Inflammation, complement activation and endothelial function in stable and unstable coronary artery disease

Background: Endothelial dysfunction plays an important role in the pathogenesis of coronary artery disease (CAD). Apart from traditional risk factors complement activation and inflammation may trigger and sustain endothelial dysfunction. We sought to assess the association between endothelial function, high sensitivity C-reactive protein (hs-CRP) and markers of complement activation in patients with either stable or unstable coronary artery disease. Methods: We prospectively recruited 78 patients, 35 patients with stable angina pectoris (SAP) and 43 patients with unstable angina pectoris (UAP). Endothelial function was assessed as brachial artery reactivity (BAR). Hs-CRP, C3a, C5a, and C1-Inhibitor (C1 inh.) were measured enzymatically. Results: Patients with IJAP showed higher median levels of hs-CRP and C3a compared to patients with SAP, while BAR was not significantly different between patient groups. In UAP patients, hs-CRP was significantly correlated with cholesterol (r = 0.27, p < 0.02), C3a (r = 0.32, p < 0.001) and C1 INH.(r = 0.41, p < 0.003), but not with flow mediated dilatation (r = 0.09, P = 0.41). Hs-CRP and C1 INH.were found to be independant predictors of IJAP in a backward stepwise logistic regression model. Conclusions: We conclude that both hs-CRP, a marker of inflammation and C3a, a marker of complement activation are elevated in patients with UAP, but not in patients with SAP. (c) 2005 Elsevier B.V. All rights reserved.

Depression and cardiovascular morbidity and mortality: cause or consequence?

Background Depression after myocardial infarction has been associated with increased cardiovascular mortality. This study assessed whether depressive symptoms were associated with adverse outcomes in people with a history of an acute coronary syndrome, and evaluated possible explanations for such an association. Methods and results Depressive symptoms were assessed using the General Health Questionnaire at least 5 months after hospital admission for acute myocardial infarction or unstable angina in 1130 participants of the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study, a multicentre, placebo-controlled, clinical trial of cholesterol-lowering treatment. Cardiovascular symptoms, self-rated general health, cardiovascular risk factors, employment status, social support and life events were also assessed at the baseline visit. Cardiovascular death (n=114), non-fatal myocardial infarction (n=108), non-fatal stroke (n=53) and unstable angina (n=274) were documented during a median follow-up period of 8.1 years. Individuals with depressive symptoms (General. Health Questionnaire score greater than or equal to5; 22% of participants) were more likely to report angina, dyspnoea, claudication, poorer general health, not being in paid employment, few social contacts and/or adverse life events (P

White blood cell count predicts reduction in coronary heart disease mortality with pravastatin

Background-Elevated serum inflammatory marker levels are associated with a greater long-term risk of cardiovascular events. Because 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) may have an antiinflammatory action, it has been suggested that patients with elevated inflammatory marker levels may have a greater reduction in cardiovascular risk with statin treatment. Methods and Results-We evaluated the association between the white blood cell count (WBC) and coronary heart disease mortality during a mean follow-up of 6.0 years in the Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID) Study, a clinical trial comparing pravastatin (40 mg/d) with a placebo in 9014 stable patients with previous myocardial infarction or unstable angina. An increase in baseline WBC was associated with greater coronary heart disease mortality in patients randomized to placebo (hazard ratio for 1 X 10(9)/L increase in WBC, 1.18; 95% CI, 1.12 to 1.25; P<0.001) but not pravastatin (hazard ratio, 1.02; 95% CI, 0.96 to 1.09; P=0.56; P for interaction=0.004). The numbers of coronary heart disease deaths prevented per 1000 patients treated with pravastatin were 0, 9, 30, and 38 for baseline WBC quartiles of <5.9, 6.0 to 6.9, 7.0 to 8.1, and >8.2X10(9)/L, respectively. WBC was a stronger predictor of this treatment benefit than the ratio of total to high-density lipoprotein cholesterol and a global measure of cardiac risk. There was also a greater reduction (P=0.052) in the combined incidence of cardiovascular mortality, nonfatal myocardial infarction, and stroke with pravastatin as baseline WBC increased ( by quartile: 3, 41, 61, and 60 events prevented per 1000 patients treated, respectively). Conclusions-These data support the hypothesis that individuals with evidence of inflammation may obtain a greater benefit from statin therapy.

