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Background: The TIPTOP (Early Short-term Doxycycline Therapy In Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction to Prevent The Ominous Progression to Adverse Remodelling) trial demonstrated that a timely, short-term therapy with doxycycline is able to reduce LV dilation, and both infarct size and severity in patients treated with primary percutaneous intervention (pPCI) for a first ST-elevation myocardial infarction (STEMI) and left ventricular (LV) dysfunction. In this secondary, pre-defined analysis of the TIPTOP trial we evaluated the relationship between doxycycline and plasma levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs)., Methods: In 106 of the 110 (96%) patients enrolled in the TIPTOP trial, plasma MMPs and TIMPs were measured at baseline, and at post-STEMI days 1, 7, 30 and 180. To evaluate the remodeling process, 2D-Echo studies were performed at baseline and at 6months. A (99m)Tc-SPECT was performed to evaluate the 6-month infarct size and severity., Results: Doxycycline therapy was independently related to higher plasma TIMP-2 levels at day 7 (p<0.05). Plasma TIMP-2 levels above the median value at day 7 were correlated with the 6-month smaller infarct size (3% [0%-16%] vs. 12% [0%-30%], p=0.002) and severity (0.55 [0.44-0.64] vs. 0.45 [0.29-0.60], p=0.002), and LV dilation (-1ml/m(2) [from -7ml/m(2) to 9ml/m(2)] vs. 3ml/m(2) [from -2ml/m(2) to 19ml/m(2)], p=0.04), compared to their counterpart., Conclusions: In this clinical setting, doxycycline therapy results in higher plasma levels of TIMP-2 which, in turn, inversely correlate with 6month infarct size and severity as well as LV dilation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Data on long term - more than 1-year - prognostic value of global platelet reactivity (G-HPR) - by adenosine diphosphate (ADP) and arachidonic acid (AA) - in patients with STEMI undergoing PCI are limited. High C-reactive protein (CRP) levels have been suggested to be associated with post-PCI atherothrombotic events. Our aim was to evaluate the long-term prognostic impact of G-HPR and CRP levels in STEMI patients., Methods and Results: We evaluated 494 STEMI patients (366 M/128 F; age: 65.8 ± 12.4 yrs) undergoing PCI with stent implantation. At a median follow-up of 2.3 years (1.09-4.06), in 58 patients we documented cardiovascular death (11.7%). Platelet reactivity was assessed by light transmission aggregometry by 1mM AA (AA-LTA) and 10 microM ADP (ADP-LTA). By the ROC curve analysis, 17%, 52% and 12 mg/L were found to be the values of AA-LTA, ADP-LTA and CRP associated with the highest specificity and sensitivity for death. G-HPR was defined as the presence of both AA-LTA ≥ 17% and ADP-LTA ≥ 52%. At Cox regression analysis adjusted for age, sex, cardiovascular risk factors, multivessel disease, ejection fraction, renal insufficiency, G-HPR and elevated CRP levels were associated with long-term mortality [HR=1.78 (95%CI 1.04-3.03), p=0.036 and HR=2.91 (1.54-5.52, p=0.001), respectively]. The contemporary presence of G-HPR and elevated CRP levels was associated with the highest risk of death [HR=5.1 (95%CI 1.9-13.4), p=0.001]., Conclusion: G-HPR and CRP are independent long-term prognostic markers in STEMI patients. The contemporary presence of G-HPR and CRP identifies a subgroup of patients at significantly higher risk of cardiovascular death., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Among plasma proteins, fibrinogen represents a major target of oxidative modifications. In patients with post-acute myocardial infarction (6 months after the acute event), fibrinogen oxidation-induced carbonyls and fibrinogen function were estimated using in vitro and ex vivo approaches. Fibrinogen structural features and clot architecture were also explored., Approach and Results: In 39 patients with post-acute myocardial infarction and 28 age-, sex-, and risk factor-matched controls, oxidative stress markers (in plasma and in purified fibrinogen fractions), thrombin-catalyzed fibrin polymerization, and plasmin-induced fibrin lysis were estimated. Circular dichroism spectra of purified fibrinogen extracts, electron microscopy, and differential interference contrast microscopy analyses of fibrin clots were also performed. Marked signs of oxidative stress in plasma (P<0.01 versus controls) and, correspondingly, an increased extent of fibrinogen carbonylation (3.5-fold over control values; P<0.01 versus controls) were observed in patients. Furthermore, fibrinogen fractions purified from patients exhibited significantly reduced clotting ability and decreased susceptibility to plasmin-induced lysis (P<0.01 versus controls). Alterations in fibrinogen secondary structure, as suggested by circular dichroism spectroscopy, and in fibrin clot architecture, as analyzed by electron and differential interference contrast microscopy, were also identified., Conclusions: Here, we report for the first time that patients with post-acute myocardial infarction present with an overall imbalance in redox status and marked fibrinogen carbonylation associated with altered fibrinogen function, thus suggesting a role for carbonylation as a direct mechanism of fibrinogen function. The observed features occur along with modifications in protein structure and in clot architecture., (© 2014 American Heart Association, Inc.)

