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  • 2801.
    Yuan, Shuai
    et al.
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Nobels Vag 13, S-17177 Stockholm, Sweden..
    Burgess, Stephen
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, MRC, Biostat Unit, Cambridge, England..
    Laffan, Mike
    Imperial Coll London, Ctr Haematol, London, England..
    Mason, Amy M.
    Univ Cambridge, British Heart Fdn Cardiovasc Epidemiol Unit, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, Natl Inst Hlth Res, Cambridge Biomed Res Ctr, Cambridge, England.;Cambridge Univ Hosp, Cambridge, England..
    Dichgans, Martin
    Ludwig Maximilians Univ Munchen, Univ Hosp, Inst Stroke & Dementia Res, Munich, Germany.;Munich Cluster Syst Neurol SyNergy, Munich, Germany.;German Ctr Neurodegenerat Dis DZNE, Munich, Germany..
    Gill, Dipender
    Imperial Coll London, Sch Publ Hlth, Dept Biostat & Epidemiol, London, England.;St Georges Univ London, Clin Pharmacol & Therapeut Sect, Inst Med & Biomed Educ, London, England.;St Georges Univ Hosp NHS Fdn Trust, Clin Pharmacol Grp, Pharm & Med Directorate, London, England.;Imperial Coll London, Ctr Pharmacol & Therapeut, Dept Med, Hammersmith Campus, London, England.;Novo Nordisk Res Ctr Oxford, Oxford, England..
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Nobels Vag 13, S-17177 Stockholm, Sweden..
    Genetically Proxied Inhibition of Coagulation Factors and Risk of Cardiovascular Disease: A Mendelian Randomization Study2021In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 10, no 8, article id e019644Article in journal (Refereed)
    Abstract [en]

    Background We conducted Mendelian randomization analyses investigating the linear associations of genetically proxied inhibition of different coagulation factors with risk of common cardiovascular diseases.

    Methods and Results Genetic instruments proxying coagulation factor inhibition were identified from genome-wide association studies for activated partial thromboplastin time and prothrombin time in BioBank Japan (up to 58 110 participants). Instruments were identified for 9 coagulation factors (fibrinogen alpha, beta, and gamma chain; and factors II, V, VII, X, XI, and XII). Age- and sex-adjusted estimates for associations of the instruments with the outcomes were derived from UK Biobank and the FinnGen, CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis), and MEGASTROKE consortia with numbers of incident and prevalent cases of 820 to 60 810. Genetically proxied inhibition of fibrinogen alpha, beta, and gamma chain, factor II, and factor XI were associated with reduced risk of venous thromboembolism (P<0.001). With the exception of fibrinogen beta and factor II, inhibition of these factors was also associated with reduced risk of any ischemic stroke and cardioembolic stroke (P <= 0.002). Genetically proxied inhibition of fibrinogen beta and gamma were associated with reduced large-artery stroke risk (P=0.001). There were suggestive protective associations of genetically proxied inhibition of factors V, VII, and X with ischemic stroke (P<0.05), and suggestive adverse associations of genetically proxied inhibition of factors II and XII with subarachnoid hemorrhage.

    Conclusions This study supports targeting fibrinogen and factor XI for reducing venous thromboembolism and ischemic stroke risk, and showed suggestive evidence that inhibition of factors V, VII, and X might reduce ischemic stroke risk.

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  • 2802.
    Yuan, Shuai
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, SE-17177 Stockholm, Sweden.
    Bäck, Magnus
    Karolinska Inst, Dept Med, Ctr Mol Med, SE-17176 Stockholm, Sweden;Karolinska Univ Hosp, Div Valvular & Coronary Dis, Heart & Vasc Theme, SE-17176 Stockholm, Sweden.
    Bruzelius, Maria
    Karolinska Univ Hosp, Dept Hematol, Coagulat Unit, SE-17176 Stockholm, Sweden;Karolinska Inst, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Mason, Amy M.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England.
    Burgess, Stephen
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England;Univ Cambridge, MRC Biostat Unit, Cambridge CB2 0SR, England.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, SE-17177 Stockholm, Sweden.
    Plasma Phospholipid Fatty Acids, FADS1 and Risk of 15 Cardiovascular Diseases: A Mendelian Randomisation Study2019In: Nutrients, E-ISSN 2072-6643, Vol. 11, no 12, article id 3001Article in journal (Refereed)
    Abstract [en]

    Whether circulating fatty acids (FAs) play a causal role in the development of cardiovascular disease (CVD) remains unclear. We conducted a Mendelian randomisation study to explore the associations between plasma phospholipid FA levels and 15 CVDs. Summary-level data from the CARDIoGRAMp1usC4D, MEGASTROKE, and Atrial Fibrillation consortia and UK Biobank were used. Sixteen single-nucleotide polymorphisms (SNPs) associated with ten plasma FAs were used as instrumental variables. SNPs in or close to the FADS1 gene were associated with most FAs. We performed a secondary analysis of the association between a functional variant (rs174547) in FADS1, which encodes Delta 5-desaturase (a key enzyme in the endogenous FA synthesis), and CVD. Genetic predisposition to higher plasma alpha-linolenic, linoleic, and oleic acid levels was associated with lower odds of large-artery stroke and venous thromboembolism, whereas higher arachidonic and stearic acid levels were associated with higher odds of these two CVDs. The associations were driven by SNPs in or close to FADS1. In the secondary analysis, the minor allele of rs174547 in FADS1 was associated with significantly lower odds of any ischemic stroke, large-artery stroke, and venous thromboembolism and showed suggestive evidence of inverse association with coronary artery disease, abdominal aortic aneurysm and aortic valve stenosis. Genetically higher plasma alpha-linolenic, linoleic, and oleic acid levels are inversely associated with large-artery stroke and venous thromboembolism, whereas arachidonic and stearic acid levels are positively associated with these CVDs. The associations were driven by FADS1, which was also associated with other CVDs.

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  • 2803.
    Yuan, Shuai
    et al.
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, SE-17177 Stockholm, Sweden..
    Carter, Paul
    Univ Cambridge, Dept Med, Cambridge CB2 0QQ, England..
    Mason, Amy M.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England.;Univ Cambridge, Natl Inst Hlth Res Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England..
    Burgess, Stephen
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England.;Univ Cambridge, MRC Biostat Unit, Cambridge CB2 0SR, England..
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, SE-17177 Stockholm, Sweden..
    Coffee Consumption and Cardiovascular Diseases: A Mendelian Randomization Study2021In: Nutrients, E-ISSN 2072-6643, Vol. 13, no 7, article id 2218Article in journal (Refereed)
    Abstract [en]

    Coffee consumption has been linked to a lower risk of cardiovascular disease in observational studies, but whether the associations are causal is not known. We conducted a Mendelian randomization investigation to assess the potential causal role of coffee consumption in cardiovascular disease. Twelve independent genetic variants were used to proxy coffee consumption. Summary-level data for the relations between the 12 genetic variants and cardiovascular diseases were taken from the UK Biobank with up to 35,979 cases and the FinnGen consortium with up to 17,325 cases. Genetic predisposition to higher coffee consumption was not associated with any of the 15 studied cardiovascular outcomes in univariable MR analysis. The odds ratio per 50% increase in genetically predicted coffee consumption ranged from 0.97 (95% confidence interval (CI), 0.63, 1.50) for intracerebral hemorrhage to 1.26 (95% CI, 1.00, 1.58) for deep vein thrombosis in the UK Biobank and from 0.86 (95% CI, 0.50, 1.49) for subarachnoid hemorrhage to 1.34 (95% CI, 0.81, 2.22) for intracerebral hemorrhage in FinnGen. The null findings remained in multivariable Mendelian randomization analyses adjusted for genetically predicted body mass index and smoking initiation, except for a suggestive positive association for intracerebral hemorrhage (odds ratio 1.91; 95% CI, 1.03, 3.54) in FinnGen. This Mendelian randomization study showed limited evidence that coffee consumption affects the risk of developing cardiovascular disease, suggesting that previous observational studies may have been confounded.

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  • 2804. Yuan, Shuai
    et al.
    Carter, Paul
    Mason, Amy M
    Yang, Fangkun
    Burgess, Stephen
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology. Karolinska Institutet, Stockholm, Sweden.
    Genetic Liability to Rheumatoid Arthritis in Relation to Coronary Artery Disease and Stroke Risk2022In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 74, no 10, p. 1638-1647Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess the causality of the associations of rheumatoid arthritis (RA) with coronary artery disease (CAD) and stroke using the Mendelian randomization approach.

    METHODS: Independent single-nucleotide polymorphisms strongly associated with RA (n = 70) were selected as instrumental variables from a genome-wide association meta-analysis including 14,361 RA patients and 43,923 controls of European ancestry. Summary-level data for CAD, all stroke, any ischemic stroke and its subtypes, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage were obtained from meta-analyses of genetic studies, international genetic consortia, the UK Biobank, and the FinnGen consortium. We obtained summary-level data for common cardiovascular risk factors and related inflammatory biomarkers to assess possible mechanisms.

    RESULTS: Genetic liability to RA was associated with an increased risk of CAD and ICH. For a 1-unit increase in log odds of RA, the combined odds ratios were 1.02 (95% confidence interval [1.01, 1.03]; P = 0.003) for CAD and 1.05 (95% confidence interval [1.02, 1.08]; P = 0.001) for ICH. Genetic liability to RA was associated with increased levels of tumor necrosis factor and C-reactive protein (CRP). The association with CAD was attenuated after adjustment for genetically predicted CRP levels. There were no associations of genetic liability to RA with the other studied outcomes.

    CONCLUSION: This study found that genetic liability to RA was associated with an increased risk of CAD and ICH and that the association with CAD might be mediated by CRP. The heightened cardiovascular risk should be actively monitored and managed in RA patients, and this may include dampening systemic inflammation.

