| 131. |
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| 132. |
- Ross, Stephanie, et al.
(author)
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Association of cyclooxygenase-2 genetic variant with cardiovascular disease
- 2014
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 35:33, s. 2242-2248
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Journal article (peer-reviewed)abstract
- Aim Agenetic variant (rs20417) of the PTGS2 gene, encoding for COX-2, has been associated with decreased COX-2 activity and a decreased risk of cardiovascular disease (CVD). However, this genetic association and the role of COX-2 in CVD remain controversial. Methods and results The association of rs20417 with CVD was prospectively explored in 49 232 subjects (ACTIVE-A, CURE, epiDREAM/DREAM, ONTARGET, RE-LY, and WGHS) and the effect of potentially modifiable risk factors on the genetic association was further explored in 9363 INTERHEART participants. The effect of rs20417 on urinary thromboxane and prostacyclin metabolite concentrations was measured in 117 healthy individuals. Carriage of the rs20417 minor allele was associated with a decreased risk of major CVD outcomes (OR = 0.78, 95% CI: 0.70-0.87; P = 1.2 x 10(-5)). The genetic effect was significantly stronger in aspirin users (OR: 0.74, 95% CI: 0.64-0.84; P = 1.20 x 10(-5)) than non-users (OR: 0.87, 95% CI: 0.72-1.06; P = 0.16) (interaction P-value: 0.0041). Among patients with previous coronary artery disease (CAD), rs20417 carriers had a stronger protective effect on risk of major adverse events when compared with individuals without previous CAD (interaction P-value: 0.015). Carriers had significantly lower urinary levels of thromboxane (P = 0.01) and prostacyclin (P = 0.01) metabolites when compared with non-carriers. Conclusion The rs20417 polymorphism is associated with a reduced risk of major cardiovascular events and lower levels of thromboxane and prostacyclin. Our results suggest that a genetic decrease in COX-2 activity may be beneficial with respect to CVD risk, especially, in higher risk patients on aspirin.
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| 133. |
- Salam, Abdul, et al.
(author)
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Effects of blood pressure lowering on cardiovascular events, in the context of regression to the mean : a systematic review of randomized trials
- 2019
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In: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 37:1, s. 16-23
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Research review (peer-reviewed)abstract
- Objective: To assess the clinical relevance of regression to the mean for clinical trials and clinical practice. Methods: MEDLINE was searched until February 2018 for randomized trials of BP lowering with over 1000 patient-years follow-up per group. We estimated baseline mean BP, follow-up mean (usual) BP amongst patients grouped by 10 mmHg strata of baseline BP, and assessed effects of BP lowering on coronary heart disease (CHD) and stroke according to these BP levels. Results: Eighty-six trials (349 488 participants), with mean follow-up of 3.7 years, were included. Most mean BP change was because of regression to the mean rather than treatment. At high baseline BP levels, even after rigorous hypertension diagnosis, downwards regression to the mean caused much of the fall in BP. At low baseline BP levels, upwards regression to the mean increased BP levels, even in treatment groups. Overall, a BP reduction of 6/3 mmHg lowered CHD by 14% (95% CI 11-17%) and stroke by 18% (15-22%), and these treatment effects occurred at follow-up BP levels much closer to the mean than baseline BP levels. In particular, more evidence was available in the SBP 130-139 mmHg range than any other range. Benefits were apparent in numerous high-risk patient groups with baseline mean SBP less than 140 mmHg. Conclusion: Clinical practice should focus less on pretreatment BP levels, which rarely predict future untreated BP levels or rule out capacity to benefit from BP lowering in high cardiovascular risk patients. Instead, focus should be on prompt, empirical treatment to maintain lower BP for those with high BP and/or high risk.
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| 134. |
- Schmidt, Amand F., et al.
(author)
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PCSK9 genetic variants and risk of type 2 diabetes : a mendelian randomisation study
- 2017
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In: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:2, s. 97-105
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Journal article (peer-reviewed)abstract
- Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way off sets their substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely eff ects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA 1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0.09 mmol/L, 95% CI 0.02 to 0.15), bodyweight (1.03 kg, 0.24 to 1.82), waist-to-hip ratio (0.006, 0.003 to 0.010), and an odds ratio for type diabetes of 1.29 (1.11 to 1.50). Based on the collected data, we did not identify associations with HbA 1c (0.03%, -0.01 to 0.08), fasting insulin (0.00%, -0.06 to 0.07), and BMI (0.11 kg/m(2), -0.09 to 0.30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefi ts of PCSK9 inhibitor treatment, as was previously done for statins.
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| 135. |
- Schmidt, Amand F., et al.
