Risk Of Atherothrombotic Events Research Articles

Risk of Cardiovascular Events After Influenza: A Population-Based Self-Controlled Case Series Study, Spain, 2011–2018

Abstract This study explores the relationship between influenza infection, both clinically diagnosed in primary care and laboratory confirmed in hospital, and atherothrombotic events (acute myocardial infarction and ischemic stroke) in Spain. A population-based self-controlled case series design was used with individual-level data from electronic registries (n = 2 230 015). The risk of atherothrombotic events in subjects ≥50 years old increased more than 2-fold during the 14 days after the mildest influenza cases in patients with fewer risk factors and more than 4-fold after severe cases in the most vulnerable patients, remaining in them more than 2-fold for 2 months. The transient increase of the association, its gradient after influenza infection, and the demonstration by 4 different sensitivity analyses provide further evidence supporting causality. This work reinforces the official recommendations for influenza prevention in at-risk groups and should also increase the awareness of even milder influenza infection and its possible complications in the general population.

Reducing Thrombotic Risk From Polyvascular Disease in Primary Care.

At the end of the activity, participants will be able to:Describe the burden of disease and risk of atherothrombotic events in patients with polyvascular disease-peripheral arterial disease (PAD) and coronary artery disease (CAD). Implement screening and diagnostic procedures to improve detection of polyvascular disease and accurately assess overall atherothrombotic risk. Select evidence-based treatment to reduce cardiovascular and limb events in patients with polyvascular disease.

Early atherosclerosis and acute vascular events in ulcerative colitis patients-a case series

Introduction: In inflammatory bowel disease uncontrolled inflammation may play a role in the early progression of systemic atheromatosis with increased cardiovascular risk. Endothelial dysfunction is mediated by pro-inflammatory cytokines but also by an increased level of CRP which is involved in the expression of adhesion molecules and atheroma plaque rupture. Tailored treatment with better control of the ulcerative colitis and endoscopic healing might result in decrease risk of atherothrombotic events. Aim: We decided to use a well-established method (vascular Doppler ultrasound with media-intimate index measurement) to detect an increased incidence of endothelial lesions as predictors of early atheromatosis in patients with ulcerative colitis treated with biological or conventional therapy. Material and methods: We prospectively analyzed 25 patients with RCUH with a mean age of 40 years, 16 with biological treatment. The Student t test, the Mann Whitney U test and the ANOVA test were used to compare continuous variables. Results: A discriminant analysis was performed with the presence of atheroma plaque as a dependent variable and several predictor variables, such as age, triglycerides, cholesterol of patients with ulcerative colitis. Univariate ANOVA analyzes revealed that the presence or absence of atheroma plaque differs in the variables predicting the age, INR and ecoIMT of patients with ulcerative colitis (in the age of patients (F = 8.511, degrees of freedom = 11, p = 0.014) Patients ‚INR (F = 50,437, degrees of freedom = 11, p = 0.001) and Patients’ ecoIMT (F = 7,398, degrees of freedom = 11, p = 0.020) In another analysis of discriminatory function s -introduced the predictor variables specific to measuring the evolution of ulcerative colitis, respectively Mayo and Mayo E (age (F = 0.8511, degrees of freedom = 11, p = 0.014), INR (F = 50.437, degrees of freedom = 11, p = 0.001), ecoIMT (F = 7.398, df = 11, p = 0.020) and Mayo (F = 14.885, degrees of freedom = 11, p = 0.003). Conclusions: Age, endoscopic activity, and INR were correlated with predictive ultrasound changes for atheromatosis. Strengths are the prospective nature of the study and weaknesses are the limited number of patients and the fact that most patients were in remission and treated with biologicals, which could create bias in the sense of reducing the atherosclerotic risk directly correlated with active inflammation.