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  • 2805.
    Yuan, Shuai
    et al.
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden..
    Chen, Jie
    Zhejiang Univ, Affiliated Hosp 2, Sch Med, Ctr Clin Big Data & Analyt,Dept Big Data Hlth Sci,, Hangzhou, Peoples R China..
    Fu, Tian
    Cent South Univ, Dept Gastroenterol, Changsha, Peoples R China..
    Li, Xue
    Zhejiang Univ, Affiliated Hosp 2, Sch Med, Ctr Clin Big Data & Analyt,Dept Big Data Hlth Sci,, Hangzhou, Peoples R China..
    Bruzelius, Maria
    Karolinska Inst, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Hematol, Coagulat Unit, Stockholm, Sweden..
    Akesson, Agneta
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden..
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden.;Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden..
    Ultra-processed food intake and incident venous thromboembolism risk: Prospective cohort study2023In: Clinical Nutrition, ISSN 0261-5614, E-ISSN 1532-1983, Vol. 42, no 8, p. 1268-1275Article in journal (Refereed)
    Abstract [en]

    Background & aims: Ultra-processed food (UPF) intake has been associated with multiple health outcomes, but data on the association between UPF intake and venous thromboembolism (VTE) risk are lacking. We conducted this study to examine the association between UPF intake and the risk of incident VTE.

    Methods: This prospective cohort study was based on 186,323 participants free of baseline VTE from the UK Biobank. UPF intake was assessed by 24-h recall questionnaires. Data on incident VTE came from the nationwide inpatient and primary care datasets and the death registry. Cox proportional hazards regression was used to estimate the association between UPF intake and incident VTE risk. Multiplicative interactions and stratified analyses by age, sex, and body mass index were performed.

    Results: During a 10.5-year (median) follow-up, 4235 incident VTE cases were diagnosed. After adjusting for covariates, the hazard ratio of VTE among individuals with the highest quintile of UPF intake was 1.05 (95% confidence interval [CI] 0.94, 1.17) for UPF in servings, 1.12 (95% CI 1.01, 1.24) in grams, 1.10 (95% CI 1.00, 1.22) in grams %, 1.21 (95% CI 1.10, 1.33) in energy, and 1.15 (95% CI 1.05, 1.27) in energy % compared to those in the lowest quintile. Age, sex, and body mass index did not modify the associations (Pinteraction > 0.05).

    Conclusions: Higher UPF intake was associated with a moderately increased risk of VTE.

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  • 2806.
    Yuan, Shuai
    et al.
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutrit Epidmiol, Stockholm, Sweden..
    Karhunen, Ville
    Res Unit Math Sci, Oulu, Finland.;Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland..
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutrit Epidmiol, Stockholm, Sweden.
    Gill, Dipender
    Imperial Coll London, Sch Publ Hlth, Dept Epidmiol & BioStat, London, England.;Novo Nordisk, Chief Sci Advisor Off, Res & Early Dev, Copenhagen, Denmark.;Univ Cambridge, Med Res Council BioStat Unit, Cambridge, England..
    Anthropometric Traits and Risk of Mitral Valve Prolapse: A Mendelian Randomization Study2022In: Circulation: Genomic and Precision Medicine, E-ISSN 2574-8300 , Vol. 15, no 5, p. 473-475, article id e003830Article in journal (Other academic)
  • 2807.
    Yuan, Shuai
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Nobelsvag 13, S-17177 Stockholm, Sweden.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Nobelsvag 13, S-17177 Stockholm, Sweden.
    No association between coffee consumption and risk of atrial fibrillation: A Mendelian randomization study2019In: NMCD. Nutrition Metabolism and Cardiovascular Diseases, ISSN 0939-4753, E-ISSN 1590-3729, Vol. 29, no 11, p. 1185-1188Article in journal (Refereed)
    Abstract [en]

    Background and aims: Some observational studies have found that habitual coffee and caffeine consumption might reduce the risk of atrial fibrillation (AF). We conducted a two-sample Mendelian randomization study to explore the potential association between coffee consumption and AF.

    Methods and results: This study was based on summary-level data from the Atrial Fibrillation Consortium, including 588 190 individuals (65 446 cases and 522 744 non-cases). Nine single-nucleotide polymorphisms associated with coffee consumption at significance level of P < 5 x 10(-8) were used as instrumental variables and were obtained from a genome-wide association study that included up to 375 833 individuals. The odds ratio of AF per genetically-predicted 50% increase of coffee consumption was 0.98 (95% confidence interval, 0.88, 1.10; P = 0.80) in the standard inverse-variance weighted analysis. Results were consistent in sensitivity analyses using the weighted median and MR-Egger methods, and no directional pleiotropy (P = 0.37) was observed. Moreover, complementary analyses that separated the coffee-related single-nucleotide polymorphisms based on their association with blood levels of caffeine metabolites (lower, higher, unrelated or unknown association) revealed no association with AF.

    Conclusions: This study does not support a causal association between habitual coffee consumption and risk of AF. 

  • 2808.
    Yuan, Shuai
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, SE-17177 Stockholm, Sweden.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, SE-17177 Stockholm, Sweden.
    Plasma Phospholipid Fatty Acids and Risk of Atrial Fibrillation: A Mendelian Randomization Study2019In: Nutrients, E-ISSN 2072-6643, Vol. 11, no 7, article id 1651Article in journal (Refereed)
    Abstract [en]

    Available evidence on the associations of dietary and circulating levels of long-chain n-3 fatty acids, which have potential antiarrhythmic properties, and other fatty acids with atrial fibrillation is conflicting and limited. We conducted a Mendelian randomization study to assess the associations between plasma phospholipid fatty acid levels and atrial fibrillation. Summary-level data of atrial fibrillation were available from 65,446 cases and 522,744 non-cases included in the Atrial Fibrillation Consortium. Sixteen single-nucleotide polymorphisms associated with ten fatty acids at significance level of p < 5 x 10(-8) were identified as instrumental variables from the hitherto largest genome-wide association studies for plasma fatty acids. The fixed-effects inverse-variance weighted method was used to assess the association of individual plasma fatty acids and atrial fibrillation risk. The random-effects inverse-variance weighted method, weighted median method, and Mendelian randomization (MR)-Egger method were employed as the sensitivity analyses. Genetic predisposition to higher levels of any of the ten individual fatty acids was not associated with atrial fibrillation risk.

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  • 2809.
    Yuan, Shuai
    et al.
    Karolinska Inst, Unit Cardiovasc & Nutr Epidemiol, Inst Environm Med, S-17165 Stockholm, Sweden..
    Li, Xue
    Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Big Data Hlth Sci,Sch Publ Hlth,Ctr Clin Big, Hangzhou 310058, Peoples R China..
    Morange, Pierre-Emmanuel
    La Timone Hosp, Haematol Lab, F-13385 Marseille, France.;Univ Aix Marseille, Ctr CardioVasc & Nutr Res C2VN, Inst Natl Rech Agron INRA, INSERM, F-13385 Marseille, France.;HemoVasc, Ctr Ressources Biol Assistance Publ Hop Marseille, F-13385 Marseille, France..
    Bruzelius, Maria
    Karolinska Inst, Dept Med Solna, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Hematol, Coagulat Unit, S-17165 Stockholm, Sweden..
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology. Karolinska Inst, Unit Cardiovasc & Nutr Epidemiol, Inst Environm Med, S-17165 Stockholm, Sweden..
    Plasma Phospholipid Fatty Acids and Risk of Venous Thromboembolism: Mendelian Randomization Investigation2022In: Nutrients, E-ISSN 2072-6643, Vol. 14, no 16, article id 3354Article in journal (Refereed)
    Abstract [en]

    Circulating fatty acids may affect thrombosis but epidemiological data on the associations between fatty acids and risk of venous thromboembolism (VTE) are limited and conflicting. We conducted a Mendelian randomization study to examine the causal associations of 10 circulating fatty acids with VTE risk. Genetic variants strongly associated with ten fatty acids and without linkage disequilibrium were selected as instrumental variables from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Genetic associations for VTE and its subtypes were obtained from the International Network Against Venous Thrombosis Consortium (30,234 cases and 172,122 controls) and the FinnGen study (11,288 VTE cases and 254,771 controls). Estimates from the two data sources were combined. Per standard deviation increase in genetically predicted fatty acid levels, the combined odds ratio (OR) of VTE was 0.88 (95% confidence interval [CI] 0.84-0.92) for alpha-linolenic acid, 0.92 (95% CI 0.90-0.95) for linoleic acid, 0.85 (95% CI 0.78-0.92) for palmitoleic acid, 0.77 (95% CI 0.77-0.84) for oleic acid, 1.16 (95% CI 1.10-1.23) for eicosapentaenoic acid, 1.10 (95% CI 1.06-1.14) for docosapentaenoic acid, 1.06 (95% CI 1.04-1.08) for arachidonic acid, and 1.19 (95% CI 1.11-1.28) for stearic acid. Genetically predicted levels of docosahexaenoic acid or palmitoleic acid were not associated with VTE risk. Four and eight out of ten genetically predicted fatty acid levels were associated with risk of pulmonary embolism and deep vein thrombosis, respectively. This study suggests that strategies targeting at fatty acids may act as prevention approaches for VTE.

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  • 2810.
    Yuan, Shuai
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden..
    Lin, Ang
    Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden..
    He, Qi-qiang
    Wuhan Univ, Sch Hlth Sci, Wuhan, Peoples R China..
    Burgess, Stephen
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, MRC Biostat Unit, Cambridge, England..
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden..
    Circulating interleukins in relation to coronary artery disease, atrial fibrillation and ischemic stroke and its subtypes: A two-sample Mendelian randomization study2020In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 313, p. 99-104Article in journal (Refereed)
    Abstract [en]

    Background: The causal role of interleukins (ILs) for cardiovascular disease has not been fully elucidated. Weconducted a Mendelian randomization study to investigate the associations of circulating ILs with coronary artery disease (CAD), atrial fibrillation (AF), and ischemic stroke. Methods and results: Single-nucleotide polymorphisms associated with IL-1 beta, IL-1 receptor antagonist (IL-1ra), IL-2 receptor subunit alpha, IL-6, IL-16, IL-17 and IL-18 were identified from genome-wide association studies. Summary-level data of the outcomes were obtained from three large consortia. Genetic predisposition to higher IL-1ra levels were significantly associated with CAD. The odds ratio was 1.36 (95% confidence interval (CI), 1.14-1.63; P= 5.37 x 10(-4)) per one standard deviation increase in IL-1ra levels. Genetically higher IL-6 levels, predicted by a variant in the IL6R gene and corresponding to reduced IL-6 bio-function, were significantly inversely associated with CAD and AF. The odds ratios per one standard deviation increase in IL-6 levels were 0.64 (95%CI, 0.54-0.76; P = 2.22 x 10(-7)) for CAD and 0.70 (95%CI, 0.62-0.80; P = 1.34 x 10(-7)) for AF. There was a suggestive positive association of IL-1ra with cardioembolic stroke and suggestive inverse associations of IL-6 with any ischemic stroke, cardioembolic stroke, and small vessel stroke, and of IL-16 with CAD. The other ILs were not associated with any outcome. Conclusions: These results strengthen the evidence that IL-6 inhibition may offer a therapeutic approach for prevention of CAD, AF, and ischemic stroke. In contrast, IL-1 inhibition through raised IL-1ra levels may confer increased risk of CAD and cardioembolic stroke. The role of IL-16 for CAD warrants further investigation.

