| 1. |
- Patel, Riyaz S., et al.
(författare)
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Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events : A GENIUS-CHD Study of Individual Participant Data
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
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| 2. |
- Patel, Riyaz S., et al.
(författare)
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Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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| 3. |
- Andersen, Thomas, et al.
(författare)
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C-X-C Ligand 16 Is an Independent Predictor of Cardiovascular Death and Morbidity in Acute Coronary Syndromes
- 2019
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 39:11, s. 2402-2410
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Tidskriftsartikel (refereegranskat)abstract
- Objective:The chemokine CXCL16 (C-X-C motif ligand 16) is a scavenger receptor for OxLDL (oxidized low-density lipoproteins) and involved in inflammation at sites of atherosclerosis. This study aimed to investigate the association of CXCL16 with clinical outcome in patients with acute coronary syndrome.Approach and Results:Serial measurements of CXCL16 were performed in a subgroup of 5142 patients randomized in the PLATO trial (Platelet Inhibition and Patient Outcome). Associations between CXCL16 and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and the individual components were assessed by multivariable Cox regression analyses. The hazard ratio per 50% increase in admission levels of CXCL16 analyzed as continuous variable was 1.64 (95% CI, 1.44-1.88), P<0.0001. This association remained statistically significant after adjustment for randomized treatment, clinical variables, CRP (C-reactive protein), leukocytes, cystatin C, NT-proBNP (N-terminal pro-brain natriuretic peptide), troponin T, GDF-15 (growth differentiation factor 15), and other biomarkers; hazard ratio 1.23 (1.05-1.45), P=0.0126. The admission level of CXCL16 was independently associated with cardiovascular death (1.50 [1.17-1.92], P=0.0014) but not with ischemic events alone, in fully adjusted analyses. No statistically independent association was found between CXCL16 measured at 1 month, or change in CXCL16 from admission to 1 month, and clinical outcomes.Conclusions:In patients with acute coronary syndrome, admission level of CXCL16 is independently related to adverse clinical outcomes, mainly driven by an association to cardiovascular death. Thus, CXCL16 measurement may enhance risk stratification in patients with this condition.
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| 4. |
- Kessler, Thorsten, et al.
(författare)
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Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention
- 2019
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Ingår i: Cardiovascular Research. - : OXFORD UNIV PRESS. - 0008-6363 .- 1755-3245. ; 115:10, s. 1512-1518
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Tidskriftsartikel (refereegranskat)abstract
- Aim A common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention. Methods and results The association of GUCY1A3 genotype and on-aspirin platelet reactivity was analysed in the genetics substudy of the ISAR-ASPI registry (n = 1678) using impedance aggregometry. The clinical outcome cardiovascular death or stent thrombosis within 30 days after stenting was investigated in a meta-analysis of substudies of the ISAR-ASPI registry, the PLATO trial (n = 3236), and the Utrecht Coronary Biobank (n = 1003) comprising a total 5917 patients. Homozygous GUCY1A3 risk allele carriers (GG) displayed increased on-aspirin platelet reactivity compared with non-risk allele (AA/AG) carriers [150 (interquartile range 91-209) vs. 134 (85-194) AU.min, P < 0.01]. More homozygous risk allele carriers, compared with non-risk allele carriers, were assigned to the high-risk group for ischaemic events (>203AU.min; 29.5 vs. 24.2%, P = 0.02). Homozygous risk allele carriers were also at higher risk for cardiovascular death or stent thrombosis (hazard ratio 1.70, 95% confidence interval 1.08-2.68; P = 0.02). Bleeding risk was not altered. Conclusion We conclude that homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30 days after coronary stenting, likely due to higher on-aspirin platelet reactivity. Whether GUCY1A3 genotype helps to tailor antiplatelet treatment remains to be investigated.
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| 5. |
- Parker, William A E, et al.
