Showing papers by "David E. Newby published in 1999"

Endothelial Dysfunction, Impaired Endogenous Fibrinolysis, and Cigarette Smoking A Mechanism for Arterial Thrombosis and Myocardial Infarction

Abstract: Background—Effective endogenous fibrinolysis requires rapid release of tissue plasminogen activator (tPA) from the vascular endothelium. Smoking is a known risk factor for arterial thrombosis and myocardial infarction, and it causes endothelial dysfunction. We therefore examined the effects of cigarette smoking on substance P–induced tPA release in vivo in humans. Methods and Results—Blood flow and plasma fibrinolytic factors were measured in both forearms of 12 smokers and 12 age- and sex-matched nonsmokers who received unilateral brachial artery infusions of substance P (2 to 8 pmol/min). In both smokers and nonsmokers, substance P caused dose-dependent increases in blood flow and local release of plasma tPA antigen and activity (P<0.001 for all) but had no effect on the local release of plasminogen activator inhibitor type 1. Compared with nonsmokers, increases in forearm blood flow (P=0.03) and release of tPA antigen (P=0.04) and activity (P<0.001) caused by substance P were reduced in smokers. The ar...

Effects of Acute Angiotensin II Type 1 Receptor Antagonism and Angiotensin Converting Enzyme Inhibition on Plasma Fibrinolytic Parameters in Patients With Heart Failure

Abstract: To the Editor: We read with interest the study by Goodfield et al1 comparing the effects of the acute administration of a single dose of enalapril or losartan on fibrinolytic parameters. We would like to raise several concerns about the design of this study that we believe should temper the authors’ interpretation of their results. First, a well-described diurnal variation exists in plasminogen activator inhibitor-1 (PAI-1) antigen and activity. In this study, subjects received oral doses of enalapril and losartan at 10:00 am; blood samples were drawn before drug administration and at 4:00 pm. However, in carefully controlled studies, we have shown that in subjects with an activated renin-angiotensin system (RAS), plasma PAI-1 antigen levels fall spontaneously by ≈50% over that same …

Placebo-controlled comparison of candoxatril, an orally active neutral endopeptidase inhibitor, and captopril in patients with chronic heart failure

Abstract: Aims: To compare the effects on exercise capacity of the neutral endopeptidase inhibitor candoxatril, and the angiotensin converting enzyme inhibitor captopril, in patients with mild to moderate heart failure. Methods: In this multi-centre double-blind placebo controlled study, 60 patients with NYHA Class I–III heart failure were randomised to candoxatril 200 mg b.d. (n = 22), captopril 25–50 mg b.d. (n = 23) or placebo (n = 15), Treadmill exercise tests were carried out weekly during a 5-week single-blind placebo run-in phase until a stable baseline was achieved, and repeated at 4 weekly intervals during the 12-week double-blind treatment phase. Results: Nine patients withdrew from the study — four candoxatril and five captopril. The placebo-adjusted increase in exercise duration after 12 weeks was 56 s (95% CI, −26 to + 137 s; P = 0.12) with candoxatril and 37 s (− 40 to + 117 s; P = 0.29) with captopril. Conclusions: Both candoxatril and captopril were well tolerated and treadmill exercise duration appeared to increase during 12 weeks of therapy but this did not achieve statistical significance. This study tentatively suggests that in patients with heart failure, neutral endopeptidase inhibition may provide similar symptomatic benefits to angiotensin converting enzyme inhibition.

Early therapeutic experience with the endothelin antagonist BQ-123 in pulmonary hypertension after congenital heart surgery

Abstract: OBJECTIVE—To assess the effect of endothelin type A (ETA) receptor antagonism in infants with pulmonary hypertension following corrective surgery for congenital heart disease. DESIGN—Open label, preliminary study. SETTING—Tertiary paediatric cardiothoracic surgical centre. PATIENTS—Three infants (aged 3 weeks, 7 weeks, and 8 months) with postoperative pulmonary hypertension unresponsive to conventional treatment, including inhaled nitric oxide. INTERVENTIONS—Patients received incremental intravenous infusions (0.1 to 0.3 mg/kg/h) of the ETA receptor antagonist BQ-123. MAIN OUTCOME MEASURES—The response to BQ-123 administration was determined using continuous invasive monitoring of cardiorespiratory variables. RESULTS—BQ-123 infusion caused a reduction in the ratio of pulmonary to systemic pressures (0.62 (0.01) to 0.52 (0.03), mean (SEM)) with an accompanying decrease in right ventricular stroke work index (4.6 (0.4) to 2.5 (0.3) g/m) and a tendency for the cardiac index to rise (2.1 (0.2) to 2.7 (0.6) l/min/kg/m2). This was associated with a well tolerated fall in the arterial partial pressure of oxygen (16.5 (4.1) to 12.4 (3.3) kPa) and mean systemic arterial pressure (57 (3) to 39 (3) mm Hg). CONCLUSIONS—ETA receptor antagonism in infants with postoperative pulmonary hypertension after corrective surgery for congenital heart disease led to significant improvement in pulmonary haemodynamic indices. However, these benefits were associated with reductions in systemic blood pressure and arterial oxygen saturation, the latter consistent with a ventilation-perfusion mismatch. On the basis of these results, studies in pulmonary hypertension will need to proceed with caution. Keywords: endothelin-1; pulmonary hypertension; receptor antagonism; congenital heart disease

Lower cardiac mortality in smokers following thrombolysis.

Abstract: Sir, In their recent paper,1 Purcell and colleagues confirm earlier observations that, in comparison to non-smokers, smokers have a higher frequency of reperfusion with thrombolytic therapy and consequently have a lower in-hospital mortality during acute myocardial infarction—the so-called \`smokers' paradox'. The authors conclude that \`smokers may have enhanced systemic fibrinolysis following thrombolysis in acute myocardial infarction'. We believe that this conclusion is not supported by the data, and that alternative and more likely explanations can explain the smokers' paradox. The authors cite 1-h plasma fibrinogen concentrations as a surrogate marker of the effectiveness of systemic fibrinolysis following thrombolytic therapy with streptokinase. However, although they state that `…current smokers as a group are less likely than non-smokers to have a suboptimal fibrinolytic response to thrombolysis…', there was no difference in 60-min plasma fibrinogen concentrations between smokers and non-smokers as a group: 0.27 (0.14–0.73) vs. 0.31 (0.15–0.67) g/l, respectively; p =NS. Apparent differences were only seen on further subgroup analysis which could alternatively be interpreted as demonstrating that in smokers, systemic fibrinolysis occurred whether the infarct-related artery reperfused or not: plasma fibrinogen concentration 0.27 (0.12–0.61) vs. 0.28 (0.10–0.77) g/l, respectively. Moreover, the lowest plasma fibrinogen concentrations were seen in non-smokers with evidence of reperfusion. In mitigation, smokers have significantly higher basal plasma fibrinogen concentrations,4 and one could argue that smokers may have had a proportionately greater fall in fibrinogen levels following thrombolytic therapy. Did the authors measure the plasma fibrinogen …