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  • 2811.
    Yuan, Shuai
    et al.
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Nobelsvag 13, S-17177 Stockholm, Sweden..
    Mason, Amy M.
    Univ Cambridge, Dept Publ Hlth & Primary Care, British Heart Fdn Cardiovasc Epidemiol Unit, Cambridge, England.;Univ Cambridge, Natl Inst Hlth Res, Cambridge Biomed Res Ctr, Cambridge, England.;Cambridge Univ Hosp, Cambridge, England..
    Burgess, Stephen
    Univ Cambridge, Dept Public Hlth & Primary Care, Cambridge, England.;Univ Cambridge, MRC Biostat Unit, Cambridge, England..
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Nobelsvag 13, S-17177 Stockholm, Sweden..
    Genetic liability to insomnia in relation to cardiovascular diseases: a Mendelian randomisation study2021In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 36, no 4, p. 393-400Article in journal (Refereed)
    Abstract [en]

    The present study aimed to determine the associations between insomnia and cardiovascular diseases (CVDs) using Mendelian randomisation (MR) analysis. As instrumental variables, we used 208 independent single-nucleotide polymorphisms associated with insomnia at the genome-wide significance threshold in a meta-analysis of genome-wide association studies in the UK Biobank and 23andMe including a total of 397 959 self-reported insomnia cases and 933 057 non-cases. Summary-level data for nine CVDs were obtained from the UK Biobank including 367 586 individuals of European ancestry. After correction for multiple testing, genetic liability to insomnia was associated with higher odds of six CVDs, including peripheral arterial disease (odd ratio (OR) 1.22; 95% confidence interval (CI), 1.21, 1.33), heart failure (OR 1.21; 95% CI, 1.13, 1.30), coronary artery disease (OR 1.19; 95% CI, 1.14, 1.25), ischaemic stroke (OR 1.15; 95% CI, 1.06, 1.25), venous thromboembolism (OR 1.13; 95% CI, 1.07, 1.19) and atrial fibrillation (OR 1.10; 95% CI, 1.05, 1.15). There were suggestive associations for aortic valve stenosis (OR, 1.17; 95% CI, 1.04, 1.32) and haemorrhagic stroke (OR 1.14; 95% CI, 1.00, 1.29) but no association for abdominal aortic aneurysm (OR, 1.14, 95% CI, 0.98, 1.33). The patterns of associations remained with mild attenuation in multivariable MR analyses adjusting for genetically correlated phenotypes and potential mediators, including sleep duration, depression, body mass index, type 2 diabetes and smoking. The present MR study suggests potential causal associations of genetic liability to insomnia with increased risk of a broad range of CVDs.

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  • 2812. Yuan, Shuai
    et al.
    Tang, Bowen
    Zheng, Jie
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology.
    Circulating Lipoprotein Lipids, Apolipoproteins and Ischemic Stroke.2020In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 88, no 6, p. 1229-1236Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: We conducted a Mendelian randomization (MR) study to disentangle the comparative effects of lipids and apolipoproteins on ischemic stroke.

    METHODS: Single-nucleotide polymorphisms associated with low- and high-density lipoprotein (LDL and HDL) cholesterol, triglycerides, and apolipoprotein A-I and B (apoA-I and apoB) at the level of genomewide significance (p < 5 × 10-8 ) in the UK Biobank were used as instrumental variables. Summary-level data for ischemic stroke and its subtypes were obtained from the MEGASTROKE consortium with 514,791 individuals (60,341 ischemic stroke cases, and 454,450 non-cases).

    RESULTS: Increased levels of apoB, LDL cholesterol, and triglycerides were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke in the main and sensitivity univariable MR analyses. In multivariable MR analysis including apoB, LDL cholesterol, and triglycerides in the same model, apoB retained a robust effect (p < 0.05), whereas the estimate for LDL cholesterol was reversed, and that for triglycerides largely attenuated. Decreased levels of apoA-I and HDL cholesterol were robustly associated with increased risk of any ischemic stroke, large artery stroke, and small vessel stroke in all univariable MR analyses, but the association for apoA-I was attenuated to the null after mutual adjustment.

    INTERPRETATION: The present MR study reveals that apoB is the predominant trait that accounts for the etiological basis of apoB, LDL cholesterol, and triglycerides in relation to ischemic stroke, in particular large artery and small vessel stroke. Whether HDL cholesterol exerts a protective effect on ischemic stroke independent of apoA-I needs further investigation. ANN NEUROL 2020;88:1229-1236.

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  • 2813.
    Yuan, Shuai
    et al.
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden..
    Xu, Fengzhe
    Westlake Univ, Sch Life Sci, Key Lab Growth Regulat & Translat Res Zhejiang Pro, Hangzhou, Peoples R China..
    Zhang, Han
    Zhejiang Univ, Affiliated Hosp 2, Ctr Clin Big Data & Analyt, Dept Big Data Hlth Sci,Sch Publ Hlth,Sch Med, Hangzhou, Peoples R China..
    Chen, Jie
    Zhejiang Univ, Affiliated Hosp 2, Ctr Clin Big Data & Analyt, Dept Big Data Hlth Sci,Sch Publ Hlth,Sch Med, Hangzhou, Peoples R China..
    Ruan, Xixian
    Cent South Univ, Xiangya Hosp 3, Dept Gastroenterol, Changsha, Peoples R China..
    Li, Yuying
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Burgess, Stephen
    Univ Cambridge, Med Res Council, Biostat Unit, Cambridge, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Akesson, Agneta
    Li, Xue
    Zhejiang Univ, Affiliated Hosp 2, Ctr Clin Big Data & Analyt, Dept Big Data Hlth Sci,Sch Publ Hlth,Sch Med, Hangzhou, Peoples R China..
    Gill, Dipender
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England..
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden..
    Proteomic insights into modifiable risk of venous thromboembolism and cardiovascular comorbidities2024In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 22, no 3, p. 738-748Article in journal (Refereed)
    Abstract [en]

    Background: Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown.

    Objectives: We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities.

    Methods: A 2-stage network Mendelian randomization analysis was conducted to explore the associations between 15 MFs, 1151 blood proteins, and VTE using data from a genome-wide meta-analysis including 81 190 cases of VTE. We used protein data from 35 559 individuals as the discovery analysis, and from 2 independent studies including 10 708 and 54 219 participants as the replication analyses. Based on the identified proteins, we assessed the druggability and examined the cardiovascular pleiotropy.

    Results: The network Mendelian randomization analyses identified 10 MF-VTE, 86 MF-protein, and 34 protein-VTE associations. These associations were overall consistent in the replication analyses. Thirty-eight pathways with directionally consistent direct and indirect effects in the MF-protein-VTE pathway were identified. Lowdensity lipoprotein receptor-related protein 12 (LRP12: 34.3%-58.1%) and coagulation factor (F)XI (20.6%-39.6%) mediated most of the associations between 3 obesity indicators and VTE. Likewise, coagulation FXI mediated most of the smoking-VTE association (40%; 95% CI, 20%-60%) and insomnia-VTE association (27%; 95% CI, 5%49%). Many VTE-associated proteins were highly druggable for thrombotic conditions. 1, and low-density lipoprotein receptor-related protein 4) were associated with VTE and its cardiovascular comorbidities.

    Conclusion: This study suggests that coagulation FXI, a druggable target, is an important mediator of the associations of obesity, smoking, and insomnia with VTE risk.

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  • 2814. Yuan, Shuai
    et al.
    Zheng, Ju-Sheng
    Mason, Amy M
    Burgess, Stephen
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology. Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Sweden..
    Genetically predicted circulating vitamin C in relation to cardiovascular disease.2021In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 28, no 16, p. 1829-1837Article in journal (Refereed)
    Abstract [en]

    AIM: We conducted a two-sample Mendelian randomization (MR) study to assess the associations of genetically predicted circulating vitamin C levels with cardiovascular diseases (CVDs).

    METHODS AND RESULTS: Ten lead single-nucleotide polymorphisms associated with plasma vitamin C levels at the genome-wide significance level were used as instrumental variables. Summary-level data for 15 CVDs were obtained from corresponding genetic consortia, the UK Biobank study, and the FinnGen consortium. The inverse-variance-weighted method was the primary analysis method, supplemented by the weighted median and MR-Egger methods. Estimates for each CVD from different sources were combined. Genetically predicted vitamin C levels were not associated with any CVD after accounting for multiple testing. However, there were suggestive associations of higher genetically predicted vitamin C levels (per 1 standard deviation increase) with lower risk of cardioembolic stroke [odds ratio, 0.79; 95% confidence interval (CI), 0.64, 0.99; P = 0.038] and higher risk of atrial fibrillation (odds ratio, 1.09; 95% CI, 1.00, 1.18; P = 0.049) in the inverse-variance-weighted method and with lower risk of peripheral artery disease (odds ratio, 0.76, 95% CI, 0.62, 0.93; P = 0.009) in the weighted median method.