Environmental noise exposure is associated with atherothrombotic risk

There is growing evidence that environmental noise exposure could increase the risk of atherothrombotic events, including acute myocardial infarction (MI). We analysed the burden of environmental noise on atherothrombotic risk in MI patients. From the RICO survey, 879 consecutive MI patients included from 2004 to 2008 and living in an urban unit of > 237,000 inhabitants were analysed. Atherothrombotic risk was calculated using the TRS-2P score. TRS-2P categories were split into low (TRS-2P = 0/1) (40.8%), medium–low (TRS-2P = 2) (25.7%), medium–high (TRS-2P = 3) (21.8%) and high risk (TRS-2P ≥ 4) (11.6%). Noise exposure was associated with atherothrombotic risk, with the LAeq,24 h (OR (95% CI): 1.165 (1.026–1.324)) and Lnight (OR (95CI): 1.157 (1.031–1.298)), for each 10 dB(A) increase. After adjustment, noise exposure remained a predictor of atherothrombotic risk, with LAeq,24 h (OR (95% CI): 1.162 (1.011–1.337)) and with Lnight (OR (95% CI): 1.159 (1.019–1.317)). The relationship with transportation Lnight was significant for men (OR (95% CI): 1.260 (1.078–1.472)) but not for women (OR (95% CI): 0.959 (0.763–1.205)). We found a significant association between residential traffic noise exposure and atherothrombotic risk in men but not in women. These results could have major consequences for secondary prevention.

456-P: Ongoing Knowledge Gaps in Antiplatelet Therapy for High-Risk Diabetes Patients with CAD

Patients with diabetes and coronary artery disease (CAD) are at increased risk for atherothrombotic events compared to CAD patients without diabetes. Current antiplatelet therapy may not be adequate in these high-risk patients, and several recent clinical trials have evaluated the use of more potent agents in this setting. Therefore, it is crucial to educate clinicians about their results and clinical practical implications. CMHC organized a CME virtual symposium to educate multi-disciplinary clinicians and assessed the changes in knowledge and competence using pre-/post assessment questions. A Chi-Square test was used to analyze the percentage of correct responses and determine statistical significance (p <0.05). The activity took place on Oct. 23, 2020, with participation of 263 healthcare professionals (MD/DO, PAs, RNs, NPs, PharmDs) representing specialties that treat high-risk diabetes patients with CAD (including 48% PCPs, 24% cardiologists, 23% endocrinologists). A slight increase in knowledge about recent clinical trial results was observed, though not statistically significant (9.2% relative increase in knowledge compared to baseline, p = 0.5). Conversely, a significant increase in competency in selecting correct treatment regimens to prevent adverse CVD events in high-risk diabetes patients with CAD was demonstrated (58% relative increased to baseline, p=.0002); however, only ~60% of participants opted for the correct option. According to post-activity evaluation (n=208), 29% identified insurance and financial issues, 28% identified formulary restriction, and 9% not knowing treatment-related adverse events as the primary barriers to implementing change in their practices. It is evident from the outcomes of this educational activity that there was a noticeable gap in attendee’s knowledge about advances in antiplatelet therapy in patients with diabetes and CAD. A series of educational activities is imperative to increase awareness and improve patient outcomes. Disclosure S. Karandrea: None. N. Agarwal: None. A. Jamrogiewicz: None. Funding AstraZeneca (62051961)

Abstract 15044: Impact of Chronic Kidney Disease on the Pharmacodynamic and Pharmacokinetic Effects of Ticagrelor in Patients With Diabetes Mellitus and Coronary Artery Disease

Background: Diabetes mellitus (DM) is a key risk factor for the development of chronic kidney disease (CKD) and patients having both risk factors have increased risk of atherothrombotic events, underscoring the importance of antiplatelet therapy. Ticagrelor reduces ischemic events compared with clopidogrel, with the greatest risk reduction in patients with both DM and CKD. However, how CKD status affects the pharmacodynamic (PD) and pharmacokinetic (PK) profiles of different ticagrelor dosing regimens in DM patients is unknown. Methods: This was a prospective, randomized, cross-over study testing the PD/PK profiles of ticagrelor 90mg bid and 60mg bid among DM patients with and without CKD. All patients had coronary artery disease and were on dual antiplatelet therapy with aspirin (81mg qd) and clopidogrel (75mg qd). PD and PK assessments were performed at 3 visits: baseline, after 7-10 days of ticagrelor therapy (pre-crossover; peak and trough), and after 7-10 days of alternative ticagrelor regimen (post-crossover; peak and trough). Results: A total of 92 patients were randomized (CKD-, n=48; CKD+, n=44). Platelet reactivity as assessed by multiple assays (VASP-PRI; VerifyNow P2Y12; LTA) was increased with 60mg compared with 90 mg, which was statistically significant in CKD- but not in CKD+ patients for most PD measures (Figure). Although trough levels of platelet reactivity were numerically lower in CKD+ patients compared with CKD-, there was no significant difference in the pre-defined primary endpoint (trough levels of VASP-PRI following ticagrelor 90 mg dosing) between DM subjects with and without CKD (31±20 vs 25±14; mean difference= 6.4; 95% CI: -1.1 to 14.3; p=0.105; primary endpoint; Figure). PK assessments tracked PD profiles. Conclusions: In patients with DM, platelet inhibition by ticagrelor is similar irrespective of CKD status. However, the PD effects of the 60mg ticagrelor regimen is reduced compared with the 90mg regimen in patients without CKD.

