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Long-standing aspirin is the cornerstone to prevent recurrence of thrombotic events in patients with ischemic heart disease. However, clopidogrel, a more potent antiplatelet agent, is preferred over aspirin in targeted populations, including those with a high risk of gastrointestinal bleeding. In addition, clopidogrel offers superior oral tolerance, and it may reduce the rates of intracranial hemorrhages compared with aspirin. However, an extensive inhibition of the coagulation cascade seems to be reasonable to minimize thrombotic events in such patients. After several failed exploratory investigations in the past with vitamin K antagonists, the newest direct oral anticoagulants may represent an alternative. To counterbalance bleeding complications, a low dose of these agents should be considered. Few publications have already showed promising results with the combination of clopidogrel and low-dose direct oral anticoagulants. Further investigations should be addressed to elucidate whether this is the downfall of the aspirin era for secondary prevention of atherosclerotic cardiovascular events.

Background: Smoking is a potent risk factor for coronary artery disease; however, prior studies describe increased platelet inhibition with clopidogrel among smokers, and some studies report improved outcomes among smokers, a finding described as the smoker's paradox. This study assessed the relationship between platelet reactivity and clinical outcomes after percutaneous coronary interventions among current smokers and nonsmokers., Methods: ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a prospective, multicenter registry of patients treated with coronary drug-eluting stents. Platelet reactivity was assessed by the VerifyNow point-of-care assay; high on-treatment platelet reactivity (HPR) was defined as P2Y12 reaction units >208. A propensity-adjusted multivariable analysis was performed to determine the relationship between current smoking, platelet reactivity, and subsequent adverse events., Results: Among 8582 patients, 22.6% were active smokers at the time of their percutaneous coronary intervention procedure. Current smokers were younger and had fewer comorbidities compared with nonsmokers. Current smokers had lower mean P2Y12 reaction units and lower rates of HPR compared with nonsmokers. Current smokers had similar rates of adverse events compared with nonsmokers. HPR was associated with higher rates of adverse events for both smokers and nonsmokers; however, there was evidence of interaction between smoking status and the effect of HPR. Smokers with HPR had significantly higher rates of stent thrombosis. Adverse event rates were highest among current smokers with HPR., Conclusions: Current smoking was associated with lower P2Y12 reaction units and lower rates of HPR on average; however, the combination of current smoking and HPR was associated with high rates of stent thrombosis., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00638794.

We hypothesized that the combination of a high neutrophil to lymphocyte ratio (NLR) and mean platelet volume (MPV) would be a stronger predictor of future cardiovascular events after percutaneous coronary intervention (PCI). Both NLR and MPV were measured in 364 consecutive patients undergoing PCI. The primary end point was the incidence of major adverse cardiovascular events (MACEs), including cardiac death, nonfatal myocardial infarction, and stent thrombosis. The median values of NLR and MPV were 2.8 and 8.2 fL, respectively. There were 26 MACEs during a median follow-up duration of 29.3 months. Kaplan-Meier analysis revealed that the higher NLR group had a significantly higher MACE rate than the lower NLR group and that the higher MPV group had a significantly higher MACE rate than the lower MPV group (log-rank: P = .0064 and P = .0004, respectively). The cumulative MACE-free survival can be further stratified by the combination of NLR and MPV. This value was especially useful in patients with acute coronary syndrome (ACS). By multivariate Cox proportional hazards model, the combination of high NLR and high MPV was independently associated with MACE ( P = .026). The combination of a high NLR and high MPV is an independent predictor of MACE after PCI, especially in patients with ACS.

Allergic, IgE-mediated inflammation is thought to play a role in atherogenesis and atherosclerotic disease progression. In this study, total IgE and mast cell tryptase were measured in a series of forensic autopsy cases including non-allergic cardiac deaths (14 cases with minimal or no coronary atherosclerosis, 14 cases with significant coronary artery atherosclerosis without acute coronary thrombosis, and 14 cases with significant coronary artery atherosclerosis and acute coronary thrombosis or myocardial infarction) and non-allergic non-cardiac deaths (21 cases with death due to hanging and 21 cases with death due to intracranial gunshot wounds), in order to correlate laboratory results with morphological findings and compare them to conclusions reported in the clinical setting. In cardiac death cases, postmortem serum total IgE levels were increased in 7 out of 42 cases and mast cell tryptase levels were increased in 3 out of 42 cases. In non-cardiac death cases, postmortem serum total IgE levels were not increased in 39 out of 42 cases and mast cell tryptase levels were not increased in any of these cases. These preliminary findings seem to indicate that a portion of coronary deaths characterized by coronary artery atherosclerosis of various severities are also characterized by increased total IgE and mast cell tryptase levels, thus corroborating the data previously reported in both clinical and forensic literature on this topic as well as the necessity of combining morphological investigations focusing on the heart and coronary arteries with biochemical analyses., (Copyright © 2018. Published by Elsevier Ltd.)

Background: For patients who have an indication for anticoagulation, it is controversial whether dual therapy with an oral anticoagulant and single antiplatelet agent can be used after percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS) instead of triple therapy with an oral anticoagulant and dual antiplatelet therapy., Participants and Methods: Twelve observational studies and four clinical trials were identified from three electronic databases from their inception to December, 2017. Pooled estimates were calculated using a random-effects model for meta-analysis., Results: Compared with the triple therapy, dual therapy was associated with significantly lower risk of major bleeding [relative risk (RR), 0.63; 95% confidence interval (CI), 0.50-0.80] without statistically significant increase in major adverse cardiac events (RR, 1.04; 95% CI, 0.84-1.29), all-cause death (RR, 1.15; 95% CI, 0.77-1.71), cardiac death (RR, 1.04; 95% CI, 0.67-1.61), myocardial infarction (RR, 1.25; 95% CI, 0.98-1.59), stroke (RR, 1.27; 95% CI, 0.79-2.06), stent thrombosis (RR, 1.52; 95% CI, 0.96-2.41), and repeat revascularization (RR, 1.15; 95% CI, 0.87-1.52). Although risks of myocardial infarction and stent thrombosis were marginally higher in the dual therapy group, this trend was attenuated after excluding studies that exclusively included patients undergoing PCI for ACS, but not stable coronary artery disease., Conclusion: Dual therapy may be a reasonable alternative to triple therapy after PCI in patients with indication for chronic anticoagulation. However, further studies are needed to investigate efficacy of dual therapy, especially in the patients with higher ischemic risk, such as in ACS.

The optimal antithrombotic treatment regimen for patients with atrial fibrillation undergoing percutaneous coronary intervention with stent implantation represents a challenge in clinical practice. In 2016, an updated opinion of selected experts from the United States and Canada on the treatment of patients with atrial fibrillation undergoing percutaneous coronary intervention was reported. After the 2016 North American consensus statement on the management of antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention, results of pivotal clinical trials assessing the type of oral anticoagulant agent and the duration of antiplatelet treatment have been published. On the basis of these results, this focused update on the antithrombotic management of patients with atrial fibrillation undergoing percutaneous coronary intervention recommends that a non-vitamin K antagonist oral anticoagulant be preferred over a vitamin K antagonist as the oral anticoagulant of choice. Moreover, a double-therapy regimen (oral anticoagulant plus single antiplatelet therapy with a P2Y 12 inhibitor) by the time of hospital discharge should be considered for most patients, whereas extending the use of aspirin beyond hospital discharge (ie, triple therapy) should be considered only for selected patients at high ischemic/thrombotic and low bleeding risks and for a limited period of time. The present document provides a focused updated on the rationale for the new expert consensus-derived recommendations on the antithrombotic management of patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention.