    CONCLUSION: We found limited evidence with MR techniques for an overall protective role of vitamin C in the primary prevention of CVD. The associations of vitamin C levels with cardioembolic stroke, atrial fibrillation, and peripheral artery disease need further study.

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  • 2815.
    Yuan, Xiaotian
    et al.
    Karolinska Inst, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden;Karolinska Inst, Ctr Mol Med, SE-17176 Stockholm, Sweden;Karolinska Univ Hosp Solna, SE-17176 Stockholm, Sweden.
    Kronstrom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Hellenius, Mai-Lis
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, SE-17176 Solna, Sweden.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Xu, Dawei
    Karolinska Inst, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden;Karolinska Inst, Ctr Mol Med, SE-17176 Stockholm, Sweden;Karolinska Univ Hosp Solna, SE-17176 Stockholm, Sweden.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Longitudinal changes in leukocyte telomere length and mortality in elderly Swedish men2018In: Aging, ISSN 1945-4589, E-ISSN 1945-4589, Vol. 10, no 10, p. 3005-3016Article in journal (Refereed)
    Abstract [en]

    Telomere length (TL) is considered an indicator of aging and age-related diseases, but longitudinal studies on TL changes and mortality are few. We therefore analyzed TL and longitudinal changes in TL in relation to all-cause, cardiovascular, and cancer mortality in 247 elderly Swedish men. TL was determined by the qPCR method at ages 71 and 81 and subsequent mortality cases were identified from the Swedish cause-of-death registry. Cox proportional hazard ratios were calculated during a mean follow-up of 7.4 years, during which 178 deaths occurred. Short telomeres at baseline was strongly associated with mortality risks, with a 40 to 70% increased risk of all-cause mortality, and a 2-fold increased risk of cancer mortality. Longitudinal changes in TL revealed shortening in 83% of individuals, whilst 10% extended their telomeres. TL attrition did not predict all-cause or cancer mortality, but we found a 60% decreased risk for cardiovascular mortality in those who shortened their telomeres. Our data show an increased risk of mortality in individuals with short baseline telomeres, but no relations to all-cause, and cancer mortality for changes in TL. Intriguingly, our data indicate lower risk of cardiovascular mortality with shortening of telomeres. The latter should be interpreted cautiously.

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  • 2816.
    Zachrisson, Karin
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Radiol, Gothenburg, Sweden..
    Krupic, Ferid
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Orthoped & Anesthesiol, Gothenburg, Sweden..
    Svensson, Mikael
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Hlth Metr Unit, Gothenburg, Sweden..
    Wigelius, Ann
    Umeå Univ Hosp, Dept Radiat Sci, Diagnost Radiol, Umeå, Sweden..
    Jonsson, Andreas
    Umeå Univ Hosp, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Dimopoulou, Angeliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Stenborg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Jensen, Gert
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med Nephrol, Gothenburg, Sweden..
    Herlitz, Hans
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med Nephrol, Gothenburg, Sweden..
    Gottsäter, Anders
    Skane Univ Hosp, Vasc Ctr, Clin Vasc Dis Res, Malmö, Sweden..
    Falkenberg, Mårten
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Radiol, Gothenburg, Sweden..
    Results of renal artery revascularization in the post-ASTRAL era with 4 years mean follow-up2020In: Blood Pressure, ISSN 0803-7051, E-ISSN 1651-1999, Vol. 29, no 5, p. 285-290Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate contemporary results of percutaneous transluminal renal angioplasty (PTRA).

    Materials and Methods: A multicentre retrospective study analysing all patients treated with PTRA for primary symptomatic renal artery stenosis (RAS) between 2010 and 2013 at four tertiary centres. Procedures during the preceding four years were counted to evaluate for change in PTRA frequency.

    Results: The number of PTRA procedures decreased by approximately 50% from 2006 to 2013. Patients treated in the post-ASTRAL period (n = 224) had a significant reduction in mean systolic pressure (168 to 146 mmHg, p < 0.01), diastolic pressure (84 to 76 mmHg, p < 0.01), number of anti-hypertensive drugs (3.54 to 3.05, p < 0.01), and anti-hypertensive treatment index (21.75 to 16.92, p < 0.01) compared to before PTRA. These improvements were maintained at one year and at the last clinical evaluation after a mean follow-up of 4.31 years. Renal function increased transiently without sustained improvement, or deterioration, during later follow-up. Thirteen patients (5.8%) eventually required dialysis, nine of these had eGFR <20 ml/min/1.73 m2 before PTRA. There was no difference in outcomes between subgroups differentiated by different indications for PTRA.

    Conclusion: The frequency of PTRA has decreased, indicating a higher threshold for invasive treatment of RAS in recent years. The reduction in blood pressures, the reduced need for anti-hypertensive medication, and stabilization of renal function over time suggest a clinical benefit for most patients who are now being treated with PTRA.

  • 2817.
    Zanetti, Daniela
    et al.
    Stanford Univ, Div Cardiovasc Med, Dept Med, Sch Med, Stanford, CA 94305 USA.;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.;Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA 94305 USA..
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Assimes, Themistocles L.
    Stanford Univ, Div Cardiovasc Med, Dept Med, Sch Med, Stanford, CA 94305 USA.;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA..
    Ingelsson, Erik
    Stanford Univ, Div Cardiovasc Med, Dept Med, Sch Med, Stanford, CA 94305 USA.;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.;Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA 94305 USA..
    Comprehensive Investigation of Circulating Biomarkers and Their Causal Role in Atherosclerosis-Related Risk Factors and Clinical Events2020In: Circulation: Genomic and Precision Medicine, E-ISSN 2574-8300 , Vol. 13, no 6, p. 671-685Article in journal (Refereed)
    Abstract [en]

    Background: Circulating biomarkers have been previously associated with atherosclerosis-related risk factors, but the nature of these associations is incompletely understood.

    Methods: We performed multivariable-adjusted regressions and 2-sample Mendelian randomization analyses to assess observational and causal associations of 27 circulating biomarkers with 7 cardiovascular traits in up to 451 933 participants of the UK Biobank.

    Results: After multiple-testing correction (alpha=1.3x10(-4)), we found a total of 15, 9, 21, 22, 26, 24, and 26 biomarkers strongly associated with coronary artery disease, ischemic stroke, atrial fibrillation, type 2 diabetes, systolic blood pressure, body mass index, and waist-to-hip ratio; respectively. The Mendelian randomization analyses confirmed strong evidence of previously suggested causal associations for several glucose- and lipid-related biomarkers with type 2 diabetes and coronary artery disease. Particularly interesting findings included a protective role of IGF-1 (insulin-like growth factor 1) in systolic blood pressure, and the strong causal association of lipoprotein(a) in coronary artery disease development (beta, -0.13; per SD change in exposure and outcome and odds ratio, 1.28; P=2.6x10(-4) and P=7.4x10(-35), respectively). In addition, our results indicated a causal role of increased ALT (alanine aminotransferase) in the development of type 2 diabetes and hypertension (odds ratio, 1.59 and beta, 0.06, per SD change in exposure and outcome; P=4.8x10(-11) and P=6.0x10(-5)). Our results suggest that it is unlikely that CRP (C-reactive protein) and vitamin D play causal roles of any meaningful magnitude in development of cardiometabolic disease.

    Conclusions: We confirmed and extended known associations and reported several novel causal associations providing important insights about the cause of these diseases, which can help accelerate new prevention strategies.

  • 2818.
    Zanetti, Daniela
    et al.
    Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr,Mail Code 5773, Stanford, CA 94305 USA;Stanford Univ, Sch Med, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
    Tikkanen, Emmi
    Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr,Mail Code 5773, Stanford, CA 94305 USA.
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford University School of Medicine, CA..
    Priest, James R.
    Stanford Univ, Sch Med, Div Cardiol, Dept Pediat, Stanford, CA 94305 USA.
    Burgess, Stephen
    Univ Cambridge, Biostat Unit, MRC, Cambridge, England;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr,Mail Code 5773, Stanford, CA 94305 USA;Stanford Univ, Sch Med, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
    Birthweight, Type 2 Diabetes Mellitus, and Cardiovascular Disease Addressing the Barker Hypothesis With Mendelian Randomization2018In: Circulation: Genomic and Precision Medicine, E-ISSN 2574-8300 , Vol. 11, no 6, article id UNSP e002054Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Low birthweight has been associated with a higher risk of hypertension, type 2 diabetes mellitus (T2D), and cardiovascular disease. The Barker hypothesis posits that intrauterine growth restriction resulting in lower birthweight is causal for these diseases, but causality is difficult to infer from observational studies. METHODS: We performed regression analyses to assess associations of birthweight with cardiovascular disease and T2D in 237 631 individuals from the UK Biobank. Further, we assessed the causal relationship of such associations using Mendelian randomization. RESULTS: In the observational analyses, birthweight showed inverse associations with systolic and diastolic blood pressure (beta, -0.83 and -0.26; per raw unit in outcomes and SD change in birthweight; 95% confidence interval [CI], -0.90 to -0.75 and -0.31 to -0.22, respectively), T2D (odds ratio, 0.83; 95% CI, 0.79-0.87), lipid-lowering treatment (odds ratio, 0.84; 95% CI, 0.81-0.86), and coronary artery disease (hazard ratio, 0.85; 95% CI, 0.78-0.94), whereas the associations with adult body mass index and body fat (beta, 0.04 and 0.02; per SD change in outcomes and birthweight; 95% CI, 0.03-0.04 and 0.01-0.02, respectively) were positive. The Mendelian randomization analyses indicated inverse causal associations of birthweight with low-density lipoprotein cholesterol, 2-hour glucose, coronary artery disease, and T2D and positive causal association with body mass index but no associations with blood pressure. CONCLUSIONS: Our study indicates that lower birthweight, used as a proxy for intrauterine growth retardation, is causally related with increased susceptibility to coronary artery disease and T2D. This causal relationship is not mediated by adult obesity or hypertension.