Platelet reactivity among patients with acute coronary syndromes and multivessel coronary artery disease

Abstract Background Patients with multivessel or complex coronary artery disease (CAD) are at increased risk of atherothrombotic events. It has been suggested that these patients may derive an incremental benefit with more intense antiplatelet strategies, according to prior subgroup analyses from randomized clinical trials. However, whether there is any association between the presence and extension of multivessel CAD and platelet aggregability (PA) in patients with acute coronary syndromes (ACS) is unknown. Purpose To analyze the independent association between PA and presence of multivessel CAD in patients with ACS. Methods Patients with ACS on dual antiplatelet therapy (aspirin plus clopidogrel) were included in this study. Multivessel CAD was defined as the presence of significant ≥50% stenosis at two or more major epicardic vessels. Platelet aggregability was assessed by VerifyNow P2Y12 assay expressed in P2Y12 Reactivity Units (PRU) on the day of discharge from the coronary care unit. High On-treatment platelet reactivity (HPR) was defined as PRU ≥208. Stepwise linear and logistic regression models were applied to adjust for confounders. Models were adjusted for: age, sex, race, diabetes, hypertension, smoking, dyslipidemia, prior MI, prior PCI, prior CABG, prior HF, prior stroke and ACS phenotype (STEMI vs. Non-ST-segment elevation ACS). Results A total of 237 patients were included, among whom 143 (60.3%) had multivessel CAD at the coronary angiogram and 175 (73.8%) were submitted to PCI during index hospitalization. Patients with multivessel disease were older (mean age 64.8±12.1 vs. 58.9±11.2 years; p<0.001) and more likely to have a history of diabetes (47.6% vs. 29.8%; p=0.006) and non-ST-segment elevation ACS as the index event (55.2% vs. 28.7%; p<0.001), compared to patients without multivessel CAD. After adjustments, presence of multivessel CAD was associated with higher PA (mean 161.4±74 PRU in patients with versus 140.3±70.9 PRU in patients without multivessel CAD; adjusted mean difference 23.7 PRU; 95% CI 4.8 to 42.5; p=0.014). Additionally, there was an incremental of 12.5 PRU (95% CI 2.8 to 22.3; adj p=0.012) for each diseased vessel and of 4.67 PRU (95% CI 0.11 to 9.22; adj p=0.045) for each diseased coronary segment. Compared to patients with single-vessel disease, patients with three-vessel disease had higher rates of HPR. (Figure). Conclusion In patients with ACS, the presence and extension of multivessel CAD were associated with higher levels of platelet aggregability and higher rates of high on-treatment platelet reactivity with clopidogrel. This finding may explain the incremental benefit with more intense antiplatelet therapies seen in this particular subgroup in prior clinical trials. Prevalence of HPR and extension of CAD Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Sao Paulo Research Foundation (FAPESP)

