scholarly journals PCTP (Phosphatidylcholine Transfer Protein) is Regulated By RUNX1 in Platelets/Megakaryocytes and is Associated with Adverse Cardiovascular Events

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 365-365 ◽  
Author(s):  
Natthapol Songdej ◽  
Guangfen Mao ◽  
Deepak Voora ◽  
Lawrence E. Goldfinger ◽  
Fabiola Del Carpio-Cano ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Platelet Aggregation ◽  
Cardiovascular Events ◽  
Calcium Mobilization ◽  
Upstream Region ◽  
Transfer Protein ◽  
Specific Manner ◽  
Hel Cells ◽  
Phosphatidylcholine Transfer Protein

Abstract Transcription factor (TF) mutations are increasingly recognized to play a major role in inherited platelet abnormalities. RUNX1, a major hematopoietic TF, acts in a combinatorial manner with other TFs to regulate numerous megakaryocyte (MK)/platelet genes. Human RUNX1 haplodeficiency is associated with thrombocytopenia, platelet function defects, and increased leukemia risk. We have described a patient with multiple abnormalities in platelet aggregation and secretion responses with a heterozygous RUNX1 nonsense mutation (Sun et al Blood 2004; 103; 948-54). Transcript expression profiling of patient platelets (Sun et al J Thromb Haemost 2007; 5:146-54)showed several genes were significantly downregulated, including myosin light chain (MYL9), platelet factor 4 (PF4), protein kinase C-θ (PRCKQ), and 12-lipoxygenase (ALOX12); these have been shown by us to be regulated by RUNX1. The profiling data also showed 10-fold downregulation of phosphatidylcholine transfer protein (PCTP) gene (fold change ratio 0.09, p=0.02) in the patient compared with normal controls. PCTP regulates the intermembrane transfer of phosphatidylcholine (PC), a major plasma membrane phospholipid. Platelet PCTP expression is associated with increased platelet aggregation and calcium mobilization upon activation of protease-activated receptor 4 (PAR4) thrombin receptors in black subjects as compared to white subjects (Edelstein et al Nat Med 2013; 19:1609-16). Pharmacologic inhibition of PCTP decreased platelet aggregation in response to PAR4 agonist and siRNA knockdown of PCTP in megakaryocytic cells blunted calcium mobilization induced by PAR4 (Edelstein et al Nat Med 2013; 19:1609-16). Little is known regarding the regulation of PCTP in MKs/platelets and its role in cardiovascular events. Based on the decreased platelet PCTP expression in our patient, we pursued the hypothesis that PCTP is regulated by RUNX1 and contributes to cardiovascular events. Corrected total cellular immunofluorescence with anti-PCTP antibody showed significantly reduced platelet PCTP expression by 58% in our patient compared to a normal control. In silico analysis revealed 5 RUNX1 consensus binding sites up to ~ 1 kb of the PCTP 5' upstream region from ATG. To assess for interaction of RUNX1 with the PCTP promoter, chromatin immunoprecipitation (ChIP) assay with anti-RUNX1 antibody was performed using human erythroid leukemia (HEL) cells treated with phorbol 12-myristate 13-acetate (PMA) for 48 hours to induce megakaryocytic transformation. The ChIP studies showed RUNX1 binding to PCTP chromatin in the regions encompassing RUNX1 binding site 1 (-345/-340), site 3 (-632/-627), and encompassing sites 4 and 5 (-974/-969, -997/-992). Electrophoretic mobility shift assay (EMSA) using PMA-treated HEL cell nuclear extracts showed RUNX1 binding to DNA probes (28-37 bp) containing site 1 (-345/-340) and both sites 4 and 5 (-974/-969, -997/-992). PCTP mRNA and protein expression were increased with RUNX1 overexpression and reduced with RUNX1 knockdown in HEL cells, indicating that PCTP is regulated by RUNX1. To assess the clinical relevance of the findings, the relationship between RUNX1 and PCTP in peripheral blood RNA, and PCTP and death or myocardial infarction (MI) events were assessed in two separate patient cohorts (n = 587 total patients) with cardiovascular disease. RUNX1 is transcribed from two alternate promoters (P1 and P2) resulting in different isoforms. In both patient cohorts, there was strong correlation between RUNX1 and PCTP expression in a promoter specific manner. RUNX1 P1 probe sets were strongly and inversely correlated with PCTP expression (p < 0.0001), while the P2 probe sets were not. PCTP expression was associated with death or MI in both patient cohorts (odds ratio 2.1, 95% CI [1.61-2.95], P-value < 0.0001) independent of age, sex, race, platelet count, and cardiovascular risk factors. Conclusions: Our results provide evidence that PCTP is regulated by RUNX1 (potentially in a promoter specific manner), and that PCTP expression is associated with death or myocardial infarction in patients with cardiovascular disease. RUNX1 regulation of PCTP may play a role in the pathogenesis of platelet-mediated cardiovascular events. Disclosures No relevant conflicts of interest to declare.