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  • 2819.
    Zarrouk, M.
    et al.
    Skane Univ Hosp, Dept Vasc Dis, S-20502 Malmo, Sweden..
    Lundqvist, A.
    IHE, Swedish Inst Hlth Econ, Lund, Sweden..
    Holst, J.
    Skane Univ Hosp, Dept Vasc Dis, S-20502 Malmo, Sweden..
    Troeng, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Gottsater, A.
    Skane Univ Hosp, Dept Vasc Dis, S-20502 Malmo, Sweden..
    Cost-effectiveness of Screening for Abdominal Aortic Aneurysm in Combination with Medical Intervention in Patients with Small Aneurysms2016In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 51, no 6, p. 766-773Article in journal (Refereed)
    Abstract [en]

    Objectives: Screening for abdominal aortic aneurysm (AAA) among 65 year old men has been proven costeffective, but nowadays is conducted partly under new conditions. The prevalence of AAA has decreased, and endovascular aneurysm repair (EVAR) has become the predominant surgical method for AAA repair in many centers. At the Malmo Vascular Center pharmacological secondary prevention with statins, antiplatelet therapy, and blood pressure reduction is initiated and given to all patients with AAA. This study evaluates the costeffectiveness of AAA screening under the above mentioned conditions. Methods: This was a Markov cohort simulation. A total of 4,300 65 year old men were invited to annual AAA screening; the attendance rate was 78.3% and AAA prevalence was 1.8%. A Markov model with 11 health states was used to evaluate cost-effectiveness of AAA screening. Background data on rupture risks, costs, and effectiveness of surgical interventions were obtained from the participating unit, the national Swedvasc Registry, and from the scientific literature. Results: The additional costs of the screening strategy compared with no screening were 169 per person and year. The incremental health gain per subject in the screened cohort was 0.011 additional quality adjusted life years (QALYs), corresponding to an incremental cost-effectiveness ratio (ICER) of 15710 per QALY. Assuming a 10% reduction of all cause mortality, the incremental cost of screening was 175 per person and year. The gain per subject in the screened cohort was 0.013 additional QALYs, corresponding to an ICER of 13922 per QALY Conclusions: AAA screening remains cost-effective according to both the Swedish recommendations and the UK National Institute for Health and Care Excellence recommendations in the new era of lower AAA prevalence, EVAR as the predominant surgical method, and secondary prevention for all AAA patients.

  • 2820.
    Zeitouni, Michel
    et al.
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Giczewska, Anna
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Lopes, Renato D.
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Wojdyla, Daniel M.
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    De Caterina, Raffaele
    Univ Pisa, Cardiothorac & Vasc Dept, Div Cardiovasc Med, Pisa, Italy.
    Steg, Philippe Gabriel
    Univ Paris, Hop Bichat, AP HP, Cardiol Dept,FACT, Paris, France;INSERM, Paris, France.
    Granger, Christopher B.
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Alexander, John H.
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Clinical and Pharmacological Effects of Apixaban Dose Adjustment in the ARISTOTLE Trial2020In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 75, no 10, p. 1145-1155Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, patients with atrial fibrillation and >= 2 dose-adjustment criteria (age >= 80 years, weight <= 60 kg, or creatinine >= 1.5 mg/dl [133 mu mol/l]) were randomized to receive apixaban 2.5 mg twice daily or warfarin.

    OBJECTIVES: The purpose of this study was to describe the effects of apixaban dose adjustment on clinical and pharmacological outcomes.

    METHODS: Patients receiving the correct dose of study drug were included (n = 18,073). The effect of apixaban 2.5 mg twice daily versus warfarin on population pharmacokinetics, D-dimer, prothrombin fragment 1 + 2 (PF1+2), and clinical outcomes was compared with the standard dose (5 mg twice daily).

    RESULTS: Patients receiving apixaban 2.5 mg twice daily exhibited lower apixaban exposure (median area under the concentration time curve at a steady state 2,720 ng/ml vs. 3,599 ng/ml; p < 0.0001) than those receiving the standard dose. In patients with >= 2 dose-adjustment criteria, reductions in D-dimers (p interaction = 0.20) and PF1+2 (p interaction = 0.55) were consistent with those observed in the standard-dose population. Patients with >= 2 dose-adjustment criteria (n = 751) were at higher risk for stroke/systemic embolism, major bleeding, and all-cause death than the standard-dose population (0 or 1 dose-adjustment criterion, n = 17,322). The effect of apixaban 2.5 mg twice daily versus warfarin in the >= 2 dose-adjustment criteria population was consistent with the standard dose in the reductions in stroke or systemic embolism (p interaction = 0.26), major bleeding (p interaction = 0.25), and death (p interaction = 0.72).

    CONCLUSIONS: Apixaban drug concentrations were lower in patients receiving 2.5 mg twice daily compared with 5 mg twice daily. However, the effects of apixaban dose adjustment to 2.5 mg versus warfarin were consistent for coagulation biomarkers and clinical outcomes, providing reassuring data on efficacy and safety. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984) 

  • 2821.
    Zethelius, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eliasson, Björn
    Eeg-Olofsson, Katarina
    Svensson, Ann-Marie
    Gudbjörnsdottir, Soffia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Cederholm, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    A new model for 5-year risk of cardiovascular disease in type 2 diabetes, from the Swedish National Diabetes Register (NDR)2011In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 93, no 2, p. 276-284Article in journal (Refereed)
    Abstract [en]

    AIM:

    We assessed the association between risk factors and cardiovascular disease (CVD) in an observational study of type 2 diabetes patients from the Swedish National Diabetes Register.

    METHODS:

    A derivation sample of 24,288 patients, aged 30-74 years, 15.3% with previous CVD, baseline 2002, 2488 CVD events when followed for 5 years until 2007. A separate validation data set of 4906 patients, baseline 2003, 522 CVD events when followed for 4 years.

    RESULTS:

    Adjusted hazard ratios at Cox regression for fatal/nonfatal CVD were: onset-age 1.59, diabetes duration 1.55, total-cholesterol-to-HDL-cholesterol ratio 1.20, HbA1c 1.12, systolic BP 1.09, BMI 1.07 (1 SD increase in natural log continuous variables); males 1.41, smoker 1.35, microalbuminuria 1.27, macroalbuminuria 1.53, atrial fibrillation 1.50, previous CVD 1.98 (all p<0.001 except BMI p=0.0018). All 12 variables were used to elaborate an equation for 5-year CVD risk in the derivation dataset: mean 5-year risk 11.9±8.4%. Calibration in the validation dataset was adequate: ratio predicted 4-year risk/observed rate 0.97. Discrimination was sufficient: C statistic 0.72, sensitivity 51% and specificity 78% for top quartile.

    CONCLUSION:

    This CVD risk model from a large observational study of patients in routine care showed adequate calibration and discrimination, and can be useful for clinical practice.

  • 2822.
    Zethelius, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gudbjörnsdottir, S.
    Göteborgs universitet.
    Eliasson, B.
    Göteborgs universitet.
    Eeg-Olofsson, K.
    Göteborgs universitet.
    Cederholm, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Level of physical activity associated with risk of cardiovascular diseases and mortality in patients with type-2 diabetes: report from the Swedish National Diabetes Register.2014In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 21, no 2, p. 244-251Article in journal (Refereed)
  • 2823. Zeymer, Uwe
    et al.
    Leiva, Orly
    Hohnloser, Stefan H
    Steg, Philippe Gabriel
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Nickenig, Georg
    Gabor Kiss, Robert
    Ongen, Zeki
    Navarro Estrada, Jose
    Oude Ophuis, Ton
    Lip, Gregory Y H
    Nordaby, Matias
    Miede, Corinna
    Ten Berg, Jurrien M
    Bhatt, Deepak L
    Cannon, Christopher P
    Dual antithrombotic therapy with dabigatran in patients with atrial fibrillation after percutaneous coronary intervention for ST elevation myocardial infarction: results from the randomised RE-DUAL PCI trial.2021In: EuroIntervention, ISSN 1774-024X, E-ISSN 1969-6213, Vol. 17, no 6, p. 474-480, article id EIJ-D-20-00799Article in journal (Refereed)
    Abstract [en]

    AIMS: To investigate the safety and efficacy of dabigatran dual therapy (110 or 150 mg twice daily, plus clopidogrel or ticagrelor) vs warfarin triple therapy in patients with atrial fibrillation undergoing PCI for ST elevation myocardial infarction (STEMI).

    METHODS AND RESULTS: In RE-DUAL PCI, 305 patients with STEMI were randomised to dabigatran 110 mg (n=113 versus 106 warfarin) or 150 mg (n=86 versus 84 warfarin). Primary endpoint was time to first major or clinically relevant non-major bleeding event (MBE/CRNMBE). The thrombotic endpoint was a composite of death, thromboembolic events, or unplanned revascularisation. In STEMI patients, dabigatran 110 mg (HR 0.39, 95% CI 0.20-0.74) and 150 mg (0.43, 0.21-0.89) dual therapy reduced the risk of MBE/CRNMBE versus warfarin triple therapy (p interaction vs all other patients = 0.31 and 0.16). Risk of thrombotic events, for dabigatran 110 mg (HR 1.61, 95% CI: 0.85-3.08) and 150 mg (0.56, 0.20-1.51) had p interactions of 0.20 and 0.33, respectively. For net clinical benefit, HRs were 0.74 (95% CI 0.46-1.17) and 0.49 (0.27-0.91) for dabigatran 110 and 150 mg (p interaction = 0.80 and 0.12).

    CONCLUSIONS: In patients after PCI for STEMI, dabigatran dual therapy had lower risks of bleeding events versus warfarin triple therapy with similar risks of thromboembolic events, supporting the use of dabigatran dual therapy even in patients with high thrombotic risk.

