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Biomedical subjects

H D White

Publications and source records attributed to H D White.

At least 73 records · Page 4Linked to original sources
PubMed2000

Influence of diabetes mellitus on clinical outcomes across the spectrum of acute coronary syndromes. Findings from the GUSTO-IIb study. GUSTO IIb Investigators.

AIMS: We examined the characteristics, outcomes, and effects of hirudin vs heparin treatment of diabetic patients across the spectrum of acute coronary syndromes. METHODS AND RESULTS: We studied the 12,142 patients enrolled in the randomized GUSTO-IIb study. Diabetic patients (n=2175) were older, more often female, more often had prior cardiovascular disease, hypertension, and hyperlipidaemia, and less often were current smokers. Diabetic patients had a higher overall incidence of death or (re)infarction at 30 days (13.1% vs 8.5%, P=0.0001), whether they presented with ST-segment elevation (13.9% vs 9.9%, P=0.0017) or not (12.8% vs 7.8%, P=0.0001), and at 6 months (18.8% vs 11.4%, P=0.0001). Among diabetic patients, hirudin was associated with a tendency toward a lower risk of death or (re)infarction at 30 days (12.2% vs 13.9% with heparin) and 6 months (17.8% vs 20.2%). Diabetic patients had more major bleeding, stroke, heart failure, shock, atrioventricular block, and atrial arrhythmias, but no increased risk for ocular bleeding. CONCLUSIONS: Diabetic patients with acute coronary syndromes had worse 30-day and 6-month outcomes, particularly those without ST-segment elevation. The statistically non-significant trend toward improved outcomes with hirudin was similar among patients with and without diabetes, with a greater point estimate for the absolute difference in patients with diabetes.

Aged↗
PubMed2000

New atrial fibrillation after acute myocardial infarction independently predicts death: the GUSTO-III experience.

BACKGROUND: Atrial fibrillation (AF) or flutter occurring after myocardial infarction may occur alone or in association with other complications. Whether the arrhythmia portends a poor prognosis independent of other complications with contemporary therapy is unknown. METHODS AND RESULTS: As part of the Global Use of Strategies To Open occluded coronary arteries (GUSTO-III) trial, we evaluated whether postinfarction complications were associated with the subsequent development of AF and whether AF independently predicted death over periods of 30 days and 1 year. Information including exact timing was collected on deaths and major in-hospital postinfarction complications up to 30 days. Of the 13,858 patients with sinus rhythm at enrollment, 906 later had AF or flutter and 12, 952 did not. We compared outcomes between these 2 groups, adjusting for differences in baseline characteristics and prefibrillation complications. Worsening heart failure, hypotension, third-degree heart block, and ventricular fibrillation were independent predictors of new-onset AF. The unadjusted odds ratio (OR) for death among patients with versus those without AF was 2.74 (95% confidence interval [95% CI], 2.56-3.34). After adjusting for baseline differences, the OR was reduced to 1.63 (95% CI, 1.31-2.02). Adjustment for other in-hospital complications before the onset of AF further reduced the OR to 1.49 (95% CI, 1.17-1.89). CONCLUSIONS: Atrial fibrillation or flutter occurs secondary to other postinfarction complications but independently portends a worse prognosis. Prevention and management may improve outcome.

Aged↗
PubMed2000

Medical treatment for acute coronary syndromes.

The medical treatment of acute coronary syndromes with thrombolytic, antithrombin, and antiplatelet agents is a major area of research and a vast topic for clinical review. This review summarizes important recent findings on the background of existing pathological and clinical knowledge to provide an understanding of the basis of current therapy and the new therapies that are likely to be introduced in the near future. Current controversies regarding the management of these conditions and the choice between medical, interventional, and combined strategies in different situations are also discussed.

Angina, Unstable↗
PubMed2000

A method for the dispersal and characterization of leukocytes from the human female reproductive tract.

PROBLEM: The isolation of human female reproductive tract (RT) cells that maintain viability and are representative of the entire population is essential for a thorough evaluation of mucosal immunity in the reproductive tract mucosa. Here, we describe the isolation of RT cells in high yields and with high viability from the Fallopian tube, uterine endometrium, endocervix, ectocervix and vagina. METHOD OF STUDY: This cell dispersion method uses an enzyme cocktail composed of pancreatin, hyaluronidase, and collagenase (PHC), and employs a 250-microm mesh screen to facilitate cell dispersion. RESULTS: The yields of cells isolated per gram of tissue in the presence of this PHC cocktail were compared and found to be strikingly higher relative to the yields obtained with other enzyme cocktails or in the absence of enzymes. Flow cytometry was used to characterize leukocyte subsets isolated from uterine endometrium in the presence of the various enzyme cocktails. The common leukocyte antigen marker CD45, pan T-cell marker CD3, monocyte/macrophage marker CD14 and B-cell marker CD19 were retained after exposure to the PHC cocktail of enzymes. The expression of CD8 and CD4 was lost after exposure to added enzymes but regained after culture overnight. CONCLUSION: These studies demonstrate the feasibility of using enzymatic digestion for the isolation of whole populations of Fallopian tube, endometrial, cervical and vaginal cells, including leukocyte subsets in high yields, and provide a foundation for investigating mucosal immune cell function in the human female RT.

