Inflammatory biomarkers and long-term outcome in young patients three months after a first myocardial infarction.

BACKGROUND: Studies on predictive value of circulating inflammatory biomarkers after myocardial infarction (MI) have often been limited by blood sampling only in an acute setting and short follow-up time. We aimed to compare the long-term predictive value of nine inflammatory biomarkers, known to be involved in atherosclerosis, in young patients investigated three months after a first-time MI. METHODS: Nine biomarkers (high-sensitivity C-reactive protein, interleukin (IL)-6, IL-18, monocyte chemoattractant protein-1, matrix metalloproteinase (MMP)-1, MMP-3, MMP-9, serum amyloid A and tumor necrosis factor-alfa) were sampled in 382 young (<60 years) patients and in age and sex-matched controls, three months after a first-time MI between 1996 and 2000. Swedish national patient registers were used to determine cardiovascular (CV) outcomes during 20 years of follow-up. RESULTS: In cases, random forest models identified IL-6 as the most important predictor of the primary composite endpoint of death, heart failure (HF) or MI hospitalization, and the separate endpoints death and HF hospitalization. IL-18 was the most important predictor of MI hospitalization. In a Cox regression, the highest tertile of IL-6 was associated with the composite endpoint (HR (95% CI) 1.91 (1.31-2.79)), death (2.38 (1.42-3.98)) and HF hospitalization (2.70 (1.32-5.50)), when adjusting for age, sex and CV risk factors. The highest tertile of IL-18 was associated with MI hospitalization (2.31 (1.08-4.91)) when severity of coronary atherosclerosis was added to the same type of model. CONCLUSIONS: When nine inflammatory markers involved in atherosclerosis were analyzed three months after the acute event in young MI patients, IL-6 and IL-18 were the most important biomarkers to predict long-term CV outcomes during 20 years of follow-up.

Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility.

Ath1 is a quantitative trait locus on mouse chromosome 1 that renders C57BL/6 mice susceptible and C3H/He mice resistant to diet-induced atherosclerosis. The quantitative trait locus region encompasses 11 known genes, including Tnfsf4 (also called Ox40l or Cd134l), which encodes OX40 ligand. Here we report that mice with targeted mutations of Tnfsf4 had significantly (P

A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis.

All-trans retinoic acid, controlled by cytochrome P450, family 26 (CYP26) enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26 subfamily B, polypeptide 1 (CYP26B1) in atherosclerosis and the effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries, and CYP26B1 and the macrophage marker CD68 were colocalized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic arteries than in normal arteries. Databases were queried for nonsynonymous CYP26B1 single nucleotide polymorphisms (SNPs) and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophagelike cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions, as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.

Multi-organ expression profiling uncovers a gene module in coronary artery disease involving transendothelial migration of leukocytes and LIM domain binding 2: the Stockholm Atherosclerosis Gene Expression (STAGE) study.

Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n = 66/tissue) and atherosclerotic and unaffected arterial wall (n = 40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n = 15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n = 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n = 49/48) and one visceral fat (n = 59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P = 0.008 and P = 0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n = 55/54) relating to carotid stenosis (P = 0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n = 16/17, P<10(-27 and-30)). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, by cellular and lesion expression of LDB2, and by the expression of 13 TEML genes in Ldb2-deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research.

A functional interleukin-1 receptor antagonist polymorphism influences atherosclerosis development. The interleukin-1beta:interleukin-1 receptor antagonist balance in atherosclerosis.

BACKGROUND: Interleukin (IL)-beta plays a central role in inflammation and atherosclerosis, but levels of IL-1beta, its natural antagonist, IL-1Ra, and their balance in human atherosclerotic lesions, are unknown. Knowledge of protein levels in atherosclerosis and the influence of a functional IL-1Ra polymorphism would increase the understanding of atherosclerosis pathogenesis. METHODS AND RESULTS: Fresh and endotoxin-stimulated explanted human atherosclerotic and normal arteries were analyzed for IL-1beta, IL-1Ra and IL-1 receptor 1 (IL-1R1) using TaqMan PCR and enzyme-linked immunosorbent assay. Two hundred forty-three survivors of a first myocardial infarction were genotyped for a polymorphism in IL-1Ra and their coronary atherosclerosis analyzed by using coronary angiography. Levels of IL-1beta, IL-1Ra and IL-1R1 mRNA were significantly increased in atherosclerotic arteries compared with normal arteries. Endotoxin stimulation increased IL-1beta levels more than IL-1Ra levels (ie, promoted a pro-inflammatory state). A polymorphism in IL-1Ra known to increase levels of IL-1Ra was associated with decreased mean coronary artery plaque area. CONCLUSIONS: Activation of innate immunity changed the balance between IL-1beta and IL-1Ra in atherosclerotic arteries towards a more pro-inflammatory state. In line with this, the presence of an IL-1Ra intron 2 polymorphism known to increase IL-1Ra levels, and possibly the IL-1Ra:IL-1beta ratio, was associated with reduced coronary atherosclerosis.