(author)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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In: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Journal article (peer-reviewed)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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| 136. |
- Sicard, Pierre, et al.
(author)
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Global topics and novel approaches in the study of air pollution, climate change and forest ecosystems
- 2016
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In: Environmental Pollution. - : Elsevier BV. - 0269-7491 .- 1873-6424. ; 213, s. 977-987
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Journal article (peer-reviewed)abstract
- Research directions from the 27th conference for Specialists in Air Pollution and Climate Change Effects on Forest Ecosystems (2015) reflect knowledge advancements about (i) Mechanistic bases of tree responses to multiple climate and pollution stressors, in particular the interaction of ozone (O-3) with nitrogen (N) deposition and drought; (ii) Linking genetic control with physiological whole-tree activity; (iii) Epigenetic responses to climate change and air pollution; (iv) Embedding individual tree performance into the multi-factorial stand-level interaction network; (v) Interactions of biogenic and anthropogenic volatile compounds (molecular, functional and ecological bases); (vi) Estimating the potential for carbon/pollution mitigation and cost effectiveness of urban and periurban forests; (vii) Selection of trees adapted to the urban environment; (viii) Trophic, competitive and host/parasite relationships under changing pollution and climate; (ix) Atmosphere -iosphere-pedosphere interactions as affected by anthropospheric changes; (x) Statistical analyses for epidemiological investigations; (xi) Use of monitoring for the validation of models; (xii) Holistic view for linking the climate, carbon, N and O-3 odelling; (xiii) Inclusion of multiple environmental stresses (biotic and abiotic) in critical load determinations; (xiv) Ecological impacts of N deposition in the under-investigated areas; (xv) Empirical models for mechanistic effects at the local scale; (xvi) Broad-scale N and sulphur deposition input and their effects on forest ecosystem services; (xvii) Measurements of dry deposition of N; (xviii) Assessment of evapotranspiration; (xix) Remote sensing assessment of hydrological parameters; and (xx) Forest management for maximizing water provision and overall forest ecosystem services. Ground-level O-3 is still the phytotoxic air pollutant of major concern to forest health. Specific issues about O-3 are: (xxi) Developing dose response relationships and stomatal O-3 flux parameterizations for risk assessment, especially, in under-investigated regions; (xxii) Defining biologically based O-3 standards for protection thresholds and critical levels; (xxiii) Use of free-air exposure facilities; (xxiv) Assessing O-3 impacts on forest ecosystem services.
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| 137. |
- 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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| 138. |
- Siegbahn, Agneta, 1947-, et al.
(author)
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Multiplex protein screening of biomarkers associated with major bleeding in patients with atrial fibrillation treated with oral anticoagulation.
- 2021
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In: Journal of Thrombosis and Haemostasis. - : John Wiley & Sons. - 1538-7933 .- 1538-7836. ; 19:11, s. 2726-2737
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Journal article (peer-reviewed)abstract
- BACKGROUND: Oral anticoagulants (OAC) in patients with atrial fibrillation (AF) prevent thromboembolic events, but are associated with significant risk of bleeding.OBJECTIVES: To explore associations between a wide range of biomarkers and bleeding risk in patients with AF on OAC.METHOD: Biomarkers were analyzed in a random sample of 4200 patients, 204 cases with major bleedings, from ARISTOTLE. The replication cohort included 344 cases with major bleeding and 1024 random controls from RE-LY. Plasma samples obtained at randomization were analyzed by the Olink Proximity Extension Assay cardiovascular and inflammation panels and conventional immunoassays. The associations between biomarker levels and major bleeding over 1 to 3 years of follow-up were evaluated by random survival forest/Boruta analyses and Cox regression analyses to assess linear associations and hazard ratios for identified biomarkers.RESULTS: Out of 268 proteins, nine biomarkers were independently associated with bleeding in both cohorts. In the replication cohort the linear hazard ratios (95% confidence intervals) per interquartile range were for these biomarkers: TNF-R1 1.748 (1.456, 2.098), GDF-15 1.653 (1.377, 1.985), EphB4 1.575 (1.320, 1.880), suPAR 1.548 (1.294, 1.851), OPN 1.476 (1.240, 1.757), OPG 1.397 (1.156, 1.688), TNF-R2 1.360 (1.144,1.616), cTnT-hs 1.232 (1.067, 1.423), and TRAIL-R2 1.202 (1.069, 1.351).CONCLUSIONS: In patients with AF on OAC, GDF-15, cTnT-hs, and seven novel biomarkers were independently associated with major bleedings and reflect pathophysiologic processes of inflammation, apoptosis, oxidative stress, vascular calcification, coagulation, and fibrinolysis. Investigations of the utility of these markers to refine risk stratification and guide the management of patients at high risk of bleeding are warranted.