CD4 Antigens↗
PubMed2000

Low-molecular-weight heparin and platelet glycoprotein IIb/IIIa receptor blockade in the treatment of acute coronary syndromes: complementary or competing therapies?

Clinical trials have reported the beneficial effects of platelet glycoprotein (GP) IIb/IIIa receptor antagonists and low-molecular-weight heparins in patients presenting with unstable angina or non-ST elevation myocardial infarction. In an overview of all trials comparing GP IIb/IIIa antagonists with control treatment (i.e., heparin or placebo on a background of aspirin therapy), the incidence of death/myocardial infarction at 30 days was reduced by 11%, from 13% to 11.7% (p = 0.008).Overall, the trials of low-molecular-weight heparin have shown a non-significant 10% reduction in the incidence of death/myocardial infarction at 30 days (4.8% versus 5.5% with unfractionated heparin; p = 0.2). There has been no evidence of heterogeneity (p = 0.1) in these trials. In contrast to the examination of all the low-molecular-weight heparins, when the results of the two trials of enoxaparin were combined, there was an 18% reduction in death/myocardial infarction at 43 days (7.1% versus 8.6%; p = 0.02). Given the differing mechanisms of action of GP IIb/IIIa antagonists and low-molecular-weight heparins, and these encouraging trial results, the use of both agents was tested in a small pilot study of patients randomized to receive tirofiban plus either unfractionated heparin or enoxaparin. There was a trend for greater inhibition of platelet aggregation and shorter bleeding times in those who had received tirofiban plus enoxaparin. These data support the theoretical potential of this combination for the treatment of patients with acute coronary syndromes, but prospective randomized trials will need to be conducted to assess efficacy and safety.

Acetates↗
PubMed1999

Risk stratification with a point-of-care cardiac troponin T test in acute myocardial infarction. GUSTOIII Investigators. Global Use of Strategies To Open Occluded Coronary Arteries.

Troponin T has been used successfully to risk stratify patients with acute coronary syndromes, but the utility of this approach using a rapid bedside assay in patients undergoing thrombolysis for ST-segment elevation acute myocardial infarction has not been assessed in a large population. We assessed whether a point-of-care, qualitative troponin T test at enrollment could independently risk-stratify patients randomized to receive alteplase or reteplase in the GUSTO-III trial. Complete troponin T data were available for 12,666 patients (84%) enrolled at 550 hospitals. The primary end point was mortality at 30 days, and the predictive ability of an elevated baseline troponin T level was analyzed (after adjustment for baseline characteristics) with multiple logistic regression. Patients with an elevated troponin T result at enrollment (8.9%) had significantly higher mortality at 30 days (unadjusted 15.7% vs 6.2% for negative patients; p = 0.001), which persisted even after adjustment for age, heart rate, location of infarction, Killip class, and systolic blood pressure. In a multivariable regression model, a positive troponin T result added independently to the prediction of 30-day mortality (chi-square 46, p = 0.001). A positive result with qualitative troponin T testing on admission is an independent marker of higher 30-day mortality. Troponin T testing could be a valuable addition to the evaluation strategy for patients with acute myocardial infarction.

Aged↗
PubMed1999

Combination therapy with tirofiban and enoxaparin in acute coronary syndromes.