Unlabelled: In ST-elevation myocardial infarction (STEMI) patients, residual platelet reactivity soon after a loading dose (LD) of prasugrel or ticagrelor is higher than that reported for healthy volunteers or subjects with stable coronary artery disease; and the majority of primary percutaneous coronary intervention (PPCI) procedures with bivalirudin monotherapy are performed without proper platelet inhibition. However, ticagrelor LD is just the daily dose, whereas prasugrel LD is 6-fold the long-term daily dose. We hypothesized that an increased ticagrelor LD may result in a faster and more effective platelet inhibition as compared with the standard prasugrel LD., Methods: Fifty patients with STEMI, pretreated with intravenous aspirin, undergoing PPCI were randomized to receive prasugrel 60-mg LD (n = 25) or ticagrelor 360-mg LD (n = 25). Residual platelet reactivity was assessed by VerifyNow at baseline and 1, 2, 4, and 12 hours after drug LD., Results: At the time of LD, 90% of enrolled patients had an aspirin reactivity unit value <550. P2Y12 reaction units 1 hour after the LD (study primary end point) were 236 (129-289) and 248 (115-304) in the prasugrel and ticagrelor group, respectively (P = .899). High residual platelet reactivity (P2Y12 reaction units ≥240) was found in 43% and 56% of patients (P = .386) at 1 hour and in 30% and 32% of patients (P = .907) at 2 hours, respectively. There was no significant difference in bleeding, arrhythmias, or dyspnea episodes in the 2 groups., Conclusions: In patients with STEMI undergoing PPCI, double (360 mg) ticagrelor LD failed to achieve a faster and more intense platelet inhibition as compared with the standard prasugrel LD. Intravenously administered aspirin allowed to achieve a very early inhibition of acid arachidonic pathway., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Introduction: High platelet reactivity (HPR) on dual antiplatelet therapy is a risk factor for adverse vascular events in acute coronary syndrome (ACS) patients. Several studies have shown that reactive oxygen species (ROS) may be involved in modulating platelet function., Methods: In Non-ST elevation myocardial infarction (NSTEMI) patients (n = 132) undergoing percutaneous coronary intervention (PCI) on dual antiplatelet therapy blood samples were collected within 24 h from 600 mg clopidogrel loading dose. Platelet reactivity was assessed by light transmission aggregometry using 10 μM ADP, 1 mM arachidonic acid (AA) and 2 μg/ml collagen. ROS production and lipoperoxidation of circulating cells were determined. by FACSCanto flow cytometry. In these patients, we investigated: 1) the relationship between the amount of cellular ROS production/lipoperoxidation and platelet reactivity; 2) the association of cellular ROS production with the presence of high platelet reactivity to ADP and arachidonic acid (AA)., Results: Significantly higher levels of platelet and leukocyte-derived ROS were detected in 49 dual HPR (with platelet aggregation by AA ≥ 20% and by ADP ≥ 70%) compared to non-HPR patients (n = 49) [Platelet-derived ROS: +142%; Leukocyte-derived ROS: +14%, p < 0.0001]. Similarly, dual HPR patients had significantly higher platelet and leukocyte lipoperoxidation than non-HPR patients [Platelet lipoperoxidation: +131%; Leukocyte lipoperoxidation: +14%, p < 0.001]. After adjustment for several potential confounders, platelet-, leukocyte-derived ROS and platelet and leukocyte lipoperoxidation remained significantly associated to dual HPR. The significant predictors of ADP, AA, and collagen platelet aggregation at multiple linear regression analysis, after adjusting for age, cardiovascular risk factors, procedural parameter, medications, leukocyte number and MPV, were platelet-, leukocyte-derived ROS and platelet and leukocyte lipoperoxidation (p < 001)., Conclusions: Our results demonstrate that in NSTEMI patients on dual antiplatelet therapy, ROS production by and lipoperoxidation of platelets are strictly correlated to the different pathways of platelet aggregation and that ROS production and lipoperoxidation of platelets and leukocytes are predictors of non responsiveness to dual antiplatelet treatment., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

A 31-year-old athlete was admitted to our hospital for previous inferior myocardial infarction (MI), diagnosed by transthoracic echocardiography, myocardial scintigraphy, and cardiac magnetic resonance, while coronary angiography revealed normal coronary arteries. Laboratory investigations excluded acquired or inherited thrombophilia, immunologic disorders, cardiotropic agents infection, and drug abuse. Antiplatelet therapy was started but, after 15 days, he was rehospitalized with diagnosis of multiple left renal infarctions. A transesophageal echocardiography (TEE) was so performed which excluded a right-to-left shunt, suggestive of patent foramen ovale, or other cardioembolic sources in heart chambers and valve apparatus. Antiplatelet therapy was replaced with oral anticoagulants without any further embolic event at one-year follow-up. This case raises two important questions regarding young patients with cryptogenic MI. First, if TEE should be part of a complete diagnostic pathway; second, if oral anticoagulants should be preferred over antiplatelets for secondary prevention particularly when the cause of MI remains unknown.

