Jan Kaufmann

Soluble P-selectin level correlates with acetylsalicylic acid but not with clopidogrel response in patients with stable coronary artery disease after a percutaneous coronary intervention.

BackgroundImpaired response to dual antiplatelet therapy is associated with worse cardiovascular outcome. Besides antiplatelet effects, there is evidence that both clopidogrel and acetylsalicylic acid (ASA) have anti-inflammatory properties. However, little is known about the relationship between platelet function and inflammation under dual antiplatelet therapy in patients with stable coronary artery disease. PurposeThe purpose of the study was to investigate the correlation of platelet function with soluble (s)P-selectin and soluble (s)CD40L in patients undergoing elective percutaneous coronary intervention. Poor response to ASA and clopidogrel could lead to increased levels of inflammatory markers. MethodsA total of 148 patients were included. Eighty percent of the patients were on 100 mg ASA and all patients were clopidogrel naive. They underwent percutaneous coronary intervention and received a loading dose of 600 mg clopidogrel. Platelet function was assessed by light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein analysis at baseline, 24 h after loading, and after 1 month of maintenance therapy, respectively. Plasma levels of sP-selectin and sCD40L were measured. To classify low responders to clopidogrel, patients were screened for genetic variants determining clopidogrel absorption and metabolization. ResultssP-selectin levels correlated with LTA findings after stimulation with arachidonic acid (P=0.012). Further, in addition to decreased platelet reactivity observed on LTA, lower sP-selectin levels were seen in patients under ASA therapy (P=0.004). CYP2C19*2 allele carriers had a higher platelet reactivity after clopidogrel loading measured by adenosine diphosphate-induced aggregation in LTA (P=0.008) and vasodilator-stimulated phosphoprotein phosphorylation (P=0.035); however, there was no difference in the inflammatory markers. Multiple regression analysis showed that variables significantly related to sP-selectin plasma levels were sCD40L (P<0.001), LTA after stimulation with arachidonic acid (P<0.001), adenosine diphosphate (20 µmol/l, P=0.009), collagen (P<0.001), and ejection fraction (P=0.001). ConclusionsP-selectin was decreased in patients receiving ASA but did not reflect a CYP2C19*2-defined clopidogrel response. This underlines that sP-selectin is a useful marker for ASA, but not for clopidogrel response, in stable coronary artery disease.

Clopidogrel pharmacokinetics and pharmacodynamics in out-of-hospital cardiac arrest patients with acute coronary syndrome undergoing target temperature management.

BACKGROUND Target temperature management (TTM) after cardiac arrest (CA) improves outcome in patients with acute coronary syndrome (ACS). Previous data point to an interaction between hypothermia and drug metabolism, potentially impacting on platelet function in patients on antiplatelet therapy. PURPOSE To compare clopidogrel metabolism and platelet function in clopidogrel naïve ACS patients treated with TTM (33°C, n=15) and in ACS patients (troponin positive) without TTM (n=18). METHODS Platelet function was measured by multiple electrode platelet aggregometry (MEA), light transmittance aggregometry (LTA) and VASP analysis before and after administration of a 600mg clopidogrel loading dose. Plasma levels of clopidogrel and its metabolites were measured. All patients were screened for CYP2C19*2 polymorphism and scheduled for PCI. TTM was carried out for 24h at a target temperature of 33°C using a computer feedback surface cooling device in cardiac arrest patients. RESULTS Plasma concentration of clopidogrel and metabolites was lower in the TTM group after 2 and 4h, respectively (all p<0.005 vs. controls), and platelet function tests revealed an attenuated response to clopidogrel with respect to baseline platelet activity in the TTM group. This was significant for MEA, LTA and VASP analysis (all p<0.05). Moreover, there was no significant difference in genotype and platelet function determined ex vivo at 33 or 37°C, respectively. CONCLUSION Inhibition of platelet function is significantly lessened in TTM at 33°C, likely due to reduced clopidogrel absorption. Patients with TTM might thus have a higher risk for further cardiovascular events despite antiplatelet therapy with clopidogrel.

Increased circulating placental growth factor during percutaneous coronary intervention is associated with applied radiocontrast agent.

Background and aim of the studyRecent studies have suggested placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) as promising new biomarkers for risk stratification in acute coronary syndromes (ACS). However, little is known about the influence of percutaneous coronary intervention (PCI) on circulating PlGF and VEGF levels. MethodsThirty-five patients with ACS, 27 patients with stable coronary artery disease (sCAD), and nine healthy controls were enrolled in the study. Although all patients with ACS and 14 patients with stable angina pectoris underwent PCI, 13 patients with coronary artery disease required no revascularization (sCAD). PlGF and VEGF plasma concentrations were measured by immunoassay during and at the end of PCI and coronary angiography. ResultsPlasma PlGF levels were comparable in patients with ACS and sCAD on admission. Although coronary angiography or heparin alone did not alter PlGF and VEGF levels, immediately after PCI a dramatic increase was seen in circulating PlGF and a decrease in VEGF, which was independent of the clinical presentation of the patients, heparin administration, or the angiographic procedure itself, but was associated with the extent of coronary artery disease and the amount of the injected contrast media. In-vitro experiments revealed that radiocontrast agents induced the release of PlGF from endothelial cells without altering PlGF mRNA expression. ConclusionPatients undergoing PCI exhibit an increase in circulating PlGF, probably caused by posttranslational modifications of radiocontrast agents in endothelial cells. Therefore, analysis of plasma PlGF and VEGF levels may consider the timing of blood sampling with respect to PCI and contrast media exposure.

The impact of stem cell therapy on atherosclerosis progression in ST-elevation myocardial infarction patients.

Myocardial infarction (MI) accounts for over 800 000 acute care hospitalizations annually in the USA, with nearly a third of patients suffering from ST-elevation myocardial infarction (STEMI) [1]. Enormous improvements in patient care, including rapid reperfusion by percutaneous coronary intervention (PCI) and evidenced-based pharmacotherapy such as antithrombotics, inhibitors of the renin–angiotensin–aldosterone system, and β-blockers, have led to a significant decrease in acute coronary syndrome (ACS)/MI mortality over the past decade [1–3]. However, epidemiologic studies show that improvements in survival are counterbalanced by increased morbidity in ACS/MI patients driven by the development of heart failure (HF) occurring in about a quarter of ACS/MI patients [4–6]. The occurrence of HF, either at index ACS/MI or after discharge (late-onset), has prognostic importance [7,8]. A recently published retrospective cohort study investigated first-time ACS/ MI patients with no previous HF (9406 STEMI, 11 008 non-STEMI, and 4910 unstable angina) and found a cumulative HF rate of 23.4% in STEMI, 25.4% in nonSTEMI, and 16% in patients with unstable angina at 1 year [8]. In this study, HF was associated with an over four times higher 1-year mortality rate in both index HF (13.9%) and postdischarge HF (10.6%) compared with that in patients with no HF (2.4%) [8]. Moreover, during the course of the disease, HF patients often require hospital re-admission for symptom control and suffer from loss in quality of life and productivity, placing high demands on resources.