  • 2824.
    Zhang, Cuili
    et al.
    Harbin Med Univ, Affiliated Hosp 1, Dept Cardiol, Harbin, Peoples R China..
    Miao, Xiao
    Shanghai Univ Tradit Chinese Med, Innovat Res Inst Tradit Chinese Med, Shanghai, Peoples R China..
    Wang, Biqi
    Univ Massachusetts, Dept Med, Chan Med Sch, Worcester, MA 01655 USA..
    Thomas, Robert J. J.
    Beth Israel Deaconess Med Ctr, Dept Med, Div Pulm Crit Care & Sleep Med, Boston, MA USA..
    Horta Ribeiro, Antônio
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control.
    Brant, Luisa C. C.
    Univ Fed Minas Gerais, Hosp Clin, Fac Med, Belo Horizonte, Brazil.;Univ Fed Minas Gerais, Telehlth Ctr, Hosp Clin, Belo Horizonte, Brazil..
    Ribeiro, Antonio L. P.
    Univ Fed Minas Gerais, Hosp Clin, Fac Med, Belo Horizonte, Brazil.;Univ Fed Minas Gerais, Telehlth Ctr, Hosp Clin, Belo Horizonte, Brazil..
    Lin, Honghuang
    Univ Massachusetts, Dept Med, Chan Med Sch, Worcester, MA 01655 USA..
    Association of lifestyle with deep learning predicted electrocardiographic age2023In: Frontiers in Cardiovascular Medicine, E-ISSN 2297-055X, Vol. 10, article id 1160091Article in journal (Refereed)
    Abstract [en]

    Background: People age at different rates. Biological age is a risk factor for many chronic diseases independent of chronological age. A good lifestyle is known to improve overall health, but its association with biological age is unclear.

    Methods: This study included participants from the UK Biobank who had undergone 12-lead resting electrocardiography (ECG). Biological age was estimated by a deep learning model (defined as ECG-age), and the difference between ECG-age and chronological age was defined as Delta age. Participants were further categorized into an ideal (score 4), intermediate (scores 2 and 3) or unfavorable lifestyle (score 0 or 1). Four lifestyle factors were investigated, including diet, alcohol consumption, physical activity, and smoking. Linear regression models were used to examine the association between lifestyle factors and Delta age, and the models were adjusted for sex and chronological age.

    Results: This study included 44,094 individuals (mean age 64 +/- 8, 51.4% females). A significant correlation was observed between predicted biological age and chronological age (correlation coefficient = 0.54, P < 0.001) and the mean Delta age (absolute error of biological age and chronological age) was 9.8 +/- 7.4 years. Delta age was significantly associated with all of the four lifestyle factors, with the effect size ranging from 0.41 +/- 0.11 for the healthy diet to 2.37 +/- 0.30 for non-smoking. Compared with an ideal lifestyle, an unfavorable lifestyle was associated with an average of 2.50 +/- 0.29 years of older predicted ECG-age.

    Conclusion: In this large contemporary population, a strong association was observed between all four studied healthy lifestyle factors and deaccelerated aging. Our study underscores the importance of a healthy lifestyle to reduce the burden of aging-related diseases.

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  • 2825.
    Zhang, Liang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkerström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Mollazadegan, Kazhan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Beuschlein, Felix
    Univ Spital Zurich USZ, Klin Endokrinol Diabetol Klin Ernahrung, Zurich, Switzerland.;Univ Zurich UZH, Zurich, Switzerland.;Klinikum Univ Munchen, Med Klin & Poliklin 4, Munich, Germany..
    Pacak, Karel
    NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Huma, Sect Med Neuroendocrinol, Bethesda, MD USA..
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Risk of complications after core needle biopsy in pheochromocytoma/paraganglioma2023In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 30, no 7, article id e220354Article in journal (Refereed)
    Abstract [en]

    Core needle biopsy (CNB) has been used with caution in pheochromocytoma and paraganglioma (PPGL) due to concerns about catecholamine-related complications. While it is unclear what scientific evidence supports this claim, it has limited the acquisition of biological samples for diagnostic purposes and research, especially in metastatic PPGL. We performed a systematic review and individual patient meta-analysis to evaluate the risk of complications after CNB in PPGL patients. The primary and secondary objectives were to investigate the risk of death and the occurrence of complications requiring intervention or hospitalization, respectively. Fifty-six articles describing 86 PPGL patients undergoing CNB were included. Of the patients (24/71), 34% had metastases and 53.4% (31/58) had catecholamine-related symptoms before CNB. Of the patients (14/41), 34.1% had catecholamine excess testing prior to the biopsy. No CNB-related deaths were reported. Four patients (14.8%, 4/27) experienced CNB-related complications requiring hospitalization or intervention. One case had a temporary duodenal obstruction caused by hematoma, two cases had myocardial infarction, and one case had Takotsubo cardiomyopathy. Eight patients (32%, 8/25) had CNB-related catecholamine symptoms, mainly transient hypertension, excessive diaphoresis, tachycardia, or hypertensive crisis. The scientific literature does not allow us to make any firm conclusion on the safety of CNB in PPGL. However, it is reasonable to argue that CNB could be conducted after thorough consideration, preparation, and with close follow-up for PPGL patients with a strong clinical indication for such investigation.

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  • 2826.
    Zheng, Rui
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    A combined observational and Mendelian randomization investigation reveals NMR-measured analytes to be risk factors of major cardiovascular diseases2024In: Scientific Reports, E-ISSN 2045-2322, Vol. 14, no 1, article id 10645Article in journal (Refereed)
    Abstract [en]

    Dyslipidaemias is the leading risk factor of several major cardiovascular diseases (CVDs), but there is still a lack of sufficient evidence supporting a causal role of lipoprotein subspecies in CVDs. In this study, we comprehensively investigated several lipoproteins and their subspecies, as well as other metabolites, in relation to coronary heart disease (CHD), heart failure (HF) and ischemic stroke (IS) longitudinally and by Mendelian randomization (MR) leveraging NMR-measured metabolomic data from 118,012 UK Biobank participants. We found that 123, 110 and 36 analytes were longitudinally associated with myocardial infarction, HF and IS (FDR < 0.05), respectively, and 25 of those were associated with all three outcomes. MR analysis suggested that genetically predicted levels of 70, 58 and 7 analytes were associated with CHD, HF and IS (FDR < 0.05), respectively. Two analytes, ApoB/ApoA1 and M-HDL-C were associated with all three CVD outcomes in the MR analyses, and the results for M-HDL-C were concordant in both observational and MR analyses. Our results implied that the apoB/apoA1 ratio and cholesterol in medium size HDL were particularly of importance to understand the shared pathophysiology of CHD, HF and IS and thus should be further investigated for the prevention of all three CVDs.

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  • 2827.
    Zhong, You
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden.;Beijing Hosp, Dept Cardiol, Beijing, Peoples R China..
    Rosengren, Annika
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden..
    Fu, Michael
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden..
    Welin, Lennart
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden.;Lidkoping Hosp, Dept Med, Lidkoping, Sweden..
    Welin, Catharina
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden..
    Caidahl, Kenneth
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Mandalenakis, Zacharias
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden..
    Dellborg, Mikael
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden..
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine. Uppsala Univ, Dept Publ Hlth & Caring Sci, Family Med & Prevent Med Sect, Uppsala, Sweden..
    Hansson, Per-Olof
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden..
    Secular changes in cardiovascular risk factors in Swedish 50-year-old men over a 50-year period: The study of men born in 1913, 1923, 1933, 1943, 1953 and 19632017In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 24, no 6, p. 612-620Article in journal (Refereed)
    Abstract [en]

    Background: During the past decades, declining trends in mean cholesterol levels and smoking have been observed in Western Europe, whereas obesity and a sedentary lifestyle have increased. Simultaneously, there has been a marked decrease in mortality from cardiovascular (CV) diseases. Methods: The aim of the study was to determine whether these trends in CV risk factors continued over a period of 50 years. Six systematic or random population samples of 50-year-old men (n = 3563) living in Gothenburg, Sweden, were investigated between 1963 and 2013. Results: During the 50 years, mean body mass index (BMI) at 50 years of age increased by 2 kg/m(2), from 24.8 kg/m(2) in 1963 to 26.8 kg/m(2) in 2013 (p< 0.001). A decrease in systolic blood pressure of nearly 10mmHg was observed from 1963 to 1993, but was not sustained through the past two decades. Mean serum cholesterol fell from 6.42 (SD 1.12) mmol/L to 5.34 (SD 0.97) mmol/L. The prevalence of smoking at 50 years of age decreased markedly from 56.1% in 1963 to 11.9% in 2013. The number of participants with a sedentary lifestyle during leisure time decreased until 1993, but has remained unchanged since. In 2013, 50-year-old men had a 6.9-times higher likelihood of lacking CV risk factors than 50-year-old men in 1963 (95% confidence interval (CI): 3.5-13.3, p< 0.001). The odds ratio for having four or more risk factors was only 0.13 (95% CI: 0.062-0.29, p< 0.001). Conclusion: Despite increasing body weight, the total CV risk factor burden has decreased in 50-year-old men over the past 50 years.