Platelet activation and aggregation play a pivotal role in thrombotic complications occurring during percutaneous coronary intervention (PCI), and peri-PCI anti-platelet therapy represents a standard of care. High platelet reactivity prior to PCI has been correlated with an increased incidence of peri-procedural myonecrosis. Pre-PCI platelet reactivity predicts post-PCI platelet reactivity and has a prognostic impact on subsequent ischaemic and bleeding events, so as the platelet inhibition measured post-PCI. Many anti-platelet treatment strategies, including aspirin, glycoprotein IIb/IIIa inhibitors, P2Y 12 receptor blockers and vorapaxar, are being used in the routine clinical practice to modify platelet reactivity at each stage, e.g. pre-, during and post-PCI. Anti-platelet strategies with a 'stronger and faster' pharmacodynamic effect than clopidogrel have been mostly adopted in patients with acute coronary syndromes. However, several issues regarding the anti-platelet treatment such as benefits/risks of anti-platelet therapy pre-treatment and duration, and definite association between speed and potency of various anti-platelet agents and clinical outcomes remain controversial. We believe that a better understanding of peri-PCI platelet reactivity and its relations to outcomes may lead to the development of more effective and safe treatment strategies., Competing Interests: Dr Alexopoulos reports advisory board fees (modest) from AstraZeneca, Boehringer Ingelheim, Bayer, Medtronic and speaker honoraria (modest) from AstraZeneca, Bayer and Boehringer Ingelheim. Dr Gurbel reports personal fees (modest) from AstraZeneca, Boehringer Ingelheim, Merck, Janssen Pharmaceuticals, New Haven Pharmaceuticals, Bayer and Haemonetics; grants (modest) from Haemonetics, Merck, Duke Clinical Research Institute, Harvard Clinical Research Institute, National Institutes of Health, Coramed Technologies, MedImmune and Sinnowa; Dr Gurbel has a patent for platelet function testing. Other authors have no conflicting interests., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Approximately 5 to 7% of patients undergoing percutaneous coronary intervention (PCI) for the treatment of coronary artery disease require chronic oral anticoagulation (OAC) on top of aspirin and a P2Y 12 receptor antagonist, mainly due to non-valvular atrial fibrillation (AF). The advent of non-vitamin K antagonist oral anticoagulants (NOACs) increased treatment options, while there is cumulative evidence that dual combination of a NOAC and a P2Y 12 receptor antagonist attenuates risk of bleeding, compared to traditional triple therapy, consisting of a vitamin K antagonist (VKA), aspirin, and a P2Y 12 receptor antagonist, without significantly compromising efficacy., Study Design: Greek AntiPlatElet Atrial Fibrillation (GRAPE-AF, NCT 03362788) is an observational, nationwide study of non-valvular AF patients undergoing PCI, planning to enroll over 1-year period > 500 participants in 25 tertiary and non-tertiary PCI centers in Greece. Key data to be collected pre-discharge include demographics, detailed past medical history, and antithrombotic and concomitant treatment. Patients will be followed up at 1, 6, and 12 months post hospital discharge. Αt each follow-up visit, data on antithrombotic treatment, ischemic, bleeding, and adverse events will be collected. Study's primary endpoint is clinically significant bleeding (Bleeding Academic Research Consortium, BARC ≥ 2) at 12 months, between VKAs and NOACs-treated patients, analyzed using Cox proportional hazards models, by an intention-to-treat principle. An independent endpoint committee will adjudicate all clinical events., Conclusions: This study aims at providing "real-world" information on current antithrombotic treatment patterns and clinical outcome of patients with non-valvular AF undergoing PCI.

The patient population with the need for oral anticoagulation to reduce stroke risk associated with atrial fibrillation (AF) and dual antiplatelet therapy to prevent stent thrombosis and myocardial infarction after percutaneous coronary intervention is increasing. However, patients treated with a triple therapy consisting of oral anticoagulation, aspirin, and a P2Y12 inhibitor have been demonstrated to be at high bleeding risk. The best combination of these agents and the duration of the different therapies are still uncertain. Recently, data on the safety of combinations including nonvitamin K antagonists have been published and evidence for the feasibility of a dual therapy is increasing. This review aims to provide insights to the pathophysiology of thrombus formation in AF versus coronary artery disease, summarize available data on postprocedural treatment strategies, and report current guidelines for AF patients after percutaneous coronary intervention. Furthermore, the role of stent type selection and tools to evaluate as well as strategies to reduce the individual bleeding risk will be discussed.

Platelets play a key role in the pathophysiology of coronary artery disease and acute coronary syndromes. Our understanding of platelet function in thrombus formation has increased considerably, resulting in the development of clinically effective treatment strategies and identification of new targets. An underappreciated platelet function is their contribution toward acute and chronic inflammatory processes including atherogenesis. In this review, we discuss the role of platelets in atherosclerosis and thrombosis, platelet function testing, and the pharmacology of currently available antiplatelet drugs.

Previous study has demonstrated that erythrocyte-rich thrombi contain more inflammatory cells and reflect high thrombus burden, leading to impaired myocardial reperfusion in myocardial infarction. The aim of this study is to investigate the utility of quantified frequency domain optical coherence tomography (FD-OCT) signal analysis in evaluating the erythrocyte-rich thrombus with ex-vivo materials. We evaluated 54 specimens of coronary artery thrombus obtained by thrombectomy catheter from 8 patients who underwent primary percutaneous coronary intervention. The thrombi were immersed in saline immediately after thrombectomy and FD-OCT image acquisition was performed ex-vivo. Quantitative analysis for all contiguous frames was performed by the dedicated automated software (OCT system software, Light Lab Inc.). For the maximum thrombus area, mean signal intensity (MSI) and normalized standard deviation of signal (NSD) was evaluated. All thrombi were stained using double staining of phosphotungstic acid-hematoxylin and eosin to enable automatic extraction of erythrocyte from fibrin. Computer-assisted analysis was performed using dedicated image processing software (WinROOF, Mitani Corp., Tokyo, Japan) for color identification of the erythrocyte area. Erythrocyte-rich thrombus, defined as % erythrocyte [(erythrocyte area/total thrombus area) × 100] ≥ 10%, showed significantly lower MSI [4.39 ± 0.24 vs. 4.74 ± 0.35, p = 0.002] than that of <10%. The cut-off point for prediction of erythrocyte-rich thrombus was defined as MSI ≤ 4.56, sensitivity: 87.5%, specificity: 82.9%, area under the curve: 0.836, respectively). The present ex-vivo study suggested the utility of quantified FD-OCT signal analysis on the detection of erythrocyte-rich thrombus.

