1. |
- Patel, Riyaz S., et al.
(author)
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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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In: Circulation. - 2574-8300. ; 12:4
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Journal article (peer-reviewed)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.
(author)
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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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In: Circulation. - 2574-8300. ; 12:4
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Journal article (peer-reviewed)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. |
- Zewinger, Stephen, et al.
(author)
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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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In: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:7, s. 534-543
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Journal article (peer-reviewed)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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4. |
- Nelson, C. P., et al.
(author)
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Genetically Determined Height and Coronary Artery Disease
- 2015
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 372:17, s. 1608-1618
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Journal article (peer-reviewed)abstract
- BACKGROUND The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear.METHODS We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes.RESULTS We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quar-tile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis.CONCLUSIONS There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association.
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5. |
- Zhao, J. H., et al.
(author)
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Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
- 2023
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In: Nature Immunology. - : Springer Nature. - 1529-2908 .- 1529-2916. ; 24:9, s. 1540-1551
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Journal article (peer-reviewed)abstract
- Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-alpha in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization. Here the authors identify genetic effectors of the level of inflammation-related plasma proteins and use Mendelian randomization to identify proteins that contribute to immune-mediated disease risk.
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6. |
- d'Alessandro, Elisa, et al.
(author)
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Thrombo-Inflammation in Cardiovascular Disease : An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis
- 2020
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In: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 120:4, s. 538-564
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Journal article (peer-reviewed)abstract
- Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.
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7. |
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8. |
- Batra, Gorav, et al.
(author)
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Effects of early myocardial reperfusion and perfusion on myocardial necrosis/dysfunction and inflammation in patients with ST-segment and non-ST-segment elevation acute coronary syndrome : results from the PLATelet inhibition and patients Outcomes (PLATO) trial
- 2022
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In: European Heart Journal. - : Oxford University Press. - 2048-8726 .- 2048-8734. ; 11:4, s. 336-349
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Journal article (peer-reviewed)abstract
- Aims Restoration of myocardial blood flow and perfusion during percutaneous coronary intervention (PCI) measured using Thrombolysis in Myocardial Infarction (TIMI) flow grade (TFG) and perfusion grade (TMPG) is associated with improved outcomes in acute coronary syndrome (ACS). Associations between TFG/TMPG and changes in biomarkers reflecting myocardial damage/dysfunction and inflammation is unknown. Methods and results Among 2606 patients included, TFG was evaluated in 2198 and TMPG in 1874 with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment ACS (NSTE-ACS). Biomarkers reflecting myocardial necrosis [troponin T (TnT)], myocardial dysfunction [N-terminal prohormone brain natriuretic peptide (NT-proBNP)], inflammation [interleukin-6 (IL-6) and C-reactive protein (CRP)], and oxidative stress/ageing/inflammation [growth differentiation factor-15 (GDF-15)] were measured at baseline, discharge, and 1- and 6-month post-randomization. Associations between TFG/TMPG and changes in biomarker levels were evaluated using the Mann-Whitney-Wilcoxon signed test. In total, 1423 (54.6%) patients had STEMI and 1183 (45.4%) NSTE-ACS. Complete reperfusion after PCI with TFG = 3 was achieved in 1110 (85.3%) with STEMI and in 793 (88.5%) with NSTE-ACS. Normal myocardial perfusion with TMPG = 3 was achieved in 475 (41.6%) with STEMI and in 396 (54.0%) with NSTE-ACS. Levels of TnT, NT-proBNP, IL-6, CRP, and GDF-15 were substantially lower at discharge in patients with complete vs. incomplete TFG and STEMI (P < 0.01). This pattern was not observed for patients with NSTE-ACS. Patients with normal vs. abnormal TMPG and NSTE-ACS had lower levels of NT-proBNP at discharge (P = 0.01). Conclusions Successful restoration of epicardial blood flow in STEMI was associated with less myocardial necrosis/dysfunction and inflammation. Attainment of normal myocardial perfusion was associated with less myocardial dysfunction in NSTE-ACS.
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9. |
- Nelson, Thomas A, et al.
(author)
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Differential effect of clopidogrel and ticagrelor on leukocyte count in relation to patient characteristics, biomarkers and genotype : a PLATO substudy.
- 2022
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In: Platelets. - : Taylor & Francis. - 0953-7104 .- 1369-1635. ; 33:3, s. 425-431
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Journal article (peer-reviewed)abstract
- Inflammation plays a key role in cardiovascular disease by contributing to atherothrombosis. The PLATelet inhibition and patient Outcomes (PLATO) study (NCT00391872) compared ticagrelor to clopidogrel in patients with acute coronary syndromes and demonstrated fewer cardiovascular events with ticagrelor but lower white blood cell counts (WBC) with clopidogrel. In this further analysis of the PLATO biomarker substudy, we assessed associations between WBC and clinical characteristics, biomarker levels, and CYP2C19 polymorphisms.On-treatment mean (SD) WBC in the clopidogrel group was mildly reduced at each stage of follow-up compared with either the ticagrelor group (1 month: 7.27 (2.1) and 7.67 (2.23) x109/L for clopidogrel and ticagrelor, respectively; p < .001) or following cessation of clopidogrel (7.23 (1.97) x109/L, at 6 months vs 7.56 (2.28) x109/L after treatment cessation; P < .001). This occurred independently of baseline biomarkers and CYP2C19 genotype (where known). Adjusting for clinical characteristics and other biomarkers, no significant interaction was detected between clinical risk factors and the observed effect of clopidogrel on WBC.Clopidogrel weakly suppresses WBC, independent of clinical characteristics, baseline inflammatory biomarker levels, and CYP2C19 genotype. Further work is required to determine the mechanism for this effect and whether it contributes to clopidogrel's efficacy as well as therapeutic interaction with anti-inflammatory drugs.
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10. |
- Vedin, Ola, et al.
(author)
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Associations between tooth loss and prognostic biomarkers and the risk for cardiovascular events in patients with stable coronary heart disease
- 2017
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In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 245, s. 271-276
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Journal article (peer-reviewed)abstract
- Background:Underlying mechanisms behind the hypothesized relationship between periodontal disease (PD) and coronary heart disease (CHD) have been insufficiently explored. We evaluated associations between self-reported tooth loss-a marker of PD- and prognostic biomarkers in 15,456 (97%) patients with stable CHD in the global STABILITY trial.Methods and results:Baseline blood samples were obtained and patients reported their number of teeth according to the following tooth loss levels: "26-32 (All)" [lowest level], "20-25", "15-19", "1-14", and "No Teeth" [highest level]. Linear and Cox regression models assessed associations between tooth loss levels and biomarker levels, and the relationship between tooth loss levels and outcomes, respectively.After multivariable adjustment, the relative biomarker increase between the highest and the lowest tooth loss level was: high-sensitivity C-reactive protein 1.21 (95% confidence interval, 1.14-1.29), interleukin 6 1.14 (1.10-1.18), lipoprotein-associated phospholipase A(2) activity 1.05 (1.03-1.06), growth differentiation factor 15 1.11 (1.08-1.14), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) 1.18 (1.11-1.25). No association was detected for high-sensitivity troponin T 1.02 (0.98-1.05). Some attenuation of the relationship between tooth loss and outcomes resulted from the addition of biomarkers to the multivariable analysis, of which NT-proBNP had the biggest impact.Conclusions:A graded and independent association between tooth loss and several prognostic biomarkers was observed, suggesting that tooth loss and its underlying mechanisms may be involved in multiple pathophysiological pathways also implicated in the development and prognosis of CHD. The association between tooth loss and cardiovascular death and stroke persisted despite comprehensive adjustment including prognostic biomarkers.
