Overview of pleiotropic effects of platelet P2Y12 receptor inhibitors.

Dual antiplatelet therapy consisting of one of the P2Y12 receptor inhibitors in conjunction with aspirin is the mainstay of treatment for patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary interventions (PCI). In recent years, multiple extra-platelet features of P2Y12 receptor antagonists have been reported in numerous clinical trials. The aim of this review is to summarise reported pleiotropic effects of clopidogrel, prasugrel, ticagrelor and other P2Y12 receptor blockers. We included observations made both in human and in animal models, together with proposed mechanisms of action for described features. If confirmed in randomised studies and properly applied to everyday practice, the observed extra-platelet actions could enable us to improve efficacy of ACS and post-PCI treatment, as well as to confine mortality and occurrence rate of cardiovascular events.

A critical overview on ticagrelor in acute coronary syndromes.

Until a few years ago, the mainstay of anti-platelet therapy in patients with acute coronary syndrome (ACS) was the combination of aspirin and clopidogrel, a P2Y12 receptor inhibitor. However, current clinical practice has now changed with the introduction of ticagrelor, a more potent cardiovascular drug than clopidogrel, without the limitations related to clopidogrel therapy. In this review, we provide a critical overview of ticagrelor in ACS, highlight the results with ticagrelor in several subgroups of patients and discuss the future trials.

Stress hyperglycaemia in patients with first myocardial infarction.

OBJECTIVE: To investigate the incidence of stress hyperglycaemia at first acute myocardial infarction (MI) with ST-segment elevation, occurrence of stress hyperglycaemia as a manifestation of previously undiagnosed abnormal glucose tolerance (AGT), and its relation to stress hormone levels. MATERIALS AND METHODS: The population of this prospective cohort study consisted of 243 patients. On admission glucose, adrenaline, noradrenaline and cortisol levels were measured. Patients without previously diagnosed diabetes (n = 204) underwent an oral glucose tolerance test on day 3 of hospitalisation and 3 months after discharge. RESULTS: Abnormal glucose tolerance at day 3 was observed in 92 (45.1%) patients without a previous diagnosis of diabetes mellitus and resolved after 3 months in 46 (50.0%) patients (p < 0.0001). Stress hyperglycaemia, defined as admission glycaemia ≥ 11.1 mmol/l, affected 34 (14.0%) study participants: 28 (54.9%) patients with diabetes vs. 3 (8.8%) subjects with newly detected impaired glucose intolerance (p < 0.00001) and 1 (2.2%) person with AGT at day 3 (p < 0.000001). Multivariable analysis identified elevated glycated haemoglobin (HbA(1c) ; p < 0.0000001), anterior MI (p < 0.05) and high admission cortisol concentration (p < 0.001), but not catecholamines, as independent predictors of stress hyperglycaemia. The receiver operating characteristic curve analysis revealed the optimal cut-off values of 8.2% for HbA(1c) and 47.7 µg/dl for admission cortisol with very good and sufficient diagnostic accuracies respectively. CONCLUSIONS: Newly detected AGT in patients with a first MI is transient in 50% of cases. Stress hyperglycaemia is a common finding in patients with a first MI with ST-segment elevation and diabetes mellitus, but is rarely observed in individuals with impaired glucose tolerance or transient AGT diagnosed during the acute phase of MI. The risk factors of stress hyperglycaemia occurrence include elevated HbA(1c) , anterior MI and high admission cortisol concentration.

Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study.

BACKGROUND: Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies. OBJECTIVES: To compare different assays for prediction of events during long-term follow-up. METHODS: In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator-stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA-100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12-month follow-up. RESULTS: Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c-index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA-100 (c-index < 0.70; P > 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c-index < 0.56; P > 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra-metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status. CONCLUSIONS: Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping.

Low-molecular-weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis.