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| 139. |
- Smyth, Andrew, et al.
(author)
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Alcohol Intake as a Risk Factor for Acute Stroke: The INTERSTROKE Study.
- 2023
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In: Neurology. - 1526-632X. ; 100:2
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Journal article (peer-reviewed)abstract
- There is uncertainty about the association between alcohol consumption and stroke, particularly for low-moderate intake. We explored these associations in a large international study.INTERSTROKE, a case-control study, is the largest international study of risk factors for acute stroke. Alcohol consumption was self-reported and categorised by drinks/week as low (1-7), moderate (7-14 for females, 7-21 for males) or high (>14 for females, >21 for males). Heavy episodic drinking (HED) was defined as >5 drinks on ≥1 day per month. Multivariable conditional logistic regression was used to determine associations.We included 12,913 cases and 12,935 controls; 25.0% (n=6,449) were current drinkers, 16.7% (n=4,318) former and 58.3% (n=15,076) never drinkers. Current drinkers were younger, male, smokers, active and with higher-paid occupations. Current drinking was associated with all stroke (OR 1.14; 95% CI 1.04-1.26) and intracerebral hemorrhage (ICH) (OR 1.50, 95% CI 1.21-1.84) but not ischaemic stroke (OR 1.06; 95% CI 0.95-1.19). HED pattern was associated with all stroke (OR 1.39; 95% CI 1.21-1.59), ischaemic stroke (OR 1.29; 95% CI 1.10-1.51) and ICH (OR 1.76; 95% CI 1.31-2.36). High level of alcohol intake was consistently associated with all stroke, ischaemic stroke and ICH. Moderate intake was associated with all stroke and ICH, but not ischaemic stroke. Low alcohol intake was not associated with stroke overall but there were regional differences; low intake was associated with reduced odds of stroke in Western Europe/North America (OR 0.66; 95%CI 0.45-0.96) and increased odds in India (OR 2.18; 95%CI 1.42-3.36)(p-interaction 0.037). Wine consumption was associated with reduced odds of all stroke and ischaemic stroke but not ICH. The magnitudes of association were greatest in those without hypertension and current smokers.High and moderate intake were associated with increased odds of stroke, while low intake was not associated with stroke. However, there were important regional variations, which may relate to differences in population characteristics of alcohol consumers, types or patterns of consumption.
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| 140. |
- Smyth, Andrew, et al.
(author)
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Tea and coffee consumption and risk of acute stroke: The INTERSTROKE Study
- 2024
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In: INTERNATIONAL JOURNAL OF STROKE. - 1747-4930 .- 1747-4949.
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Journal article (peer-reviewed)abstract
- Background: Stroke is a leading global cause of death and disability. Daily tea/coffee intake is consumed by > 50% of populations and may represent an important population-level exposure. Therefore, it is first essential that we better understand the associations between the tea/coffee intake and stroke. Aims: This research aims to generate hypotheses about the global associations between tea and coffee intake and stroke. These insights will identify interventions for stroke prevention that can be further explored using alternative study designs. Methods: INTERSTROKE is a large international matched case-control study of first stroke from 32 countries. Participants were asked "how many cups do you drink each day?" of coffee, green tea, black tea, and other tea. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between intake and stroke. Results: We included 13,462 cases and 13,488 controls from INTERSTROKE; mean age was 61.7 (13.4) years and 59.6% (n = 16,010) were male. Overall, 19.4% (n = 5239) did not consume tea/coffee, 47.0% (n = 12,666) consumed tea only, 14.9% (n = 4024) consumed coffee alone, and 18.6% (n = 5021) consumed both, with significant regional variations. After multivariable adjustment, there was no association between low/moderate coffee intake and stroke, but high consumption (> 4/day) was associated with higher odds of all stroke (OR = 1.37 (95% CI = 1.06-1.77)) or ischemic stroke (OR = 1.32 (95% CI = 1.00-1.74)). Tea consumption was associated with lower odds of all (OR = 0.81 (95% CI = 0.69-0.94) for highest intake) or ischemic stroke (OR = 0.81 (95% CI = 0.68-0.98) for highest intake). Conclusions: High coffee consumption was associated with higher odds of all or ischemic stroke; low-moderate coffee had no association with stroke. In contrast, tea consumption was associated with lower odds of stroke. These associations suggest that individuals consider avoiding high coffee consumption (>= five cups/day) to impact future stroke risk. Data Access Statement: The design and rationale of INTERSTROKE was published previously. Individual participant data, or other documents are not available.
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