Abstract 2655: Polymorphisms in the Gene Encoding for Cyclooxygenase-2 and the Risk of Recurrent Atherothrombotic Events

Multiple single nucleotide polymorphisms (SNP’s) in the gene encoding for cyclooxygenase-2 (COX-2) have been identified. These SNP’s may modify risk of atherothrombotic events. The COX-2 -765G->C SNP has been associated with decreased COX-2 activity and with significantly lower odds of a first atherothrombotic event. The − 1195G->A SNP on the other hand seems to be correlated with increased COX-2 activity, but has not been investigated in relation to atherothrombotic events. Our aim is to investigate whether these two functional COX-2 SNP’s are associated with the risk of recurrent atherothrombotic events. Patients hospitalized between Apr 2002 and Jan 2004 with acute coronary syndrome were genotyped for the COX-2 − 765G->C and − 1195G->A SNP’s and followed up to July 2008. The primary endpoint was a composite of cardiovascular death, myocardial infarction and/or stroke. Multivariate analysis was performed. We included a cohort of 379 consecutive patients (median age 66 y (IQR 55–73), 66% were males). Genotyping for the − 765G->C showed frequencies of 72% GG, 27% GC and 1% CC. For the − 1195G->A frequencies were 5% GG, 35% GA and 60% AA. There was strong linkage disequilibrium (D’=−1.0) between both SNP’s. The primary endpoint occurred in 82 patients (22%). The unadjusted hazard ratio for the − 765GC/CC genotypes was 1.33 (95% confidence intervals [CI] 0.84 –2.10, p= 0.22) compared with − 765GG , the adjusted hazard ratio was 1.16 (95% CI 0.72–1.88, p=0.54). Haplotype analysis of the combination of −1195- and −765-genotypes, revealed no genetic subgroup at significantly increased risk either. Previously, the COX-2 − 765G->C SNP was associated with a reduced risk for first atherothrombotic event. For the risk of recurrent events we found no effect for this SNP. In addition we studied the combination with the functional − 1195G->A SNP of COX-2, which did not show a significant effect on recurrent events either.

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Abstract 13290: GDF-15 at One Month After an Acute Coronary Syndrome is Associated With Increased Risk of Major Bleeding - A PLATO Biomarker Substudy

Circulation ◽

10.1161/circ.132.suppl_3.13290 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Daniel Lindholm ◽

Emil Hagström ◽

Stefan K James ◽

Richard C Becker ◽

Christopher P Cannon ◽

...

Keyword(s):

Primary Endpoint ◽

Major Bleeding ◽

Proportional Hazards Model ◽

Bleeding Risk ◽

Cox Proportional Hazards Model ◽

Antiplatelet Treatment ◽

Additional Information ◽

Coronary Syndrome ◽

Increased Risk ◽

Dual Antiplatelet Treatment

Introduction: Levels of Growth Differentiation Factor-15 (GDF-15) are associated with major bleeding events in acute coronary syndromes (ACS), when measured at the time of initial presentation. We hypothesized that an additional measurement of GDF-15 at 1 month after ACS provides additional information regarding risk of major bleeding. Methods: In the PLATO trial, levels of GDF-15 were determined in 4049 ACS patients at both baseline and at 1 month, using an immunoassay (Roche). The primary endpoint was non-CABG related major bleeding. A 1-month landmark analysis was performed, in relation to GDF-15 elevation status at baseline and 1 month, using a cutoff of 1800 ng/L. The relation between GDF-15 at 1 month and the primary endpoint from 1 month onward was evaluated using a Cox proportional hazards model; adjusting for baseline GDF-15, age, anemia (hemoglobin <130 g/L in men, <120 g/L in women), impaired renal function (eGFR <50 mL/min/1.73m2), and history of gastrointestinal bleeding. Results: In the unadjusted analysis, patients with GDF-15 >1800 ng/L at 1 month had increased bleeding rates during follow-up, irrespective of the baseline value. Patients with GDF-15 ≤1800 ng/L at 1 month had lower bleeding risk regardless of initial level (see figure). In the adjusted analysis, GDF-15 >1800 ng/L at 1 month was independently associated with the outcome, hazard ratio 3.39 (95% CI 1.89-6.09). Conclusions: The level of GDF-15 at 1 month after ACS is related to the risk of bleeding during dual antiplatelet treatment. Assessment of GDF-15 level at 1 month provides additional information on the subsequent bleeding risk, regardless of the patient’s index GDF-15 level in the acute phase, and may therefore be helpful for decision-making on continued dual antiplatelet treatment.