BACKGROUND: Tirofiban, an intravenous glycoprotein IIb/IIIa antagonist, and enoxaparin, a low molecular weight heparin, have each been shown to be effective at reducing cardiac ischemic events compared to unfractionated heparin alone in separate trials of patients with unstable angina and non-Q-wave myocardial infarction. The combination of these agents may offer further therapeutic benefit. MATERIALS AND METHODS: Fifty-five patients with non-Q-wave myocardial infarction were randomized to receive double-blind treatment with tirofiban (0.1 microgram/kg/min i.v.) for 48-108 h coadministered with either enoxaparin (1 mg/kg sc q 12 h) (n=26) or unfractionated heparin (i.v. adjusted to activated partial-thromboplastin time) (n=27) to evaluate pharmacokinetics, pharmacodynamics, and safety. The primary objective of the study was to investigate the effect of unfractionated heparin versus enoxaparin on the plasma clearance of tirofiban. RESULTS: Coadministration of tirofiban and enoxaparin was generally well tolerated. Plasma clearance of tirofiban was 176.7+/-59.8 and 187.5+/-81.8 ml/min, respectively, for enoxaparin and unfractionated heparin-treated patients (P=NS). The mean difference was well within the prespecified criterion for comparability. Administration of tirofiban with enoxaparin vs. unfractionated heparin resulted in lesser variability and a trend towards greater inhibition of platelet aggregation using 5 microM adenosine phosphate agonist. More patients achieved target inhibition of platelet aggregation >70% in the tirofiban and enoxaparin group (84% vs. 65%, P=0.19). Median bleeding time was 21 min for tirofiban and enoxaparin vs. > or =30 min for tirofiban and unfractionated heparin (P=NS). For a given level of inhibition of platelet aggregation, bleeding time was less prolonged with tirofiban and enoxaparin than tirofiban and unfractionated heparin (adjusted mean bleeding time 19.6 vs. 24.9 min, P=0.02). Tirofiban plasma concentration and clearance were comparable whether coadministered with enoxaparin or unfractionated heparin. There were no major or minor bleeding events in either group by the TIMI criteria. INTERPRETATION: The more consistent inhibition of platelet aggregation and lower adjusted bleeding time of tirofiban and enoxaparin vs. tirofiban and unfractionated heparin support the therapeutic potential of combining these two agents. These data from the first clinical report of coadministration of a glycoprotein IIb/IIIa receptor antagonist and a low molecular weight heparin are consistent with prior data which show differential pharmacodynamic effects of enoxaparin and unfractionated heparin on platelet aggregation.

Angina, Unstable↗
PubMed1999

Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. PRISM Study Investigators. Platelet Receptor Inhibition in Ischemic Syndrome Management.

BACKGROUND: A major challenge for physicians is to identify patients with acute coronary syndromes who may benefit from treatment with glycoprotein-IIb/IIIa-receptor antagonists. We investigated whether troponin concentrations can be used to stratify patients for benefit from treatment with tirofiban. METHODS: We enrolled 2222 patients of the Platelet Receptor Inhibition in Ischemic Syndrome Management study with coronary artery disease and who had had chest pain in the previous 24 h. All patients received aspirin and were randomly assigned treatment with tirofiban or heparin. We took baseline measurements of troponin I and troponin T. We recorded death, myocardial infarction, or recurrent ischaemia after 48 h infusion treatment and at 7 days and 30 days. FINDINGS: 629 (28.3%) patients had troponin I concentrations higher than the diagnostic threshold of 1.0 microg/L and 644 (29.0%) troponin T concentrations higher than 0.1 microg/L. 30-day event rates (death, myocardial infarction) were 13.0% for troponin-I-positive patients compared with 4.9% for troponin-I-negative patients (p<0.0001), and 13.7% compared wth 3.5% for troponin T (p<0.001). At 30 days, in troponin-I-positive patients, tirofiban had lowered the risk of death (adjusted hazard ratio 0.25 [95% CI 0.09-0.68], p=0.004) and myocardial infarction (0.37 [0.16-0.84], p=0.01). This benefit was seen in medically managed patients (0.30 [0.10-0.84], p=0.004) and those undergoing revascularisation (0.37 [0.15-0.93] p=0.02) after 48 h infusion treatment. By contrast, no treatment effect was seen for troponin-I-negative patients. Similar benefits were seen for troponin-T-positive patients. INTERPRETATION: Troponin I and troponin T reliably identified high-risk patients with acute coronary syndromes, managed medically and by revascularisation, who would benefit from tirofiban.

Aged↗
PubMed1999

Clinical outcomes of bivalirudin for ischemic heart disease.