Platelet nitric oxide responsiveness - A novel prognostic marker in acute coronary syndromes

Objectives - Nitric oxide (NO) is critically important in the regulation of vascular tone and the inhibition of platelet aggregation. We have shown previously that patients with acute coronary syndromes (ACS) or stable angina pectoris have impaired platelet responses to NO donors when compared with normal subjects. We tested the hypotheses that platelet hyporesponsiveness to NO is a predictor of (1) cardiovascular readmission and/or death and (2) all-cause mortality in patients with ACS (unstable angina pectoris or non-Q-wave myocardial infarction). Methods and Results - Patients (n = 51) with ACS had evaluation of platelet aggregation within 24 hours of coronary care unit admission using impedance aggregometry. Patients were categorized as having normal (>= 32% inhibition of ADP-induced aggregation with the NO donor sodium nitroprusside; 10 mu mol/L; n = 18) or impaired (>= 32% inhibition of ADP-induced aggregation; n = 33) NO responses. We then compared the incidence of cardiovascular readmission and death during a median of 7 years of follow-up in these 2 groups. Using a Cox proportional hazards model adjusting for age, sex, index event, postdischarge medical treatment, revascularization status, left ventricular systolic dysfunction, concurrent disease states, and cardiac risk factors, impaired NO responsiveness was associated with an increased risk of the combination of cardiovascular readmission and/or death (relative risk, 2.7; 95% CI, 1.03 to 7.10; P = 0.041) and all-cause mortality (relative risk, 6.3; 95% CI, 1.09 to 36.7; P = 0.033). Conclusions - Impaired platelet NO responsiveness is a novel, independent predictor of increased mortality and cardiovascular morbidity in patients with high-risk ACS.

Development of a dosage strategy in patients receiving enoxaparin by continuous intravenous infusion using modelling and simulation

Aim To develop an appropriate dosing strategy for continuous intravenous infusions (CII) of enoxaparin by minimizing the percentage of steady-state anti-Xa concentration (C-ss) outside the therapeutic range of 0.5-1.2 IU ml(-1). Methods A nonlinear mixed effects model was developed with NONMEM (R) for 48 adult patients who received CII of enoxaparin with infusion durations that ranged from 8 to 894 h at rates between 100 and 1600 IU h(-1). Three hundred and sixty-three anti-Xa concentration measurements were available from patients who received CII. These were combined with 309 anti-Xa concentrations from 35 patients who received subcutaneous enoxaparin. The effects of age, body size, height, sex, creatinine clearance (CrCL) and patient location [intensive care unit (ICU) or general medical unit] on pharmacokinetic (PK) parameters were evaluated. Monte Carlo simulations were used to (i) evaluate covariate effects on C-ss and (ii) compare the impact of different infusion rates on predicted C-ss. The best dose was selected based on the highest probability that the C-ss achieved would lie within the therapeutic range. Results A two-compartment linear model with additive and proportional residual error for general medical unit patients and only a proportional error for patients in ICU provided the best description of the data. Both CrCL and weight were found to affect significantly clearance and volume of distribution of the central compartment, respectively. Simulations suggested that the best doses for patients in the ICU setting were 50 IU kg(-1) per 12 h (4.2 IU kg(-1) h(-1)) if CrCL < 30 ml min(-1); 60 IU kg(-1) per 12 h (5.0 IU kg(-1) h(-1)) if CrCL was 30-50 ml min(-1); and 70 IU kg(-1) per 12 h (5.8 IU kg(-1) h(-1)) if CrCL > 50 ml min(-1). The best doses for patients in the general medical unit were 60 IU kg(-1) per 12 h (5.0 IU kg(-1) h(-1)) if CrCL < 30 ml min(-1); 70 IU kg(-1) per 12 h (5.8 IU kg(-1) h(-1)) if CrCL was 30-50 ml min(-1); and 100 IU kg(-1) per 12 h (8.3 IU kg(-1) h(-1)) if CrCL > 50 ml min(-1). These best doses were selected based on providing the lowest equal probability of either being above or below the therapeutic range and the highest probability that the C-ss achieved would lie within the therapeutic range. Conclusion The dose of enoxaparin should be individualized to the patients' renal function and weight. There is some evidence to support slightly lower doses of CII enoxaparin in patients in the ICU setting.