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11. |
- Batra, Gorav, et al.
(author)
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Biomarker-Based Prediction of Recurrent Ischemic Events in Patients With Acute Coronary Syndromes
- 2022
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In: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 80:18, s. 1735-1747
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Journal article (peer-reviewed)abstract
- BACKGROUND: In patients with acute coronary syndrome (ACS), there is residual and variable risk of recurrent ischemic events.OBJECTIVES: This study aimed to develop biomarker-based prediction models for 1-year risk of cardiovascular (CV) death and myocardial infarction (MI) in patients with ACS undergoing percutaneous coronary intervention.METHODS: We included 10,713 patients from the PLATO (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome) trial in the development cohort and externally validated in 3,508 patients from the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial. Variables contributing to risk of CV death/MI were assessed using Cox regression models, and a score was derived using subsets of variables approximating the full model.RESULTS: There were 632 and 190 episodes of CV death/MI in the development and validation cohorts. The most important predictors of CV death/MI were the biomarkers, growth differentiation factor 15, and N-terminal pro-B-type natriuretic peptide, which had greater prognostic value than all candidate variables. The final model included 8 items: age (A), biomarkers (B) (growth differentiation factor 15 and N-terminal pro-B-type natriuretic peptide), and clinical variables (C) (extent of coronary artery disease, previous vascular disease, Killip class, ACS type, P2Y12 inhibitor). The model, named ABC-ACS ischemia, was well calibrated and showed good discriminatory ability for 1-year risk of CV death/MI with C-indices of 0.71 and 0.72 in the development and validation cohorts, respectively. For CV death, the score performed better, with C-indices of 0.80 and 0.84 in the development and validation cohorts, respectively.CONCLUSIONS: An 8-item score for the prediction of CV death/MI was developed and validated for patients with ACS undergoing percutaneous coronary intervention. The ABC-ACS ischemia score showed good calibration and discrimination and might be useful for risk prediction and decision support in patients with ACS. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872; Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER]; NCT00527943)
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12. |
- Batra, Gorav, et al.
(author)
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Interleukin 6 and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Chronic Coronary Syndrome
- 2021
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In: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 6:12, s. 1440-1445
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Journal article (peer-reviewed)abstract
- Importance: Inflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. It is unclear how inflammation mediated by interleukin 6 (IL-6) in patients with CKD is linked to cardiovascular disease.Objective: To investigate associations between IL-6 and cardiovascular outcomes in patients with chronic coronary syndrome in association with kidney function.Design, Setting, and Participants: This multicenter cohort study included patients enrolled at 663 centers in 39 countries with chronic coronary syndrome who were included in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial. Patients were enrolled between December 2008 and April 2010 and were followed up for a median length of 3.7 years. Analysis in this substudy began September 2020.Exposures: Exposures were IL-6 and creatinine estimated glomerular filtration rates (eGFR), which were collected at baseline. Associations between continuous and categorical levels (<2.0 ng/L vs ≥2.0 ng/L) of IL-6 and cardiovascular outcomes were tested in association with eGFR cutoffs (normal eGFR level [≥90 mL/min/1.73 m2], mildly decreased eGFR level [60-90 mL/min/1.73 m2], and moderately to severely decreased eGFR level [<60 mL/min/1.73 m2]).Main Outcomes and Measures: Main outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke.Results: This substudy of the STABILITY trial included 14 611 patients with available IL-6 levels at baseline. The median (interquartile range) age was 65 (59-71) years, and 2700 (18.5%) were female. During follow-up, MACE occurred in 1459 individuals (10.0%). Higher levels of IL-6 were in continuous models independently associated with risk of MACE (P < .001) in all CKD strata. Using predefined strata, elevated IL-6 level (≥2.0 vs <2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio, 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [hazard ratio, 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [hazard ratio, 1.60; 95% CI, 1.28-1.99]).Conclusions and Relevance: In patients with chronic coronary syndrome, elevated levels of IL-6 were associated with risk of MACE in all CKD strata. Thus, IL-6 and CKD stage may help when identifying patients with chronic coronary syndrome for anti-inflammatory treatment.
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13. |
- Braun, Oscar, et al.
(author)
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Greater reduction of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease
- 2008
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In: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 100:4, s. 626-633
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Journal article (peer-reviewed)abstract
- Prasugrel, a novel P2Y(12) ADP-receptor antagonist, has been reported to achieve greater inhibition of platelet aggregation compared to clopidogrel as assessed by light transmission aggregometry. It was the objective of this study to investigate the effect of prasugrel on alternative markers of platelet activation in comparison to a high loading dose and the approved maintenance dose of clopidogrel. One hundred ten aspirin-treated patients with stable coronary artery disease were randomized to a loading dose (LD, day 1)/ maintenance dose (MD, days 2-29) of prasugrel 60 mg/10 mg or clopidogrel 600 mg/75 mg. Platelet activation markers were analyzed by whole blood flow cytometry pre-dose and at 2 and 24 hours after LD and pre-dose at 14 and 29 days. After stimulation with 20 muM ADP, 2 hours after LD, significantly lower expression of activated GPIIb/IIIa (4.3 vs. 21.8 [mean fluorescent intensity (MFI)], p < 0.001) and P-selectin (2.0 vs. 11.7 MFI, p < 0.001) along with decreased formation of platelet-monocyte aggregates (16.4% vs. 29.6% positive cells, p < 0.001) was observed with prasugrel versus clopidogrel. All these effects were maintained through 24 hours and during the MD period. In conclusion, prasugrel 60 mg LD and 10 mg MD inhibit several markers of platelet activation and the formation of platelet-monocyte aggregates more effectively than a 600 mg LD and 75 mg MD of clopidogrel. Attenuated platelet aggregation and reduced expression of platelet pro-coagulant and pro-inflammatory markers with prasugrel suggest the potential to reduce cardiovascular events both in the acute setting and in long-term treatment.
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14. |
- Eggers, Kai M., 1962-, et al.
(author)
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Temporal biomarker concentration patterns during the early course of acute coronary syndrome
- 2024
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In: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter. - 1434-6621 .- 1437-4331. ; 62:6, s. 1167-1176
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Journal article (peer-reviewed)abstract
- Objectives: Biomarker concentrations and their changes during acute coronary syndrome (ACS) provide clinically useful information on pathophysiological processes, e.g. myocardial necrosis, hemodynamic stress and inflammation. However, current evidence on temporal biomarker patterns early during ACS is limited, and studies investigating multiple biomarkers are lacking.Methods: We measured concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI), NT-terminal pro-B-type natriuretic peptide, C-reactive protein, and growth-differentiation factor-15 (GDF-15) in plasma samples obtained at randomization in ACS patients from the PLATelet inhibition and patient Outcomes (PLATO) trial. Linear regressions with interaction analyses were used to investigate the associations of biomarker concentrations with the time from symptom onset and to model temporal biomarker concentration patterns.Results: The study population consisted of 16,944 patients (median age 62 years; 71.3 % males) with 6,853 (40.3 %) having ST-elevation myocardial infarction (STEMI) and 10,141 (59.7 %) having non-ST-elevation ACS (NSTE-ACS). Concentrations of all biomarkers were associated with time from symptom onset (pinteraction<0.001), apart for GDF-15 (pinteraction=0.092). Concentration increases were more pronounced in STEMI compared to NSTE-ACS. Temporal biomarker patterns for hs-cTnT and hs-cTnI were different depending on sex whereas biomarker patterns for the other biomarkers were similar in cohorts defined by age and sex.Conclusions: Temporal concentration patterns differ for various biomarkers early during ACS, reflecting the variability in the activation and duration of different pathophysiological processes, and the amount of injured myocardium. Our data emphasize that the time elapsed from symptom onset should be considered for the interpretation of biomarker results in ACS.