(författare)
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Equilibrative nucleoside transporter 1 gene polymorphisms and clinical outcomes following acute coronary syndromes : findings from the PLATelet inhibition and patient Outcomes (PLATO) study
- 2019
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Ingår i: Platelets. - : Informa UK Limited. - 0953-7104 .- 1369-1635. ; 30:5, s. 579-588
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Tidskriftsartikel (refereegranskat)abstract
- In the PLATelet inhibition and patient Outcomes (PLATO) study, the P2Y12 inhibitors ticagrelor and clopidogrel were compared in the treatment of acute coronary syndromes (ACS). Ticagrelor was shown to reduce occurrence of the primary end point - a composite of death from vascular causes, myocardial infarction, or stroke - compared to clopidogrel. Ticagrelor's pleiotropic effects on reuptake of adenosine via inhibition of equilibrative nucleoside transporter 1 (ENT1) have been hypothesized to contribute to this. Several polymorphisms of ENT1 are known to exist. We explored the interaction between ENT1 polymorphisms and clinical outcomes in ACS patients participating in the PLATO genetic substudy. Using genotyping data obtained in a genome-wide association study, the gene region encoding ENT1 was assessed and 94 polymorphisms were identified. After quality control filtering, data from 9943 participants were included. Subjects were divided into discovery (phase 1, n = 3970) and replication (phase 2, n = 5973) cohorts. Cox-regression analysis of the relationship between variants and seven efficacy and safety outcomes was performed in discovery, replication, and combined cohorts. Treatment-marker interactions were also determined. Although 35 variants were found with associations to the investigated outcomes reaching p < 0.05 in the discovery cohort, only one of these was replicated in phase 2 of the analysis and also reached the predetermined level of statistical significance in the combined data, taking into account the number of tests performed: the rare polymorphism rs141034817, with a frequency of 0.2%, was significantly associated with bleeding. Thirty-three treatment-marker interactions were found with a significance level of p < 0.05 in phase 1, but none was replicated in phase 2. We found no significant interaction between ENT1 genotype and clinical outcomes in ACS patients treated with ticagrelor or clopidogrel, apart from the association between a rare polymorphism and bleeding that requires further study. If ticagrelor's pleiotropic effects on adenosine uptake are clinically relevant, these do not appear to be significantly affected by variation in the ENT1 gene.
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| 6. |
- Ueland, Thor, et al.
(författare)
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Admission Levels of DKK1 (Dickkopf-1) Are Associated With Future Cardiovascular Death in Patients With Acute Coronary Syndromes
- 2019
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 39:2, s. 294-302
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Tidskriftsartikel (refereegranskat)abstract
- Objective- The Wnt/wingless signaling antagonist DKK1 (dickkopf-1) regulates platelet-mediated inflammation and may contribute to plaque destabilization. We hypothesized that DKK1 would be associated with cardiovascular outcomes.Approach and Results- We determined DKK1 levels in serum samples obtained before randomization, at discharge, and 1 and 6 months in a subset of 5165 patients with acute coronary syndromes in the PLATO trial (Platelet Inhibition and Patient Outcomes; NCT00391872). The median (interquartile range) DKK1 concentrations were 0.61 (0.20-1.27) ng/mL at baseline and increased during follow-up. The hazard ratio (95% CIs) for the composite end point (cardiovascular death, nonprocedural spontaneous myocardial infarction, or stroke) during 1 year of follow-up, per 50% increase in baseline DKK1 concentration, was 1.06 (1.02-1.10), P=0.0011, and remained significant in fully adjusted analysis with 14 conventional clinical and demographic and 6 biochemical variables, including NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-TnT (high-sensitivity troponin T), and GDF-15 (growth differentiation factor 15; 1.05 [1.00-1.09]; P=0.028). This association was mainly driven by the association with cardiovascular death, where a gradual increase in event rates was observed with increasing quartiles of DKK1 (2.7%, 3.0%, 4.3%, and 5.0%) and remained significant and unmodified in fully adjusted analysis (hazard ratio, 1.10 [1.04-1.17]; P=0.002). Change in DKK1 and levels at 1 month were unrelated to outcomes. A modifying effect of ticagrelor on DKK1 discharge levels was observed but not associated with prognosis.Conclusions- In patients with acute coronary syndromes treated with dual antiplatelet treatment, admission DKK1 levels were independently associated with a composite of cardiovascular death, myocardial infarction, or stroke and with cardiovascular death alone.
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| 7. |
- Ueland, Thor, et al.
(författare)
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Osteoprotegerin Is Associated With Major Bleeding But Not With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes : Insights From the PLATO (Platelet Inhibition and Patient Outcomes) Trial
- 2018
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Ingår i: Journal of the American Heart Association. - : WILEY. - 2047-9980. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- Background-Elevated levels of osteoprotegerin, a secreted tumor necrosis factor-related molecule, might be associated with adverse outcomes in patients with coronary artery disease. We measured plasma osteoprotegerin concentrations on hospital admission, at discharge, and at 1 and 6months after discharge in a predefined subset (n=5135) of patients with acute coronary syndromes in the PLATO (Platelet Inhibition and Patient Outcomes) trial. Methods and Results-The associations between osteoprotegerin and the composite end point of cardiovascular death, nonprocedural spontaneous myocardial infarction or stroke, and non-coronary artery bypass grafting major bleeding during 1year of follow-up were assessed by Cox proportional hazards models. Event rates of the composite end point per increasing quartile groups at baseline were 5.2%, 7.5%, 9.2%, and 11.9%. A 50% increase in osteoprotegerin level was associated with a hazard ratio (HR) of 1.31 (95% confidence interval [CI], 1.21-1.42) for the composite end point but was not significant in adjusted analysis (ie, clinical characteristics and levels of C-reactive protein, troponin T, NT-proBNP [N-terminal pro-B-type natriuretic peptide], and growth differentiation factor-15). The corresponding rates of non-coronary artery bypass grafting major bleeding were 2.4%, 2.2%, 3.8%, and 7.2%, with an unadjusted HR of 1.52 (95% CI, 1.36-1.69), and a fully adjusted HR of 1.26 (95% CI, 1.09-1.46). The multivariable association between the osteoprotegerin concentrations and the primary end point after 1month resulted in an HR of 1.09 (95% CI, 0.89-1.33); for major bleeding after 1month, the HR was 1.33 (95% CI, 0.91-1.96). Conclusions-In patients with acute coronary syndrome treated with dual antiplatelet therapy, osteoprotegerin was an independent marker of major bleeding but not of ischemic cardiovascular events. Thus, high osteoprotegerin levels may be useful in increasing awareness of increased bleeding risk in patients with acute coronary syndrome receiving antithrombotic therapy.