  • 2828.
    Zhou, Weibin
    et al.
    Sun Yat sen Univ, Sun Yat Sen Mem Hosp, Guangzhou, Peoples R China.;Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangdong Prov Clin Res Ctr Ocular Dis, State Key Lab Ophthalmol, Guangzhou, Peoples R China.;Guangdong Prov Key Lab Arrhythmia & Electrophysiol, Guangzhou, Peoples R China..
    Liu, Keli
    Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangdong Prov Clin Res Ctr Ocular Dis, State Key Lab Ophthalmol, Guangzhou, Peoples R China..
    Zeng, Lei
    Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangdong Prov Clin Res Ctr Ocular Dis, State Key Lab Ophthalmol, Guangzhou, Peoples R China..
    He, Jiaqi
    Sun Yat sen Univ, Sun Yat Sen Mem Hosp, Guangzhou, Peoples R China.;Guangdong Prov Key Lab Arrhythmia & Electrophysiol, Guangzhou, Peoples R China..
    Gao, Xinbo
    Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangdong Prov Clin Res Ctr Ocular Dis, State Key Lab Ophthalmol, Guangzhou, Peoples R China..
    Gu, Xinyu
    Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangdong Prov Clin Res Ctr Ocular Dis, State Key Lab Ophthalmol, Guangzhou, Peoples R China..
    Chen, Xun
    Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangdong Prov Clin Res Ctr Ocular Dis, State Key Lab Ophthalmol, Guangzhou, Peoples R China..
    Jing Li, Jing
    Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangdong Prov Clin Res Ctr Ocular Dis, State Key Lab Ophthalmol, Guangzhou, Peoples R China..
    Wang, Minghui
    Sun Yat sen Univ, Sun Yat Sen Mem Hosp, Guangzhou, Peoples R China..
    Wu, Duoguang
    Sun Yat sen Univ, Sun Yat Sen Mem Hosp, Guangzhou, Peoples R China..
    Cai, Zhixiong
    Shantou Cent Hosp, Dept Cardiol, Shantou, Peoples R China..
    Claesson-Welsh, Lena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ju, Rong
    Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangdong Prov Clin Res Ctr Ocular Dis, State Key Lab Ophthalmol, Guangzhou, Peoples R China..
    Wang, Jingfeng
    Sun Yat sen Univ, Sun Yat Sen Mem Hosp, Guangzhou, Peoples R China.;Guangdong Prov Key Lab Arrhythmia & Electrophysiol, Guangzhou, Peoples R China.;Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Guangzhou 510060, Peoples R China..
    Zhang, Feng
    Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangdong Prov Clin Res Ctr Ocular Dis, State Key Lab Ophthalmol, Guangzhou, Peoples R China.;Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangdong Prov Clin Res Ctr Ocular Dis, State Key Lab Ophthalmol, Guangzhou 510060, Peoples R China..
    Chen, Yangxin
    Sun Yat sen Univ, Sun Yat Sen Mem Hosp, Guangzhou, Peoples R China.;Guangdong Prov Key Lab Arrhythmia & Electrophysiol, Guangzhou, Peoples R China.;Sun Yat Sen Univ, Sun Yat sen Mem Hosp, Guangzhou 510060, Peoples R China..
    Targeting VEGF-A/VEGFR2 Y949 Signaling-Mediated Vascular Permeability Alleviates Hypoxic Pulmonary Hypertension2022In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 146, no 24, p. 1855-1881Article in journal (Refereed)
    Abstract [en]

    Background:Pulmonary hypertension (PH) is associated with increased expression of VEGF-A (vascular endothelial growth factor A) and its receptor, VEGFR2 (vascular endothelial growth factor 2), but whether and how activation of VEGF-A signal participates in the pathogenesis of PH is unclear. Methods:VEGF-A/VEGFR2 signal activation and VEGFR2 Y949-dependent vascular leak were investigated in lung samples from patients with PH and mice exposed to hypoxia. To study their mechanistic roles in hypoxic PH, we examined right ventricle systolic pressure, right ventricular hypertrophy, and pulmonary vasculopathy in mutant mice carrying knock-in of phenylalanine that replaced the tyrosine at residual 949 of VEGFR2 (Vefgr2(Y949F)) and mice with conditional endothelial deletion of Vegfr2 after chronic hypoxia exposure. Results:We show that PH leads to excessive pulmonary vascular leak in both patients and hypoxic mice, and this is because of an overactivated VEGF-A/VEGFR2 Y949 signaling axis. In the context of hypoxic PH, activation of Yes1 and c-Src and subsequent VE-cadherin phosphorylation in endothelial cells are involved in VEGFR2 Y949-induced vascular permeability. Abolishing VEGFR2 Y949 signaling by Vefgr2(Y949F) point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure, thereby leading to alleviated PH manifestations, including muscularization of distal pulmonary arterioles, elevated right ventricle systolic pressure, and right ventricular hypertrophy. It is important that we found that VEGFR2 Y949 signaling in myeloid cells including macrophages was trivial and dispensable for hypoxia-induced vascular abnormalities and PH. In contrast with selective blockage of VEGFR2 Y949 signaling, disruption of the entire VEGFR2 signaling by conditional endothelial deletion of Vegfr2 promotes the development of PH. Conclusions:Our results support the notion that VEGF-A/VEGFR2 Y949-dependent vascular permeability is an important determinant in the pathogenesis of PH and might serve as an attractive therapeutic target pathway for this disease.

  • 2829.
    Zimerman, Andre
    et al.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Lopes, Renato D.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Stebbins, Amanda L.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Guimaraes, Patricia O.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Haque, Ghazala
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Melloni, Chiara
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Trollinger, Kathleen
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Alexander, John H.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Tricoci, Pierluigi
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Roe, Matthew T.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Ohman, Erik Magnus
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Mahaffey, Kenneth W.
    Stanford Univ, Dept Med, Stanford, CA 94305 USA..
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Tinga, Brian
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Pieper, Karen S.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Alexander, Karen P.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Pooled analysis of adverse event collection from 4 acute coronary syndrome trials2016In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 174, p. 60-67Article in journal (Refereed)
    Abstract [en]

    Background: Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied.

    Methods: Adverse event data from 4 clinical trials (APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded.

    Results: In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs.

    Conclusions: Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted.

  • 2830. Zimmermann, Stefan
    et al.
    Flachskampf, Frank A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Alff, Anna
    Schneider, Reinhard
    Dechant, Katharina
    Klinghammer, Lutz
    Stumpf, Christian
    Zopf, Yurdaguel
    Loehr, Thomas
    Brand, Georg
    Ludwig, Josef
    Daniel, Werner G
    Achenbach, Stephan
    Out-of-hospital cardiac arrest and percutaneous coronary intervention for ST-elevation myocardial infarction: Long-term survival and neurological outcome2013In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 166, no 1, p. 236-241Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Predictors of long-term outcome after ST-elevation myocardial infarction (STEMI) complicated by out-of-hospital cardiac arrest (OHCA) are incompletely understood, including the influence of successful coronary reperfusion.

    METHODS:

    We analysed clinical and procedural data as well as 1-year outcome of 72 consecutive patients who underwent primary coronary intervention (PCI) after witnessed OHCA and STEMI and compared the results with 695 patients with STEMI and PCI, but without OHCA. Neurological recovery after OHCA was assessed using the Cerebral Performance Category (CPC) scale.

    RESULTS:

    PCI was successful in 83.3% after OHCA vs. 84.3% in the non-OHCA group (p=0.87). One-year mortality was 34.7% vs. 9.5% (p<0.001). 58.3% of the OHCA-patients showed complete neurological recovery (CPC 1) or moderate neurological disability (CPC 2). Another 6.9% showed severe cerebral disability (CPC 3) or permanent vegetative status (CPC 4). Delay from collapse until start of Advanced Cardiopulmonary Life Support (ACLS) was shorter for survivors with CPC status ≤2 (median 1min, range 0-11min) compared to non-survivors or survivors with CPC status >2 (median 8min, range 0-13min), p<0.0001. Age-adjusted multivariate analysis identified 'unsuccessful PCI', 'vasopressors on admission' and 'start of ACLS after >6min' as independent predictors of negative long-term outcome (death or CPC >2).

    CONCLUSIONS:

    Mortality is high in patients with STEMI complicated by OHCA - even though PCI was performed with the same success rate as in patients without OHCA. The majority of survivors had favourable neurological outcomes at 1year, especially if advanced life support had been started within ≤6min and PCI was successful.

  • 2831.
    Zimnowodzki, Simon
    et al.
    VA San Diego Healthcare, 3350 La Jolla Village Dr, San Diego, CA 92161 USA..
    Butrum, Matthew
    Intermt Healthcare, 5171 S Cottonwood St Ste 810, Salt Lake City, UT 84107 USA..
    Kimura, Jun
    Univ Iowa, 0206 RCP, Iowa City, IA 52242 USA..
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rostedt Punga: Clinical Neurophysiology.
    Mahajan, Shalini
    Cedars Sinai Med Ctr, 8700 Beverly Blvd, Los Angeles, CA 90048 USA..
    Gao, Leland
    LA Neuromuscular Ctr, 8750 Wilshire Blvd Ste 350, Beverly Hills, CA 90211 USA..
    Emergence of F-waves after repetitive nerve stimulation2020In: Clinical Neurophysiology Practice, E-ISSN 2467-981X, Vol. 5, p. 100-103Article in journal (Refereed)
    Abstract [en]

    Aim: Absence of the F-wave may represent the inability of spinal motor neurons to be excited after periods of inactivity. Repetitive stimulation in an otherwise immobile patient acts as a voluntary movement therefore allowing for the production of an F-wave in a patient with previously demonstrated absent F-waves. Through this case report, we attempt to highlight that the absence of the F-wave may result from inexcitability of spinal motor neurons after reduced mobilization. Case: We present the case of a 48-year-old woman who had been hospitalized in an ICU setting for almost one month due to a subarachnoid hemorrhage, pancreatitis, and respiratory failure. An electromyogram and nerve conduction study (NCS) was performed for weakness in all four extremities. On routine NCS, her F-waves were absent, but after repetitive stimulation was performed, her F-waves appeared. Discussion: This may be further evidence that the absence of the F-wave may result from inexcitability of spinal motor neurons after immobilization or reduced mobility rather than true pathology of the peripheral nerve. The ability to recover F-waves after an initial absence could assist in differentiating between inexcitability of the anterior horn cell and proximal nerve conduction block. This case presentation is an attempt to show that repetitive nerve stimulation may prove to be a useful technique to restore F-waves in patients who are unable to voluntarily contract their muscles, which may help exclude certain pathologic processes. (C) 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.

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  • 2832. Zindovic, Igor
    et al.
    Sjögren, Johan
    Bjursten, Henrik
    Björklund, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Herou, Erik
    Ingemansson, Richard
    Nozohoor, Shahab
    Predictors and impact of massive bleeding in acute type A aortic dissection.2017In: Interactive Cardiovascular and Thoracic Surgery, ISSN 1569-9293, E-ISSN 1569-9285, Vol. 24, no 4, p. 498-505Article in journal (Refereed)
    Abstract [en]

    Objectives: Bleeding complications associated with acute type A aortic dissection (aTAAD) are a well-known clinical problem. Here, we evaluated predictors of massive bleeding related to aTAAD and associated surgery and assessed the impact of massive bleeding on complications and survival.

    Methods: This retrospective study of 256 patients used Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) criteria to define massive bleeding, which was met by 66 individuals (Group I) who were compared to the remaining patients (Group II). Multivariable logistic regression was used to identify independent predictors of massive bleeding and in-hospital mortality, Kaplan-Meier estimates for analysis of late survival, and Cox regression analysis to evaluate independent predictors of late mortality.