Decreased Platelet Inhibition by Thienopyridines in Hyperuricemia

PurposeHyperuricemia carries an increased risk of atherothrombotic events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). This may at least in part be due to inadequate P2Y12 inhibition. The aim of this study was to prospectively investigate the potential association between hyperuricemia and decreased platelet inhibition by P2Y12 antagonists.MethodsLevels of uric acid as well as on-treatment residual platelet reactivity in response to adenosine diphosphate (ADP) were assessed in 301 clopidogrel-treated patients undergoing elective angioplasty and stenting, and in 206 prasugrel- (n = 118) or ticagrelor-treated (n = 88) ACS patients following acute PCI. Cut-off values for high on-treatment residual ADP-inducible platelet reactivity (HRPR) were based on previous studies showing an association of test results with clinical outcomes.ResultsHyperuricemia was significantly associated with increased on-treatment residual ADP-inducible platelet reactivity in clopidogrel- and prasugrel-treated patients in univariate analyses and after adjustment for differences in patient characteristics by multivariate regression analyses. In contrast, ticagrelor-treated patients without and with hyperuricemia showed similar levels of on-treatment residual platelet reactivity to ADP. HRPR occurred more frequently in clopidogrel- and prasugrel-treated patients with hyperuricemia than in those with normal uric acid levels. In contrast, hyperuricemic patients receiving ticagrelor did not have a higher risk of HRPR compared with those with normal uric acid levels.ConclusionHyperuricemia is associated with decreased platelet inhibition by thienopyridines but a normal response to ticagrelor. It remains to be established if lowering uric acid increases the antiplatelet effects of clopidogrel and prasugrel in hyperuricemic patients with HRPR.

Abstract P335: Greater Frequency of Olive Oil Consumption is Associated with Lower Platelet Activation in Obesity

Healthy lifestyle behaviors, including maintenance of normal weight, are associated with lower risk of atherothrombotic events. In the general population, consumption of olive oil and a Mediterranean diet are associated with reduced risk of cardiovascular disease (CVD). However, less is known about how this affects individuals with obesity. We investigated whether olive oil intake is associated with reduced platelet activation in a cohort of obese, non-smoking, non-diabetic subjects without known CVD. As part of a larger prospective study of platelet function in obesity, we assessed platelet activation (surface P-selectin and PAC1 MFI) with and without agonist (0.025U thrombin, 0.1uM ADP, 0.4uM epinephrine) exposure via flow cytometry. Food frequency surveys were used to estimate diet composition. Subjects were stratified by food intake frequency and platelet activation was compared using ANOVA, with post-hoc independent samples t-testing. Among 63 subjects, the mean age was 32.2 ± 8.0 years and BMI 44.1 ± 8.5 kg/m 2 . Olive oil intake frequency was stratified into 3 groups: ≤ 1 time/wk, n=21; 1 - 3 times/wk, n=18; ≥ 4 times/wk, n=24. The groups did not differ by age, weight, BMI, waist and hip circumferences, platelet count or mean platelet volume. Subjects with more frequent olive oil intake showed lower platelet activation to agonists than those consuming olive oil ≤ 1 time/wk (Figure). Non-agonized platelet activity did not differ significantly by olive oil intake frequency. Notably, we did not observe associations between platelet activity and consumption of red meat, eggs, butter, or margarine. In metabolically healthy obese individuals, more frequent olive oil intake is associated with suppressed platelet activation. We hypothesize that phenolic compounds in olive oil may alter platelet membrane phospholipid content, making platelets less susceptible to activation. For obese individuals, olive oil intake may lower risk of cardiovascular events.

CORRELATION OF INFLAMMATION BIOMARKERS WITH THE TRADITIONAL RISK FACTORS IN PATIENTS WITH ACUTE CORONARY SYNDROME

Actuality of cardiovascular diseases today determines the high interest to study pathogenesis of atherosclerosis and to searching new risk factors which could help to optimize primary and secondary prevention. Study the correlation between biomarkers of inflammation and traditional risk factors (TRF) in patients with different forms of ischemic heart disease is really important today. Aim. To determine the correlation between TRF and the level of biomarkers of the inflammation and endothelial dysfunction in patients with acute coronary syndrome (ACS). Material and methods. Patients (n=62) aged from 24 to 50 years (mean age 43.98±4.73), who were admitted to the hospital due to ACS, were included into the study. Correlations between TRF and the levels of biomarkers of the inflammation and endothelial dysfunction were assessed. The following biomarkers levels were determined: high-sensitivity C-reactive protein (hsCRP), homocysteine, soluble vascular cell (sVCAM-1) and intracellular (sICAM-1) adhesion molecule type 1, soluble E-selectin (sE-selectin), nitrate, neopterin, matrix metalloproteinase type 3 (MMP-3). Results. TRF, including modifiable ones, were often revealed in patients of the studied group. Some correlations between TRF and high concentrations of inflammatory biomarkers were determined. Patients with the family history of early cardiovascular diseases had higher concentration of sVCAM-1 (1047.78±516.98 ng/ml) in comparison with the patients without this TRF (705.57±239.28 ng/ml), p=0.017. Patients with arterial hypertension had higher level of MMP-3 (9.31±3.63 ng/ml) versus patients without hypertension (5.02±3.66 ng/ml), р=0.011). Patients with abdominal obesity compared with patients without this TRF demonstrated higher concentration of nitrate in acute (208.45±91.85 ng/ml vs 154.53 ng/ml, р=0.028) and long-term (193.53±40.02 ng/ml vs 173.48 ng/ml, р=0.028) periods of ASC. Conclusion. The study showed the significant correlation between ТRF and high levels of some biomarkers of inflammation and endothelial dysfunctions in patients with ACS. So it is probably associated with more rapid progression of the atherosclerosis, higher risk of atherothrombotic events, complicated course of ischemic heart disease and unfavorable outcomes.