Background: Patients with peripheral arterial disease (PAD) have high rates of adverse cardiovascular events after percutaneous coronary intervention and may additionally have heightened platelet reactivity. This study assessed the relationship between platelet reactivity and clinical outcomes after percutaneous coronary interventions among subjects with and without PAD., Methods and Results: ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a prospective, multicenter registry of patients treated with coronary drug-eluting stents. Platelet reactivity was assessed by the VerifyNow point-of-care assay; high on-treatment platelet reactivity (HPR) was defined as P2Y12 reaction units >208. A propensity-adjusted multivariable analysis was performed to determine the relationship between PAD, platelet reactivity, and subsequent adverse events (definite or probable stent thrombosis, all-cause mortality, myocardial infarction, and clinically relevant bleeding). Among 8582 patients, 10.2% had a history of PAD. Patients with PAD were older and more likely to have comorbid conditions; however, mean P2Y12 reaction units and HPR were not significantly different between PAD and no PAD groups. Patients with PAD had higher 2-year rates of all-cause mortality, myocardial infarction, stent thrombosis, and clinically relevant bleeding. Associations between HPR and adverse events were similar in PAD and no PAD groups, without evidence of interaction; however, adverse event rates were highest among subjects with both PAD and HPR. In a propensity-adjusted multivariable model, both PAD and HPR were independent predictors of myocardial infarction at 2 years., Conclusions: A history of PAD was associated with ischemic and bleeding outcomes 2 years after successful coronary drug-eluting stent implantation; however, these associations did not seem to be directly mediated by heightened platelet reactivity., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794., (© 2017 American Heart Association, Inc.)

The acute cardiovascular events following thrombus formation is a primary cause of morbidity and mortality of patients with coronary artery disease (CAD). Numerous studies have shown that a prethrombotic status, which can be defined as an imbalance between the procoagulant and anticoagulant conditions, would exist for a period of time before thrombogenesis. Therefore, early diagnosis and intervention of prethrombotic status are important for reducing acute cardiovascular events. However, none of prethrombotic indicators have been identified as golden standard for diagnosis of prethrombotic status to date. MicroRNAs (miRNAs), a class of short non-coding RNAs, have been shown to be involved in pathophysiologic processes related to prethrombotic status, such as endothelial dysfunction, platelet activation, impaired fibrinolysis and elevated procoagulant factors, etc. Owing to their multiple and fine-tuning impacts on gene expression, miRNAs raise a novel understanding in the underlying mechanism of prethrombotic status. This review aims to discuss the role of miRNAs in prethrombotic status, especially the differently expressed miRNAs in CAD, which may be meaningful for developing promising diagnostic biomarkers and therapeutic strategies for CAD patients in future.

Objectives: We sought to identify angiographic predictors of 2-year stent thrombosis (ST) in the ADAPT-DES study., Background: A strong relationship between platelet reactivity and ST after implantation of drug-eluting stents (DES) was recently confirmed in the prospective, multicenter ADAPT-DES study., Methods: In a pre-specified analysis of patients enrolled in ADAPT-DES, an independent angiographic core laboratory performed detailed angiographic analyses for all cases of ST. Patients with Academic Research Consortium definite/probable target-lesion ST were matched with controls in a 1:2 ratio, and multivariable Cox regression models identified angiographic predictors of 2-year ST., Results: Among 8,582 patients who had successful percutaneous coronary intervention (PCI) and were included in the ADAPT-DES study, 92 (1.1%) patients had ST at 2-year follow-up. Target lesion-related ST was identified in 77 patients (82 lesions) who were clinically matched with 153 patients (196 lesions) without ST. Patients with ST were more likely to have longer target lesions, thrombus, moderate/severe calcification, American College of Cardiology/American Heart Association (ACC/AHA) type C lesions, and saphenous vein grafts. After adjustment for clinical covariates the angiographic variables that predicted ST were lesion complexity (ACC/AHA type C lesion, adjusted HR: 1.97, 95% CI: 1.19 to 3.26, P = 0.01) and presence of thrombus on index PCI (HR: 2.25, 95% CI: 1.40 to 3.59, P < 0.01)., Conclusions: Anatomically complex lesions and the presence of thrombus are strong predictors of 2-year ST in the DES era. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: IFN-γ-producing Th17 cells have been implicated in autoimmune disorders, but their properties in humans are known only partially. The molecular mechanisms and external factors that govern IFN-γ-producing Th17-cell bias are incompletely understood. The present work was to clarify whether (i) IFN-γ-producing Th17 cells are present in the peripheral circulation of patients with coronary atherosclerosis (CA); (ii) high mobility group box (HMGB)1 in circulation is associated with IFN-γ-producing Th17-cell bias., Methods: Thirty-six patients (17 females and 19 males; 45-84 years) diagnosed as having atherosclerosis after coronary angiography for suspected or known CA were included the study cohort. Samples of peripheral blood were collected from healthy volunteers and patients, and classical tests (flow cytometry, RT-qPCR) were used to measure blood components., Results and Conclusion: Our results clearly demonstrated that HMGB1 were up-regulated in different progressive CA patients: 5.38 ± 1.48 ng/ml, 6.30 ± 1.53 ng/ml and 5.86 ± 1.12 ng/ml vs1.45 ± 0.65 ng/ml for only atherosclerotic plaque (AP), atherosclerotic plaque and some plaque rupture, no thrombosis (PR), plaque rupture and accompanying thrombosis (TH) and volunteers, respectively, p < 0.05. The frequency of IFN-γ-producing Th17 cells was 2.33 ± 0.58%, 1.93 ± 0.2% and 2.21 ± 0.65% vs 0.38 ± 0.21% for AP, PR, TH and volunteers, p < 0.05, respectively. Furthermore, HMGB1 contributed to IFN-γ-producing Th17-cell bias by controlling expression of T-bet and RUNX3. We demonstrated, for the first time, that HMGB1 is a potential inducer of IFN-γ-producing Th17-cell bias, and that IFN-γ-producing Th17 cells might be one of the pathogenic factors in atherosclerosis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: Targeted temperature management (TTM) is part of the standard treatment of comatose patients after out-of-hospital cardiac arrest (OHCA) to attenuate neurological injury. In other clinical settings, hypothermia promotes coagulopathy leading to an increase in bleeding and thrombosis tendency. Thus, concern has been raised as to whether TTM can be applied safely, as acute myocardial infarction requiring primary percutaneous coronary intervention (PCI) with the need of effective antiplatelet therapy is frequent following OHCA. This study investigated the influence of TTM at 33 or 36°C on various laboratory and coagulation parameters., Methods and Results: In this single-center predefined substudy of the TTM trial, 171 patients were randomized to TTM at either 33 or 36°C in the postresuscitation phase. The two subgroups were compared regarding standard laboratory coagulation parameters, thrombelastography (TEG), bleeding, and stent thrombosis events. Platelet counts were lower in the TTM33-group compared to TTM36 (p=0.009), but neither standard coagulation nor TEG-parameters showed any difference between the groups. TEG revealed a normocoagulable state in the majority of patients, while approximately 20% of the population presented as hypercoagulable. Adverse events included 38 bleeding events, one stent thrombosis, and one reinfarction, with no significant difference between the groups., Conclusions: There was no evidence supporting the assumption that TTM at 33°C was associated with impaired hemostasis or increased the frequency of adverse bleeding and thrombotic events compared to TTM at 36°C. We found that TTM at either temperature can safely be applied in the postresuscitation phase after acute myocardial infarction and primary PCI., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study sought to investigate the efficacy of prasugrel compared with clopidogrel in clopidogrel nonresponders., Background: Clopidogrel nonresponsiveness is a strong marker of the risk of cardiac death and stent thrombosis after a percutaneous coronary intervention (PCI). It is unknown whether clopidogrel nonresponsiveness is a nonmodifiable risk factor or whether prasugrel with more potent and predictable platelet inhibition as measured by ex vivo techniques is associated with a positive effect on clinical outcome., Methods: The RECLOSE-3 (REsponsiveness to CLOpidogrel and StEnt thrombosis) study screened clopidogrel nonresponders after a 600-mg loading dose of clopidogrel. Clopidogrel nonresponders switched to prasugrel (10 mg/day) the day of the PCI, and an adenosine diphosphate (ADP) test (10 μmol/l of ADP) was performed 6 days after the PCI. The primary endpoint was 2-year cardiac mortality. Patient outcome was compared with the RECLOSE-2-ACS study., Results: We screened 1,550 patients, of whom 302 were clopidogrel nonresponders. The result of the ADP test was 77.6 ± 6.2%. After switching to prasugrel, the ADP test result decreased to 47.1 ± 16.8%. The 2-year cardiac mortality rate was 4% in the RECLOSE-3 study and 9.7% in nonresponders of the RECLOSE-2-ACS study (p = 0.007). The definite and probable stent thrombosis rates were 0.7% and 4.4%, respectively (p = 0.004). On multivariable analysis, prasugrel treatment was related to the risk of 2-year cardiac death (hazard ratio: 0.32, p = 0.036)., Conclusions: Clopidogrel nonresponsiveness can be overcome by prasugrel (10 mg/day), and optimal platelet aggregation inhibition on prasugrel treatment is associated with a low rate of long-term cardiac mortality and stent thrombosis., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In case of coronary artery disease (CAD), diabetic patients are at higher risk than their non-diabetic counterparts. Antithrombotics are therefore of key importance to decrease the risk of ischemic complications. A careful assessment of the benefit-risk balance is however needed to limit the risk of bleeding. Diabetic CAD patients are characterized by a pro-thrombotic milieu and by an impaired response to both aspirin and P2Y12 receptor inhibitors, especially to clopidogrel. When combined with aspirin, the new P2Y12 receptor inhibitors prasugrel and ticagrelor provide superior efficacy for the diabetic patients with acute coronary syndromes. In stable CAD, antiplatelet monotherapy (aspirin) remains for the time being the reference treatment for diabetic as well as for non-diabetic patients; further studies are however ongoing to test whether the antithrombotic strategy should be reinforced, particularly in case of diabetes mellitus. Finally, although chronic oral anticoagulation is rarely indicated for CAD management in itself, it is often prescribed for the concomitant treatment of atrial fibrillation. The combination of anticoagulation and antiplatelet therapy is associated with a high risk of bleeding and should only be prescribed for limited periods of time when the estimated benefits exceed the risks.