Objectives: This study sought to compare the action of prasugrel and ticagrelor in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI)., Background: It has been documented that prasugrel and ticagrelor are able to provide effective platelet inhibition 2 h after a loading dose (LD). However, the pharmacodynamic measurements after prasugrel and ticagrelor LD have been provided by assessing only healthy volunteers or subjects with stable coronary artery disease., Methods: Fifty patients with STEMI undergoing PPCI with bivalirudin monotherapy were randomized to receive 60 mg prasugrel LD (n = 25) or 180 mg ticagrelor LD (n = 25). Residual platelet reactivity was assessed by VerifyNow at baseline and 2, 4, 8, and 12 h after LD., Results: Platelet reactivity units (PRU) 2 h after the LD (study primary endpoint) were 217 (12 to 279) and 275 (88 to 305) in the prasugrel and ticagrelor groups, respectively (p = NS), satisfying pre-specified noninferiority criteria. High residual platelet reactivity (HRPR) (PRU ≥240) was found in 44% and 60% of patients (p = 0.258) at 2 h. The mean time to achieve a PRU <240 was 3 ± 2 h and 5 ± 4 h in the prasugrel and ticagrelor groups, respectively. The independent predictors of HRPR at 2 h were morphine use (odds ratio: 5.29; 95% confidence interval: 1.44 to 19.49; p = 0.012) and baseline PRU value (odds ratio: 1.014; 95% confidence interval: 1.00 to 1.03; p = 0.046)., Conclusions: In patients with STEMI, prasugrel showed to be noninferior as compared with ticagrelor in terms of residual platelet reactivity 2 h after the LD. The 2 drugs provide an effective platelet inhibition 2 h after the LD in only a half of patients, and at least 4 h are required to achieve an effective platelet inhibition in the majority of patients. Morphine use is associated with a delayed activity of these agents. (Rapid Activity of Platelet Inhibitor Drugs Study, NCT01510171)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

High on-treatment platelet reactivity (HPR) by ADP, which primarily reflects the effect of thienopyridines, has been found to be an independent predictor of ischemic events in patients with acute coronary syndrome (ACS) on dual antiplatelet therapy. CYP2C19*2 is associated with HPR by ADP. The aim of our study was to evaluate if high on-clopidogrel platelet reactivity (HPR) by ADP is associated with an increased risk of major adverse coronary events (MACE) after ACS independent of CYP2C19*2 allele, i.e. whether genotyping patients for CYP2C19*2 polymorphism is sufficient to identify those to be switched to novel antiplatelets. A total of 1187 patients were included (CYP2C19 *1/*1 n = 892; *1/*2 n = 264; *2/*2 n = 31); 76 MACE (CV death and non-fatal MI) were recorded in non-carriers of CYP2C19*2 (8.5%) and 39 in carriers of CYP2C19*2 (13.2%). At the landmark analysis in the first 6 months, HPR by ADP and CYP2C19*2 allele were both significantly and independently associated with MACE [HPR by ADP: HR = 2.0 (95% CI 1.2-3.4), p = 0.01; CYP2C19*2 allele: HR = 2.3 (95% CI 1.3-3.9), p = 0.003]. At the land mark analysis from 7 to 12 months, only HPR by ADP remained significantly associated with the risk of MACE [HPR by ADP: HR = 2.7 (95% CI 1.4-5.3), p = 0.003; CYP2C19*2: HR = 0.8 (95% CI 0.2-1.1), p = ns]. CYP2C19*2 allele and HPR by ADP are both independently associated with an increased risk of MACE in the first 6 months after ACS. HPR by ADP is associated with an increased risk until 12 months of follow-up. Therefore, both phenotype and genotype are clinically relevant for the evaluation of the antiplatelet effect of clopidogrel and for the prognostic stratification of ACS patients.

Context: High residual platelet reactivity (HRPR) in patients receiving clopidogrel has been associated with high risk of ischemic events after percutaneous coronary intervention (PCI)., Objective: To test the hypothesis that HRPR after clopidogrel loading is an independent prognostic marker of risk of long-term thrombotic events in patients with acute coronary syndromes (ACS) undergoing an invasive procedure and antithrombotic treatment adjusted according to the results of platelet function tests., Design, Setting, and Patients: Prospective, observational, referral center cohort study of 1789 consecutive patients with ACS undergoing PCI from April 2005 to April 2009 at the Division of Cardiology of Careggi Hospital, Florence, Italy, in whom platelet reactivity was prospectively assessed by light transmittance aggregometry., Interventions: All patients received 325 mg of aspirin and a loading dose of 600 mg of clopidogrel followed by a maintenance dosage of 325 mg/d of aspirin and 75 mg/d of clopidogrel for at least 6 months. Patients with HRPR as assessed by adenosine diphosphate test (≥70% platelet aggregation) received an increased dose of clopidogrel (150-300 mg/d) or switched to ticlopidine (500-1000 mg/d) under adenosine diphosphate test guidance., Main Outcome Measures: The primary end point was a composite of cardiac death, myocardial infarction, any urgent coronary revascularization, and stroke at 2-year follow-up. Secondary end points were stent thrombosis and each component of the primary end point., Results: The primary end point event rate was 14.6% (36/247) in patients with HRPR and 8.7% (132/1525) in patients with low residual platelet reactivity (absolute risk increase, 5.9%; 95% CI, 1.6%-11.1%; P = .003). Stent thrombosis was higher in the HRPR group compared with the low residual platelet reactivity group (6.1% [15/247] vs 2.9% [44/1525]; absolute risk increase, 3.2%; 95% CI, 0.4%-6.7%; P = .01). By multivariable analysis, HRPR was independently associated with the primary end point (hazard ratio, 1.49; 95% CI, 1.08-2.05; P = .02) and with cardiac mortality (hazard ratio, 1.81; 95% CI, 1.18-2.76; P = .006)., Conclusion: Among patients receiving platelet reactivity-guided antithrombotic medication after PCI, HRPR status was significantly associated with increased risk of ischemic events at short- and long-term follow-up., Trial Registration: clinicaltrials.gov Identifier: NCT01231035.