Abstract P019: A Single Model For Predicting Major Adverse Cardiovascular Events In Individuals With And Without History Of Atherosclerotic Cardiovascular Disease: The Atherosclerosis Risk In Communities (aric) Study

Circulation ◽  
2021 ◽  
Vol 143 (Suppl_1) ◽  
Author(s):  
Yejin Mok ◽  
Lena Mathews ◽  
Ron C Hoogeveen ◽  
Michael J Blaha ◽  
Christie M Ballantyne ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
High Risk ◽  
Risk Stratification ◽  
Cardiovascular Events ◽  
Major Adverse Cardiovascular Events ◽  
Atherosclerotic Cardiovascular Disease ◽  
Single Model ◽  
History Of ◽  
Very High

Background: In the 2018 AHA/ACC Cholesterol guideline, risk stratification is an essential element. The use of a Pooled Cohort Equation (PCE) is recommended for individuals without atherosclerotic cardiovascular disease (ASCVD), and the new dichotomous classification of very high-risk vs. high-risk has been introduced for patients with ASCVD. These distinct risk stratification systems mainly rely on traditional risk factors, raising the possibility that a single model can predict major adverse cardiovascular events (MACEs) in persons with and without ASCVD. Methods: We studied 11,335 ARIC participants with (n=885) and without (n=10,450) a history of ASCVD (myocardial infarction, ischemic stroke, and symptomatic peripheral artery disease) at baseline (1996-98). We modeled factors in the PCE and the new classification for ASCVD patients (Figure legend) in a single CVD prediction model. We examined their associations with MACEs (myocardial infarction, stroke, and heart failure) using Cox models and evaluated the discrimination and calibration for a single model including those factors. Results: During a median follow-up of 18.4 years, there were 3,658 MACEs (3,105 in participants without ASCVD). In general, the factors in the PCE and the risk classification system for ASCVD patients were associated similarly with MACEs regardless of baseline ASCVD status, although age and systolic blood pressure showed significant interactions. A single model with these predictors and the relevant interaction terms showed good calibration and discrimination for those with and without ASCVD (c-statistic=0.729 and 0.704, respectively) (Figure). Conclusion: A single CVD prediction model performed well in persons with and without ASCVD. This approach will provide a specific predicted risk to ASCVD patients (instead of dichotomy of very high vs. high risk) and eliminate a practice gap between primary vs. secondary prevention due to different risk prediction tools.

scholarly journals The Impact of Cytochrome P450 2C19 Polymorphism on Cardiovascular Events in Indonesian Patients with Coronary Artery Disease

2017 ◽  
pp. 18-24
Author(s):  
Muzakkir Amir ◽  
Mirnawati Mappiare ◽  
Paskalis Indra
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery Disease ◽  
Platelet Aggregation ◽  
Cardiovascular Events ◽  
Cardiovascular Death ◽  
Cyp2c19 Genotype ◽  
Cyp2c19 Polymorphism ◽  
Cytochrome P450 2C19 ◽  
Artery Disease ◽  
The Impact