Objectives: The aim of this study was to evaluate the pathophysiological features and response to primary percutaneous coronary intervention (PCI) of nonruptured/eroded plaque versus ruptured plaque as a cause of ST-segment elevation myocardial infarction (STEMI)., Background: Autopsy series identified nonruptured/eroded plaque and ruptured plaque as the principal pathological substrates underlying coronary thrombosis in STEMI. The real incidence of different plaque morphologies, associated biological factors, superimposed thrombus, and their interaction with primary PCI remain largely unknown., Methods: In a prospective study, 140 patients with STEMI underwent optical coherence tomography of the infarct-related artery (IRA) before PCI, after everolimus-eluting stent implantation and at 9-month follow-up. Histopathology and immunohistochemistry of thrombus aspirates and serum biomarkers were assessed at baseline., Results: Culprit plaque morphology was adjudicated in 97 patients: 32 plaques (33.0%) with an intact fibrous cap (IFC), 63 (64.9%) plaques with a ruptured fibrous cap (RFC), and 2 (2.1%) spontaneous dissections. Patients with an IFC and RFC had similar clinical characteristics, and serum inflammatory and platelets biomarkers. An IFC presented more frequently with a patent IRA (56.2% vs. 34.9%; p = 0.047), and had fewer lipid areas (lipid-rich areas: 75.0% vs. 100.0%; p < 0.001) and less residual thrombus before stenting (white thrombus: 0.41 mm(3) vs. 1.52 mm(3); p = 0.001; red thrombus: 0 mm(3) vs. 0.29 mm(3); p = 0.001) with a lower peak of creatine kinase-myocardial band (66.6 IU/l vs. 149.8 IU/l; p = 0.025). At the 9-month optical coherence tomography, IFC and RFC had similar high rates of stent strut coverage (92.5% vs. 91.2%; p = 0.15) and similar percentage of volume obstruction (12.6% vs. 10.2%; p = 0.27). No significant differences in clinical outcomes were observed up to 2 years., Conclusions: In the present study, an IFC was observed at the culprit lesion site of one-third of STEMIs. IFC, compared with RFC, was associated with higher rates of patent IRA at first angiography, fewer lipid areas, and residual endoluminal thrombus. However, no difference in vascular response to everolimus-eluting stent was observed. (Optical Coherence Tomography Assessment of Gender Diversity in Primary Angioplasty [OCTAVIA]; NCT01377207)., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

We evaluated the impact of clopidogrel 150 mg/d in patients with chronic kidney disease (CKD) having clopidogrel resistance (CR) after percutaneous coronary intervention (PCI); 1076 consecutive patients with coronary artery disease (CAD) having CKD were enrolled. Maximal platelet aggregation (MPA) was assessed before, 24 hours, and 30 days after a 300-mg loading dose of clopidogrel prior to PCI. After PCI, 370 patients with CR were randomized to receive clopidogrel 75 mg/d (n = 184) or 150 mg/d (n = 186) for 30 days. Stent thrombosis (ST), major adverse cardiac events (MACEs), and bleeding were analyzed after 1 month. Patients in the 150 mg group had significant lower rates of ST and MACE. There was no significant difference in major or minor bleeding. Patients in the 150 mg group had lower MPA and greater inhibition of platelet aggregation. One-month administration of 150 mg/d of clopidogrel decreases the rate of ST and MACE without increasing bleeding in patients with CKD having CR after PCI., (© The Author(s) 2014.)

Atherosclerosis is the proximate cause of arterial thrombosis, leading to acute occlusive cardiovascular syndromes. Thrombosis in atherosclerosis usually results from rupture of the fibrous cap of atherosclerotic plaques with a smaller proportion resulting from superficial endothelial erosion. Ruptured plaques are often associated with intimal and adventitial inflammation, increased size of lipid-rich necrotic core with thinned out collagen-depleted fibrous cap, outward remodeling, increased plaque neovascularity, intraplaque hemorrhage, and microcalcification. By inference, non-ruptured plaques with similar compositional features are considered to be at risk for rupture and hence are labeled vulnerable plaques or high-risk plaques. Identification of vulnerable plaques may help in predicting the risk of acute occlusive syndromes and may also allow targeting for aggressive systemic and possibly local therapies. Plaque rupture is believed to result from extracellular matrix (which comprises the protective fibrous cap) dysregulation due to excessive proteolysis in the context of diminished matrix synthesis. Inflammation is believed to play a key role by providing matrix-degrading metalloproteinases and also by inducing death of matrix-synthesizing smooth muscle cells. Systemic markers of inflammation are thus the most logical forms of potential biomarkers which may predict the presence of vulnerable or high-risk plaques. Several studies have suggested the potential prognostic value of a variety of systemic markers, but regrettably, their overall clinical predictive value is modestly incremental at best, especially for individual subjects compared to groups of patients. Nevertheless, continued investigation of reliable, cost-effective biomarkers that predict the presence of a high-risk plaque and future athero-thrombotic cardiovascular events with greater sensitivity and specificity is warranted.