High plasma concentrations of autoantibodies against native peptide 210 of apoB-100 are related to less coronary atherosclerosis and lower risk of myocardial infarction.

AIMS: We examined whether antibodies against peptides 45 and 210 of apoB-100 are related to myocardial infarction (MI) and severity of coronary atherosclerosis. METHODS AND RESULTS: Three hundred and eighty-seven survivors of a first MI (aged <60 years) and 387 sex- and age-matched controls were characterized in detail. IgG and IgM autoantibodies against native and malondialdehyde (MDA)-modified peptides 45 and 210 of apoB-100 (amino acids 661-680 and 3136-3155) were quantified in plasma and quantitative coronary angiography was performed in 243 patients. Post-infarction patients had significantly lower IgG against the native peptide 210 (IgG-p210(nat)) and higher IgM against the MDA-modified peptide 210 (IgM-p210(MDA)) compared with controls, whereas no differences were found for other antibodies. Plasma concentrations of IgG-p210(nat), but not IgM-p210(MDA), were independently and inversely related to the degree of coronary atherosclerosis in patients. In multiple logistic regression analysis (including established risk indicators), MI risk was 0.55 (95%CI: 0.37-0.81) for individuals in the IgG-p210(nat) upper quartile compared with the remaining individuals. CONCLUSION: Circulating IgG antibodies against the native peptide 210 of apoB-100 are inversely related to the severity of coronary atherosclerosis and associated with lower risk of MI. Epitope 210 of apoB-100 emerges as a target for immunization against atherosclerosis in humans.

[ST-elevation myocardial infarction and dual antiplatelet therapy: new guidelines]. / ST-höjningsinfarkt och dubbel trombocythämning: nya riktlinjer - Europeiska kardiologföreningens rekommendationer kommenteras av Svenska kardiologföreningens arbetsgrupp.

This report summarizes some of the most important changes and new recommendations from the ESC ST-elevation myocardial infarction and double antiplatelet therapy guidelines for 2017, which are of interest for physicians managing patients with coronary artery disease.

Haplotype effect of the matrix metalloproteinase-1 gene on risk of myocardial infarction.

Myocardial infarction (MI) is commonly caused by atherosclerotic plaque rupture following excessive degradation of collagen fibers in the atherosclerotic lesion. We investigated whether interindividual variability in risk of MI was related to polymorphisms in the gene encoding matrix metalloproteinase (MMP)-1, a key fibrillar collagen-degrading enzyme. Several single nucleotide polymorphisms in the MMP1 gene promoter were identified following sequencing DNA samples from 30 individuals. An analysis of the polymorphisms in a cohort of British whites with coronary atherosclerosis, including 639 patients with MI and 538 non-MI subjects, revealed a haplotype effect of the -519A>G and -340T>C polymorphisms on risk of MI, with the A(-519)-C(-340) and G(-519)-T(-340) haplotypes being protective (odds ratio=0.70 [0.57 to 0.86]; P=0.0007), whereas the G(-519)-C(-340) haplotype increased MI risk (odds ratio=1.94 [1.15 to 3.28]; P=0.013). This finding was replicated in a subsequent analysis of 387 Swedish MI patients and 387 healthy controls (odds ratio=0.70 [0.55 to 0.89], P=0.003, for A(-519)-C(-340) and G(-519)-T(-340); odds ratio=1.54 [0.97 to 2.46], P=0.07, for G(-519)-C(-340)). In vitro assays showed that compared with the A(-519)-T(-340) haplotype, the A(-519)-C(-340) and G(-519)-T(-340) haplotypes had lower promoter activity, whereas the G(-519)-C(-340) haplotype had greater promoter strength, in driving gene expression in human macrophages. Haplotype-specific differences in MMP1 mRNA level in atherosclerotic tissues were also detected. The data indicate that MMP1 gene variation is a genetic factor contributing to interindividual differences in MI risk.