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P6419Machine learning in critical care: the role of diabetes and age in acute coronary syndromes

European Heart Journal ◽

10.1093/eurheartj/ehz746.1013 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

E Cenko ◽

M Van Der Schaar ◽

J Yoon ◽

Z Vasiljevic ◽

S Kedev ◽

...

Keyword(s):

Medical Treatment ◽

Primary Endpoint ◽

Left Ventricular ◽

Adverse Outcomes ◽

Secondary Endpoint ◽

Coronary Syndrome ◽

Increased Risk ◽

All Cause Mortality ◽

Patients With Diabetes ◽

The Impact

Abstract Background Patients with diabetes and non-ST elevation acute coronary syndrome (NSTE-ACS) have an increased risk of mortality and adverse outcomes following percutaneous coronary intervention (PCI). Purpose We aimed to investigate the impact of early, within 24 hours PCI compared with only routine medical treatment on clinical outcomes in a large international cohort of patients with NSTE-ACS and diabetes. Methods We identified 1,250 patients with diabetes and NSTE-ACS from a registry-based population between October 2010 and April 2016. The primary endpoint was 30-day all-cause mortality. The secondary endpoint was the composite outcome of 30-day all-cause mortality and left ventricular dysfunction (ejection fraction <40%). We undertook analyses to explore the heterogeneity of treatment effects using meta-classification (MC) algorithms followed by propensity score matching and inverse-probability-of-treatment weighting (IPTW) from a landmark of 24 hours from hospitalization. Results Of 1,250 NSTE-ACS first-day survivors with diabetes (median age 67 years; 59%, men), 470 (37.6%) received early PCI and 780 routine medical treatment. The overall 30-day all-cause mortality rates were higher in the routine medical treatment than the early PCI group (6.3% vs. 2.5%). The prediction results of the MC algorithms accounted for only one interaction term that was statistically significant: age ≥65 years. After propensity-matched analysis as well as IPTW, early PCI was associated with reduced 30-day all-cause mortality in the older age (OR: 0.35; 95% CI: 0.14 to 0.92 and 0.43; 95% CI: 0.21 to 0.86, respectively), whereas younger age had no association with the primary endpoint. Similar results were also obtained for the secondary endpoint. Conclusions Among patients with diabetes hospitalized for NSTE-ACS, an early, within 24 hours, PCI strategy is associated with reduced odds of 30-day mortality only for patients aged 65 years or over. MC algorithms provide accurate identification of treatment effect modifiers.

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Increased risk of incident stroke associated with the cyclooxygenase 2 (COX-2) G−765C polymorphism in African-Americans: The Atherosclerosis Risk in Communities Study

Atherosclerosis ◽

10.1016/j.atherosclerosis.2007.02.010 ◽

2008 ◽

Vol 196 (2) ◽

pp. 926-930 ◽

Cited By ~ 39

Author(s):

Shun Kohsaka ◽

Kelly A. Volcik ◽

Aaron R. Folsom ◽

Kenneth K. Wu ◽

Christie M. Ballantyne ◽

...

Keyword(s):

African Americans ◽

Cyclooxygenase 2 ◽

Atherosclerosis Risk In Communities ◽

Increased Risk ◽

Atherosclerosis Risk ◽

Cox 2

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Blood pressure and mortality in patients with type 2 diabetes and a recent coronary event in the ELIXA trial

Cardiovascular Diabetology ◽

10.1186/s12933-020-01150-0 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Magnus O. Wijkman ◽

Brian Claggett ◽

Rafael Diaz ◽

Hertzel C. Gerstein ◽

Lars Køber ◽

...