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether early administration of aspirin might optimize vein graft patency. More than 250 papers were found using the reported search, of which 4 new papers in addition to the previous 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Early postoperative aspirin administered within 6 h following coronary artery bypass grafting (CABG) has been shown to be optimal for prevention of vein graft occlusion. Early aspirin has significant benefit in reducing vein graft occlusion, mortality, myocardial infarction, stroke, renal failure and bowel infarction. The efficacy of early postoperative aspirin on vein graft patency diminishes the later it is administered. It has optimal benefit at 6 h, some benefit at 24 h and no benefit after 48 h post CABG. ACC/AHA, EACTS and ACCP have issued guidelines recommending administration of early aspirin or an alternative (clopidogrel, ticlopidine and indobufen) at 6 h or soon after bleeding has settled as the standard of care for optimization of vein graft patency. The ACCP guideline has also suggested that optimal prevention of cardiovascular complication should have higher value than prevention of postoperative bleeding. Several randomized, controlled studies, including a meta-analysis, have shown that early administration of aspirin following CABG is not associated with increased blood loss or transfusion requirement. Postoperative bleeding has been identified as a significant reason for non administration of early aspirin in a prospective study. It is essential to define/quantify the postoperative blood loss that precludes administration of early aspirin. This will enhance prompt administration in some cases and guide judgement, especially in patients with high-risk factors for vein graft thrombosis. Administration at 6 h is the optimal time to give aspirin as long as bleeding has settled., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: The Stent Thrombosis In Belgium (STIB) trial aimed to determine whether assessing platelet reactivity (PR) in patients with stable coronary artery disease undergoing elective percutaneous coronary intervention (PCI) could predict the risk of ischaemic complications and adverse clinical events up to 30 days post PCI., Methods and Results: PR before intervention was determined in 891 patients undergoing PCI for stable angina pectoris. Twelve to 24 hours before PCI, all patients received a 600 mg clopidogrel dose followed by 75 mg daily, and 500 mg of aspirin followed by 80-100 mg daily. Residual PR was assessed by VerifyNow point-of-care aspirin and P2Y12 assay before PCI. "Non-responders" to antiplatelet therapy were defined as aspirin reaction unit (ARU) >550 and as P2Y12 reaction unit (PRU) >230. The endpoint of the study was the composite of periprocedural myonecrosis, stent thrombosis, non-fatal myocardial infarction (MI), stroke and death at 30 days in patients with or without high PR. The endpoint was observed in 180 patients: four deaths, one stroke, 11 Q-wave MI, three non-Q-wave MI and 161 periprocedural myonecroses. At multivariate analysis, the endpoint was predicted by total stent length (OR: 1.020), GFR <60 ml/min (OR: 1.87), history of PCI (OR: 0.58), white blood cell count (OR: 1.95) and diabetes (OR: 1.83). No significant association was found between residual PR and the primary endpoint or any of its components., Conclusions: PR measured before PCI in stable patients undergoing elective PCI who are preloaded with 500 mg of aspirin and 600 mg of clopidogrel is not predictive of periprocedural myocardial injury or adverse ischaemic complications up to 30 days.

Objectives: This multicenter registry aimed to assess the ClearWay™ (CW) perfusion catheter in reduction of thrombus burden and improvement of the coronary flow during percutaneous coronary intervention (PCI)., Background: The presence or development of thrombus during PCI is associated with poor prognosis., Methods: The utility of the CW perfusion catheter was assessed in patients who presented with intracoronary thrombus and were subjected to PCI. Data were collected by online survey from 15 US sites. Angiographic assessment of the coronary thrombus burden and the coronary flow after intracoronary infusion of glycoprotein (GP) IIb/IIIa inhibitors via the CW catheter was evaluated at baseline, immediately after infusion, and at the end of the procedure. The cohort included 102 patients; 71.6% presented with ST-elevation myocardial infarction (MI), 21.6% with non-ST-elevation MI, 5.9% with stable angina pectoris, and 2.9% with silent ischemia. The mean cohort age was 59.9±14.5years and comprised mostly of men (72.5%)., Results: GP IIb/IIIa inhibitors were infused via the CW catheter on average 1.1±0.3 times, with a mean pressure of 4.2±2.7atm and a mean infusion time of 55±55s. Following the infusion, Thrombolysis In Myocardial Infarction (TIMI) flow improved by 1° in 71 patients (69.6%) and by 2° in 51 patients (50%), while visible thrombus was reduced by 52% (p<0.001). In the final angiogram, TIMI flow was restored in 90.2% and clearance of a visible thrombus was obtained in 91.8% of the lesions., Conclusion: Intracoronary infusion of GP IIb/IIIa inhibitors via the perfusion CW catheter is associated with significant reduction in thrombus burden and with improvement of the coronary flow in patients presenting or developing thrombus burden during PCI., (Copyright © 2013. Published by Elsevier Inc.)

This manuscript reviews the studies performed with ALX-0081 (INN: caplacizumab), a Nanobody targeting von Willebrand factor, in the context of current antithrombotic therapy in coronary artery disease. ALX-0081 specifically inhibits platelet adhesion to the vessel wall, and may control platelet aggregation and subsequent clot formation without increasing bleeding risk. A substantial number of antithrombotics are aimed at this cascade; however, their generally indiscriminative mode of action can result in a narrow therapeutic window, defined by the risk for bleeding complications, and thrombotic events. Nonclinically, ALX-0081 compared favorably to several antithrombotics. In Phase I studies in healthy subjects and stable angina patients undergoing percutaneous coronary intervention (PCI), ALX-0081 was well tolerated, and effectively inhibited pharmacodynamic markers. Following these results, a phase II study was initiated in high-risk acute coronary syndrome patients undergoing PCI. Based on its mechanism of action, ALX-0081 is also being developed for acquired thrombotic thrombocytopenic purpura.

Renal dysfunction is a strong independent predictor of stent thrombosis. The aim of the present study was to evaluate the strength and direction of the association between kidney function and clopidogrel efficacy. The study group consisted of consecutive patients (n = 275) who underwent stent implantation. Drug efficacy was measured using the vasodilator-stimulated phosphoprotein (VASP) index 20 ± 4 hours after clopidogrel 600 mg. Nonresponse was defined as an VASP index ≥50%. Renal function was determined using serum cystatin C. The upper reference levels are 1.12 mg/L for ≤65 years of age and 1.21 mg/L for >65 years of age. Estimated glomerular filtration was calculated using cystatin C. The median value of cystatin C was 1.16 mg/L (twenty-fifth and seventy-fifth percentiles 0.96 and 1.43); 47.63% of the study population had cystatin C above reference levels and 33.1% of patients were nonresponders to clopidogrel. No correlation was found between clopidogrel efficacy assessed with the VASP index and kidney function assessed with cystatin C (Spearman r = -0.070, p = 0.248). Based on cystatin C the proportion of nonresponders to clopidogrel was 34.4% versus 31.9% (p = 0.702) in patients with impaired renal function compared to normal renal function, respectively. The proportion of clopidogrel nonresponders did not differ (p = 0.902) among groups with normal (28.8%), mildly impaired (34.8%), moderately impaired (32.9%), and severely impaired (34.8%) renal function. In conclusion, renal function assessed by cystatin C does not predict clopidogrel efficacy. Renal dysfunction is a complex entity and its significant relation to stent thrombosis cannot be explained simply by a decrease in clopidogrel efficacy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The clinical pharmacology of antiplatelet drugs has been reviewed previously by the European Society of Cardiology (ESC) Task force and by the 8th American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines. Moreover, information on the efficacy and safety of antiplatelet drugs in the treatment and prevention of atherothrombosis is provided by collaborative meta-analyses of 287 secondary prevention trials and 6 primary prevention trials. The present document intends to provide practicing physicians with an updated instrument to guide their choice of the most suitable antiplatelet strategy for the individual patient at risk, or with different clinical manifestations, of atherothrombosis.