A high-fat meal is accompanied by increased plasma interleukin-6 concentrations.

BACKGROUND AND AIM: Enhanced and prolonged postprandial lipaemia is associated with coronary heart disease (CHD). However, the mechanisms linking postprandial lipaemia to the increased risk of atherosclerosis and CHD remain to be determined. The aim of the present study was to examine the effects of a high-fat meal on plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) and cellular adhesion molecules in CHD patients and control subjects. METHODS AND RESULTS: Forty-one middle-aged men with premature CHD and 26 healthy male controls were investigated. The plasma triglyceride response to the high-fat meal was significantly greater among cases than controls. The oral fat load induced a twofold increase in plasma concentrations of IL-6, an increase that was similar in CHD patients and control subjects. No changes could be detected in plasma concentrations of cellular adhesion molecules in response to postprandial lipaemia in either CHD patients or control subjects. CONCLUSION: The results of the present study suggest that a high-fat meal affects mechanisms that induce increased inflammatory activity, which is recognised as a key modulator in the development of atherosclerosis and CHD. However, the increased levels of plasma IL-6 appear not to be determined by the magnitude of the postprandial triglyceridaemia.

Plasma interleukin (IL)-18 concentrations is elevated in patients with previous myocardial infarction and related to severity of coronary atherosclerosis independently of C-reactive protein and IL-6.

AIM: Interleukin-18 (IL-18) is a pro-inflammatory cytokine with a central role in the inflammatory cascade. In the present study, we investigated whether patients with precocious myocardial infarction have higher plasma IL-18 concentrations than matched controls. Furthermore, the relationships between plasma IL-18 concentrations and coronary atherosclerosis, C-reactive protein (CRP), interleukin-6 (IL-6) and traditional cardiovascular risk factors were examined. METHODS AND RESULTS: Three hundred eighty-seven unselected survivors of a first myocardial infarction aged less than 60 years and 387 sex and age matched controls were enrolled in the study. A subset of patients (n=236) was evaluated by quantitative coronary angiography. Postinfarction patients had significantly higher mean level of plasma IL-18 than controls (309.6+/-138.6 versus 285.4+/-115.7pg IL-18/mL). Furthermore, plasma IL-18 concentration was significantly associated with coronary plaque area (r=0.17, p=0.009). This relationship remained in a partial correlation analysis adjusting for CRP (r=0.15, p=0.02), for IL-6 (r=0.15, p=0.02) and for both CRP and IL-6 (r=0.15, p=0.02). In addition, IL-18 levels were significantly associated with other cardiovascular risk factors, namely age, low density lipoprotein (LDL) cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, insulin, proinsulin, body mass index (BMI), systolic and diastolic blood pressure. CONCLUSION: The present work provides evidence that plasma IL-18 is increased in postinfarction patients and is associated with coronary atherosclerosis.

Decreased plasma CXCL16/SR-PSOX concentration is associated with coronary artery disease.

OBJECTIVES: To investigate for the first time whether the plasma CXCL16 concentration is altered in coronary artery disease (CAD) patients. BACKGROUND: Accumulating evidence suggests that the novel chemokine/scavenger receptor CXCL16/SR-PSOX is involved in the development of atherosclerosis and CAD. METHODS: Using ELISA we assessed the plasma CXCL16 concentration in 40 stable angina pectoris (SAP) patients, 17 unstable angina pectoris/non-ST-elevation myocardial infarction (UAP/non-STEMI) patients, 387 survivors of a first myocardial infarction (MI) and healthy control subjects (44 controls for SAP and UAP/non-STEMI patient groups and 387 controls for post-MI patients). RESULTS: SAP patients exhibited significantly lower median CXCL16 levels (2111 pg/ml) than the corresponding control subjects (2678 pg/ml) (P=0.0012). UAP/non-STEMI patients also appeared to have lower CXCL16 levels (2192 pg/ml) compared with controls (NS). Patients investigated 3 months after MI tended (P=0.07) to have lower CXCL16 levels (2529 pg/ml) than the corresponding controls (2638 pg/ml). There were no significant correlations between CXCL16 levels and different measures of CAD severity determined by quantitative coronary angiography in post-MI patients. Neither patients nor controls exhibited significant correlations between CXCL16 levels and plasma lipoprotein fractions, inflammatory cytokines, C-reactive protein or numbers of inflammatory cells in peripheral blood. CONCLUSIONS: The finding that lower plasma CXCL16 concentration is associated with CAD might indicate a potential atheroprotective function of CXCL16.

