased expression of ferritin light chain in CAD coronary arteries may be related to increased protein stability or upregulation of expression at the posttranscriptional level in the diseased tissues. Ferritin light chain protein mediates storage of iron in cells. We speculate that increased expression of the ferritin light chain may contribute to pathogenesis of CAD by modulating oxidation of lipids within the vessel wall through the generation of reactive oxygen species. Our results provide in situ proteomic evidence consistent with the "iron hypothesis," which proposes an association between excessive iron storage and a high risk of CAD. However, it is also possible that the increased ferritin expression in diseased coronary arteries is a consequence, rather than a cause, of CAD.

Adult↗
PubMed2003

Impact of on-site cardiac interventional facilities on management and outcome of patients with acute coronary syndromes.

OBJECTIVES: To investigate the impact of on-site cardiac interventional facilities on the management and outcome of patients with versus those without ST elevation acute coronary syndromes (ACS) in the Canadian-American Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb population. METHODS: Data from 4605 patients were analyzed in relation to the admitting hospital's capability to perform coronary procedures (noninvasive, angiography-capable and interventional hospitals). Differences in medication use, revascularization rate and patient outcome were determined. RESULTS: Whereas medication use during hospitalization and at discharge differed between non-ST elevation ACS patients treated in the three groups, these were generally more comparable among ST elevation ACS patients. In both ST segment cohorts, patients treated in interventional hospitals underwent coronary procedures more often (angiography rate greater than 70% versus 40% for noninvasive hospitals) and sooner (median two to three days versus four days in noninvasive hospitals) than those treated in other hospitals. Recurrent ischemia was significantly less common in non-ST elevation ACS patients treated in interventional hospitals (32% versus 36% in angiography-capable and 40% in noninvasive hospitals, P<0.001) and tended to be less common among ST elevation ACS patients treated in interventional hospitals. Patients treated in interventional hospitals tended to have lower mortality in the non-ST elevation ACS cohort but significantly fewer died in the ST elevation ACS during hospitalization and at 30 days, six months and one year (8.8% versus 11% in angiography-capable and 15% in noninvasive hospitals, P=0.015). These differences in mortality persisted after adjustment for key baseline covariates. Separate analysis of Canadian and American patients revealed similar mortality patterns, as to the total population, in both ST segment cohorts. CONCLUSIONS: Presence of an on-site cardiac interventional facility favourably affected the management and outcome of ACS patients in both non-ST and ST elevation cohorts.

Acute Disease↗