Importance of the Field: The present review is aimed at going over the pharmacological profile (and the clinical impact) of the emerging drugs involved in the management of patients with ST-elevation myocardial infarction (STEMI) in order to provide the cardiologists who deal with these patients in the early phase with the most recent evidence on this topic., Areas Covered in This Review: Anticoagulant and antiplatelet drugs are the main cornerstones of therapy in the treatment of STEMI patients undergoing primary percutaneous coronary intervention (PCI). The main issues that clinicians have to deal with are represented by balancing thrombotic and bleeding risks. In tailoring therapy, variables such as age, sex and previous disease should be taken into account, as well as ongoing complications (such as acute renal failure) that could affect hemostasis. Despite the well-established clinical benefits of antiplatelet agents, questions remain, mainly surrounding potential for variable platelet response, which are strictly related to non-genetic (i.e., diet, drug-drug interaction, clinical factors such as obesity, diabetes mellitus, and inflammation) and genetic determinants., What the Reader Will Gain: In their daily practice, cardiologists cannot abstract from the knowledge and updating on the ongoing research fields as well as the newly developed drugs, which they should frame in the very patient in the attempt to the develop a personalized medical strategy. These include also the pharmacological option(s) in the treatment of the reperfusion injury, the metabolic aspects and the stem cell therapy. TAKE HOME MASSAGE: In our opinion, the goal of ongoing research on the pharmacological approach to STEMI patients is a personalized medical strategy that relies on critical clinicians who merge newly developed acquisitions on this topic and a more complete, systemic and critical approach to the patient.

Background: Previous studies explored the association between hemorheological alterations and acute myocardial infarction, pointing out the role of hematological components on microvascular flow. The aim of this study was to evaluate the association between blood viscosity and infarct size, estimated by creatine kinase (CK) peak activity and cardiac Troponin I (cTnI) peak concentration in ST-segment elevation myocardial infarction (STEMI) patients after primary percutaneous coronary intervention (PCI)., Methods: The study population included 197 patients with diagnosis of STEMI undergoing PCI. Hemorheological studies were performed by assessing whole blood viscosity (measured at shear rates of 0.512 s(-1) and 94.5 s(-1)) and plasma viscosity using the Rotational Viscosimeter LS 30 and erythrocyte deformability index by Myrenne filtrometer., Results: Significant correlations between CK peak activity, cTnI peak concentration, left ventricular ejection fraction and hemorheological variables were observed. At linear regression analysis (adjusted for age, gender, traditional cardiovascular risk factors, renal dysfunction, timeliness of reperfusion, pre-PCI TIMI flow, infarct location, multivessel disease and previous coronary artery disease) leukocytes and whole blood viscosity at 0.512 s(-1) and 94.5 s(-1) were independently and positively associated with infarct size., Conclusions: These results demonstrate a significant and independent association between hemorheology and infarct size in STEMI patients after PCI suggesting that blood viscosity, in a condition of low flow, might worsen myocardial perfusion leading to an increased infarct size. The measurement of whole blood viscosity in STEMI patients could help to identify those who may benefit from new therapeutic strategies.