Background: The polymorphism of cytochrome P450 2C19 (CYP2C19) has been documented as the determinant variability in the antiplatelet effect of clopidogrel. The relation between CYP2C19 polymorphism and the antiplatelet efficacy of clopidogrel in Indonesian patients with coronary artery disease (CAD) is unknown. To address this issue, we examined the distribution of CYP2C19 genotypes and platelet aggregation, and assessed the impact of CYP2C19 polymorphism on response to clopidogrel and cardiovascular events. Methods: This observational analytic study with prospective cohort approach was conducted in Wahidin Sudirohusodo and Hasanuddin University Hospital, Makassar. We measured the CYP2C19 genotype by polymerase chain reaction-restriction fragment linked polymorphism (PCR-RFLP) method and platelet aggregation by optical platelet aggregometry with 10 μmol of adenosine diphosphate (ADP) in 69 patients with stable CAD who were treated with clopidogrel. Platelet hyperaggregation was defined as maximal platelet aggregation > 94.3%. The patients were followed up every month at the outpatient department for 6 months or at end point. The end point was acute myocardial infarction, ischemic stroke, or cardiovascular death. Results: Distribution of CYP2C19 alleles were 89.8%, 40.6%, and 11.6%, in CYP2C19*1, CYP2C19*2, and CYP2C19*3, respectively. Distribution of CYP2C19 genotype were 50.7%, 29.0%, 8.7%, 8.7%, and 2.9% in CYP2C19*1/*1, *1/*2, *1/*3, *2/*2, and *2/*3, respectively. Platelet hyper aggregation was more in patients with polymorphism than wild type (p 0.034; OR 3.707) and was associated with cardiovascular events (p 0.030; OR 13.250). There was acute myocardial infarction in 2 patients, ischemic stroke in 1 patient, and cardiovascular death in 1 patient. All of these patients were carrying at least one variant allele of CYP2C19; details of genotype were in two patients with CYP2C19*1/*2, one patient with *2/*2, and one with *2/*3 alleles. Conclusion: CYP2C19*2 and *3 were associated with cardiovascular events due to platelet hyper aggregation.

scholarly journals Predictive Value of the Cardio‐Ankle Vascular Index for Cardiovascular Events in Patients at Cardiovascular Risk

2021 ◽  
Author(s):  
Toru Miyoshi ◽  
Hiroshi Ito ◽  
Kohji Shirai ◽  
Shigeo Horinaka ◽  
Jitsuo Higaki ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Cohort Study ◽  
Arterial Stiffness ◽  
Prospective Cohort ◽  
Cardiovascular Events ◽  
Primary Outcome ◽  
Cardiovascular Death ◽  
Disease Risks

Background Arterial stiffness is an important predictor of cardiovascular events; however, indexes for measuring arterial stiffness have not been widely incorporated into routine clinical practice. This study aimed to determine whether the cardio‐ankle vascular index (CAVI), based on the blood pressure–independent stiffness parameter β and reflecting arterial stiffness from the origin of the ascending aorta, is a good predictor of cardiovascular events in patients with cardiovascular disease risk factors in a large prospective cohort. Methods and Results This multicenter prospective cohort study, commencing in May 2013, with a 5‐year follow‐up period, included patients (aged 40‒74 years) with cardiovascular disease risks. The primary outcome was the composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Among 2932 included patients, 2001 (68.3%) were men; the mean (SD) age at diagnosis was 63 (8) years. During the median follow‐up of 4.9 years, 82 participants experienced primary outcomes. The CAVI predicted the primary outcome (hazard ratio, 1.38; 95% CI, 1.16‒1.65; P <0.001). In terms of event subtypes, the CAVI was associated with cardiovascular death and stroke but not with myocardial infarction. When the CAVI was incorporated into a model with known cardiovascular disease risks for predicting cardiovascular events, the global χ 2 value increased from 33.8 to 45.2 ( P <0.001), and the net reclassification index was 0.254 ( P =0.024). Conclusions This large cohort study demonstrated that the CAVI predicted cardiovascular events. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01859897.

Meta-analysis

ESC CardioMed ◽  
2018 ◽  
pp. 3092-3098
Author(s):  
Natalie Staplin ◽  
Colin Baigent
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Statistical Method ◽  
Cardiovascular Events ◽  
Randomized Trials ◽  
Meta Analysis ◽  
Treatment Decisions ◽  
Meta Analyses ◽  
Effective Treatments

The term ‘meta-analysis’ refers to a statistical method for combining the results of several (often many) studies or experiments in order to arrive at an overall conclusion about the size and variability of the measure of interest. In the context of cardiovascular disease, such studies are most often randomized trials of therapies for the prevention or treatment of cardiovascular events, such as myocardial infarction or stroke. The specialty has now witnessed several decades of success in identifying effective treatments for cardiovascular diseases, and the technique of meta-analysis of randomized trials has played an important role in this success. Not all meta-analyses are made equal, however, and it is important to be aware of the limitations of the method. This chapter considers how the technique can be best employed to guide treatment decisions, while also highlighting the limitations of meta-analysis when the information available is inadequate or potentially biased.