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Acute Coronary Syndrome ◽

Coronary Event ◽

Hazard Ratio ◽

Risk Of Death ◽

Coronary Syndrome ◽

Increased Risk ◽

The Relationship

Abstract Background The relationship between blood pressure and mortality in type 2 diabetes (T2DM) is controversial, with concern for increased risk associated with excessively lowered blood pressure. Methods We evaluated whether prior cardiovascular disease (CVD) altered the relationship between baseline blood pressure and all-cause mortality in 5852 patients with T2DM and a recent acute coronary syndrome (ACS) who participated in the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial. Risk of death was assessed in Cox models adjusted for age, sex, race, heart rate, BMI, smoking, diabetes duration, insulin use, HbA1c, eGFR, brain natriuretic peptide (BNP), urine albumin/creatinine ratio, treatment allocation and prior coronary revascularization. Results Although overall there was no significant association between systolic blood pressure (SBP) and mortality (hazard ratio per 10 mmHg lower SBP 1.05 (95% CI 0.99–1.12) P = 0.10), lower SBP was significantly associated with higher risk of death (hazard ratio per 10 mmHg lower SBP 1.13 (95% CI 1.04–1.22) P = 0.002) in 2325 patients with additional CVD (index ACS+ at least one of the following prior to randomization: myocardial infarction other than the index ACS, stroke or heart failure). In 3527 patients with only the index ACS no significant association was observed (hazard ratio per 10 mmHg lower SBP 0.95 (0.86–1.04) P = 0.26; P for interaction 0.005). Conclusions The association between blood pressure and mortality was modified by additional CVD history in patients with type 2 diabetes and a recent coronary event. When blood pressures measured after an acute coronary event are used to assess the risk of death in patients with type 2 diabetes, the cardiovascular history needs to be taken into consideration. Trial registration ClinicalTrials.gov number NCT01147250, first posted June 22, 2010

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Association of the Three Common SNPs of Cyclooxygenase-2 Gene (rs20417, rs689466, and rs5275) with the Susceptibility of Breast Cancer: An Updated Meta-Analysis Involving 34,590 Subjects

Disease Markers ◽

10.1155/2014/484729 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Zhi-Jun Dai ◽

Yong-Ping Shao ◽

Xiao-Bin Ma ◽

Dan Xu ◽

Wei Tang ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Meta Analysis ◽

Cyclooxygenase 2 ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Increased Risk ◽

Cancer Types ◽

Cox 2

Several single nucleotide polymorphisms have been identified in cyclooxygenase-2 (COX-2) genes (e.g., −765 G>C (rs20417), −1195G>A (rs689466), and 8473 C>T (rs5275)). The association of these SNPs with the risk of different cancer types is still controversial. This study aims to evaluate the correlation between these SNPs and breast cancer risk in different ethnic groups. We have searched PubMed, Web of Knowledge, and Embase for relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of the associations. A total of 13 studies (15,330 cases and 19,260 controls) were eligible for meta-analysis. This meta-analysis showed that COX-2 rs20417 polymorphism was correlated with an increased risk of breast cancer in Caucasians, while rs689466 was associated with a decreased risk of breast cancer in Caucasians. The rs5275 polymorphism had no association with breast cancer risk.

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Uteroplacental insufficiency alters nephrogenesis and downregulates cyclooxygenase-2 expression in a model of IUGR with adult-onset hypertension

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00558.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. R1943-R1955 ◽

Cited By ~ 42

Author(s):

Mariana Baserga ◽

Merica A. Hale ◽

Zheng Ming Wang ◽

Xing Yu ◽

Christopher W. Callaway ◽

...

Keyword(s):

Animal Studies ◽

Cyclooxygenase 2 ◽

Adult Onset ◽

Nephron Number ◽

Pregnant Rat ◽

Protein Levels ◽

Increased Risk ◽

Key Enzyme ◽

Blood Pressures ◽

Cox 2

Clinical and animal studies indicate that intrauterine growth restriction (IUGR) following uteroplacental insufficiency (UPI) reduces nephron number and predisposes toward renal insufficiency early in life and increased risk of adult-onset hypertension. In this study, we hypothesized that the inducible enzyme cyclooxygenase-2 (COX-2), a pivotal protein in nephrogenesis, constitutes a mechanism through which UPI and subsequent glucocorticoid overexposure can decrease nephron number. We further hypothesized that UPI downregulates the key enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which converts corticosterone to inert 11-dehydrocorticosterone, thereby protecting both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) from the actions of corticosterone. Following bilateral uterine ligation on the pregnant rat, UPI significantly decreased renal COX-2, 11β-HSD2, and GR mRNA and protein levels, but upregulated expression of MR at birth. At day 21 of life, 11β-HSD2, GR, and also MR mRNA and protein levels were downregulated. UPI did not affect blood pressures (BP) at day 21 of life but significantly increased systolic BP in both genders at day 140. We conclude that in our animal model, UPI decreases fetal COX-2 expression during a period of active nephrogenesis in the IUGR rat, which is also characterized by decreased nephron number and adult-onset hypertension.