Residual platelet reactivity (RPR) to adenosine 5' diphosphate (ADP) was an independent predictor of stent thrombosis (ST) in patients receiving drug-eluting stents on dual-antiplatelet treatment and was associated with the cytochrome P450 (CYP)2C19*2 polymorphism. The aim was to evaluate the role of the CYP2C19*2 polymorphism in the occurrence of ST or the composite end point of ST and cardiac mortality within a 6-month follow-up in patients undergoing percutaneous coronary interventions with drug-eluting stent implantation on dual-antiplatelet treatment enrolled in the RECLOSE trial. Seven hundred seventy-two patients were studied for the CYP2C19*2 polymorphism and RPR (using 10-muM ADP-induced platelet aggregation). Patients with ST or the composite of ST and cardiac mortality showed a higher prevalence of carriers of the rare allele (54.1% vs 31.3%; p = 0.025 and 51.7% vs 31.2%; p = 0.020, respectively). At multivariate logistic regression analysis with ST or ST and cardiac mortality as dependent variables and the CYP2C19*2 polymorphism, ADP RPR, and additional previously shown clinical and procedural risk factors for ST as independent variables, the CYP2C19*2 allele (ST odds ratio [OR] 3.43, 95% confidence interval [CI] 1.01 to 12.78, p = 0.047; ST and cardiac mortality OR 2.70, 95% CI 1.00 to 8.42, p = 0.049) and ADP RPR (ST OR 3.08, 95% CI 1.23 to 7.72, p = 0.016; ST and cardiac mortality OR 2.90, 95% CI 1.08 to 12.98, p = 0.019) were independent risk factors. Subjects with the contemporary presence of the CYP2C19*2 allele and ADP RPR showed a strong risk of ST or ST and cardiac mortality (OR 5.79, 95% CI 1.04 to 39.01, p = 0.033 and OR 11.45, 95% CI 1.84 to 71.27, p = 0.009, respectively). In conclusion, the CYP2C19*2 allele was associated with the occurrence of ST or ST and cardiac mortality in high-risk vascular patients on dual-antiplatelet treatment. These findings could impact on the future design of pharmacogenetic antiaggregant strategies.

Background: The clinical impact of platelet aggregation assessed by point-of-care assays is unknown. We sought to evaluate whether high residual platelet reactivity (RPR) to ADP during clopidogrel therapy, measured by a point-of-care assay, predicts adverse clinical events in acute coronary syndrome patients undergoing percutaneous coronary intervention., Methods and Results: We used the VerifyNow P2Y12 assay (Accumetrics Inc, San Diego, Calif) to determine RPR to ADP in 683 patients with acute coronary syndrome undergoing dual-antiplatelet therapy who underwent percutaneous coronary intervention with bare-metal or drug-eluting stent implantation. All patients received a single 600-mg clopidogrel loading dose followed by 75 mg of clopidogrel daily and 100 to 325 mg of aspirin daily. The end points of the study at follow-up of 12 months were cardiovascular death, nonfatal myocardial infarction (MI), and target-vessel revascularization. At a 12-month follow-up, we found 51 ischemic events (24 cardiovascular deaths [3.5%], 27 nonfatal MIs [3.9%]) and 40 target-vessel revascularizations (5.8%). By receiver operating characteristic curve (ROC) analysis, the optimal cutoff value in predicting 12-month cardiovascular death and nonfatal MI was P2Y12 reaction unit values > or =240. RPR, defined in the presence of P2Y12 reaction unit values above this cutoff, was found to be a significant and independent predictor of cardiovascular death and nonfatal MI in a model that adjusted for cardiovascular risk factors, renal failure, reduced left ventricular ejection fraction, multivessel disease, total stent length, bifurcation lesions, number of lesions treated, type of stent, and use of glycoprotein IIb/IIIa inhibitors (cardiovascular death: hazard ratio 2.55, 95% CI 1.08 to 6.07, P=0.034; nonfatal MI: hazard ratio 3.36, 95% CI 1.49 to 7.58, P=0.004). No significant association was found between high RPR and the risk of target-vessel revascularization., Conclusions: RPR to ADP with clopidogrel therapy, measured by the point-of-care assay VerifyNow P2Y12, is able to detect acute coronary syndrome patients at risk of 12-month cardiovascular death and nonfatal MI. The optimal cutoff value was identified as being 240 P2Y12 reaction units.

The aim of this study was to evaluate hemorheologic variables in patients with acute coronary syndromes in relation to the occurrence of ST-segment elevation myocardial infarction (STEMI). In 370 consecutive patients with acute coronary syndromes, 215 with STEMIs and 155 with non-ST-segment elevation myocardial infarctions or unstable angina pectoris, who underwent percutaneous coronary intervention, hemorheologic studies were performed by assessing whole-blood viscosity (at shear rates of 0.512 and 94.5 s(-1)), plasma viscosity, and erythrocyte deformability index. A significant difference in hematocrit and in whole-blood viscosity at 0.512 s(-1) was found between the 2 groups of patients. Hematocrit at admission in the highest tertile compared with the lowest tertile remained independently associated with the occurrence of STEMI on multivariate analysis adjusted for traditional cardiovascular risk factors, previous coronary artery disease, multivessel disease, bleeding complications, and leukocyte count. In conclusion, erythrocyte concentration seems to play a role per se in the occurrence of STEMI and complete coronary artery occlusion and might be considered in stratifying high-risk cardiovascular patients and as a possible therapeutic target in patients presenting with acute coronary syndromes.