Using a clinical pathway and education to reduce inappropriate prescribing of enoxaparin in patients with acute coronary syndromes: a controlled study

Aims: To evaluate efficacy of a pathway-based quality improvement intervention on appropriate prescribing of the low molecular weight heparin, enoxaparin, in patients with varying risk categories of acute coronary syndrome (ACS). Methods: Rates of enoxaparin use retrospectively evaluated before and after pathway implementation at an intervention hospital were compared to concurrent control patients at a control hospital; both were community hospitals in south-east Queensland. The study population was a group of randomly selected patients (n = 439) admitted to study hospitals with a discharge diagnosis of chest pain, angina, or myocardial infarction, and stratified into high, intermediate, low-risk ACS or non-cardiac chest pain: 146 intervention patients (September-November 2003), 147 historical controls (August-December 2001) at the intervention hospital; 146 concurrent controls (September-November 2003) at the control hospital. Interventions were active implementation of a user-modified clinical pathway coupled with an iterative education programme to medical staff versus passive distribution of a similar pathway without user modification or targeted education. Outcome measures were rates of appropriate enoxaparin use in high-risk ACS patients and rates of inappropriate use in intermediate and low-risk patients. Results: Appropriate use of enoxaparin in high-risk ACS patients was above 90% in all patient groups. Inappropriate use of enoxaparin was significantly reduced as a result of pathway use in intermediate risk (9% intervention patients vs 75% historical controls vs 45% concurrent controls) and low-risk patients (9% vs 62% vs 41%; P < 0.001 for all comparisons). Pathway use was associated with a 3.5-fold (95% CI: 1.3-9.1; P = 0.012) increase in appropriate use of enoxaparin across all patient groups. Conclusion: Active implementation of an acute chest pain pathway combined with continuous education reduced inappropriate use of enoxaparin in patients presenting with intermediate or low-risk ACS.

Crystal structures of the DsbG disulfide isomerase reveal an unstable disulfide

Dsb proteins control the formation and rearrangement of disulfide bonds during the folding of secreted and membrane proteins in bacteria. DsbG, a member of this family, has disulfide bond isomerase and chaperone activity. Here, we present two crystal structures of DsbG at 1.7- and 2.0-Angstrom resolution that are meant to represent the reduced and oxidized forms, respectively. The oxidized structure, however, reveals a mixture of both redox forms, suggesting that oxidized DsbG is less stable than the reduced form. This trait would contribute to DsbG isomerase activity, which requires that the active-site Cys residues are kept reduced, regardless of the highly oxidative environment of the periplasm. We propose that a Thr residue that is conserved in the cis-Pro loop of DsbG and DsbC but not found in other Dsb proteins could play a role in this process. Also, the structure of DsbG reveals an unanticipated and surprising feature that may help define its specific role in oxidative protein folding. Thus, the dimensions and surface features of DsbG show a very large and charged binding surface that is consistent with interaction with globular protein substrates having charged surfaces. This finding suggests that, rather than catalyzing disulfide rearrangement in unfolded substrates, DsbG may preferentially act later in the folding process to catalyze disulfide rearrangement in folded or partially folded proteins.