BACKGROUND: Current treatment strategies for percutaneous coronary revascularization and acute coronary syndromes incorporate thrombin inhibition with either unfractionated or fractionated heparin. The peptide bivalirudin (Hirulog) is a direct thrombin inhibitor whose pharmacological properties differ from those of heparin. We conducted a systematic overview (meta-analysis) to assess the effect of bivalirudin on 4 end points: death, myocardial infarction, major hemorrhage, and the composite of death or infarction. METHODS AND RESULTS: Six trials (5674 patients) represent the randomized, controlled bivalirudin experience, including 4603 patients undergoing elective percutaneous coronary revascularization and 1071 patients with acute coronary syndromes. ORs for the 4 clinical end points were calculated for each trial. Four trials (4973 patients) that compared bivalirudin with heparin were combined with the use of a random-effects model. In these trials, bivalirudin was associated with a significant reduction in the composite of death or infarction (OR 0.73, 95% CI 0.57 to 0.95; P=0.02) at 30 to 50 days, or 14 fewer events per 1000 patients so treated. There also was a significant reduction in major hemorrhage for the same trials (OR 0.41, 95% CI 0. 32 to 0.52; P<0.001, or 58 fewer events per 1000 patients so treated). A similar analysis combined 2 dose-ranging trials (701 patients) that compared therapeutic (activated partial thromboplastin time more than twice the control time) with subtherapeutic bivalirudin anticoagulation (activated partial thromboplastin time less than twice the control time). CONCLUSIONS: Bivalirudin is at least as effective as heparin, with clearly superior safety. Thus, it provides an unprecedented net clinical benefit over heparin in patients with ischemic heart disease.

Anticoagulants↗
PubMed1999

Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock.

BACKGROUND: The leading cause of death in patients hospitalized for acute myocardial infarction is cardiogenic shock. We conducted a randomized trial to evaluate early revascularization in patients with cardiogenic shock. METHODS: Patients with shock due to left ventricular failure complicating myocardial infarction were randomly assigned to emergency revascularization (152 patients) or initial medical stabilization (150 patients). Revascularization was accomplished by either coronary-artery bypass grafting or angioplasty. Intraaortic balloon counterpulsation was performed in 86 percent of the patients in both groups. The primary end point was mortality from all causes at 30 days. Six-month survival was a secondary end point. RESULTS: The mean age of the patients was 66+/-10 years, 32 percent were women and 55 percent were transferred from other hospitals. The median time to the onset of shock was 5.6 hours after infarction, and most infarcts were anterior in location. Ninety-seven percent of the patients assigned to revascularization underwent early coronary angiography, and 87 percent underwent revascularization; only 2.7 percent of the patients assigned to medical therapy crossed over to early revascularization without clinical indication. Overall mortality at 30 days did not differ significantly between the revascularization and medical-therapy groups (46.7 percent and 56.0 percent, respectively; difference, -9.3 percent; 95 percent confidence interval for the difference, -20.5 to 1.9 percent; P=0.11). Six-month mortality was lower in the revascularization group than in the medical-therapy group (50.3 percent vs. 63.1 percent, P=0.027). CONCLUSIONS: In patients with cardiogenic shock, emergency revascularization did not significantly reduce overall mortality at 30 days. However, after six months there was a significant survival benefit. Early revascularization should be strongly considered for patients with acute myocardial infarction complicated by cardiogenic shock.

Aged↗
PubMed1999

Four-year survival of patients with acute coronary syndromes without ST-segment elevation and prognostic significance of 0.5-mm ST-segment depression.

We prospectively evaluated all patients admitted to our coronary care unit during 1993 with ischemic chest pain but without ST-segment elevation on the presenting electrocardiogram, and determined the influence of the extent of ST-segment depression, measured using calipers and blinded to the outcome, on 4-year survival. The presenting symptoms of 367 patients (mean age 64 years) were coded according to the Braunwald classification, 86% being in class IIIB (primary unstable angina with rest angina within 48 hours) and 7.4% in class IIIC (postinfarction angina). Thirty-two patients (8.6%) had myocardial infarction at presentation (defined as a creatine kinase level exceeding twice the reference range within 18 hours). During hospitalization 97% of patients received aspirin, 67% received intravenous heparin, 37% underwent angiography, and 35% underwent revascularization. The vital status of 99% of the patients was determined after a median of 52 months (interquartile range 48 to 55). At follow-up, 88% of patients were taking aspirin, 45% were taking beta blockers, and 50% had undergone revascularization. The survival rate was 70% in patients with > or = 0.5-mm ST-segment depression (53%, 77%, and 82% survival for > or = 2-, 1-, and 0.5-mm ST-segment depression, respectively; p <0.0001). Patients with a normal electrocardiogram had a greater survival rate (94%) than that of patients with 0.5-mm ST-segment depression (82%, p = 0.020), but not significantly different from that of patients with T-wave inversion (84%, p = NS). Independent predictors of mortality (odds ratio [95% confidence interval]) were: age in yearly increments (1.05 [1.03 to 1.06], p = 0.003), revascularization during follow-up (0.40 [0.29 to 0.56], p = 0.006), pulmonary edema (3.45 [2.19 to 5.45], p = 0.007), and ST-segment depression (1.37 [1.20 to 1.55], p = 0.015). Thus, ST-segment depression of > or = 0.5 mm predicts 4-year survival in patients with acute ischemic syndromes.