Response variability to antiplatelet treatment has been described and the widespread use of acetylsalicylic acid (ASA) and clopidogrel requires clarification of the residual platelet reactivity (RPR). Various glycoprotein Ia (GpIa) polymorphisms have been investigated, but their influence on platelet reactivity in myocardial infarction (MI) patients undergoing percutaneous coronary intervention (PCI) on dual antiplatelet treatment is not still elucidated. Aim of this study was to evaluate the effect of C807T, G873A and T837C polymorphisms of GpIa on modulating platelet function in MI patients on dual antiplatelet treatment undergoing PCI. We measured platelet function by both a point-of-care assay (PFA100) and platelet-rich-plasma aggregation in 289 MI patients undergoing PCI and receiving dual antiplatelet treatment. Our data show that C807T/G873A polymorphisms, but not T837C, are associated with higher platelet reactivity. Carriers of the 807T/873A allele had significantly higher platelet aggregation values after arachidonic acid (AA) and collagen stimuli and, even if they did not reach the statistical significance, after 2 and 10 microM ADP stimuli; 807T/873A allele carriers had also significantly shorter closure times on PFA100/epinephrine membranes. At the multiple analyses, C807T/G873A polymorphisms resulted an independent risk factor for RPR defined by both AA induced platelet aggregation (OR=3.0, 95%CI 1.17-7.89, p=0.022) or by PFA100/epinephrine (OR=4.1, 95%CI 1.53-10.89, p=0.005). In conclusion, this study shows the 807T/873A allele of the GpIa gene is an independent risk factor for the RPR on dual antiplatelet treatment, and extends, in a larger acute coronary syndrome population, the observation that the 807T/873A allele is associated with higher platelet reactivity.

In this study we sought to evaluate if platelet function measured after percutaneous coronary intervention (PCI) affects the severity of myocardial infarction (MI), measured by markers of cardiac necrosis. We measured platelet function by both a point-of-care assay (PFA-100) and platelet-rich plasma aggregation by two agonists (arachidonic acid -AA- and 2 and 10 microM ADP) in 367 patients with MI after PCI (200 patients on dual antiplatelet agents - group A- and 167 on dual antiplatelet agents plus GpIIb/IIIa inhibitors - group B). One hundred twenty-one (32.9%) patients were found to have a residual platelet reactivity (RPR) by PFA (CT/EPI <203 sec): 74/200 (37%) in group A and 47/167 (28.1%) in group B (p = 0.07). In 129 (35.1%) patients we found a RPR by AA-PA: 80/200 (40%) in group A and 49/167 (29.3%) in group B (p < 0.05). Seventeen out of 367 (4.6%) were found to have a RPR by ADP2-PA [15/200 (7.5%) in group A and 2/167 (1.2%) in group B; p < 0.005] and 88/367 (23.9%) by ADP10-PA [64/200 (32%) in group A and 24/167 (14.4%) in group B, p < 0.0001]. CK-MB and cTnI mean peak values were significantly higher in the first tertile of CT/ADP and CT/EPI distribution with respect to the other tertiles and they were significantly higher in patients with RPR by CT/EPI in both group A and group B patients. CK-MB and cTnI peak values were significantly higher in the third tertile of AA-PA, ADP 2 microM-PA and ADP 10 microM-PA distribution with respect to the other tertiles and were significantly higher in patients with RPR by AA-PA and by ADP 10-PA in both group A and group B patients. Multivariate analysis revealed platelet function as an independent predictor of CK-MB and cTnI peak values in both groups of patients independently of clinical, laboratory ad procedural parameters. In conclusion, we found that the severity of MI in patients with MI undergoing primary PCI is influenced by a persistent platelet activation on multiple antiplatelet therapy.

Recently, great interest has focused on the phenomenon of aspirin resistance, which may be defined as clinical or laboratory resistance. Monitoring the antiplatelet effect appears to be relevant in the presence of clinical implications, but no data are available on the possible clinical implications of the failure of aspirin to inhibit tests of platelet function in the setting of acute coronary syndromes. This study evaluated the role of aspirin resistance in the occurrence of 1-year major adverse coronary events (MACEs) in patients with acute myocardial infarction (AMI) who have undergone percutaneous coronary intervention (PCI). We prospectively evaluated 146 patients (115 men and 31 women; median age 65 years, range 30 to 84) with AMI who underwent primary PCI. Exclusion criteria were the use of glycoprotein IIb/IIIa inhibitors, hematocrit

Recently the phenomenon of aspirin resistance has been object of several studies, but no data are available on the possible role of the haemorheologic parameters in affecting platelet function and resistance to antiplatelet agents. Aim of our study was to evaluate platelet function and haemorheology in patients with acute coronary syndromes (ACS), receiving double antiplatelet therapy with aspirin and clopidogrel. The study population included 301 (231M/70F; age: 66 +/- 13 yrs) consecutive adult patients admitted to the Coronary Care Unit of the Azienda Ospedaliero-Universitaria Careggi, with diagnosis of acute myocardial infarction or unstable angina. We assessed: whole blood viscosity (WBV) at shear rates of 0.512 s(-1) and 94.5 s(-1), plasma viscosity (PLV) at 94.5 s(-1) shear rate, erythrocyte deformability index (DI) and PFA-100 closure times with ADP (PFA/ADP) and epinephrine (PFA/EPI). We considered any PFA-100-EPI result < 203 sec (95th percentile of control distribution) to be indicative of aspirin resistance. 104/301 patients (34.5%) had PFA/EPI CTs in the reference range (group 1) whereas the remaining had values higher than 203 sec (group 2). WBV at 94.5 sec (-1) s.r. was similar in group 1 and 2 (WBV: 4.43 +/- 0.25 vs 4.45 +/- 0.61 mPa.sec, respectively). PLV and WBV at 0.512 sec (-1) s.r. were slightly higher, but not significantly, in group 1 than in group 2 (PLV: 1.47+/-0.13 vs 1.44 +/- 0.15 mPa.sec; p = 0.08 and WBV: 23.37 +/- 4.6 vs 22.54 +/- 3.90 mPa.sec; p = 0.07). DI was significantly lower in group 1 with respect to group 2 (4.05 +/- 2.93 vs 5.71 +/- 3.30, p < 0.0001). White blood count (WBC) was significantly higher in group 1 than in group 2 (11464 +/- 3504 vs 7867 +/- 2162, p < 0.0001). In conclusion, these results demonstrate that in patients with acute coronary syndromes the antiaggregant effect of aspirin is modulated not only by the direct action on platelets, but also by erythrocyte deformability and white blood cell count.