BACKGROUND: The aim of the current study was to perform two separate meta-analyses of available studies comparing low-molecular-weight heparins (LMWHs) vs. unfractionated heparin (UFH) in ST-elevation myocardial infarction (STEMI) patients treated (i) with primary percutaneous coronary intervention (pPCI) or (ii) with PCI after thrombolysis. METHODS: All-cause mortality was the pre-specified primary endpoint and major bleeding complications were recorded as the secondary endpoints. Relative risk (RR) with a 95% confidence interval (CI) and absolute risk reduction (ARR) were chosen as the effect measure. RESULTS: Ten studies comprising 16,286 patients were included. The median follow-up was 2 months for the primary endpoint. Among LMWHs, enoxaparin was the compound most frequently used. In the pPCI group, LMWHs were associated with a reduction in mortality [RR (95% CI) = 0.51 (0.41-0.64), P < 0.001, ARR = 3%] and major bleeding [RR (95% CI) = 0.68 (0.49-0.94), P = 0.02, ARR = 2.0%] as compared with UFH. Conversely, no clear evidence of benefits with LWMHs was observed in the PCI group after thrombolysis. Meta-regression showed that patients with a higher baseline risk had greater benefits from LMWHs (r = 0.72, P = 0.02). CONCLUSIONS: LMWHs were associated with greater efficacy and safety than UFH in STEMI patients treated with pPCI, with a significant relationship between risk profile and clinical benefits. Based on this meta-analysis, LMWHs may be considered as a preferred anticoagulant among STEMI patients undergoing pPCI.

Ischaemic and bleeding complications with new, compared to standard, ADP-antagonist regimens in acute coronary syndromes: a meta-analysis of randomized trials.

BACKGROUND: Platelets play a pivotal role in the pathogenesis of acute coronary syndromes (ACS) and their inhibition remains a mainstay therapy in this setting. We aimed to perform a meta-analysis of randomized trials to evaluate the benefits of new oral antiplatelet regimens to block platelet ADP-receptors compared to standard-dose clopidogrel (300 mg loading dose followed by 75 mg/daily). METHODS: We obtained results from all randomized trials enrolling patients with ACS. Primary endpoint was mortality. Secondary endpoints were myocardial infarction and definite in-stent thrombosis. Safety endpoint was the risk of major bleeding complications. We prespecified subanalyses according to new antiplatelet drugs (prasugrel/ticagrelor), high-dose clopidogrel (600 mg) and patients undergoing percutaneous coronary intervention. RESULTS: A total of seven randomized trials were finally included in the meta-analysis (n = 58 591). We observed a significant reduction in mortality (2.9% vs. 3.4%, OR = 0.87, 95% CI 0.79-0.95, P = 0.002), recurrent myocardial infarction (4.2% vs. 5.2%, OR = 0.80, 95% CI 0.74-0.87, P < 0.0001), definite in-stent thrombosis (0.9% vs. 1.7%, OR = 0.52, 95% CI 0.43-0.63, P < 0.0001). The benefits in mortality and reinfarction were driven by the treatment with prasugrel or ticagrelor, without a significant difference in terms of major bleeding complications as compared to standard-dose clopidogrel (5% vs. 4.7%, OR = 1.06 95% CI 0.96-1.17, P = 0.25). CONCLUSION: This meta-analysis showed that new oral antiplatelet regimens are associated with a significant reduction in mortality, reinfarction and in-stent thrombosis in ACS patients without an overall increase of major bleeding when treated with new antiplatelet drugs.

2D-IR spectroscopy of the sulfhydryl band of cysteines in the hydrophobic core of proteins.

We investigate the sulfhydryl band of cysteines as a new chromophore for two-dimensional IR (2D-IR) studies of the structure and dynamics of proteins. Cysteines can be put at almost any position in a protein by standard methods of site-directed mutagenesis and, hence, have the potential to be an extremely versatile local probe. Although being a very weak absorber in aqueous environment, the sulfhydryl group gets strongly polarized when situated in an alpha-helix inside the hydrophobic core of a protein because of a strong hydrogen bond to the backbone carbonyl group. The extinction coefficient (epsilon=150 M(-1) cm(-1)) then is sufficiently high to perform detailed 2D-IR studies even at low millimolar concentrations. Using porcine (carbonmonoxy)hemoglobin as an example, which contains two such cysteines in its wild-type form, we demonstrate that spectral diffusion deduced from the 2D-IR line shapes reports on the overall-breathing of the corresponding alpha-helix. The vibrational lifetime of the sulfhydryl group (T1 approximately 6 ps) is considerably longer than that of the much more commonly used amide I mode (approximately 1.0 ps), thereby significantly extending the time window in which spectral diffusion processes can be observed. The experiments are accompanied by molecular dynamics simulations revealing a good overall agreement.