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Phase III Randomized, Placebo-Controlled, Double-Blind Trial of Celecoxib in Addition to Standard Chemotherapy for Advanced Non–Small-Cell Lung Cancer With Cyclooxygenase-2 Overexpression: CALGB 30801 (Alliance)

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.3743 ◽

2017 ◽

Vol 35 (19) ◽

pp. 2184-2192 ◽

Cited By ~ 29

Author(s):

Martin J. Edelman ◽

Xiaofei Wang ◽

Lydia Hodgson ◽

Richard T. Cheney ◽

Maria Q. Baggstrom ◽

...

Keyword(s):

Lung Cancer ◽

Prostaglandin E2 ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Hazard Ratio ◽

Cyclooxygenase 2 ◽

Urinary Metabolite ◽

Small Cell Lung ◽

Cox 2

Purpose Tumor overexpression of cyclooxygenase-2 (COX-2) has been associated with worse outcome in non–small-cell lung cancer (NSCLC). In Cancer and Leukemia Group B (CALGB) 30203, we found that the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved progression-free and overall survival in patients with moderate to high COX-2 expression by immunohistochemistry (IHC). CALGB 30801 (Alliance) was designed to prospectively confirm that finding. Patients and Methods Patients with NSCLC (stage IIIB with pleural effusion or stage IV according to American Joint Committee on Cancer [sixth edition] criteria) were preregistered, and biopsy specimens were analyzed for COX-2 by IHC. Patients with COX-2 expression ≥ 2, performance status of 0 to 2, and normal organ function were eligible. Chemotherapy was determined by histology: carboplatin plus pemetrexed for nonsquamous NSCLC and carboplatin plus gemcitabine for squamous histology. Patients were randomly assigned to celecoxib (400 mg twice per day; arm A) or placebo (arm B). The primary objective was to demonstrate improvement in progression-free survival in patients with COX-2 index ≥ 4 with hazard ratio of 0.645 with approximately 85% power at two-sided significance level of .05. Results The study was halted for futility after 312 of the planned 322 patients with COX-2 index ≥ 2 were randomly assigned. There were no significant differences between the groups (hazard ratio, 1.046 for COX-2 ≥ 4). Subset analyses evaluating histology, chemotherapy regimen, and incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition. Elevation of baseline urinary metabolite of prostaglandin E2, indicating activation of the COX-2 pathway, was a negative prognostic factor. Values above the third quartile may have been a predictive factor. Conclusion COX-2 expression by IHC failed to select patients who could benefit from selective COX-2 inhibition. Urinary metabolite of prostaglandin E2 may be able to identify patients who could benefit from COX-2 inhibition.

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Acute coronary syndromes in anaemic patients: the bad or the ugly?

European Heart Journal Acute Cardiovascular Care ◽

10.1093/ehjacc/zuab020.064 ◽

2021 ◽

Vol 10 (Supplement_1) ◽

Author(s):

C Saleiro ◽

D De Campos ◽

J Lopes ◽

JP Sousa ◽

L Puga ◽

...

Keyword(s):