Background: Nitric oxide is an endothelium-derived relaxing factor that contributes significantly to vascular tone regulation. In this study we investigated the role of endothelial nitric oxide synthase (eNOS) polymorphisms as predisposing factors to acute coronary syndromes (ACS)., Methods: In 477 consecutive patients admitted to the coronary intensive therapy unit of the University of Florence and in 537 unrelated controls, genotypes of eNOS G894T and T-786C polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism analysis and the repeat polymorphism 4a/4b was analyzed by polymerase chain reaction. The genotype distribution was in Hardy-Weinberg equilibrium for all variants., Results: The multivariate analysis showed that the homozygosity for the eNOS 4a rare variant represented an independent predisposition factor to ACS (odds ratio [OR] 2.5, 95% CI 1.1-5.4, P =.02) and in particular influenced the risk of acute myocardial infarction (OR 3.6, 95% CI 1.2-11.5, P =.03). Subjects carrying the 4a4a/-786CC haplotype showed a higher predisposition to the disease (OR 6.1, 95% CI 1.3-29.6, P =.02). The contemporary presence of hyperhomocysteinemia and homozygosity for the -786C variant influenced the predisposition to ACS (OR 9.1, 95% CI 1.7-46.7, P =.008)., Conclusions: The presence of the eNOS 4a4a genotype represents a predisposing condition to ACS and in particular to acute myocardial infarction. Moreover, our data provide the evidence that the -786CC pattern modulates the susceptibility to ACS in 4a4a homozygotes and in hyperhomocysteinemic patients.

Background Growing evidence was collected that non-alcoholic liver fatty disease ( NAFLD) is a risk factor for coronary atherosclerosis in terms of angiographic appearance, but its involvement in acute coronary syndromes is still debated. We investigated the prevalence and severity of NAFLD in non-diabetic patients admitted for ST-segment elevation myocardial infarction ( STEMI) and its association with multi-vessel coronary artery disease ( CAD). Materials and methods Ninety-five consecutive non-diabetic patients admitted to cardiac ICU for STEMI were studied by ultrasound within 72 h from admission. NAFLD was graded according to a semi-quantitative severity score as mild (score < 3) or moderate-severe (> 3 score). Prevalence of cardiovascular ( CV) risk factors, atherosclerotic burden markers and metabolic syndrome ( MS) was investigated. Results The overall prevalence of NAFLD was 87%. Forty-eight patients showed moderate-severe NAFLD ( SFLD). Thirty-five patients showed mild NAFLD ( MLFD group) and 12 patients had no NAFLD. Patients with SFLD were younger and showed higher prevalence of multi-vessel CAD (i.e. > 2) than patients with mild MFLD ( P < 0·01). Total cholesterol, triglycerides, body mass index and waist circumference were higher and HDL lower in SFLD than MFLD patients. About 50% of all NAFLD patients did not have MS. MS prevalence was higher in SFLD than MLFD patients ( P < 0·05) and among MS components, waist circumference and triglyceride levels showed the strongest association with SFLD ( P < 0·05). At logistic regression analysis, SFLD was independently associated with a three-fold risk of multi-vessel CAD. Conclusions In non-diabetic patients admitted for STEMI NAFLD prevalence was very high. Severe NAFLD independently increased the risk for multi-vessel CAD associated to CV events. [ABSTRACT FROM AUTHOR]

Abstract: Background and aims: During the past three decades the relationship between habitual coffee drinking and coronary heart disease (CHD) has been assessed in numerous studies, with conflicting results. The aim of this study was to systematically examine the data published on the association between habitual coffee consumption and risk of CHD. Methods and results: Thirteen case–control and 10 cohort studies were included. Case–control studies incorporated 9487 cases of CHD and 27,747 controls, and cohort studies included a total of 403,631 participants that were followed for between 3 and 44years. The summary of odds ratios (OR) for the case–control studies showed statistically significant associations between coffee consumption and CHD for the highest intake group (>4 cups/day), OR 1.83 (95% CI 1.49–2.24; P <0.0001), and for the second highest category (3–4 cups/day), OR 1.33 (95% CI 1.04–1.71; P <0.0001), while no significant association emerged for low daily coffee intake (≤2 cups/day), OR 1.03 (95% CI 0.87–1.21; P =0.45). The analysis of long-term follow-up cohort studies did not show any association between the consumption of coffee and CHD, with a relative risk (RR) of 1.16 (95% CI 0.95–1.41; P =0.14) for the highest category, and 1.05 (95% CI 0.90–1.22; P =0.57) and 1.04 (95% CI 0.90–1.19; P =0.60) for the second and third highest categories, respectively. These results did not differ substantially when controlling for region of origin, fatal and non-fatal events, year of publication, and number of years of follow-up. Conclusions: Despite a significant association between high consumption of coffee and CHD reported among case–control studies, no significant association between daily coffee consumption and CHD emerged from long-term follow-up prospective cohort studies. [Copyright &y& Elsevier]