Risk of atherothrombotic events in patients after proximal deep-vein thrombosis.

Several studies have shown high incidence of atherothrombotic events (ATEs) in patients with unprovoked pulmonary embolism. This association remains understudied in patients presenting with deep-vein thrombosis (DVT). We evaluated the risk factors for and the incidence of ATEs in patients with unprovoked proximal DVT, and compared it to patients with provoked DVT and reference patients without DVT. Patients with compression ultrasonography (CUS)-proven unprovoked proximal DVT, provoked DVT, and symptomatic patients in whom DVT was excluded by CUS were followed and scored for the occurrence of ATEs. A total of 1235 patients were enrolled: 170 patients with provoked, 74 patients with unprovoked DVT, and 991 patients without DVT. During follow-up, 128 ATEs occurred (incidence 6.5/100 patient-years). Adjusted hazard ratio was not different between patients with DVT and without DVT [hazard ratio 1.4; 95% confidence interval (CI) 0.76-2.4]. In contrast, patients with unprovoked DVT suffered from ATEs more frequently than provoked DVT patients (hazard ratio 3.16; 95% CI 1.1-9.1) and reference patients (hazard ratio 2.8; 95% CI 1.3-5.7). Notably, when fully adjusted for the known ATE risk factors, the risk differences between references, provoked, and unprovoked DVT patients diminished: hazard ratio 1.1 (95% CI 0.47-2.5) and 1.7 (95% CI 0.80-3.6), respectively. Our study confirms that the risk of ATEs in patients with unprovoked DVT was higher than in those with provoked DVT or reference patients. Interestingly, our results raise the question whether the known risk factors for ATE and venous thromboembolism attribute equally in pulmonary embolism and DVT patients, and contradict a causal relation between ATE and proximal DVT.

The correlation between traditional risk factors and the severity of acute coronary syndrome and long-term prognosis

A number of studies demonstrate that patients with traditional risk factors (TRF) have not only increases primary risk of atherothrombotic events, but are also associated with many complicates and poor prognosis.Purpose: assessment of TRF effect on the incidence of complications and outcomes in patients with acute coronary syndrome (ACS).Materials and methods: in 255 patients hospitalized with ACS were retrospective determined the TRF prevalence, frequency of the complications and correlation between the presence of TRF and the risk of complications and long-term prognosis (follow-up 1 year).Results: patients had TRF very often, 80% patients had more than 3 TRFs. The presence of some TRFs (smoking, abdominal obesity, family history) was associated with a significantly increased risk of complications in patients with ACS, including life-threatening. Effect of TRF on long-term prognosis was not determined.Conclusion: the findings suggest the need to evaluation TRF not only in primary preventive and also to improve the effectiveness of risk stratification in patients with ACS.