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| 8. |
- Zewinger, Stephen, et al.
(författare)
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Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease : a molecular and genetic association study
- 2017
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Ingår i: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:7, s. 534-543
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.Findings: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies.Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.
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| 9. |
- Åkerblom, Axel, 1977-, et al.
(författare)
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Prevalence and relevance of abnormal glucose metabolism in acute coronary syndromes : insights from the PLATelet inhibition and patient Outcomes (PLATO) trial
- 2019
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer. - 0929-5305 .- 1573-742X. ; 48:4, s. 563-569
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes mellitus (DM) and abnormal glucose metabolism are associated with cardiovascular (CV) disease. We investigated the prevalence and prognostic importance of dysglycaemia in patients with acute coronary syndromes (ACS) in the PLATelet inhibition and patient Outcomes (PLATO) trial. Diabetes was defined as known diabetes or HbA1c >= 6.5% or non-fasting glucose >= 11.1 mmol/L on admission, prediabetes as HbA1c >= 5.7% but < 6.5%, and no diabetes as HbA1c < 5.7%. The primary endpoint was the composite of CV death, spontaneous myocardial infarction type 1 (sMI) or stroke at 12 months. Multivariable Cox regression models, adjusting for baseline characteristics, and biomarkers NT-proBNP and troponin I, were used to explore the association between glycaemia and outcome. On admission, 16,007 (86.1%) patients had HbA1c and/or glucose levels available and were subdivided into DM 38.5% (6160) (1501 patients had no previous DM diagnosis), prediabetes 38.8% (6210), and no DM 22.7% (3637). Kaplan Meier event rates at 12 months for CV death, sMI or stroke per subgroups were 14.5% (832), 9.0% (522), and 8.5% (293), respectively with multivariable adjusted HRs, versus no diabetes, for diabetes: 1.71 (1.50-1.95) and for prediabetes 1.03 (0.90-1.19). Corresponding event rates for CV death were 6.9% (391), 3.4% (195) and 3.0% (102), respectively, with adjusted HRs for patients with DM of: 1.92 (1.42-2.60) and for prediabetes 1.02 (0.79-1.32). Abnormal glucose metabolism is common in ACS patients, but only patients with definite DM have an increased CV risk, indicating that prediabetes is not immediately associated with worse CV outcomes.
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| 10. |
- Åkerblom, Axel, 1977-, et al.
(författare)
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Ticagrelor in patients with heart failure after acute coronary syndromes - Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial
- 2019
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Ingår i: American Heart Journal. - : MOSBY-ELSEVIER. - 0002-8703 .- 1097-6744. ; 213, s. 57-65
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Tidskriftsartikel (refereegranskat)abstract
- Background: Heart failure (HF) following acute coronary syndromes (ACS) is associated with worse prognosis; however, the efficacy and safety of ticagrelor in patients with HF and if ticagrelor influences the risk of new-onset HF are unknown.Methods: We examined the efficacy and safety of ticagrelor compared to clopidogrel in patients with ACS in the randomized PLATelet inhibition and patient Outcomes (PLATO) trial subdivided by strata: (1) previous HF and/or clinical signs of HF on admission or (2) no HF on admission. The primary outcome was the combination of cardiovascular death, myocardial infarction, or stroke evaluated by multivariable Cox regression models. The safety outcome was major bleeding. New-onset HF was defined as an HF event after discharge in patients without previous HF.Results: Data were available in 18,556 patients, whom 2,862 (15.4%) patients had HF, including 1,584 (8.5%) patients with previous HF. Patients randomized to ticagrelor had lower risk of the composite end point regardless of HF status: hazard ratio (HR) 0.87 (95% CI: 0.73-1.03) in patients with HF and HR 0.84 (95% CI: 0.75-0.93) in patients with no HF (P = .76). Corresponding HR for major bleeding were HR 1.08 (95% CI: 0.87-1.34) and HR 1.03 (95% CI: 0.94-1.14) (P = .71). There was no difference in new-onset HF at 12 months between patients randomized to ticagrelor (4.1%, n = 278) or clopidogrel (4.0%, n = 276).Conclusions: In patients with ACS, ticagrelor is more efficacious in protecting against new ischemic events and mortality than clopidogrel irrespective of the presence of HF. There is no difference between ticagrelor or clopidogrel treatment in new-onset HF post-ACS.
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