Determinants of growth differentiation factor 15 in patients with stable and acute coronary artery disease. A prospective observational study.

BACKGROUND: Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor ß family and has been associated with inflammation, cancer, aging, diabetes mellitus (DM) and atherosclerosis. Determinants of GDF-15 have been investigated in several conditions. We aimed to investigate determinants of GDF-15 plasma levels in patients with angiographically proven coronary artery disease (CAD). METHODS: Four hundred and seventy three consecutive patients with CAD were investigated between May 2009 and February 2011. Patients were separated into those with stable CAD (SCAD) and with ST-elevation and non-ST-elevation myocardial infarction (STEMI and NSTEMI). Blood samples for determination of GDF-15 were obtained before coronary angiography. Determinant of GDF-15 levels were analyzed by logistic regression analysis in unadjusted and adjusted models. Study endpoints were cardiovascular death (CV-death), myocardial infarction, unstable angina, unplanned revascularization, stent thrombosis and stroke assessed at a mean follow-up of 188 (177.2-243) days. RESULTS: Overall median and (25-27th percentile) GDF-15 level was 1212.8 pg/ml (833.2-1957 pg/ml). GDF-15 was significantly higher in STEMI compared to SCAD and NSTEMI groups (P < 0.0001). In a multivariate regression analysis advanced age, DM, acute hyperglycemia (AHG), CRP and chronic kidney disease (CKD) were independent predictors of elevated GDF-15 levels (P < 0.05). Receiver operating curve analysis of GDF-15 for prediction of CV-death showed an area under the curve of 0.852 with a confidence interval of 0.745-0.960, P < 0.0001. The estimated cut-off was 2094.6 pg/ml with a sensitivity of 76 % and specificity of 80 %. CONCLUSION: In patients with CAD undergoing PCI with stent implantation, GDF-15 is determined by advanced age, acute and chronic hyperglycemia, inflammation and CKD. GDF-15 is a valuable predictor of CV-death in a population of CAD patients after PCI.

Variability of on-treatment platelet reactivity in patients on clopidogrel.

Response to clopidogrel therapy is subject to inter-individual variability. However, data with regard to on-treatment platelet reactivity over time in patients undergoing coronary stenting are scarce. For this prospective observational study, 102 consecutive patients on dual antiplatelet therapy undergoing coronary stenting due to stable coronary artery disease (CAD; n = 29), non ST-elevation acute coronary syndrome (NSTE-ACS; n = 45) and ST-elevation myocardial infarction (STEMI; n = 28) were enrolled. Vasodilator-stimulated phosphoprotein-phosphorylation assay was performed at baseline, as well as 1, 3 and 6 months thereafter. Platelet reactivity index (PRI) measured after 1, 3 and 6 months was lower compared to baseline values (p < 0.001). Variables responsible for reduced response to clopidogrel at baseline (reticulated platelet fraction, simvastatin therapy) and during steady-state phase (body mass index, blood glucose concentrations, cholesterol/HDL-ratio and quality of life score) were different. High on-treatment platelet reactivity (HTPR)-phenotype (cut-off = 50% PRI) within the first month changed in 31% of stable CAD, 33% of NSTE-ACS and 39% of STEMI patients, respectively. HTPR-phenotype in the steady-state phase (month 1 to 6) changed in 45% of stable CAD, 33% of NSTE-ACS and 25% of STEMI patients. Response to clopidogrel and accordingly platelet function might vary over time, especially when a cut-off based approach, is used. There was a significant reduction of on-treatment platelet reactivity within the first month after percutaneous coronary intervention with stenting which was maintained for up to 6 months. Variables associated with reduced response to clopidogrel at baseline and during steady-state phase were different, as the latter mainly reflected an unfavorable metabolic profile, comprising elevated BMI, blood glucose levels as well as cholesterol/HDL-ratio.

Admission proinsulin is associated with mortality in patients with admission hyperglycemia during acute coronary syndrome: results from a pilot observational study.

BACKGROUND: Acute hyperglycemia (AHG) is associated with mortality in patients with acute coronary syndrome (ACS). The extent to which hyperproinsulinemia contributes to worse clinical outcomes for this specific patient population is unknown. METHODS: We included 308 consecutive ACS patients who underwent coronary angioplasty in this pilot observational study. Patients were separated into 3 groups: patients with proven diabetes mellitus (DM group) (n =55), nondiabetic patients with a normal glucose concentration at admission (NAG group) (n =175), and nondiabetic patients with AHG at presentation (AHG group) (n =78). Blood samples for glucose, insulin, and proinsulin measurements were obtained at admission. The primary end point of the study was all-cause mortality, which was assessed at a mean follow-up of 19 months (interquartile range, 12-28 months). RESULTS: Patients in the AHG and DM groups had significantly (P =0.048) higher all-cause mortality compared with the NAG group. A univariate Cox regression analysis revealed that the proinsulin concentration was significantly associated with all-cause mortality for all study participants (hazard ratio, 1.013; 95% CI, 1.002-1.024; P =0.023). AHG patients with increased proinsulin concentrations showed a mortality rate similar to that of DM patients but had a significantly higher mortality rate than patients with AHG and a low proinsulin concentration (χ² =7.57; P =0.006) and patients with NAG (with or without increased proinsulin) [χ² =7.66 (P =0.006) and 13.98 (P < 0.001), respectively]. A multivariate regression analysis revealed that the concentrations of glucose and proinsulin at admission were significant (P =0.002) predictors of all-cause mortality. CONCLUSIONS: An increased proinsulin concentration may be a marker for mortality in ACS patients with hyperglycemia at admission and without known diabetes. Further studies are needed to evaluate the role of metabolic parameters such as proinsulin.