Prevalence and risk factors of atherothrombotic events among 1054 hemophilia patients: A population-based analysis

IntroductionReports on the prevalence and risk factors of atherothrombotic events (AEs) are conflicting in persons with hemophilia (PWH). MethodsThis study evaluated the prevalence and risk factors of AEs among 1054 male hemophilia patients, using data collected from Taiwan’s National Health Insurance Research Database between 1997 and 2010, by comparing variable to those of an unaffected 10540 age- and gender-matched general population. ResultsThe proportions of all AEs among PWH, including 26 ischemic stroke, 29 coronary artery disease and 5 peripheral arterial disease were comparable to those in the general population. The mean age at diagnosis of AE among PWH was younger than that in the general population: 49.0 (95% CI, 43.6-54.5) and 55.8years (95% CI, 54.5-57.0), P=0.019, respectively. PWH with Chronic Obstructive Pulmonary Disease (COPD), hypertension, and hyperlipidemia were associated with greater risk for the occurrence of AEs, with hazard ratios (95% CI) of 3.42 (1.25-9.38), 4.15 (2.11-8.17), and 2.84 (1.39-5.79), respectively. PWH who needed replacement therapy had a lower risk of AEs than those who did not need, with a hazard ratio (95% CI) of 0.41 (0.21-0.81). ConclusionsThe study indicated the prevalence of AEs among PWH was comparable to that of the general population. AEs appeared at an earlier age among PWH. COPD, hypertension, and hyperlipidemia were risk factors for AEs. PWH who needed replacement therapy may have a lower risk of AEs.

Abstract 19437: Elevated Platelet Turnover in Patients Receiving Dual Antiplatlet Therapy Could Permit the Formation of Uninhibited Platelet Clusters That Act as Seeds for Thrombus Formation

Introduction: ACS patients who also have conditions associated with increased platelet turnover, such as diabetes or chronic kidney disease, are at increased risk of atherothrombotic events despite receiving dual-antiplatelet therapy (DAPT). It may well be that aspirin and thienopyridines, such as clopidogrel or prasugrel, prescribed once daily as pharmacologically short-lived but irreversibly acting agents, are less effective in these patients because of the daily emergence of a significant subpopulation of uninhibited platelets. Hypothesis: Here we investigated the potentially crucial roles of subpopulations of uninhibited platelets in overcoming DAPT and driving aggregation. Methods: Aliquots of platelet rich plasma were incubated with aspirin, prasugrel active metabolite (PAM) plus aspirin, or vehicle and platelets were differently labelled with membrane dyes. Aliquots were then combined in various proportions and platelet responses measured in standard light transmission aggregometry. Aggregates formed in response to platelet agonists were then fixed and detailed structural analyses made by advanced imaging techniques, including confocal microscopy and ImageStream flow cytometry, to determine the interactions of different platelet populations. Results: Platelet aggregation responses and images of platelet aggregates demonstrated complex, dynamic relationships between platelet subpopulations. Summary analysis indicated that aggregates containing aspirin-treated (90-60%) and drug-free (10-40%) platelets had random distributions of drug-free platelets in response to ADP or AA. In contrast, aggregates containing DAPT-inhibited (90-60%) platelets and drug-free (10-40%) platelets showed marked clustering of drug-free platelets at aggregate cores surrounded by recruited DAPT-inhibited platelets. Conclusions: We show that a subpopulation of drug-free platelets can provide seeds for the formation of aggregates that then recruit DAPT-inhibited platelets. Such interaction between platelet subpopulations are of direct relevance to ACS patients with underlying conditions associated with elevated platelet turnover and may well provide an explanation for the failure of DAPT with aspirin and thienopyridines.

Abstract 388: Regular Aerobic Exercise Enhances Endothelium tPA Release in Adults With HIV-1