A novel common single nucleotide polymorphism in the promoter region of the C-reactive protein gene associated with the plasma concentration of C-reactive protein.

The plasma CRP concentration has consistently been shown to be associated with the risk of future coronary heart disease (CHD) and recent studies have suggested that CRP has a pathogenic role in CHD. Family studies and genotype-phenotype association studies of known polymorphisms in the intron, second exon and 3'-untranslated region (UTR) have suggested that plasma CRP concentrations are under genetic control. However, no functional polymorphisms have so far been reported in the promoter region of the CRP gene. Screening of 1600 base pair (bp) of the promoter region of the CRP gene, using denaturing high performance liquid chromatography, revealed two novel common single nucleotide polymorphisms (SNPs). One of them, a three allelic SNP located at position -286 from the transcription start, was strongly associated with the plasma CRP concentration, predominantly in patients with CHD. No difference in allele frequency was seen between middle-aged post-infarction patients and population-based controls. The prognostic role and therapeutic implications in CHD and the functionality of this polymorphism remain to be determined.

Contribution of haplotypes across the fibrinogen gene cluster to variation in risk of myocardial infarction.

Fibrinogen has consistently been recognized as an independent predictor of myocardial infarction (MI). Multiple mechanisms link fibrinogen to MI; therefore disentangling the factors underlying variation in plasma fibrinogen concentration is essential. Candidate regions in the fibrinogen gamma (FGG), alpha (FGA) and beta (FGB) genes were screened for single nucleotide polymorphisms (SNPs). Several novel SNPs were detected in the FGG and FGA genes in addition to the previously known SNPs in the fibrinogen genes. Tight linkage disequilibrium extending over various physical distances was observed between most SNPs. Consequently, eight SNPs were chosen and determined in 377 postinfarction patients and 387 healthy individuals. None of the SNPs were associated with plasma fibrinogen concentration or MI. Haplotype analyses revealed a consistent pattern of haplotypes associated with variation in risk of MI. Of the four haplotypes inferred using the FGA -58G>A and FGG 1299 +79T>C SNPs, the most frequent haplotype, FGG-FGA*1 (prevalence 46.6%), was associated with increased risk of MI (OR 1.51; 95%CI 1.18, 1.93), whereas the least frequent haplotype, FGG-FGA*4 (11.8%), was associated with lower risk of MI (OR 0.79 95%CI 0.64, 0.98). In conclusion, fibrinogen haplotypes, but not SNPs in isolation, are associated with variation in risk of MI.

Human evidence that the cystatin C gene is implicated in focal progression of coronary artery disease.

OBJECTIVE: Overexpression of elastolytic cysteine and aspartic proteases, known as cathepsins, is implicated in atherogenesis. The potential significance of imbalance in expression between cathepsins and their inhibitor cystatin C in cardiovascular disease has been highlighted by the demonstration of cystatin C deficiency in human atherosclerosis and abdominal aortic aneurysms. METHODS AND RESULTS: We identified and characterized physiologically relevant polymorphisms in the promoter region of the cystatin C gene that influence cystatin C production and used these polymorphisms as a tool to examine the significance of cystatin C in coronary atherosclerosis in vivo in humans. Seven polymorphisms, all in strong-linkage disequilibrium, were identified in the cystatin C gene, of which 2 promoter polymorphisms (-82G/C and -78T/G) were functional in vitro in electromobility shift and transient transfection assays. Genotyping of 1105 individuals (237 survivors of a first myocardial infarction before age 60 and 2 independent groups comprising a total of 868 healthy individuals) revealed that the plasma cystatin C concentration was significantly lower in carriers of the mutant haplotype. Furthermore, the mutant haplotype was associated with a higher average number of stenoses per coronary artery segment in unselected postinfarction patients (N=237) undergoing routine coronary angiography. CONCLUSIONS: These results provide human evidence for an important role of cystatin C in coronary artery disease.