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15. |
- Erlinge, David, et al.
(author)
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Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo
- 2008
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 52:24, s. 1968-77
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Journal article (peer-reviewed)abstract
- OBJECTIVES: We evaluated the prevalence and mechanism of poor responsiveness to clopidogrel and prasugrel in coronary artery disease patients with and without diabetes. BACKGROUND: Low platelet inhibition by clopidogrel is associated with ischemic clinical events. A higher 600-mg loading dose (LD) has been advocated to increase responsiveness to clopidogrel. METHODS: In this study, 110 aspirin-treated patients were randomized to double-blind treatment with clopidogrel 600 mg LD/75 mg maintenance dose (MD) for 28 days or prasugrel 60 mg LD/10 mg MD for 28 days. Pharmacodynamic (PD) response was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The PD poor responsiveness was defined with 4 definitions previously associated with worse clinical outcomes. Active metabolites (AM) of clopidogrel and prasugrel were measured. Clopidogrel AM was added ex vivo. RESULTS: The proportion of patients with poor responsiveness was greater in the clopidogrel group for all definitions at all time points from 1 h to 29 days. Poor responders had significantly lower plasma AM levels compared with responders. Patients with diabetes were over-represented in the poor-responder groups and had significantly lower levels of AM. Platelets of both poor responders and diabetic patients responded fully to AM added ex vivo. CONCLUSIONS: Prasugrel treatment results in significantly fewer PD poor responders compared with clopidogrel after a 600-mg clopidogrel LD and during MD. The mechanism of incomplete platelet inhibition in clopidogrel poor-responder groups and in diabetic patients is lower plasma levels of its AM and not differences in platelet P2Y(12) receptor function.
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16. |
- Giannitsis, Evangelos, et al.
(author)
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Outcomes after planned invasive or conservative treatment strategy in patients with non-ST-elevation acute coronary syndrome and a normal value of high sensitivity troponin at randomisation : A Platelet Inhibition and Patient Outcomes (PLATO) trial biomarker substudy.
- 2017
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In: European Heart Journal. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 6:6, s. 500-510
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Journal article (peer-reviewed)abstract
- AIMS: Current guidelines for patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) recommend early invasive treatment in intermediate-to-high risk patients based on medical history, electrocardiogram (ECG) and elevated troponin. Patients with normal levels of cardiac troponin measured with a high-sensitivity method (cTnT-hs) might not benefit from early invasive procedures.METHODS AND RESULTS: In this Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) blood-core substudy, 1232 patients presented with NSTE-ACS had a high sensitivity cardiac troponin T (cTnT-hs) level <99(th) percentile (<14 ng/l) at randomisation. The outcomes in relation to a planned invasive (n=473) vs planned conservative treatment (n=759), were evaluated by adjusted Cox proportional hazard analyses. In patients with a normal cTnT-hs at randomisation, regardless of randomised treatment, a planned invasive vs conservative treatment was associated with a 2.3-fold higher risk (7.3% vs 3.4%, p=0.0028) for cardiovascular (CV) death or myocardial infarction (MI), driven by higher rates of procedure-related MI (3.4% vs 0.1%), while there were no differences in rates of CV death (1.3% vs 1.3%, p=0.72) or spontaneous MI (3.0% vs 2.1%, p=0.28). There were significantly more major bleeds (hazard ratio (HR) 2.98, p<0.0001), mainly due to coronary artery bypass graft (CABG)-related (HR 4.05, p<0.0001) and non-CABG procedural-related major bleeding events (HR 5.31, p=0.0175), however there were no differences in non-procedure-related major bleeding (1.5% vs 1.9%, p=0.45). Findings were consistent for patients with a normal cTnI-hs at randomisation.CONCLUSIONS: In patients with NSTE-ACS and normal cTnT-hs, a planned early invasive treatment strategy was associated with increased rates of procedure-related MI and bleeding but no differences in long-term spontaneous MI, non-procedure-related bleeding or mortality.
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17. |
- Held, Claes, 1956-, et al.
(author)
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Inflammatory Biomarkers Interleukin-6 and C-Reactive Protein and Outcomes in Stable Coronary Heart Disease : Experiences From the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial
- 2017
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In: Journal of the American Heart Association. - 2047-9980. ; 6:10
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Journal article (peer-reviewed)abstract
- BackgroundEvaluation of cardiovascular prognosis in patients with stable coronary heart disease is based on clinical characteristics and biomarkers indicating dysglycemia, dyslipidemia, renal dysfunction, and possibly cardiac dysfunction. Inflammation plays a key role in atherosclerosis, but the association between inflammatory biomarkers and clinical outcomes is less studied in this population.Methods and ResultsOverall, 15 828 patients with coronary heart disease in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial werer and randomized to treatment with darapladib or placebo and observed for a median of 3.7 years. In 14 611 patients, levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein were measured in plasma samples: median levels were2.1 (interquartile range, 1.4-3.2) ng/Land1.3 (interquartile range, 0.6-3.1) mg/L, respectively. Associations between continuous levels or quartile groups and adjudicated outcomes were evaluated by spline graphs and Cox regression adjusted for clinical factors and cardiovascular biomarkers. IL-6 was associated with increased risk of major adverse cardiovascular events (quartile 4 versus quartile 1 hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.30-1.97; P< 0.0001); cardiovascular death (HR, 2.15; 95% CI, 1.53-3.04; P< 0.0001); myocardial infarction (HR, 1.53; 95% CI, 1.14-2.04; P< 0.05); all-cause mortality (HR, 2.11; 95% CI, 1.62-2.76; P< 0.0001); and risk of hospitalization for heart failure (HR, 2.28; 95% CI, 1.34-3.89; P< 0.001). Cancer death was doubled in the highest IL-6 quartile group (HR, 2.34; 95% CI, 1.20-4.53; P< 0.05). High-sensitivity C-reactive protein was associated with both cardiovascular and non-cardiovascular events in the unadjusted model, but these did not remain after multivariable adjustments.ConclusionsIL-6, an upstream inflammatory marker, was independently associated with the risk of major adverse cardiovascular events, cardiovascular and all-cause mortality, myocardial infarction, heart failure, and cancer mortality in patients with stable coronary heart disease. IL-6 might reflect a pathophysiological process involved in the development of these events.
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18. |
- Hijazi, Ziad, et al.