Background: Protein Z, a vitamin K-dependent glycoprotein, serves as a cofactor for the inhibition of activated coagulation factor X. During recent years, a role for low levels of protein Z in prothrombotic disorders such as ischemic stroke and acute coronary syndromes (ACS) has been reported. The aims of this study were to test changes in protein Z and their association with outcome at 1-year follow-up in 193 (150 male, 43 female) patients with ACS. Results: Protein Z plasma levels were significantly lower (p<0.0001) after 1 year [1600 (28–3736) ng/mL] compared to the baseline [1695 (294–4068) ng/mL]. Regression analysis showed a significant association between baseline protein Z below the 5th percentile of our control group and subsequent adverse cardiac events at follow-up (odds ratio 3.3; 95% CI 1.04–10.7; p=0.04). Moreover, Cox regression analysis showed that low protein Z levels at admission were significant predictors of major adverse cardiac events (cardiac death, non-fatal recurrent myocardial infarction, and need for target lesion revascularization) after 1 year (hazard risk 2.5; 95% CI 1.02–6.5, p=0.04). Conclusions: Our results show that in patients with ACS: 1) protein Z decreases moving from the acute to the convalescent phase; and 2) low levels of baseline protein Z are significantly associated with adverse outcome at 1-year follow-up. Clin Chem Lab Med 2006;44:1098–102. [ABSTRACT FROM AUTHOR]

In this study the concentration of plasma breakdown products of cross-linked fibrin (XDP), serum fibrinogen-fibrin degradation products (FDP), and plasma fibrinogen were measured before and at the end of the administration of single- chain recombinant tissue-type plasminogen activator (rt-PA, 100 mg IV over three hours) or streptokinase (1.5 million units over one hour), respectively, in two groups, each composed of 22 patients with acute myocardial infarction. The XDP concentration was not statistically different between the two groups at the end of thrombolytic treatment, whereas FDP and fibrinogen concentrations were significantly different (FDP: streptokinase 396 ± 287 vs rt-PA 177 ± 222 μg/mL, p < 0.01; fibrinogen: streptokinase 71 ± 43 vs rt-PA 181 ± 49 mg/dL, p < 0.001). These results indicate that the two drugs have equipotent thrombolytic activity at this administration regimen but that rt-PA causes a markedly more selective lysis of fibrin in comparison with streptokinase. [ABSTRACT FROM AUTHOR]

Introduction Thrombin generation (TG) is a central step of the coagulation system involved in hemostatic and thrombotic roles. Scarce data evaluating in the acute phase the association between TG and the risk of cardiovascular death of acute coronary syndrome (ACS) patients are available, in the era of percutaneous coronary intervention (PCI) and stenting with the use of dual antiplatelet treatment. Materials and methods We investigated TG in 292 ACS patients undergoing PCI with stent implantation on dual antiplatelet treatment. Venous samples were obtained 12–24 h after PCI. TG was assessed using the Calibrated Automated Thrombogram (CAT). Results At two years of follow-up, 57 out of 292 patients (19.5%) died from cardiovascular causes. Higher values of endogenous thrombin potential (ETP) [1115.9 (705–1441.3) vs 940.2 (666.0–1253.1), p = 0.049], peak [176.1 (80.5–259.4) vs 107.3 (59.9–181.1), p = 0.002] and velocity index [61.75 (21.03–97.88) vs 25.64 (11.95–50.90), p < 0.001] were observed in relation to survival patients. At the multivariate model adjusted for the Global Registry of Acute Coronary Events risk score, the association between TG and cardiovascular death remained significant for ETP [OR (95% CI): 2.58 (1.10–6.03), p = 0.029], peak [OR (95%CI): 3.27 (1.35–7.92), p = 0.009] and velocity index [OR (95% CI): 3.06 (1.27–7.39), p = 0.013]. This result was confirmed after adjustment for high on-treatment platelet reactivity [ETP: OR (95% CI) 2.35 (1.11–5.00), p = 0.027; peak: OR (95% CI) 2.42 (1.13–5.15), p = 0.022; velocity index: OR (95% CI) 2.43 (1.14–5.20), p = 0.022]. Conclusions ACS patients with a residual TG after PCI and stent implantation have a significantly higher risk of long-term cardiovascular death. These results might be useful in improving risk stratification for ACS patients and support the need of a tailored antithrombotic therapy. [ABSTRACT FROM AUTHOR]