Thyroid ultrasound in diabetic patients without overt thyroid disease.

PURPOSE: To assess thyroid volume and to evaluate possible lesions in the gland structure using thyroid ultrasound in patients with diabetes mellitus type 1 (DM1) and 2 (DM2) without overt thyroid disease. MATERIAL AND METHODS: Consecutive adult patients with DM2 (n = 98) and DM1 (n = 30) without overt thyroid disease referred to our department because of poorly controlled disease and/or diabetic complications were prospectively analyzed. Thyroid volumes, gland echogenicity, thyroid nodules incidence, and TSH levels were compared with control groups (n = 50 and 38) and matched according to sex and age. RESULTS: Significant increases in median thyroid volume were observed in both subjects with DM1 (17.3 cm3, interquartile range (IR) 13.9-21.6 cm3 versus 14.4 cm3, IR 11.3-18.3 cm3; P < 0.05) and DM2 (20.5 cm3, IR 14.9-27.1 cm3 versus 14.1 cm3, IR 11.3-18.3 cm3; P < 0.001) in comparison to their control groups. Moreover, in the population of type 2 diabetics, thyroid nodules (OR 2.37, 95% CI 1.14-4.93), parenchymatous goiter (OR 5.40, 95% CI 1.20-24.30), and all kinds of thyroid goiter according to the WHO definition (OR 4.18, 95% CI 2.02-8.66) were remarkably more frequent. In our patients, reduced (but within normal range) TSH level occurred in DM1 (median 0.97 mIU/l, IR 0.61-1.58 mIU/l versus median 1.66 mIU/l, IR 0.76-2.09 mIU/l; P < 0.05). The presence of a negative linear correlation between thyroid volume and TSH concentration was noticed in patients with DM2 (RS = -0.38, P < 0.01). CONCLUSION: In individuals with DM1 and DM2 treated for poorly controlled disease and/or diabetic complications, thyroid volumes were significantly higher than in the normal population. Moreover, nodular thyroid structure and parenchymatous goiter occurred more frequently in these type 2 diabetic patients.

Percutaneous coronary intervention triggers a systemic inflammatory response in patients treated for in-stent restenosis -- comparison with stable and unstable angina.

OBJECTIVE AND DESIGN: It is believed that the magnitude of the systemic inflammatory response induced by percutaneous coronary intervention (PCI) impacts on the long-term outcomes in patients with stable angina (SA) and unstable angina (UA). We aimed to determine whether an inflammatory response appears in in-stent restenosis (ISR) patients undergoing balloon angioplasty and to assess its pattern and magnitude in relation to SA and UA subjects. SUBJECTS: 80 patients (59 with SA, 10 with UA, 11 with ISR) were enrolled into the prospective study. TREATMENT: SA and UA patients undergoing single vessel coronary balloon angioplasty followed by stenting versus ISR subjects in whom only balloon angioplasty was performed. METHODS: C-reactive protein (CRP), serum amyloid A (SAA), tumor necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) were measured in blood samples collected before and 6, 24 h and 1 month after the procedure. RESULTS: A comparable pattern of inflammatory response in terms of CRP and SAA concentrations in subjects undergoing PCI due to ISR and SA was discovered while in unstable patients its magnitude was substantially higher. CRP and SAA levels increased significantly in each group with the peak value at 24 h and the baseline levels remarkably correlated with the highest markers' concentrations. In contrast, preprocedural TNF-alpha concentrations were higher in ISR group when compared with SA and UA patients. Additionally, in ISR group a twofold increase in their values of borderline significance at 6 h was noted. SA and UA subjects were found to have significantly lower TNF-alpha levels at 6 and 24 h after the intervention though the marker concentrations markedly increased with peak values at 1 month. The levels of IL-10 did not differ at any time point between the groups. CONCLUSIONS: We suggest that PCI triggers a systemic inflammatory response in patients with ISR and considerable differences in its pattern when compared with SA and UA patients were demonstrated. Moreover, a high preprocedural TNF-alpha level and its increase provoked by PCI in the ISR group warrant the need for further investigation of its possible involvement in the restenosis process.