Background: Type-2 diabetes is accompanied by a prothrombotic state influenced by endothelial dysfunction, inflammatory condition and platelet hyperreagibility. We aimed to characterize the relationship of inflammation and residual platelet aggregability (RPA) under antiplatelet therapy with regard to prognosis in an unselected PCI-cohort of diabetics., Methods: In a first step, a consecutive collective of 75 type 2 diabetics compared to 153 non-diabetic controls was evaluated at the time of PCI. Inflammatory markers, Interleukin 6 and C-reactive protein were measured by immunoassays. ADP and Aspirin assays were performed by multiple electrode aggregometry. Then, we consecutively evaluated ADP-induced RPA in 542 diabetics and 1,161 non-diabetics undergoing PCI and treated by standard antiplatelet therapy. Major CV-events were assessed at 30 days after PCI., Results: Inflammatory markers were significantly increased in diabetics with peri-interventional hyperglycemic state and inversely correlated with responsiveness to clopidogrel and aspirin. In a large scale cohort, diabetics showed a higher RPA compared to non-diabetics (median 38.1 vs. 28.8%; p < 0.001). After adjustment for relevant co-factors, diabetes remained a strong predictor for increased RPA (OR 4.39; 95% CI 1.95-6.83; p < 0.001). Furthermore, diabetics with high RPA had an increased risk for 30-day MI and CV-death than diabetics with low RPA (adjusted HR 1.05; 95% CI 1.02-1.07; p < 0.001)., Conclusions: We demonstrate that peri-interventional inflammatory degree and glycaemic control correlate with decreased antiplatelet drug responsiveness in diabetics. In addition, we identified high RPA as strong predictor for short-term CV-events in this group. Therefore, approaches to treat these entities are needed to improve outcome in diabetics undergoing PCI.

Background: Regulation of the fibrinolytic balance between plasminogen activators and inhibitors is modulated by the renin-angiotensin system. Thus, alterations in the renin-angiotensin system by ACE inhibitors probably result in modification of the fibrinolytic system. We examined the effect of a short-term treatment with the ACE inhibitor enalapril in 47 patients with severe coronary artery disease requiring coronary artery bypass grafting (CABG)., Methods: Patients received either 20 mg/d enalapril or placebo for 6 days. Tissue-type plasminogen activator (TPA), plasminogen activator inhibitor-1 (PAI-1), plasmin-a2-antiplasmin-complex (PAP) and D-dimers were measured initially and after treatment., Results: In the enalapril group PAI-1 levels were significantly reduced after treatment (11.9 +/- 2.3 U/ml vs. 17.1 +/- 3.0 U/l; P < 0.05). In the placebo group PAP levels were significantly higher ( P < 0.05) after treatment compared to initial values. No differences could be detected between the study groups with regard to TPA and D-dimers., Conclusion: Although PAI-1 activity levels are reduced after short-term treatment with ACE inhibitors in patients with stable angina pectoris while TPA antigen is unaffected, treatment with ACE inhibitors does not lead to a marked change in plasmin activation., (Georg Thieme Verlag KG Stuttgart New York.)

The PERTINENT study measured biomarkers of atherosclerosis and thrombosis in a stable coronary artery disease population from EUROPA receiving ACE inhibition with perindopril 8 mg/day or placebo. Biomarkers of inflammation, C-reactive protein (CRP), fibrinogen, and tumor necrosis factor-alpha (TNF-alpha), and a biomarker of thrombosis, D-dimer, were measured at baseline and 1 year. CRP was recorded in 1157 patients; fibrinogen, TNF-alpha, and D-dimer in 291 patients. There was no significant effect of treatment on CRP or fibrinogen. In contrast, there were significant reductions in TNF-alpha (27.60-25.20 pg/mL; P<0.05) and D-dimer (0.24-0.18 microg/mL; P<0.05) with perindopril over 1 year. Survival analysis of the prognostic significance of baseline CRP failed to detect a significant role for the prediction of cardiovascular events over 4 years (lower versus higher tertile: 1.54; 95% confidence interval 0.88-2.68; P=0.16). In conclusion, in the PERTINENT trial, we observed significant effects of ACE inhibition on biomarkers of the atherothrombotic complications (D-dimer) and the proinflammatory cytokine TNF-alpha, but not on biomarkers of inflammation associated with atherosclerosis (CRP and fibrinogen).

Platelets newly released from the bone marrow are RNA-containing and more haemostatically active than mature platelets. Immature platelets are reliably quantified by flow cytometry, and the immature platelet fraction (IPF) reflects platelet production and the rate of platelet turnover. It was the objective of this study to evaluate the presence of immature platelets in healthy subjects, patients with stable coronary artery disease (CAD) and patients with acute coronary syndromes. Flow cytometric determination of immature platelets was performed with an automated analyzer (Sysmex XE-2100) using RNA fluorescent dyes. IPF was determined in 420 individuals: 22 healthy subjects, 39 patients with stable CAD, 182 patients with unstable angina/non-ST-segment elevation myocardial infarction (non-STEMI) and 177 patients with acute STEMI. The geometric mean [95% confidence interval] of IPF was 2.51 [2.04-3.10] in healthy subjects, 2.87 [2.45-3.36] in CAD patients, 2.93 [2.72-3.15] in the non-STEMI/unstable angina group and 3.71 [3.45-3.99] in patients with STEMI (ANOVA: p < 0.0001). This difference remained significant after adjusting for baseline characteristics (p = 0.0003). In active smokers, IPF was 18% higher than in non-smoking individuals (p = 0.007), and IPF was 16% higher in diabetics compared with non-diabetics (p = 0.060). In conclusion, the fraction of immature platelets is increased in acute coronary syndromes, especially in the acute phase of STEMI. Immature platelets with an increased haemostatic potential may contribute to coronary thrombus formation.

Background: The loading dose of ticlopidine is 500 mg in both the US and Europe and 200 mg in Japan. A lower loading dose of clopidogrel might achieve adequate platelet inhibition in Japanese patients., Methods and Results: Platelet aggregation was serially measured at baseline, and 2, 4, 6, and 8 h after 150-mg (n=20) and 300-mg (n=20) clopidogrel loading. Platelets were stimulated with 5 and 20 micromol/L adenosine diphosphate (ADP) and aggregation was assessed by optical aggregometry. Pretreatment ADP-induced platelet aggregation in the 150-mg clopidogrel group did not differ from that of the 300-mg group. The administration of 300-mg clopidogrel loading dose resulted in lower platelet aggregation 2 h after the administration (5 micromol/L ADP: 53+/-9% vs 61+/-12%, p<0.05 and 20 micromol/L ADP: 61+/-10% vs 68+/-9%, p<0.05). A lower platelet aggregation induced with 20 micromol/L ADP was still observed 4 h after the 300-mg clopidogrel loading (58+/-10% vs 65+/-9%, p<0.05)., Conclusions: The 150-mg clopidogrel loading does not achieve rapid platelet inhibition. The 300-mg loading dose should be used to suppress platelet function rapidly even in Japanese patients undergoing coronary stent placement.