Antiplatelet Therapy ◽

Primary Endpoint ◽

Anticoagulation Therapy ◽

Left Ventricular ◽

Lv Function ◽

Prognostic Impact ◽

Coronary Syndrome ◽

Increased Risk ◽

All Cause Mortality ◽

The Impact

Abstract Funding Acknowledgements Type of funding sources: None. Background Patients with anaemia are at increased risk of composite cardiovascular (CV) events and all-cause mortality. However, anaemia poses a challenge to doctors when in the context of an acute coronary syndrome (ACS) and the urge to offer intervention treatment and therefore antiplatelet therapy. Purpose To study the prognostic impact of anaemia in a population with ACS. Methods 436 ACS patients admitted to a single coronary care with anaemia (male gender, haemoglobin [Hb] <13 g/dL; female gender, Hb < 12 g/dL) who were discharged from hospital were included. The primary endpoint was long-term all-cause mortality. Cox regression was conducted to evaluate the impact on the primary endpoint. The median of follow-up was 36 (± 31) months. Results Sixty-four percent of the patients were male, with a mean age 75 ± 10 years old. The majority (47%) was admitted with non-ST elevation myocardial infarction. Most of them had previous history of hypertension (87%), dyslipidaemia (63%) and chronic kidney disease (58%), while a minority had a diagnosis of diabetes mellitus (46%). Most of the patients remained in Killip-Kimbal class I throughout hospital-stay. Coronary angiography was not conducted in 15% of the patients. Thirty-six percent of the patients were conservatively treated (not submitted to percutaneous coronary intervention or coronary artery bypass graft). At discharge, 1% of the patients had no antiplatelet or anticoagulation therapy prescribed; 7% had simple antiplatelet therapy; 1% only had anticoagulation therapy; 67% had double antiplatelet therapy; 1% had double therapy (anticoagulation plus a single antiplatelet agent) and 5% had triple therapy (anticoagulation plus two antiplatelets agents); missing data about therapy at discharge in 18% of the patients. 224 patients met the primary outcome. In univariate analysis, nor antiplatelet neither anticoagulation strategies were related to the outcome (P = 0.59; P = 0.73, respectively). In a multivariable model adjusted for age, Hb level, glomerular filtration rate, heart failure diagnosis, left ventricular function (3 categories), maximum troponin I and treatment option (conservative vs revascularization), Hb level remains an important prognosis predictor (HR 0.86, 95% CI 0.77-0.97, per each g/dL increase). In this model, besides from Hb level, only age (HR 1.04, 95% CI 1.02-1.05) and moderate to severely impaired LV function (HR 1.91, 95% CI 1.38-2.63) remained associated with the outcome. Conclusion The outcome attributed to anaemia patients seems to be independent of treatment strategies and it is related to the Hb level itself. This reinforces the need to explore reversible causes of anaemia, as small increases in Hb level may have a major impact on the prognosis of these patients.

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MCP-1 Predicts Recurrent Cardiovascular Events in Patients with Persistent Inflammation

Journal of Clinical Medicine ◽

10.3390/jcm10051137 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1137

Author(s):

Luis M. Blanco-Colio ◽

Nerea Méndez-Barbero ◽

Ana María Pello Lázaro ◽

Álvaro Aceña ◽

Nieves Tarín ◽

...

Keyword(s):

Plasma Levels ◽

Cardiovascular Events ◽

Recurrent Events ◽

Primary Outcome ◽

Troponin I ◽

Monocyte Chemoattractant Protein 1 ◽

Coronary Syndrome ◽

Persistent Inflammation ◽

Increased Risk ◽

Galectin 3

Clinical data indicate that patients with C-reactive protein (CRP) levels higher than 2 mg per liter suffer from persistent inflammation, which is associated with high risk of cardiovascular disease (CVD). We determined whether a panel of biomarkers associated with CVD could predict recurrent events in patients with low or persistent inflammation and coronary artery disease (CAD). We followed 917 patients with CAD (median 4.59 ± 2.39 years), assessing CRP, galectin-3, monocyte chemoattractant protein-1 (MCP-1), N-terminal fragment of brain natriuretic peptide (NT-proBNP) and troponin-I plasma levels. The primary outcome was the combination of cardiovascular events (acute coronary syndrome, stroke or transient ischemic event, heart failure or death). Patients with persistent inflammation (n = 343) showed higher NT-proBNP and MCP-1 plasma levels compared to patients with CRP < 2 mg/L. Neither MCP-1 nor NT-proBNP was associated with primary outcome in patients with CRP < 2 mg/L. However, NT-proBNP and MCP-1 plasma levels were associated with increased risk of the primary outcome in patients with persistent inflammation. When patients were divided by type of event, MCP-1 was associated with an increased risk of acute ischemic events. A significant interaction between MCP-1 and persistent inflammation was found (synergy index: 6.17 (4.39–7.95)). In conclusion, MCP-1 plasma concentration is associated with recurrent cardiovascular events in patients with persistent inflammation.

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