Levels of von Willebrand factor and ADAMTS13 determine clinical outcome after cardioversion for atrial fibrillation.

Von Willebrand factor (vWF) plays an essential role in platelet adhesion and thrombus formation. Patients with atrial fibrillation (AF) exhibit higher plasma vWF and lower ADAMTS13 antigen levels compared to controls. Little is known about vWF and ADAMTS13 in AF patients treated with cardioversion (CV). Thus we investigated the alterations of plasma vWF and ADAMTS13 after CV and evaluated the predictive value of these parameters for recurrence of AF. In this observational study we determined plasma levels of vWF and ADAMTS13 in 77 patients before and immediately after CV, as well as 24 hours (h) and six weeks thereafter, by means of commercially available assays. The vWF/ADAMTS13-ratio was significantly elevated immediately after CV (p=0.02) and 24 h after CV (p=0.002) as compared to baseline levels. ADAMTS13, 24 h after CV, exhibited a significant association with recurrence of AF (HR: 0.97; p=0.037). Accordingly, tertiles of ADAMTS13 showed a stepwise inverse correlation with the risk of recurrent AF (HR: 0.50; p=0.009). After adjustment for confounders, ADAMTS13 remained significant as an independent predictor of recurrent AF (HR: 0.61; p=0.047). Similarly, the vWF/ADAMTS13-ratio, 24 h after CV, was associated with rhythm stability and remained an independent predictor of recurrent AF (HR: 1.88; p=0.028). The regulation of vWF and its cleaving protease ADAMTS13 after CV might play a critical role in producing a pro-thrombotic milieu immediately after CV for AF. Since ADAMTS13 plasma concentration and the vWF/ADAMTS13-ratio are independently associated with rhythm stability, these indexes might be used for prediction of recurrence of AF.

Multiple electrode aggregometry and vasodilator stimulated phosphoprotein-phosphorylation assay in clinical routine for prediction of postprocedural major adverse cardiovascular events.

Reduced antiplatelet effect of clopidogrel assessed with multiple electrode aggregometry (MEA) and vasodilator stimulated phosphoprotein-phosphorylation (VASP-P) assay has been proven to predict major adverse cardiovascular events (MACE) after coronary stenting. So far no consecutive registry has evaluated the usefulness of different adenosine diphosphate-based platelet function tests to predict outcome in unselected patients. Hence, our objective was to determine the feasibility of MEA and VASP-P for clinical routine and whether low-response to clopidogrel as determined by MEA and/or the VASP-P assays predicts MACE in a "real-life" population undergoing coronary stenting. Three-hundred consecutive patients were included in this prospective registry. Blood was sampled 6-24 hours after stenting to measure MEA and VASP-P. The use of glycoprotein-IIb/IIIa-blockers limited MEA to 196 measurements. Concerning the VASP-P assay, 300 measurements were achieved. Receiver Operating Characteristics (ROC)-curves of sensitivity and specificity estimates for MACE were plotted for VASP-P assay. The area under the ROC-curve was 0.683 (p=0.014) for the platelet reactivity index (PRI) calculated from median fluorescence intensities (FI) with an optimal cut-off at 60.2% PRI. Patients above 60.2% had a significantly increased risk for MACE at six months follow-up (p=0.007). Estimating the cut-offs for the PRI from mean FI (52%) or from geometric mean FI (56.6%) led to clinically relevant differences. VASP-P assay is feasible for clinical routine to measure clopidogrel effects and to predict post-procedural MACE in unselected patients. With regard to differing cut-offs, exact standardisation of the VASP-P assay is mandatory. The use of GP-IIb/IIIa-blockers prevents MEA testing and limits its usability in unselected patients.

Impact of concomitant treatment with proton pump inhibitors and clopidogrel on clinical outcome in patients after coronary stent implantation.

The aim of the study was to evaluate the effect of the concomitant treatment with proton-pump inhibitors (PPIs) and clopidogrel on the incidence of stent thrombosis, acute coronary syndrome (ACS) and death in patients who underwent percutaneous coronary intervention (PCI) and stent implantation. In total, 1,210 patients under dual antiplatelet therapy, who underwent PCI and stent implantation, were included in a prospective registry from January 2003 until December 2006. The patients were divided retrospectively into those with or without long-term PPI treatment (for the duration of dual antiplatelet therapy). All-cause mortality, cardiovascular death, re-hospitalisation for re-ACS, stent thrombosis, as well as the combined endpoint all-cause death, re-ACS or stent thrombosis were evaluated over a mean follow-up period of 7.8 (± 3.63) months (range 1-12 months). Propensity score analysis was performed to reduce potential selection bias and exhibited no significant difference between the two study groups with respect to all-cause mortality, cardiovascular death, re-ACS, stent thrombosis and the combined endpoint. In pre-specified subgroup analyses performed in patients presenting with ACS and referred for acute PCI or for stable patients referred for elective PCI, receiving drug-eluting stents or bare metal stents, in diabetics or non-diabetics, in males or females, and in patients older than 75 years or ≤75 years of age use of PPIs had no significant impact on clinical outcome. Our data suggest that a combined use of clopidogrel as part of dual antiplatelet therapy (DAPT) after coronary stenting and PPIs does not significantly influence the clinical outcome.