Adrenergic beta-Antagonists↗
PubMed1999

Sex, clinical presentation, and outcome in patients with acute coronary syndromes. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes IIb Investigators.

BACKGROUND: Studies have reported that women with acute myocardial infarction have in-hospital and long-term outcomes that are worse than those of men. METHODS: To assess sex-based differences in presentation and outcome, we examined data from the Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes IIb study, which enrolled 12,142 patients (3662 women and 8480 men) with acute coronary syndromes, including infarction with ST-segment elevation, infarction with no ST-segment elevation, and unstable angina. RESULTS: Overall, the women were older than the men, and had significantly higher rates of diabetes, hypertension, and prior congestive heart failure. They had significantly lower rates of prior myocardial infarction and were less likely ever to have smoked. A smaller percentage of women than men had infarction with ST elevation (27.2 percent vs. 37.0 percent, P<0.001), and of the patients who presented with no ST elevation (those with myocardial infarction or unstable angina), fewer women than men had myocardial infarction (36.6 percent vs. 47.6 percent, P<0.001). Women had more complications than men during hospitalization and a higher mortality rate at 30 days (6.0 percent vs. 4.0 percent, P<0.001) but had similar rates of reinfarction at 30 days after presentation. However, there was a significant interaction between sex and the type of coronary syndrome at presentation (P=0.001). After stratification according to coronary syndrome and adjustment for base-line variables, there was a nonsignificant trend toward an increased risk of death or reinfarction among women as compared with men only in the group with infarction and ST elevation (odds ratio, 1.27; 95 percent confidence interval, 0.98 to 1.63; P=0.07). Among patients with unstable angina, female sex was associated with an independent protective effect (odds ratio for infarction or death, 0.65; 95 percent confidence interval, 0.49 to 0.87; P=0.003). CONCLUSIONS: Women and men with acute coronary syndromes had different clinical profiles, presentation, and outcomes. These differences could not be entirely accounted for by differences in base-line characteristics and may reflect pathophysiologic and anatomical differences between men and women.

Aged↗
PubMed1999

Functional significance of the conserved residues in the flexible hinge region of the myosin motor domain.

Analysis of the three-dimensional crystal structure of the Dictyostelium myosin motor domain revealed that the myosin head is required to bend at residues Ile-455 and Gly-457 to produce the conformation changes observed in the ternary complexes that resemble the pre- and post-hydrolysis states (Fisher, A. J., Smith, C. A., Thoden, J. B., Smith, R., Sutoh, K., Holden, H. M., and Rayment, I. (1995) Biochemistry 34, 8960-8972). Asp-454, Ile-455, and Gly-457 of smooth muscle myosin were substituted by Ala, Met, and Ala, respectively, and the mechano-enzymatic activities were determined to study the role of these residues in myosin motor function. Whereas the basal steady-state Mg2+-ATPase activity of D454A was higher than that of the wild type, the rate of the hydrolytic step is reduced approximately 2,000-fold and becomes rate-limiting. M-ATP rather than M-ADP-P is the predominant steady-state intermediate, and the initial Pi burst and the ATP-induced enhancement of intrinsic tryptophan fluorescence are absent in D454A. D454A binds actin in the absence of ATP but is not dissociated from actin by ATP. Moreover, actin inhibits rather than activates the ATPase activity; consequently, D454A does not support actin translocating activity. I455M has normal actin-activated ATPase activity, Pi burst, and ATP-induced enhancement of intrinsic tryptophan fluorescence, suggesting that the enzymatic properties are normal. However, the actin translocating activity was completely inhibited. This suggests that the side chain at Ile-455 is critical for myosin motor activity but not for relatively normal enzymatic function, which indicates an apparent uncoupling between enzymatic activity and motile function. Although G457A has normal ATP-dependent actin dissociation, ATP hydrolytic step is reduced by approximately 10(5)-fold in the presence or absence of actin; consequently, G457A does not have actin translocating activity. These results indicate the importance of these conserved residues at the hinge region for normal myosin motor function.

Actins↗
PubMed1999

Acute coronary syndromes: the clot is there.

Attempts to extract clot from an infarct-related coronary artery have underestimated the frequency and pathophysiologic significance of thrombus in acute coronary syndromes. The overwhelming body of evidence garnered over the last 20 years, especially the achievement of reperfusion (Thrombolysis In Myocardial Infarction trial grade 2 and 3 flow) with most of the newer thrombolytic agents in >80% of cases, incontrovertibly establishes a critical role for thrombus in acute occlusive coronary artery disease.

Coronary Disease↗