HIV-1 infection is associated with vascular endothelial dysfunction and increased risk of cardiovascular disease. We have previously demonstrated that the capacity of the endothelium to release tissue-type plasminogen activator (t-PA), the primary activator of endogenous fibrinolysis, is markedly impaired in HIV-1-seropositive compared with seronegative adults, regardless of antiretroviral therapy. Endothelial fibrinolytic dysfunction underlies thrombogenesis and is thought to contribute to the increased risk of atherothrombotic events in HIV-1-infected adults. Regular aerobic exercise can beneficially affect vascular health and reduce cardiovascular risk. However, whether aerobic exercise training can alleviate HIV-1-related endothelial fibrinolytic dysfunction is unknown. In an ongoing study, we are testing the hypothesis that regular aerobic exercise improves endothelial t-PA release in HIV-1 seropositive adults. Net endothelial release of t-PA was determined, in vivo, in response to intrabrachial infusions of bradykinin (BK: 125-500 ng/min) and sodium nitroprusside (SNP: 2-8 μg/min) before and after a 3-month aerobic exercise intervention. To date, 10 HIV-1 seropositive adults (age: 38+2 yr; 8 M/2 F) have completed the exercise intervention (walking ~5.1 d/wk, ~50 min/d @ ~70% of maximal heart rate). There were no changes in body weight, % body fat, or maximal oxygen consumption after exercise training, however, treadmill exercise time to exhaustion increased 25% (from 9.0+0.4 to 11.2+0.4 min; p<0.01). The capacity of the endothelium to release t-PA in response to BK was significantly higher after (-0.58+1.5 to 102.3+15.5 ng/100 mL tissue/min) vs before (-0.8+1.0 to 48.7+10.1 ng/100 mL tissue/min) exercise training. In addition, total amount of t-PA released (area under the BK curve) was increased more than two-fold (329+73 vs 728+108 ng/100 mL tisuue) in response to the exercise intervention. There was no effect of exercise training on either t-PA release to SNP or endothelial release of plasminogen activator inhibitor-1. These initial results indicate that habitual aerobic exercise is an effective lifestyle intervention strategy for improving endothelial fibrinolytic capacity in HIV-1 infected adults.

TRIOLOGY ACS: No benefit/No harm

[first paragraph of article] Potent and consistent P2Y12 receptor inhibition is associated with reduced risk of atherothrombotic events in patients presenting with acute coronary syndromes (ACS), but with inevitable increased risk of bleeding as demonstrated in TRITON and PLATO trials – a finding that is especially pertinent to the treatment of medically managed NSTE ACS patients, who typical have a greater burden of comorbidities that predispose to bleeding. Given the significant proportion of non-ST elevation myocardial infarction (NSTE) ACS patients managed medically worldwide and the need to mitigate both ischemic and bleeding risks in this vulnerable, high-risk population, novel clinical trials are needed.

Screening for and Management of Elevated Lp(a)

While lipoprotein(a) (Lp(a)) has long been an intriguing subject for basic researchers and clinicians alike, it is only recently that this unique cardiovascular risk factor has begun to be broadly utilized as part of risk prediction. This has dovetailed with the recognition, from genetic studies, that Lp(a) is indeed causal for atherothrombotic disease rather than being merely a marker. Yet, significant questions remain the subject of ongoing study including: what patients groups benefit the most from determination of plasma Lp(a) concentrations; how can elevated plasma Lp(a) concentrations be most effectively managed; does reduction in plasma Lp(a) concentrations reduce risk for atherothrombotic events; and what is the molecular mechanism or mechanisms underlying the risk attributed to elevated Lp(a)? This review summarizes recent progress in genetic studies, basic laboratory research, and epidemiology with a focus on how Lp(a) might be incorporated into clinical practice.

Mecanismos de acción de los diferentes agentes antiplaquetarios

The clinical manifestations of atherosclerot ic diseases such as acute coronary syndromes, cerebrovascular events and peripheral arterial disease are major causes of mortality and morbidity worldwide. Platelet activation and aggregation are ultimately responsible for the progression and clinical presentation of the disease and, therefore, antiplatelet agents have become one of the mainstays of pharmacological treatment of these patients. A wide variety of surface receptors such as integrin family receptors, receptors rich in Leucine, protein G linked transmembrane receptor, tyrosine kinase receptors as well as intraplatelet molecules, trigger and regulate platelet activation/aggregation. All these molecules are potential targets for antiplatelet drugs to prevent and treat arterial thrombosis. Despite the overall clinical benefit obtained with aspirin (cyclooxygenase inhibitor), clopidogrel (ADP receptor antagonist P2Y12) and antagonists of the glycoprotein IIb/IIIa (abciximab, eptifibatide, tirofiban, lamifiban) to significantly reduce the risk of atherothrombotic events, residual morbidity and mortality remain high. Therefore efforts have focused on the search for new antiplatelet treatments to improve their effectiveness and safety. In fact, new drugs are in development and various drugs have already reached clinical use. Among them, new P2Y12 receptor blockers (prasugrel, ticagrelor, cangrelor and elinogrel), antagonists of the PAR1 thrombin receptor (vorapaxar and atopaxar) as well as intraplatelet signaling molecules. This review explores the mechanisms of action of the currently used antiplatelet armamentarium as well as new therapeutic approaches.