Autoantibodies against basement membrane collagen type IV are associated with myocardial infarction.

BACKGROUND: Collagen type IV is the major constituent of basement membranes underlying endothelial cells and is important for endothelial cell attachment and function. Autoantibodies against native collagen type IV have been found in various autoimmune diseases. Oxidation of LDL in the vascular wall results in the formation of reactive aldehydes, which could modify surrounding matrix proteins. Like oxidized LDL, these modified matrix proteins are likely to induce immune responses. We examined whether autoantibodies against native or aldehyde-modified collagen type IV are associated with myocardial infarction. METHODS: IgM and IgG against native and aldehyde-modified collagen type IV were measured by ELISA in serum from 387 survivors of a first myocardial infarction and 387 age- and sex-matched controls. RESULTS: Post-infarction patients had significantly increased levels of IgM against native collagen type IV, and IgG against native collagen type IV was present at detectable level in 17% of patients as opposed to 7% of controls (p < 0.001). Controlling for major cardiovascular risk factors demonstrated that the presence of IgG against native collagen type IV was associated with myocardial infarction (OR 2.9 (1.6-5.4), p = 0.001). Similarly, subjects in the highest quartile of IgM against native collagen type IV had increased risk of having suffered myocardial infarction (OR 3.11 (1.8-5.4), p < 0.001) after adjusting for cardiovascular risk factors. In contrast, IgG against aldehyde-modified collagen type IV was decreased in myocardial infarction patients, but this association was not independent of established cardiovascular risk factors. CONCLUSION: Autoantibodies against collagen type IV are associated with myocardial infarction independently of traditional cardiovascular risk factors.

Locating Ath8, a locus for murine atherosclerosis susceptibility and testing several of its candidate genes in mice and humans.

A previous study revealed that the difference in susceptibility to atherosclerotic lesions between inbred mouse strains SM/J and NZB/BlNJ was determined by one major locus (Ath8). In this study a (SM/J x NZB/BlNJ) F(1) x SM/J backcross localized Ath8 by quantitative trait locus mapping to chromosome 4 with a suggestive LOD score of 2.7. This quantitative trait locus (QTL) was confirmed using an (SM/J x NZB/BlNJ) intercross; Ath8 mapped to a 23cM region with a significant LOD score of 3.6. The genes for toll-like receptor 4 (T1r4), arachidonic acid epoxygenase (Cyp2j5), and angiopoietin-like protein 3 (Angptl3) map to this region. These candidate genes were analyzed for expression and sequence differences in the mouse and for associations with cardiovascular traits in human. Sequence analysis of Angptl3 shows a base pair substitution in SM, the susceptible strain, giving rise to an amino acid change in the fibrinogen homology domain of the protein. We found a significant association between ANGPTL3 and atherosclerotic lesions (P < 0.05) in human. These results suggest that Angptl3 is involved in atherosclerosis susceptibility in both mouse and human.

Serum 25-hydroxyvitamin D concentration, established and emerging cardiovascular risk factors and risk of myocardial infarction before the age of 60 years.

OBJECTIVE: We examined the relationships of serum 25-hydroxyvitamin D (25(OH)D) concentration to established and emerging cardiovascular risk factors and risk of myocardial infarction (MI) in a population-based case-control study of MI before the age of 60 years. METHODS: A total of 387 survivors of a first MI and 387 sex- and age-matched controls were included. Fasting blood samples drawn three months after the MI in cases and at the same time in the matched controls were used for biochemical analyses. RESULTS: Serum concentrations of 25(OH)D, adjusted for seasonal variation, were lower in cases than controls (55.0 (40.0-71.0) nmol/L vs 60.5 (47.0-75.0) nmol/L; median (interquartile range); standardized odds ratio (OR) for MI with 95% confidence interval in univariable analysis: 0.80 (0.69-0.93); p = 0.003). The 25(OH)D association with MI disappeared after adjustment for established and emerging risk factors (OR: 1.01 (0.82-1.25)). Current smoking and plasma levels of proinsulin and PAI-1 activity were independently associated with 25(OH)D in controls, whereas waist circumference, plasma triglycerides, proinsulin, PAI-1 activity and cystatin C, and non-Nordic ethnicity were independently associated with 25(OH)D in patients. Serial measurements of 25(OH)D (samples drawn <4 h and 3 months after the onset of MI) in 57 patients showed no systematic differences between sampling times. CONCLUSION: Vitamin D insufficiency, which is associated with a multitude of metabolic, procoagulant and inflammatory perturbations, is not independently related to premature MI. This suggests that vitamin D insufficiency either constitutes an epiphenomenon or increases the risk of MI by promoting established risk factor mechanisms that predispose to atherothrombosis.