(author)
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Growth-differentiation factor 15 and risk of major bleeding in atrial fibrillation : Insights from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial
- 2017
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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 190, s. 94-103
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To evaluate and validate the prognostic value of growth-differentiation factor 15 (GDF-15) beyond clinical characteristics and other biomarkers concerning bleeding and stroke outcomes in patients with atrial fibrillation in the RE-LY trial.METHODS: GDF-15 was measured in samples collected at randomization in 8,474 patients with a median follow-up time of 1.9 years. Patients were stratified based on predefined GDF-15 cutoffs: group 1, <1,200 ng/L (the 90th percentile in healthy individuals); group 2, 1,200-1,800; and group 3, >1,800 ng/L (high-risk individuals). Efficacy and safety outcomes were compared across groups of GDF-15 in Cox models adjusted for baseline characteristics, cardiac (N-terminal pro-b-type natriuretic peptide, high-sensitive troponin T), inflammatory (interleukin 6, C-reactive protein) and coagulation (D-dimer) biomarkers, and randomized treatment.RESULTS: GDF-15 concentrations were <1,200 ng/L in 2,647 (31.2%), between 1,200 and 1,800 ng/L in 2,704 (31.9%), and >1,800 ng/L in 3,123 (36.9%) participants, respectively. Annual rates of stroke, major bleeding, and mortality increased with higher GDF-15 levels. The prognostic value of GDF-15 was independent of clinical characteristics for these outcomes. In models also adjusted for biomarkers, GDF-15 remained significantly associated with major bleeding (hazard ratio [95% CI] group 3 vs group 1 1.76 [1.28-2.42], P < .0005) and all-cause mortality (hazard ratio 1.72 [1.30-2.29], P < .0005). GDF-15 improved the c index of both the HAS-BLED (0.62-0.69) and ORBIT (0.68-0.71) bleeding risk scores.CONCLUSIONS: In patients with atrial fibrillation, GDF-15 is an independent risk indicator for major bleeding and all-cause mortality, but not for stroke. Therefore, GDF-15 seems useful as a specific marker of bleeding in patients with AF on oral anticoagulant treatment.
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19. |
- Hilvo, Mika, et al.
(author)
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Prediction of Residual Risk by Ceramide-Phospholipid Score in Patients With Stable Coronary Heart Disease on Optimal Medical Therapy
- 2020
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In: Journal of the American Heart Association. - : WILEY. - 2047-9980. ; 9:10
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Journal article (peer-reviewed)abstract
- BACKGROUND: Identification of patients with stable coronary heart disease who are at significant residual risk could be helpful for targeted prevention. Our aim was to determine the prognostic value of the recently introduced ceramide-and phospholipid-based risk score, the Cardiovascular Event Risk Test (CERT2), in patients with stable coronary heart disease on optimal medical therapy and to identify biological processes that contribute to the CERT2 score. METHODS AND RESULTS: Plasma samples (n=11 222) obtained from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were analyzed using a tandem liquid chromatography-mass spectrometry method. STABILITY was a trial in patients with stable coronary heart disease randomized to the lipoprotein-associated phospholipase A2 inhibitor darapladib or placebo on optimized medical therapy at baseline, with a median follow-up of 3.7 years. Hazard ratios per SD for the CERT2 risk score were 1.32 (95% CI, 1.25-1.39) for major adverse cardiovascular event, 1.47 (95% CI, 1.35-1.59) for cardiovascular death, 1.32 (95% CI, 1.16-1.49) for stroke, 1.23 (95% CI, 1.14-1.33) for myocardial infarction, and 1.56 (95% CI, 1.39-1.76) for hospitalization due to heart failure, when adjusted for traditional cardiovascular risk factors. CERT2 showed correlation (P<0.001, r>0.2) with inflammatory markers high-sensitivity C-reactive protein, interleukin 6, the heart failure marker N-terminal pro-B-type natriuretic peptide, and low-density lipoprotein cholesterol. After also adjusting for levels of other prognostic biomarkers, the CERT2 score was still independently related to the risk of cardiovascular death but not to nonfatal events. CONCLUSIONS: The CERT2 risk score can detect residual risk in patients with stable coronary heart disease and is associated with biomarkers indicating inflammation, myocardial necrosis, myocardial dysfunction, renal dysfunction, and dyslipidemia.
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20. |
- Hjort, Marcus, 1988-, et al.
(author)
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Biomarker Concentrations and Their Temporal Changes in Patients With Myocardial Infarction and Nonobstructive Compared With Obstructive Coronary Arteries : Results From the PLATO Trial
- 2023
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In: Journal of the American Heart Association. - : American heart association. - 2047-9980. ; 12:1
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Journal article (peer-reviewed)abstract
- Background: The pathobiology of myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is often uncertain. Investigating biomarker concentrations and their changes may offer novel pathophysiological insights.Methods and Results: In this post hoc study of the PLATO (Platelet Inhibition and Patient Outcomes) trial, concentrations of hs‐cTnT (high‐sensitivity cardiac troponin T), NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), hs‐CRP (high‐sensitivity C‐reactive protein), and GDF‐15 (growth differentiation factor 15) were measured in patients with MINOCA at baseline (n=554) and at 1‐month follow‐up (n=107). For comparisons, biomarkers were also measured in patients with MI with obstructive (stenosis ≥50%) coronary artery disease (baseline: n=11 106; follow‐up: n=2755]). Adjusted linear regression models were used to compare concentrations and their short‐ and long‐term changes. The adjusted geometric mean ratios (GMRs) in patients with MINOCA (median age, 61 years; 50.4% women) indicated lower hs‐cTnT (GMR, 0.77 [95% CI, 0.68–0.88]) but higher hs‐CRP (GMR, 1.21 [95% CI, 1.08–1.37]) and GDF‐15 concentrations (GMR, 1.06 [95% CI, 1.02–1.11]) at baseline compared with patients with MI with obstructive coronary artery disease, whereas NT‐proBNP concentrations were similar. Temporal decreases in hs‐cTnT, NT‐proBNP, and hs‐CRP concentrations until 1‐month follow‐up were more pronounced in patients with MINOCA. At follow‐up, patients with MINOCA had lower concentrations of hs‐cTnT (GMR, 0.71 [95% CI, 0.60–0.84]), NT‐proBNP (GMR, 0.45 [95% CI, 0.36–0.56]), and hs‐CRP (GMR, 0.68 [95% CI, 0.53–0.86]). One‐month GDF‐15 concentrations were similar between both groups with MI.Conclusions: Biomarker concentrations suggest greater initial inflammatory activity, similar degree of myocardial dysfunction, and less pronounced myocardial injury during the acute phase of MINOCA compared with MI with obstructive coronary artery disease but also faster myocardial recovery.CLINICAL TRAIL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.
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21. |
- Jernberg, Tomas, et al.
(author)
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Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease
- 2006
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 27:10, s. 1166-1173
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Journal article (peer-reviewed)abstract
- AIMS: This study was designed to compare the degree of inhibition of platelet aggregation (IPA) of prasugrel with that of clopidogrel in stable aspirin-treated patients with coronary artery disease (CAD). METHODS AND RESULTS: Subjects (n=101) were randomly assigned to the following loading dose (LD) (day 1)/maintenance dose (MD) (days 2-28) combinations: prasugrel, 40 mg/5 mg; 40 mg/7.5 mg; 60 mg/10 mg; 60 mg/15 mg; or clopidogrel, 300 mg/75 mg. Turbidometric platelet aggregation was measured at multiple timepoints during the study. At 4 h after dosing, with 20 microM ADP, both prasugrel LDs achieved significantly higher mean IPA levels (60.6% and 68.4 vs. 30.0%, respectively; all P<0.0001) and lower percentage (3 vs. 52%, P<0.0001) of pharmacodynamic non-responders (defined as IPA <20%) than clopidogrel. Prasugrel 10 and 15 mg MDs achieved consistently higher mean IPA than clopidogrel 75 mg at day 28 (all P<0.0001). At pre-MD on day 28, there were no non-responders in the 10 and 15 mg prasugrel group, compared with 45% in the clopidogrel group (P=0.0007). CONCLUSION: In this population, prasugrel (40-60 mg LD and 10-15 mg MD) achieves greater IPA and a lower proportion of pharmacodynamic non-responders compared with the approved clopidogrel dosing.