Laropiprant attenuates EP3and TP prostanoid receptor-mediated thrombus formation

The use of the lipid lowering agent niacin is hampered by a frequent flush response which is largely mediated by prostaglandin (PG) D2. Therefore, concomitant administration of the D-type prostanoid (DP) receptor antagonist laropiprant has been proposed to be a useful approach in preventing niacin-induced flush. However, antagonizing PGD2, which is a potent inhibitor of platelet aggregation, might pose the risk of atherothrombotic events in cardiovascular disease. In fact, we found that in vitro treatment of platelets with laropiprant prevented the inhibitory effects of PGD2 on platelet function, i.e. platelet aggregation, Ca flux, P-selectin expression, activation of glycoprotein IIb/IIIa and thrombus formation. In contrast, laropiprant did not prevent the inhibitory effects of acetylsalicylic acid or niacin on thrombus formation. At higher concentrations, laropiprant by itself attenuated platelet activation induced by thromboxane (TP) and E-type prostanoid (EP)3 receptor stimulation, as demonstrated in assays of platelet aggregation, Ca flux, P-selectin expression, and activation of glycoprotein IIb/IIIa. Inhibition of platelet function exerted by EP4 or I-type prostanoid (IP) receptors was not affected by laropiprant. These in vitro data suggest that niacin/laropiprant for the treatment of dyslipidemias might have a beneficial profile with respect to platelet function and thrombotic events in vascular disease. Citation: Philipose S, Konya V, Lazarevic M, Pasterk LM, Marsche G, et al. (2012) Laropiprant Attenuates EP3 and TP Prostanoid Receptor-Mediated Thrombus Formation. PLoS ONE 7(8): e40222. doi:10.1371/journal.pone.0040222 Editor: Christian Schulz, Heart Center Munich, Germany Received April 17, 2012; Accepted June 2, 2012; Published August 1, 2012 Copyright: 2012 Philipose et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Dr. Philipose was funded by the PhD Program in Molecular Medicine of the Medical University of Graz. This study was supported by the Jubilaumsfonds of the Austrian National Bank (OeNB, grants 13487 and 14263) and the Austrian Science Fund (FWF; grants P22521-B18, P19473-B05, P21004-B02 and P22976-B18. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: akos.heinemann@medunigraz.at

High On‐Aspirin Platelet Reactivity and Clinical Outcome in Patients With Stable Coronary Artery Disease: Results From ASCET (Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial)

BackgroundPatients with stable coronary artery disease on single-antiplatelet therapy with aspirin are still at risk for atherothrombotic events, and high on-aspirin residual platelet reactivity (RPR) has been suggested as a risk factor.Methods and ResultsIn this randomized trial, the association between platelet function determined by the PFA100 platelet function analyzer system (Siemens Healthcare Diagnostics, Germany) and clinical outcome in 1001 patients, all on single-antiplatelet therapy with aspirin (160 mg/d) was studied. Patients were randomized to continue with aspirin 160 mg/d or change to clopidogrel 75 mg/d. A composite end point of death, myocardial infarction, ischemic stroke, and unstable angina was used. At 2-year follow-up, 106 primary end points were registered. The prevalence of high RPR was 25.9%. High on-aspirin RPR did not significantly influence the primary end point in the aspirin group (13.3% versus 9.9%, P=0.31). However, in post hoc analysis, patients with von Willebrand factor levels or platelet count below median values and high on-aspirin RPR had a statistically significant higher end point rate than that of patients with low RPR (20% versus 7.5%, P=0.014, and 18.2% versus 10.8%, P=0.039, respectively). The composite end point rate in patients with high on-aspirin RPR treated with clopidogrel was not different from that of patients treated with aspirin (7.6% versus 13.3%, P=0.16).ConclusionsIn stable, aspirin-treated patients with coronary artery disease, high on-aspirin RPR did not relate to clinical outcome and did not identify a group responsive to clopidogrel. Post hoc subgroup analysis raised the possibility that high on-aspirin RPR might be predictive in patients with low von Willebrand factor or platelet count, but these findings will require confirmation in future studies.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov Unique identifier: NCT00222261. (J Am Heart Assoc. 2012;1:e000703 doi: 10.1161/JAHA.112.000703.)