Efficacy and safety of clopidogrel after PCI with stenting in patients on oral anticoagulants with acute coronary syndrome.

AIMS: To evaluate crude cardiovascular risk in patients with acute coronary syndrome (ACS) who are on oral anticoagulants (OAC) after percutaneous coronary intervention with stents (PCI-S) and also to evaluate if the patients on OAC after PCI-S benefit from clopidogrel. METHODS AND RESULTS: Data from RIKS-HIA and SCAAR on patients admitted to coronary care units 1997 to 2005, undergoing PCI-S (n=27,972), were evaluated. OAC were prescribed to 4.2% (n=1,183) of the patients and they had higher crude 1-year mortality than the non-OAC group, (3.6% [n=42] vs. 1.5% [n= 413], p=0.008), but after adjusting for pre-treatment patient characteristics there were no significant difference in 1-year mortality (adjusted risk ratio [adj. RR] 0.82 [95% CI 0.58-1.16]). Of patients on OAC, 56% (n=659) were also on clopidogrel at discharge. Incidence of death or myocardial infarction (MI) within one year did not differ between the clopidogrel and non-clopidogrel group, adj. RR 0.93 (95% CI 0.65-1.34). Triple therapy (OAC, clopidogrel plus aspirin) was associated with four times higher risk of any bleeding than OAC plus aspirin, adj. RR 4.27 (95% CI 1.2-15.1) but a lower incidence of death or MI than OAC plus clopidogrel adj. RR 0.63 (95% CI 0.40-0.99). CONCLUSIONS: Patients discharged on OAC after PCI-S in ACS have higher crude 1-year mortality than patients not on OAC, largely explained by age and comorbidities. Adding clopidogrel is not associated with lower incidence of death or MI at one year. Triple therapy is associated with higher risk of any bleeding than OAC plus aspirin but lower risk of death or MI than OAC plus clopidogrel.

A common polymorphism in the promoter region of the TNFSF4 gene is associated with lower allele-specific expression and risk of myocardial infarction.

BACKGROUND: The TNFSF4/TNFRSF4 system, along with several other receptor-ligand pairs, is involved in the recruitment and activation of T-cells and is therefore tentatively implicated in atherosclerosis and acute coronary syndromes. We have previously shown that genetic variants in TNFSF4 are associated with myocardial infarction (MI) in women. This prompted functional studies of TNFSF4 expression. METHODS AND RESULTS: Based on a screening of the TNFSF4 genomic region, a promoter polymorphism (rs45454293) and a haplotype were identified, conceivably involved in gene regulation. The rs45454293T-allele, in agreement with the linked rs3850641G-allele, proved to be associated with increased risk of MI in women. Haplotype-specific chromatin immunoprecipitation of activated polymerase II, as a measure of transcriptional activity in vivo, suggested that the haplotype including the rs45454293 and rs3850641 polymorphisms is functionally important, the rs45454293T- and rs3850641G-alleles being associated with lower transcriptional activity in cells heterozygous for both polymorphisms. The functional role of rs45454293 on transcriptional levels of TNFSF4 was clarified by luciferase reporter assays, where the rs45454293T-allele decreased gene expression when compared with the rs45454293C-allele, while the rs3850641 SNP did not have any effect on TNFSF4 promoter activity. Electromobility shift assay showed that the rs45454293 polymorphism, but not rs3850641, affects the binding of nuclear factors, thus suggesting that the lower transcriptional activity is attributed to binding of one or more transcriptional repressor(s) to the T-allele. CONCLUSIONS: Our data indicate that the TNFSF4 rs45454293T-allele is associated with lower TNFSF4 expression and increased risk of MI.