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22. |
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23. |
- Lindholm, Daniel, 1982-, et al.
(author)
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Biomarker-Based Risk Model to Predict Cardiovascular Mortality in Patients With Stable Coronary Disease
- 2017
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In: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 70:7, s. 813-826
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Journal article (peer-reviewed)abstract
- Background Currently, there is no generally accepted model to predict outcomes in stable coronary heart disease (CHD).Objectives This study evaluated and compared the prognostic value of biomarkers and clinical variables to develop a biomarker-based prediction model in patients with stable CHD.Methods In a prospective, randomized trial cohort of 13,164 patients with stable CHD, we analyzed several candidate biomarkers and clinical variables and used multivariable Cox regression to develop a clinical prediction model based on the most important markers. The primary outcome was cardiovascular (CV) death, but model performance was also explored for other key outcomes. It was internally bootstrap validated, and externally validated in 1,547 patients in another study.Results During a median follow-up of 3.7 years, there were 591 cases of CV death. The 3 most important biomarkers were N-terminal pro–B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and low-density lipoprotein cholesterol, where NT-proBNP and hs-cTnT had greater prognostic value than any other biomarker or clinical variable. The final prediction model included age (A), biomarkers (B) (NT-proBNP, hs-cTnT, and low-density lipoprotein cholesterol), and clinical variables (C) (smoking, diabetes mellitus, and peripheral arterial disease). This “ABC-CHD” model had high discriminatory ability for CV death (c-index 0.81 in derivation cohort, 0.78 in validation cohort), with adequate calibration in both cohorts.Conclusions This model provided a robust tool for the prediction of CV death in patients with stable CHD. As it is based on a small number of readily available biomarkers and clinical factors, it can be widely employed to complement clinical assessment and guide management based on CV risk. (The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial [STABILITY]; NCT00799903)
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24. |
- Lindholm, Daniel P, 1982-, et al.
(author)
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Growth Differentiation Factor 15 at 1 Month After an Acute Coronary Syndrome Is Associated With Increased Risk of Major Bleeding.
- 2017
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In: Journal of the American Heart Association. - 2047-9980. ; 6:4
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Journal article (peer-reviewed)abstract
- BACKGROUND: Growth differentiation factor-15 (GDF-15) is related to major bleeding when measured at initial presentation in patients with acute coronary syndromes (ACSs) treated with dual antiplatelet therapy. It is unknown whether follow-up measurements provide additional information. The objective of this study was to investigate whether GDF-15 measured 1 month after an ACS provides additional information beyond the baseline levels with regard to the risk of major bleeding.METHODS AND RESULTS: GDF-15 was measured at baseline and at 1 month after an ACS in 4049 patients included in the PLATelet inhibition and patient Outcomes (PLATO) trial. The association between 1-month GDF-15 level and non-coronary artery bypass grafting surgery-related major bleeding was assessed by a multivariable Cox model, adjusting for baseline GDF-15, age, anemia, impaired renal function, history of gastrointestinal bleeding, and sex. Elevated GDF-15 (>1800 ng/L) at 1 month was associated with an increased risk of non-coronary artery bypass grafting-related major bleeding (3.9% versus 1.2%; hazard ratio, 3.38; 95% CI, 1.89-6.06), independent of baseline GDF-15. Patients who had elevated GDF-15 levels at baseline and subsequent nonelevated GDF-15 at 1 month had a similar risk as patients who had nonelevated levels at both measurements.CONCLUSIONS: GDF-15 at 1 month after an ACS is related to the risk of bleeding during DAPT and provides additional information on the bleeding risk beyond baseline GDF-15 levels. GDF-15 levels may therefore be useful as part of decision support concerning long-term antithrombotic treatment in patients post-ACS.CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.
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25. |
- Lowenstern, Angela, et al.
(author)
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Platelet-related biomarkers and their response to inhibition with aspirin and p2y12-receptor antagonists in patients with acute coronary syndrome
- 2017
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In: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 44:2, s. 145-153
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Journal article (peer-reviewed)abstract
- The PLATelet inhibition and patient Outcomes (PLATO) trial showed that treatment with ticagrelor reduced the rate of death due to vascular causes, myocardial infarction and stroke when compared to clopidogrel in patients with ST-elevation or non-ST-elevation acute coronary syndrome (ACS). While the comparative benefit of ticagrelor over clopidogrel increased over time, event rates accrued in both groups during the study period. The purpose of our biomarker-based exploratory analysis was to determine whether long-term platelet inhibition may be associated with platelet adaptation. A sample of 4000 participants from the PLATO trial also consented to participate in a prospectively designed biomarker substudy. Blood samples were procured at baseline, immediately prior to hospital discharge and at 1 and 6 months. Markers of platelet activity, including platelet count, serum CD40-ligand and soluble P-selectin were analyzed. Mean levels were compared at discharge, 1 and 6 months following study drug initiation-first for all patients and subsequently stratified by treatment group. A linear mixed model was used to estimate the short-term change rate (baseline to 1 month) and long-term change rate (1-6 months) for each biomarker. A Cox proportional hazards model was used to calculate hazard ratios for each change in biomarker over the two time periods examined: baseline to 1 month and 1 to 6 months. Prior to randomized treatment (baseline), sCD40 ligand and sP-selectin levels were elevated above the normal range of the assay (0.39 and 33.5 A μg/L, respectively). The mean level of each biomarker was significantly different at 1 month compared to baseline (p < 0.0001). When stratified by treatment group, at 1 month patients treated with ticagrelor had a larger increase in platelet count compared to those treated with clopidogrel (p < 0.0001). Similarly, when comparing biomarker levels for all patients at 6 months with those at 1 month, each differed significantly (p < 0.05). There was no significant difference between treatment groups during this time period. The rate of change for both platelet count and sP-selectin were significantly different between baseline and 1 month when compared to the 1 to 6-month time period (p < 0.0001). When comparing treatment groups, the rate of increase in platelets from baseline to 1 month was greater for patients treated with ticagrelor (p < 0.0001). This was no longer observed in the 1 to 6-month interval. Using a Cox proportional hazard model, the increase in platelet count from 1 to 6 months was associated with ischemic-thrombotic events, while sCD40 ligand decrease from 1 to 6 months was associated with hemorrhagic events. There were no differences between treatment groups for the associations with clinical endpoints. Dynamic changes in platelet count, sCD-40 ligand and sP-selectin occur over time among patients with ACS. Platelet-directed therapy with a P2Y12 receptor inhibitor in combination with aspirin modestly impacts the expression of these biomarkers. Platelet count and sCD40 ligand may offer modest overall predictive value for future ischemic-thrombotic or hemorrhagic clinical events, respectively. The existence of a platelet adaptome and its overall clinical significance among patients at risk for thrombotic events will require a more in-depth and platelet-biology specific investigation.
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26. |
- Mahmoodi, Bakhtawar K., et al.