A high platelet turnover rate produce a population of immature reticulated platelets (RP) that could confer, despite of antiplatelet drugs, a residual platelet reactivity (RPR) in coronary artery disease (CAD) patients. To assess the influence of RP on platelet reactivity in CAD patients on dual antiplatelet therapy we measured RP in 372 patients by using the Sysmex XE-2100 haematology analyzer and platelet function by optical platelet aggregometry (PA) on platelet-rich-plasma induced by 1 mmol arachidonic acid (AA-PA) and 10 microM ADP (ADP-PA). RPR was defined as either AA-PA>20% or ADP-PA>70%. RP were expressed as a percentage of RP of the total optical platelet count (immature platelet fraction; IPF) and as the percentage of RP highly fluorescent (highly fluorescent immature platelet fraction; H-IPF). Moderate but significant positive correlations between PA, IPF, H-IPF, and mean platelet volume (MPV) were found. According to tertiles of IPF, H-IPF and MPV, a significant trend for an increase of platelet aggregation by AA and ADP was evidenced. Furthermore, a significant difference for IPF, H-IPF and MPV between patients with and without RPR was observed. A linear regression analysis showed that IPF, H-IPF and MPV significantly affected PA measured by AA and ADP. At multivariate linear regression analysis these associations were confirmed. Moreover, a logistic regression analysis demonstrated that IPF, H-IPF and MPV significantly influenced the risk of RPR, and in the multivariate model these results remained significant. This study indicates that a high rate of platelet turnover is a new mechanism associated with platelet reactivity in high risk CAD patients on dual antiplatelet therapy.

Platelets are now regarded as playing a dominant role in cardiovascular medicine since our recent understanding of acute coronary syndrome as an atherothrombotic process. This development has led to the widespread use of antiplatelet agents, such as aspirin, thienopyridines and glycoprotein-IIb/IIIa receptor blockers, for the prevention of ischemic heart disease. Nevertheless, recent evidence suggests that not all patients receive appropriate antiplatelet therapy because there may be resistance or a variable response to the drug used or because of an increased risk of hemorrhage. Moreover, the reported lack of efficacy of the combination of clopidogrel and aspirin when used for primary prevention has raised concerns about the general concept that greater inhibition implies greater efficacy. At present, research efforts are focused on improving current antiplatelet treatment with the aim of increasing efficacy and safety. Alternative ADP-receptor antagonists (e.g., prasugrel, cangrelor and AZD6140) and thrombin-receptor antagonists (e.g., E5555 and SCH 530348) are being developed. They may provide faster, more potent and more stable platelet inhibition. In addition, new insights into platelet structure and into the mechanisms underlying thrombus formation could lead to the discovery of new therapeutic targets. This article reviews what is known about the pathophysiological role of platelets in the atherothrombotic process, considers the current state of the art in antiplatelet therapy, and provides a commentary on new therapeutic approaches.

Tissue factor is a cell surface protein that is expressed constitutively by monocytes, macrophages and fibroblasts, but also by some other cells in response to a variety of stimuli. The main function of the tissue factor is to form a complex with factor VII/VIIa that converts factors IX and X to their active forms. Tissue factor is also involved in the pathophysiology of systemic inflammatory disorders, coagulopathies, atherosclerotic disease, tumor angiogenesis and metastasis. Increased tissue factor expression either locally in the coronary plaques or systematically on circulating blood elements of patients with acute coronary syndromes may be responsible for increased thrombin generation, thus leading to platelet activation and fibrin formation. Tissue factor therefore plays a pivotal role in the initiation of thrombotic complications in patients with coronary artery disease.

Background: It is unlikely that mechanical stress altering a single vulnerable plaque leads to myocardial infarction from almost simultaneous proximal atherothrombotic closure of the right coronary artery and the left anterior descending coronary artery. ACUTE MANAGEMENT: Immediate catheter diagnosis and revascularization including stent deployment restored TIMI III flow in both coronary arteries. After an initial bolus, abciximab was continuously infused to optimize myocardial perfusion. LABORATORY TESTS ON ADMISSION: The patient's white blood cell count was markedly elevated and the level of C-reactive protein slightly so. After interventional recanalization, C-reactive protein rose steeply before falling again after two days., Follow-Up: Thirty days after acute myocardial infarction, the patient was fully recovered and asymptomatic. Echocardiography revealed only mild-to-moderate global left ventricular hypokinesia., Conclusion: Widespread inflammation associated with multifocal plaque rupture and subsequent two-vessel acute myocardial infarction is a rare phenomenon, usually associated with sudden cardiac death. Widespread inflammation is one of the reasons why the widely accepted theory of the single vulnerable plaque for such events can be contradicted.

Background: Evidence suggests that soluble CD40-ligand (sCD40L) is elevated in coronary artery disease (CAD) and is released from activated platelets during the acute myocardial infarction (AMI). Although sCD40L is part of immune response, the mechanisms regulating its release in different disease states remain unknown., Materials and Methods: This study enrolled 596 subjects: 201 patients with stable CAD, 109 patients with AMI and 286 healthy controls. Circulating levels of sCD40L, interleukin-6 (IL-6), soluble vascular cell adhesion molecule-a (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) were determined by enzyme-linked immunosorbent assay (ELISA)., Results: Patients with AMI (n = 109) had higher levels of sCD40L and IL-6 compared to both CAD (n = 201) (P < 0.01) and controls (n = 286) (P < 0.01), while CAD also had higher levels of sCD40L and IL-6 compared to controls (P < 0.01). Similarly, sICAM-1 and sVCAM-1 levels were higher in CAD and AMI compared to controls (P < 0.05). IL-6 was the only parameter independently associated with sCD40L in healthy individuals [beta (SE):0.491(0.096), P = 0.0001]. However, in CAD or AMI, only diabetes mellitus [beta (SE): 2.689 (1.082), P = 0.044 and beta (SE): 10.406 (3.215), P = 0.002, respectively] and smoking [beta (SE): 3.470 (1.111), P = 0.002 and beta (SE): 9.694 (2.478), P = 0.0001, respectively] (but not IL-6), were independently associated with sCD40L levels., Conclusions: Both CAD and AMI are accompanied by increased levels of sCD40L in parallel with an elevation of proinflammatory cytokine IL-6 and adhesion molecules sVCAM-1 and sICAM-1. Diabetes mellitus and smoking (but not IL-6 or adhesion molecules) were the only factors independently associated with sCD40L levels in CAD and AMI patients.

Background: Increased levels of oxidized low-density lipoprotein (ox-LDL) are related to plaque instability, so the aim of the present study was to investigate whether there is a relationship between angiographic coronary plaque morphology in patients with unstable angina pectoris (UAP) and the level of ox-LDL., Methods and Results: Plasma ox-LDL levels were measured in 149 patients with UAP and in 88 control subjects, using a highly sensitive enzyme-linked immunosorbent assay method. Angiographic morphology of the culprit lesion was classified as either simple or complex based on the Ambrose classification. Plasma ox-LDL levels in patients with Braunwald class III were significantly higher than in patients with class I (p<0.0001) or in control subjects (p<0.0001). In each of the 3 Braunwald classes, plasma ox-LDL levels in patients with a complex lesion were significantly higher than in patients with a simple lesion. Multivariate logistic regression analysis revealed that ox-LDL level and Braunwald class III were independent factors associated with angiographically detected complex lesions., Conclusion: In each Braunwald class of UAP, elevated plasma levels of ox-LDL closely relate to the presence of angiographically detected complex and thrombotic lesion morphology.