scholarly journals Comparative Effect of Statins and Omega-3 Supplementation on Cardiovascular Events: Meta-Analysis and Network Meta-Analysis of 63 Randomized Controlled Trials Including 264,516 Participants

Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2218 ◽  
Author(s):  
Tung Hoang ◽  
Jeongseon Kim
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Randomized Controlled Trials ◽  
Cardiovascular Events ◽  
Meta Analysis ◽  
Controlled Trials ◽  
Omega 3 ◽  
Randomized Controlled

Statins and omega-3 supplementation have been recommended for cardiovascular disease prevention, but comparative effects have not been investigated. This study aimed to summarize current evidence of the effect of statins and omega-3 supplementation on cardiovascular events. A meta-analysis and a network meta-analysis of 63 randomized controlled trials were used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs) for the effects of specific statins and omega-3 supplementation compared with controls. Overall, the statin group showed significant risk reductions in total cardiovascular disease, coronary heart disease, myocardial infarction, and stroke; however, omega-3 supplementation significantly decreased the risks of coronary heart disease and myocardial infarction only, in the comparison with the control group. In comparison with omega-3 supplementation, pravastatin significantly reduced the risks of total cardiovascular disease (RR = 0.81, 95% CI = 0.72–0.91), coronary heart disease (RR = 0.75, 95% CI = 0.60–0.94), and myocardial infarction (RR = 0.71, 95% CI = 0.55–0.94). Risks of total cardiovascular disease, coronary heart disease, myocardial infarction, and stroke in the atorvastatin group were statistically lower than those in the omega-3 group, with RRs (95% CIs) of 0.80 (0.73–0.88), 0.64 (0.50–0.82), 0.75 (0.60–0.93), and 0.81 (0.66–0.99), respectively. The findings of this study suggest that pravastatin and atorvastatin may be more beneficial than omega-3 supplementation in reducing the risk of total cardiovascular disease, coronary heart disease, and myocardial infarction.

scholarly journals Disparities in Cardiovascular Disease Outcomes Among Pregnant and Post‐Partum Women

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Mohamed M. Gad ◽  
Islam Y. Elgendy ◽  
Ahmed N. Mahmoud ◽  
Anas M. Saad ◽  
Toshiaki Isogai ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Pulmonary Embolism ◽  
Black Women ◽  
Cardiovascular Events ◽  
White Women ◽  
Post Partum ◽  
Peripartum Cardiomyopathy ◽  
Median Income ◽  
Major Cardiovascular Events

Background The incidence of cardiovascular disease among pregnant women is rising in the United States. Data on racial disparities for the major cardiovascular events during pregnancy are limited. Methods and Results Pregnant and post‐partum women hospitalized from January 2007 to December 2017 were identified from the Nationwide Inpatient Sample. The outcomes of interest included: in‐hospital mortality, myocardial infarction, stroke, pulmonary embolism, and peripartum cardiomyopathy. Multivariate regression analysis was used to assess the independent association between race and in‐hospital outcomes. Among 46 700 637 pregnancy‐related hospitalizations, 21 663 575 (46.4%) were White, 6 302 089 (13.5%) were Black, and 8 914 065 (19.1%) were Hispanic. The trends of mortality and stroke declined significantly in Black women, but however, were mostly unchanged among White women. The incidence of mortality and cardiovascular morbidity was highest among Black women followed by White women, then Hispanic women. The majority of Blacks (62.3%) were insured by Medicaid while the majority of White patients had private insurance (61.9%). Most of Black women were below‐median income (71.2%) while over half of the White patients were above the median income (52.7%). Compared with White women, Black women had the highest mortality with adjusted odds ratio (aOR) of 1.45, 95% CI (1.21–1.73); myocardial infarction with aOR of 1.23, 95% CI (1.06–1.42); stroke with aOR of 1.57, 95% CI (1.41–1.74); pulmonary embolism with aOR of 1.42, 95% CI (1.30–1.56); and peripartum cardiomyopathy with aOR of 1.71, 95 % CI (1.66–1.76). Conclusions Significant racial disparities exist in major cardiovascular events among pregnant and post‐partum women. Further efforts are needed to minimize these differences.