(author)
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Factor V Leiden Does Not Modify the Phenotype of Acute Coronary Syndrome or the Extent of Myocardial Necrosis
- 2021
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In: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980. ; 10:11
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Journal article (peer-reviewed)abstract
- BACKGROUND: The prothrombotic defect factor V Leiden (FVL) may confer higher risk of ST-segment-elevation myocardial infarction (STEMI), compared with non-ST-segment-elevation acute coronary syndrome, and may be associated with more myocardial necrosis caused by higher thrombotic burden. METHODS AND RESULTS: Patients without history of cardiovascular disease were selected from 2 clinical trials conducted in patients with acute coronary syndrome. FVL was defined as G-to-A substitution at nucleotide 1691 in the factor V (factor V R506Q) gene. Odds ratios were calculated for the association of FVL with STEMI adjusted for age and sex in the overall population and in the subgroups including sex, age (>= 70 versus <70 years), and traditional cardiovascular risk factors. The peak biomarker levels (ie, creatine kinase-myocardial band and high-sensitivity troponin I or T) after STEMI were contrasted between FVL carriers and noncarriers. Because of differences in troponin assays, peak high-sensitivity troponin levels were converted to a ratio scale. The prevalence of FVL mutation was comparable in patients with STEMI (6.0%) and non-ST-segment-elevation acute coronary syndrome (5.8%). The corresponding sex-and age-adjusted odds ratio was 1.06 (95% CI, 0.86-1.30; P=0.59) for the association of FVL with STEMI. Subgroup analysis did not show any differences. In patients with STEMI, neither the median peak creatine kinase-myocardial band nor the peak high-sensitivity troponin ratio showed any differences between wild-type and FVL carriers (P for difference: creatine kinase-myocardial band=0.33; high sensitivity troponin ratio=0.54). CONCLUSIONS: In a general population with acute coronary syndrome, FVL did not discriminate between a STEMI or non-ST-segment-elevation acute coronary syndrome presentation and was unrelated to peak cardiac necrosis markers in patients with STEMI.
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27. |
- Sandhu, Roopinder K., et al.
(author)
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Obesity paradox on outcome in atrial fibrillation maintained even considering the prognostic influence of biomarkers : insights from the ARISTOTLE trial
- 2018
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In: Open heart. - : BMJ. - 2053-3624. ; 5:2
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Journal article (peer-reviewed)abstract
- ObjectiveWe investigated the association between obesity and biomarkers indicating cardiac or renal dysfunction or inflammation and their interaction with obesity and outcomes.MethodsA total of 14 753 patients in the Apixaban for Reduction In STroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial provided plasma samples at randomisation to apixaban or warfarin. Median follow-up was 1.9 years. Body Mass Index (BMI) was measured at baseline and categorised as normal, 18.5-25 kg/m(2); overweight, >25 to <30 kg/m(2); and obese, >= 30 kg/m(2). We analysed the biomarkers high-sensitivity C reactive protein (hs-CRP), interleukin 6 (IL-6), growth differentiation factor-15 (GDF-15), troponin T and N-terminal B-type natriuretic peptide (NT-pro-BNP). Outcomes included stroke/systemic embolism (SE), myocardial infarction (MI), composite (stroke/SE, MI, or all-cause mortality), all-cause and cardiac mortality, and major bleeding.ResultsCompared with normal BMI, obese patients had significantly higher levels of hs-CRP and IL-6 and lower levels of GDF-15, troponin T and NT-pro-BNP. In multivariable analyses, higher compared with normal BMI was associated with a lower risk of all-cause mortality (overweight: HR 0.73 (95% CI 0.63 to 0.86); obese: 0.67 (0.56 to 0.80), p<0.0001), cardiac death (overweight: HR 0.74 (95% CI 0.60 to 0.93); obese: 0.71 (0.56 to 0.92), p=0.01) and composite endpoint (overweight: 0.80 (0.70 to 0.92); obese: 0.72 (0.62 to 0.84), p<0.0001).ConclusionsRegardless of biomarkers indicating inflammation or cardiac or renal dysfunction, obesity was independently associated with an improved survival in anticoagulated patients with AF.
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28. |
- Sharma, Abhinav, et al.
(author)
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Use of Biomarkers to Predict Specific Causes of Death in Patients With Atrial Fibrillation : Insights From the ARISTOTLE Trial
- 2018
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In: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 138:16, s. 1666-1676
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Journal article (peer-reviewed)abstract
- Background: Atrial fibrillation is associated with an increased risk of death. High-sensitivity troponin T, growth differentiation factor-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and interleukin-6 levels are predictive of cardiovascular events and total cardiovascular death in anticoagulated patients with atrial fibrillation. The prognostic utility of these biomarkers for cause-specific death is unknown. Methods: The ARISTOTLE trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) randomized 18201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14798 patients (1.9 years median follow-up). Cox models were used to identify clinical variables and biomarkers independently associated with each specific cause of death. Results: In total, 1272 patients died: 652 (51%) cardiovascular, 32 (3%) bleeding, and 588 (46%) noncardiovascular/nonbleeding deaths. Among cardiovascular deaths, 255 (39%) were sudden cardiac deaths, 168 (26%) heart failure deaths, and 106 (16%) stroke/systemic embolism deaths. Biomarkers were the strongest predictors of cause-specific death: a doubling of troponin T was most strongly associated with sudden death (hazard ratio [HR], 1.48; P<0.001), NT-proBNP with heart failure death (HR, 1.62; P<0.001), and growth differentiation factor-15 with bleeding death (HR, 1.72; P=0.028). Prior stroke/systemic embolism (HR, 2.58; P>0.001) followed by troponin T (HR, 1.45; P<0.0029) were the most predictive for stroke/ systemic embolism death. Adding all biomarkers to clinical variables improved discrimination for each cause-specific death. Conclusions: Biomarkers were some of the strongest predictors of cause-specific death and may improve the ability to discriminate among patients' risks for different causes of death. These data suggest a potential role of biomarkers for the identification of patients at risk for different causes of death in patients anticoagulated for atrial fibrillation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00412984.
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29. |
- Siegbahn, Agneta, et al.
(author)
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D-dimer and factor VIIa in atrial fibrillation : prognostic values for cardiovascular events and effects of anticoagulation therapy. A RE-LY substudy
- 2016
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In: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 115:5, s. 921-930
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Journal article (peer-reviewed)abstract
- Coagulation markers may improve monitoring the risk of stroke and bleeding in patients with atrial fibrillation (AF) during anticoagulant treatment. We examined baseline levels of D-dimer and their association with stroke, cardiovascular death and major bleeding in 6,202 AF patients randomised to dabigatran or warfarin in the RE-LY trial. The effects of treatment on serial levels of D-dimer and coagulation factor (F) VIIa in 2,567 patients were also analysed. Baseline D-dimer levels were related to the rate of stroke/systemic embolism (SEE) with 0.64 % in the lowest quartile (Q1, as reference) (D-dimer < 298 µg/l), 1.38 % Q2 (D-dimer 298-473 µg/l), 1.71 % Q3 (D-dimer 474-822 µg/l) and 2.00 % in Q4 (D-dimer > 822 µg/l) (p=0.0007). Similar associations were shown for cardiovascular death and major bleeding. Addition of baseline D-dimer to established clinical risk factors improved prediction of stroke/SEE, cardiovascular death and major bleeding (C-index increased from 0.66 to 0.68, 0.71 to 0.73 and 0.66 to 0.67, respectively). Dabigatran provided a greater reduction of D-dimer levels than warfarin regardless of baseline anticoagulant treatment. On-treatment levels of FVIIa were markedly reduced by warfarin (median 12.1-13.8 mU/ml) but significantly higher with dabigatran (median 39.4-49.0 mU/ml) at all-time points. Dabigatran is associated with greater reduction in D-dimer without the pronounced reduction of FVIIa seen with warfarin. These different effects on the coagulation system might explain the better efficacy and less intracranial bleeding observed with dabigatran compared with warfarin.
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30. |
- Siegbahn, Agneta, 1947-, et al.