Atherosclerosis remains the underlying cause of cardiovascular disease and is a dynamic process involving inflammation, haemostasis, endothelial dysfunction, and angiogenesis. Studies of circulating factors from peripheral blood can provide an insight into this pathophysiology but may remain indicative of a more generalized, systemic process. More localized interaction(s) within the heart may be better studied from coronary blood samples. Indeed, an increasing number of prospective studies show good correlation between indices of these processes and clinical outcomes. As local sampling offers a unique way of assessing the local cardiac milieu, this may prove useful in the monitoring of both local/systemic drug therapies and interventional technologies.

Aims: The contribution of homocysteine and group B vitamins in determining cardiovascular risk is debated. We assessed the predictive value of total homocysteine (tHcy), vitamin B12, folate, and vitamin B6 on the long-term occurrence of coronary and cerebral atherothrombotic events in a nested case-control study., Methods and Results: Within a cohort of 1021 healthy subjects (490 men and 531 women) recruited in 1987, 66 first-ever coronary and 43 first-ever cerebrovascular events were recorded at a 12-year follow-up (cases, n=109). A total of 109 control subjects (remaining free from events) were matched with cases according to age, sex, smoking, hypertension, dyslipidaemia, and body mass index. Serum samples obtained in 1987 at baseline were used to measure tHcy, folate, and vitamins B12 and B6, as well as C-reactive protein plasma concentrations. We found a significant graded association between tHcy levels and the risk of coronary and cerebrovascular events [odds ratio (OR) for uppermost vs. lowermost quartile=1.34, 95% CI 1.01-1.76)]. Folate and vitamin B12 did not significantly differ between cases and controls, but were negatively (P<0.01) correlated with tHcy. Vitamin B6 did not correlate with tHcy levels, but differed significantly between cases and controls: for subjects in the uppermost quartile vs. the lowermost quartile of vitamin B6, OR=0.69 (95% CI 0.49-0.98). For subjects in the lowermost quartile of vitamin B6 and the uppermost quartile of tHcy, OR=17.50 (95% CI 1.97, 155.59). Cases and controls were not different as to C-reactive protein., Conclusion: tHcy and plasma vitamin B6 are long-term independent risk factors for coronary and cerebrovascular events.

The purpose of the study was to evaluate the effects of hyperhomocysteinemia (HHC) on vascular-thrombocyte and coagulation hemostasis and the development of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (DM2). DM 2 patients with or without CAD were examined; high incidence of HHC (40.3%) was revealed. The level of homocysteine was significantly higher in DM2 patients with CAD vs. non-CAD subjects. Among patients with DM2 and CAD the level of the amino acid was elevated in 77.1% of cases with a history of myocardial infarction. In patients with DM2, CAD, and HHC, vascular-thrombocyte hemostasis factors were found to be hyperactive, while anticoagulatory ones were suppressed. These changes in the hemostatic system in HHC increase the probability of thrombus formation and CAD progress.

Objective: Hypofibrinolysis promotes atherosclerosis progression and recurrent ischemic events in premature coronary artery disease. We investigated the role of fibrin physical properties in this particular setting., Methods and Results: Biomarkers of recurrent thrombosis and premature coronary artery disease (CAD) were measured in 33 young post-myocardial infarction patients with angiographic-proven CAD and in 33 healthy volunteers matched for age and sex. Ex vivo plasma fibrin physical properties were assessed by measuring fibrin rigidity and fibrin morphological properties using a torsion pendulum and optical confocal microscopy. The fibrinolysis rate was derived from continuous monitoring of the viscoelastic properties after addition of lytic enzymes. Young CAD patients had a significant increase in plasma concentration of fibrinogen, von Willebrand factor, plasminogen activator inhibitor type 1, and lipoprotein(a) as compared with controls (P<0.05). Fibrin of young CAD patients was stiffer (P=0.002), made of numerous (P=0.002) and shorter fibers (P=0.04), and lysed at a slower rate than that of controls (P=0.03). Fibrin stiffness was an independent predictor for both premature CAD and hypofibrinolysis., Conclusions: This first detailed study of clot properties in such a group of patients demonstrated that abnormal plasma fibrin architecture is an important feature of both premature CAD and fibrinolysis rate. The determinants of this particular phenotype warrant further investigation.

The Centers for Disease Control and Prevention estimate that 6% of the US population meets diagnostic criteria for diabetes mellitus, with at least one third of this group being undiagnosed. A majority of adult blindness, renal insufficiency, and limb amputation may be directly attributed to diabetes. Although the incidence of type 1, autoimmune-mediated diabetes remains relatively stable, increasing age, physical inactivity, and obesity have produced explosive growth in insulin resistance and type 2 diabetes. A direct association between diabetes and atherothrombotic disease remains indisputable. However, recent data further suggest that even minor elevations of fasting plasma glucose, in "nondiabetic" subjects, increase cardiovascular risk. Alterations in hemostasis may play an important contributory role. Both hyperglycemia and hyperinsulinemia induce prothrombotic characteristics, including overexpression of vascular endothelial plasminogen activator inhibitor-1 (PAI-1), down-regulation of fibrinolysis, elevation of plasma coagulation proteins (ie, fibrinogen, factor VII, factor X), and enhanced platelet activation. Furthermore, endothelial dysfunction-characterized by an inflammatory phenotype-commonly accompanies diabetes. Given data supporting prothrombotic potential of both acute and chronic hyperglycemia, aggressive perioperative glucose control appears imperative.

The aim of the study was to compare lipoprotein(a) [Lp(a)] levels in patients with cTroponin-I (cTn-I)-positive or -negative unstable angina and to investigate their relationship with atherothrombosis. A total of 202 consecutive patients were enrolled in the study. Lp(a), fibrinogen, plasminogen, PAI-1 and t-PA levels were measured and C-reactive protein (CRP) assays were performed on admission for all patients, and venous blood samples were drawn 12 and 24 h later for cTn-I measurements. The patients were divided into cTn-I-negative (cTn-I < 1 ng/ml) and -positive (cTn-I > or = 1 ng/ml) unstable angina groups. Lp(a) levels of the cTn-I-positive patients were higher than those of the cTn-I-negative patients (52.9 +/- 6.0 and 15.7 +/- 2.5 mg/dl, p < 0.0001). There was a positive correlation between Lp(a) and cTn-I levels (r = 0.692; p = 0.0001). Increase in coagulation activity and impairment in fibrinolytic activity were significant in the cTn-I-positive patients. Elevated Lp(a) levels may have a role in the development of myocardial damage in patients with unstable angina.

Forty-seven patients: group A--17 patients with acute ischemic atherothrombotic stroke and group B--30 patients with acute Q-formation myocardial infarction. The levels of dynamics and comparative clinical relevance of crioglobulinemia in patients of the both groups have been evaluated. Crioglobulines (CG) in the peripheral blood serum were determined at 1, 2, 3, 7th and 14th days after the disease development. On the 1st day, the elevated CG level similar in the both groups as well as similarity of crioglobulinemia dynamics in whole was observed. In the group A, but not in the group B, the CG level was directly correlated with disease severity (p<0,05). In the group B, there was a trend, which depended on the blood CG level on the 1st day of the disease and on the presence of previous stenocardia (p<0,1).