A Meta-Analysis of Randomized Controlled Trials of Aspirin in Primary Prevention of Cardiovascular Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 174-174
Author(s):  
Nina C Raju ◽  
Magda Sobieraj-Teague ◽  
John W Eikelboom
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Primary Prevention ◽  
Cardiovascular Mortality ◽  
Cardiovascular Events ◽  
Conflicts Of Interest ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Controlled Trials ◽  
All Cause Mortality

Abstract Abstract 174 Primary prevention with aspirin reduces the risk of non-fatal cardiovascular events but has not been demonstrated to reduce mortality. We performed an updated meta-analysis of randomised controlled trials of aspirin in primary prevention to obtain best estimates of the benefits and harm of aspirin compared with no aspirin with a focus on mortality. Eligible articles were identified by computerized search of MEDLINE, EMBASE, Cochrane library and CINAHL databases, review of bibliographies of relevant publications and a related article search using PubMed. The outcomes of interest included all cause mortality, cardiovascular mortality, the composite of myocardial infarction, stroke or death, and bleeding. 2 reviewers independently extracted study information and data. Data were pooled from individual trials using the DerSimonian-Laird random-effects model and results are presented as relative risk (RR) and 95% confidence intervals (CI). 8 studies comprising a total of 96,726 subjects were included. Aspirin reduced all-cause mortality (RR 0.94; 95%CI 0.88–1.00), the composite of myocardial infarction, stroke or cardiovascular death (RR 0.87; 95%CI 0.82–0.93), and myocardial infarction (RR 0.8; 95%CI 0.66–0.98) but did not significantly reduce cardiovascular mortality (RR 0.94; 95%CI 0.82–1.08) or stroke (RR 0.93; 95%CI 0.81–1.07). Aspirin increased the risk of major bleeding (RR; 1.69 95%CI 1.38–2.08), gastrointestinal bleeding (RR 1.38; 95%CI 1.16–1.65) and hemorrhagic stroke (RR 1.36; 95%CI 1.01–1.84). There was no interaction between subjects with or without diabetes for the outcomes of all cause mortality, cardiovascular mortality, the composite of myocardial infarction, stroke or death. Aspirin therapy in subjects with no prior history of cardiovascular disease reduces the risk of cardiovascular events, myocardial infarction and overall mortality. These benefits are achieved at the expense of increased bleeding. Disclosures: No relevant conflicts of interest to declare.

P3350Design of a multicenter, open-label, randomized controlled trial: effects of intensive systolic blood pressure lowering treatment in reducing risk of vascular events (ESPRIT)

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Liu ◽  
J Li ◽  
X H Huang
Keyword(s):  
Myocardial Infarction ◽  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Randomized Controlled Trial ◽  
Cardiovascular Events ◽  
Controlled Trial ◽  
Elevated Blood ◽  
Open Label ◽  
Randomized Controlled ◽  
Major Cardiovascular Events

Abstract Background Patients with cardiovascular diseases (CVD) are at high risk for recurrent major cardiovascular events. Effective public health strategies to lower blood pressure (BP) are necessary to reduce risk of cardiovascular disease. However, substantial uncertainty remains about the optimal target level to lower BP in patients with cardiovascular disease. Purpose To assess the effects on the incidence of major cardiovascular events in patients with CVD during the scheduled treatment period of greater reduction in blood pressure with a systolic BP (SBP) target <120 mmHg versus <140 mmHg. Methods This study is a multicenter, open-label, randomized controlled trial comparing two strategies for lowering SBP: lowering SBP to the standard target of <140 mmHg; and lowering BP to a more intensive target of <120 mmHg. This study will enroll 12,000 Chinese participants from 100–200 hospitals, follow-up for about 3 years. We will include participants aged ≥50 years old with SBP ≥130 mmHg, having a history of vascular disease (including myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, carotid endarterectomy or carotid stenting, peripheral artery disease with revascularization, abdominal aortic aneurysm ≥5 cm with repair) or stroke. The primary outcome is the first occurrence of major cardiovascular events defined as a composite of myocardial infarction, stroke, coronary or non-coronary revascularization events, and cardiovascular death. Secondary outcomes include the components of the primary composite outcome, hospitalized heart failure and all cause of death and non-cardiovascular outcomes (kidney disease and cognitive outcomes). Results Regarding the results, we hypothesize that comparing with SBP target of <140 mmHg, more intensive SBP target of <120 mmHg can further reduce the occurrence of cardiovascular events in CVD patients with elevated blood pressure. Conclusion This study can provide reliable evaluation on whether more intensive SBP target of <120 mmHg is more desirable than SBP target of <140 mmHg in CVD patients with elevated blood pressure.

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