(author)
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Development and validation of a quantitative Proximity Extension Assay instrument with 21 proteins associated with cardiovascular risk (CVD-21)
- 2023
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 18:11
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Journal article (peer-reviewed)abstract
- Background Treatment of cardiovascular diseases (CVD) is a substantial burden to healthcare systems worldwide. New tools are needed to improve precision of treatment by optimizing the balance between efficacy, safety, and cost. We developed a high-throughput multi-marker decision support instrument which simultaneously quantifies proteins associated with CVD. Methods and findings Candidate proteins independently associated with different clinical outcomes were selected from clinical studies by the screening of 368 circulating biomarkers. We then custom-designed a quantitative PEA-panel with 21 proteins (CVD-21) by including recombinant antigens as calibrator samples for normalization and absolute quantification of the proteins. The utility of the CVD-21 tool was evaluated in plasma samples from a case-control cohort of 4224 patients with chronic coronary syndrome (CCS) using multivariable Cox regression analyses and machine learning techniques. The assays in the CVD-21 tool gave good precision and high sensitivity with lower level of determination (LOD) between 0.03-0.7 pg/ml for five of the biomarkers. The dynamic range for the assays was sufficient to accurately quantify the biomarkers in the validation study except for troponin I, which in the modeling was replaced by high-sensitive cardiac troponin T (hs-TnT). We created seven different multimarker models, including a reference model with NT-proBNP, hs-TnT, GDF-15, IL-6, and cystatin C and one model with only clinical variables, for the comparison of the discriminative value of the CVD-21 tool. All models with biomarkers including hs-TnT provided similar discrimination for all outcomes, e.g. c-index between 0.68-0.86 and outperformed models using only clinical variables. Most important prognostic biomarkers were MMP-12, U-PAR, REN, VEGF-D, FGF-23, TFF3, ADM, and SCF. Conclusions The CVD-21 tool is the very first instrument which with PEA simultaneously quantifies 21 proteins with associations to different CVD. Novel pathophysiologic and prognostic information beyond that of established biomarkers were identified by a number of proteins.
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31. |
- Sumaya, Wael, et al.
(author)
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Fibrin clot properties independently predict adverse clinical outcome following acute coronary syndrome : a PLATO substudy
- 2018
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 39:13, s. 1078-1085
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Journal article (other academic/artistic)abstract
- Aims To determine whether fibrin clot properties are associated with clinical outcomes following acute coronary syndrome (ACS).Methods and results Plasma samples were collected at hospital discharge from 4354 ACS patients randomized to clopidogrel or ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. A validated turbidimetric assay was employed to study plasma clot lysis time and maximum turbidity (a measure of clot density). One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO-defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were estimated using Cox proportional hazards models. After adjusting for CV risk factors, each 50% increase in lysis time was associated with CV death/spontaneous MI [HR 1.17, 95% confidence interval (CI) 1.05-1.31; P < 0.01] and CV death alone (HR 1.36, 95% CI 1.17-1.59; P < 0.001). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death (HR 1.24, 95% CI 1.03-1.50; P = 0.024). After adjustment for other prognostic biomarkers (leukocyte count, high-sensitivity C-reactive protein, high-sensitivity troponin T, cystatin C, N-terminal pro B-type natriuretic peptide, and growth differentiation factor15), the association with CV death remained significant for lysis time (HR 1.2, 95% CI 1.01-1.42; P = 0.042) but not for maximum turbidity. These associations were consistent regardless of randomized antiplatelet treatment (all interaction P > 0.05). Neither lysis time nor maximum turbidity was associated with major bleeding events.Conclusion Fibrin clots that are resistant to lysis independently predict adverse outcome in ACS patients. Novel therapies targeting fibrin clot properties might be a new avenue for improving prognosis in patients with ACS.
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32. |
- Sumaya, Wael, et al.
(author)
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Impaired Fibrinolysis Predicts Adverse Outcome in Acute Coronary Syndrome Patients with Diabetes : A PLATO Sub-Study
- 2020
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In: Thrombosis and Haemostasis. - : GEORG THIEME VERLAG KG. - 0340-6245 .- 2567-689X. ; 120:3, s. 412-422
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Journal article (peer-reviewed)abstract
- Hypofibrinolysis is a key abnormality in diabetes but the role of impaired clot lysis in predicting vascular events and mortality in this population is yet to be determined. We aimed to investigate the relationship between fibrin clot properties and clinical outcomes in patients with diabetes and recent acute coronary syndrome (ACS). Plasma samples were collected at hospital discharge from 974 ACS patients with diabetes randomised to clopidogrel or ticagrelor in the PLATO trial. A validated turbidimetric assay was employed to study fibrin clot lysis and maximum turbidity. One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO-defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were determined using Cox proportional analysis. After adjusting for CV risk factors, each 50% increase in lysis time was associated with increased risk of CV death/MI (HR 1.21; 95% confidence interval [CI] 1.02-1.44; p = 0.026) and CV death alone (HR 1.38; 1.08-1.76; p = 0.01). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death/MI (HR 1.25; 1.02-1.53; p = 0.031) and CV death alone (HR 1.49; 1.08-2.04; p = 0.014). The relationship between lysis time and the combined outcome of CV death and MI remained significant after adjusting for multiple prognostic vascular biomarkers ( p = 0.034). Neither lysis time nor maximum turbidity was associated with major bleeding events. Impaired fibrin clot lysis predicts 1-year CV death and MI in diabetes patients following ACS.
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33. |
- Thomas, Mark R., et al.
(author)
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Prognostic impact of baseline inflammatory markers in patients with acute coronary syndromes treated with ticagrelor and clopidogrel.
- 2019
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In: European Heart Journal. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 10:2, s. 153-163
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Journal article (peer-reviewed)abstract
- BACKGROUND: Inflammation plays a major role in the pathophysiology of coronary artery disease. We aimed to determine whether baseline inflammatory markers were associated with clinical outcomes and the observed superiority of ticagrelor compared to clopidogrel in patients with acute coronary syndromes in the PLATO study.METHODS: Blood samples were collected from 16,400 patients within 24 hours of the onset of acute coronary syndrome, at the time of random assignment to ticagrelor or clopidogrel in the PLATO study and prior to invasive procedures. The differential white blood cell count and plasma levels of C-reactive protein, interleukin-6 and interleukin-10 were determined and their relationships with clinical outcomes were assessed according to quartiles and using continuous models. The substudy primary endpoint was a composite of cardiovascular death and myocardial infarction.RESULTS: Compared to the lowest quartile, the risk of the primary endpoint was significantly elevated in patients in the highest quartile of white blood cell count (hazard ratio (HR) 1.30; P=0.01), neutrophil count (HR 1.33; P=0.007), monocyte count (HR 1.24; P=0.004), C-reactive protein (HR 1.93; P<0.001) and interleukin-6 (HR 2.29; P<0.001). This was predominantly driven by an association with cardiovascular death. Following adjustment for clinical characteristics, troponin, cystatin C and N-terminal pro-brain-type natriuretic peptide, only white blood cell count and neutrophil count maintained a significant association with the primary endpoint. Ticagrelor had a consistent relative cardiovascular benefit compared to clopidogrel in each quartile of each of the inflammatory markers.CONCLUSIONS: Acute coronary syndrome patients with elevated levels of baseline inflammatory markers are at increased risk of adverse cardiovascular events, particularly cardiovascular death. The consistent cardiovascular benefit of ticagrelor compared to clopidogrel tended to confer a greater absolute risk reduction in patients with the highest levels of inflammatory markers, as they were at highest risk.
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34. |
- Tomasdottir, Maria, et al.
(author)
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Risk markers of incident atrial fibrillation in patients with coronary heart disease
- 2021
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In: American Heart Journal. - : Elsevier. - 0002-8703 .- 1097-6744. ; 233, s. 92-101
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Journal article (peer-reviewed)abstract
- BackgroundIn patients with coronary heart disease (CHD), atrial fibrillation (AF) is associated with increased morbidity and mortality. We investigated the associations between clinical risk factors and biomarkers with incident AF in patients with CHD.Methods and resultsAround 13,153 patients with optimally treated CHD included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial with plasma samples obtained at randomization. Mean follow-up time was 3.5 years. The association between clinical risk factors and biomarkers with incident AF was estimated with Cox-regression models. Validation was performed in 1,894 patients with non-ST-elevation acute coronary syndrome included in the FRISC-II trial.The median (min-max) age was 64 years (range 26-92) and 2,514 (19.1%) were women. A total of 541 patients, annual incidence rate of 1.2%, developed AF during follow-up. In multivariable models, older age, higher levels of NT-proBNP, higher body mass index (BMI), male sex, geographic regions, low physical activity, and heart failure were independently associated with increased risk of incident AF with hazard ratios ranging from 1.04 to 1.79 (P ≤ .05). NT-proBNP improved the C-index from 0.70 to 0.71. In the validation cohort, age, BMI, and NT-proBNP were associated with increased risk of incident AF with similar hazard ratios.ConclusionsIn patients with optimally treated CHD, the incidence of new AF was 1.2% per year. Age, NT-proBNP as a marker of impaired cardiac function, and BMI were the strongest factors, independently and consistently associated with incident AF. Male sex and low physical activity may also contribute to the risk of AF in patients with CHD.
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35. |
- Varenhorst, Christoph, et al.
(author)
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Assessment of P2Y(12) inhibition with the point-of-care device VerifyNow P2Y12 in patients treated with prasugrel or clopidogrel coadministered with aspirin
- 2009
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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 157:3, s. 562.e1-9
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Journal article (peer-reviewed)abstract
- BACKGROUND: Variability in response to thienopyridines has led to the development of point-of-care devices to assess adenosine diphosphate (ADP)-induced platelet aggregation. These tests need to be evaluated in comparison to reference measurements of P2Y(12) function during different thienopyridine treatments. METHODS: After a run-in on 75 mg aspirin, 110 subjects were randomized to double-blind treatment with clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD. Antiplatelet effects were evaluated by VerifyNow P2Y12 (VN-P2Y12) device (Accumetrics, San Diego, CA), vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay, and light transmission aggregometry (LTA). Prasugrel's and clopidogrel's active metabolite concentration were also determined. RESULTS: Dose- and time-dependent inhibition of P2Y(12) was evident with VN-P2Y12. There was strong correlation with VN-P2Y12 and VASP or LTA for all treatments through a wide range of P2Y(12) function. At high levels of P2Y(12) inhibition, platelet function measured by VN-P2Y12 was maximally inhibited and could not reflect further changes seen with VASP or LTA methods. Correlation was also observed between exposure to clopidogrel's active metabolite and VN-P2Y12 during MD and LD, whereas it was observed only with prasugrel MD. CONCLUSION: The VN-P2Y12 correlated strongly with inhibition of P2Y(12) function, as measured with either VASP or LTA. VN-P2Y12 also correlated to exposure to the active metabolite of prasugrel and clopidogrel up to levels associated with assumed saturation of the P2Y(12) receptor.
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36. |
- Vessby, Johan, 1972-, et al.
(author)
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Tissue factor in ulcerative colitis, with and without concomitant primary sclerosing cholangitis
- 2019
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In: Upsala Journal of Medical Sciences. - : Taylor & Francis Group. - 0300-9734 .- 2000-1967. ; 124:4, s. 238-245
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Journal article (peer-reviewed)abstract
- Background: Ulcerative colitis (UC) in patients with the severe disease primary sclerosing cholangitis (PSC) constitutes a distinct clinical phenotype (PSC-UC) with a high incidence of colorectal cancer. Today, PSC-UC diagnosis is built on clinical observations only. Tissue factor (TF) has a potential use in UC diagnostics, and also in colorectal cancer prognostication. Here we evaluate TF expression in an inflammatory bowel disease (IBD) cohort, with special focus on differences between UC and PSC-UC patients.Materials and methods: Colonic biopsies from UC (n = 23), PSC (n = 24), and healthy controls (n = 11) were stained for TF by immunohistochemistry. Mononuclear cell contribution to TF expression was verified using flow cytometry.Results: TF was distributed at three distinct colonic locations: in subepithelial pericryptal sheath cells, in mononuclear cells, and in the intestinal stroma. In contrast to UC-where inflammation was accompanied with TF up-regulation-PSC-UC activity remained low during inflammation. Stromal TF positivity was found exclusively in ongoing inflammation.Conclusion: Our study provides additional support for a divergent pathogenesis in PSC-UC, with an inflammatory environment that differs from classical UC. Stromal TF emerges as a new marker of colonic inflammation.
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37. |
- Wallentin, Lars, 1943-, et al.
(author)
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Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease
- 2008
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 29:1, s. 21-30
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Journal article (peer-reviewed)abstract
- AIMS: P2Y(12) receptor antagonism and platelet inhibition by prasugrel vs. clopidogrel were investigated in patients with stable coronary artery disease. METHODS AND RESULTS: One hundred and ten aspirin treated subjects were randomized to double-blind treatment with clopidogrel (n = 55) 600 mg loading dose (LD) and 75 mg maintenance dose (MD) or prasugrel (n = 55) 60 mg LD and 10 mg MD for 28 days. Concentrations of prasugrel and clopidogrel active metabolites were determined. Platelet aggregation to 20 microM adenosine diphosphate, measured by light transmission aggregometry, was reported as maximal platelet aggregation (MPA). P2Y(12) function was assessed by the vasodilator-stimulated phosphoprotein assay and reported as platelet reactivity index (PRI). The same pharmacodynamic measurements were performed after ex vivo addition of clopidogrel's active metabolite. At 2 h post-LD, mean MPA was 31 vs. 55%, and mean PRI 8.3 vs. 55.9% for prasugrel and clopidogrel, respectively (P < 0.001). During MD on day 14 and 28, mean MPA was 42 vs. 54% and mean PRI was 25 vs. 51%, respectively (P < 0.001). Peak level of the active metabolite and P2Y(12) inhibition occurred earlier and was greater with prasugrel (P < 0.001). Mean area under the time-concentration curve (AUC; microM.h) of the respective active metabolite was higher with prasugrel vs. clopidogrel post-LD (1.11 vs. 0.24) and post-MD (0.16 vs. 0.062). Ex vivo addition of clopidogrel's active metabolite further reduced PRI in all patients whose platelets were not already maximally inhibited. CONCLUSION: In aspirin-treated subjects with coronary artery disease, prasugrel 60/10 mg provides faster onset and greater inhibition of P2Y(12) receptor-mediated platelet aggregation than clopidogrel 600/75 mg, because of greater and more efficient generation of the active metabolite.
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38. |
- Åkerblom, Axel, 1977-, et al.
(author)
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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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In: Journal of Thrombosis and Thrombolysis. - : Springer. - 0929-5305 .- 1573-742X. ; 48:4, s. 563-569
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Journal article (peer-reviewed)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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