    Results: Independent predictors of massive bleeding included symptom duration (odds ratio [OR], 0.974 per hour increment; 95% confidence interval [CI], 0.950-0.999; P  =   0.041) and DeBakey type 1 dissection (OR, 2.652; 95% CI, 1.004-7.008; P  =   0.049). In-hospital mortality was higher in Group I (30.3% vs 8.0%, P  <0.001). Kaplan-Meier estimates of survival indicated poorer survival for Group I at 1, 3 and 5 years (68.8 ± 5.9% vs 92.8 ± 1.9%; 65.2 ± 6.2% vs 85.3 ± 2.7%; 53.9 ± 6.9% vs 82.1 ± 3.3 %, respectively; log rank P  <   0.001). Re-exploration for bleeding was an independent predictor of in-hospital (OR, 3.109; 95% CI, 1.044-9.256; P  =   0.042) and late mortalities (hazard ratio, 3.039; 95% CI, 1.605-5.757; P  =   0.001).

    Conclusions: Massive bleeding in patients with aTAAD is prompted by shorter symptom duration and longer extent of dissection and has deleterious effects on outcomes of postoperative complications as well as in-hospital and late mortalities.

  • 2833.
    Zoerner, Frank
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Department of Operative- and Intensive Care Medicine, Hallands Hospital Halmstad, Halmstad, Sweden.
    Novel Interventions in Cardiac Arrest: Targeted Temperature Management, Methylene Blue, S-PBN, Amiodarone, Milrinone and Esmolol,  Endothelin and Nitric Oxide In Porcine Resuscitation Models2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    It is a major clinical problem that survival rates after out-of-hospital cardiac arrest have not markedly improved during the last decades, despite extensive research and the introduction of new interventions. However, recent studies have demonstrated promising treatments such as targeted temperature management (TTM) and methylene blue (MB).

    In our first study, we investigated the effect of MB administered during experi-mental cardiopulmonary resuscitation (CPR) in the setting of postponed hypother-mia in piglets. We set out to study if MB could compensate for a delay to establish targeted TTM. The study demonstrated that MB more than compensated for 30 min delay in induction of TTM. The effect of MB added to that of TTM.

    The second study examined the effects of TTM and S-PBN on the endothelin system and nitric oxide synthases (NOS) after prolonged CA in a porcine CPR mod-el. The study was designed to understand the cardioprotective mechanism of S-PBN and TTM by their influence on the endothelin system and NOS regulation. We veri-fied for the first time, that these two cardioprotective postresuscitative interventions activate endothelin-1 and its receptors concomitantly with eNOS and nNOS in the myocardium. We concluded that nitric oxide and endothelin pathways are implicated in the postresuscitative cardioprotective effects of TTM.

    The third study compared survival and hemodynamic effects of low-dose amio-darone and vasopressin to vasopressin in a porcine hypovolemic CA model. The study was designed to evaluate whether resuscitation with amiodarone and vasopressin compared to vasopressin alone would have an impact on resuscitation success, survival, and hemodynamic parameters after hemorrhagic CA. We found that combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters and smaller myocardial injury compared to resuscitation with vasopressin only.

    In our fourth study we planned to compare hemodynamic parameters between the treatment group (milrinone, esmolol and vasopressin; MEV) and control group (vasopressin only) during resuscitation from prolonged cardiac arrest in piglets. The study was designed to demonstrate if MEV treatment improved hemodynamics or cardiac damage compared to controls. We demonstrated that MEV treatment reduced cardiac injury compared with vasopressin alone.

    List of papers
    1. Improved neuroprotective effect of methylene blue with hypothermia after porcine cardiac arrest
    Open this publication in new window or tab >>Improved neuroprotective effect of methylene blue with hypothermia after porcine cardiac arrest
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    2013 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 57, no 8, p. 1073-1082Article in journal (Refereed) Published
    Abstract [en]

    Background

    Induced mild hypothermia and administration of methylene blue (MB) have proved to have neuroprotective effects in cardiopulmonary resuscitation (CPR); however, induction of hypothermia takes time. We set out to determine if MB administered during CPR could add to the histologic neuroprotective effect of hypothermia.

    Methods

    A piglet model of extended cardiac arrest (12 min of untreated cardiac arrest and 8 min of CPR) was used to assess possible additional neuroprotective effects of MB when administered during CPR before mild therapeutic hypothermia induced 30 min after restoration of spontaneous circulation (ROSC). Three groups were compared: C group (n = 8) received standard CPR; PH group (n = 8) received standard CPR but 30 min after ROSC these piglets were cooled to 34°C; the PH+MB group (n = 8) received an MB infusion 1 min after commencement of CPR and the same cooling protocol as the PH group. Three hours later, the animals were killed. Immediately after death, the brains were harvested pending histological and immunohistological analysis.

    Results

    Circulatory variables were similar in the groups except that cardiac output was greater in the PH+MB group 2–3 h after ROSC. Cerebral cortical neuronal injury and blood–brain barrier disruption was greatest in the C group and least in the MB group. The neuroprotective effect of MB and hypothermia was significantly greater than that of delayed hypothermia alone.

    Conclusion

    Administration of MB during CPR added to the short term neuroprotective effects of induced mild hypothermia induced 30 min after ROSC.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-199854 (URN)10.1111/aas.12106 (DOI)000323075000017 ()23577658 (PubMedID)
    Available from: 2013-05-17 Created: 2013-05-17 Last updated: 2024-04-18Bibliographically approved
    2. Therapeutic hypothermia activates the endothelin and nitric oxide systems after cardiac arrest in a pig model of cardiopulmonary resuscitation
    Open this publication in new window or tab >>Therapeutic hypothermia activates the endothelin and nitric oxide systems after cardiac arrest in a pig model of cardiopulmonary resuscitation
    2013 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 5, p. e64792-Article in journal (Refereed) Published
    Abstract [en]

    Post-cardiac arrest myocardial dysfunction is a major cause of mortality in patients receiving successful cardiopulmonary resuscitation (CPR). Mild therapeutic hypothermia (MTH) is the recommended treatment after resuscitation from cardiac arrest (CA) and is known to exert neuroprotective effects and improve short-term survival. Yet its cytoprotective mechanisms are not fully understood. In this study, our aim was to determine the possible effect of MTH on vasoactive mediators belonging to the endothelin/nitric oxide axis in our porcine model of CA and CPR. Pigs underwent either untreated CA or CA with subsequent CPR. After state-of-the-art resuscitation, the animals were either left untreated, cooled between 32-34°C after ROSC or treated with a bolus injection of S-PBN (sodium 4-[(tert-butylimino) methyl]benzene-3-sulfonate N-oxide) until 180 min after ROSC, respectively. The expression of endothelin 1 (ET-1), endothelin converting enzyme 1 (ECE-1), and endothelin A and B receptors (ETAR and ETBR) transcripts were measured using quantitative real-time PCR while protein levels for the ETAR, ETBR and nitric oxide synthases (NOS) were assessed using immunohistochemistry and Western Blot. Our results indicated that the endothelin system was not upregulated at 30, 60 and 180 min after ROSC in untreated postcardiac arrest syndrome. Post-resuscitative 3 hour-long treatments either with MTH or S-PBN stimulated ET-1, ECE-1, ETAR and ETBR as well as neuronal NOS and endothelial NOS in left ventricular cardiomyocytes. Our data suggests that the endothelin and nitric oxide pathways are activated by MTH in the heart.

    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-200585 (URN)10.1371/journal.pone.0064792 (DOI)000319435600076 ()23717659 (PubMedID)
    Available from: 2013-05-31 Created: 2013-05-31 Last updated: 2024-04-18Bibliographically approved
    3. Resuscitation with amiodarone increases survival after hemorrhage and ventricular fibrillation in pigs
    Open this publication in new window or tab >>Resuscitation with amiodarone increases survival after hemorrhage and ventricular fibrillation in pigs
    2014 (English)In: Journal of Trauma and Acute Care Surgery, ISSN 2163-0755, E-ISSN 2163-0763, Vol. 76, no 6, p. 1402-1408Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: The aim of this experimental study was to compare survival and hemodynamic effects of a low-dose amiodarone and vasopressin compared with vasopressin in hypovolemic cardiac arrest model in piglets. METHODS: Eighteen anesthetized male piglets (with a weight of 25.3 [1.8] kg) were bled approximately 30% of the total blood volume via the femoral artery to a mean arterial blood pressure of 35 mm Hg in a 15-minute period. Afterward, the piglets were subjected to 4 minutes of untreated ventricular fibrillation followed by 11 minutes of open-chest cardiopulmonary resuscitation. At 5 minutes, circulatory arrest amiodarone 1 mg/kg was intravenously administered in the amiodarone group (n = 9), while the control group received the same amount of saline (n = 9). At the same time, all piglets received vasopressin 0.4 U/kg intravenously administered and hypertonic-hyperoncotic solution 3-mL/kg infusion for 20 minutes. Internal defibrillation was attempted from 7 minutes of cardiac arrest to achieve restoration of spontaneous circulation. The experiment was terminated 3 hours after resuscitation. RESULTS: Three-hour survival was greater in the amiodarone group (p = 0.02). After the successful resuscitation, the amiodarone group piglets had significantly lower heart rate as well as greater systolic, diastolic, and mean arterial pressure. Troponin I plasma concentrations were lower and urine output was greater in the amiodarone group. CONCLUSION: Combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters, and smaller myocardial injury compared with resuscitation with vasopressin only.

    Keywords
    Amiodarone, cardiac arrest, ventricular fibrillation, hemorrhage, pigs
    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-228547 (URN)10.1097/TA.0000000000000243 (DOI)000337145500011 ()
    Available from: 2014-07-17 Created: 2014-07-16 Last updated: 2024-04-18Bibliographically approved
    4. Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest
    Open this publication in new window or tab >>Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest
    Show others...
    2015 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 59, no 4, p. 465-474Article in journal (Refereed) Published
    Abstract [en]

    Background: Long-term survival after cardiac arrest (CA) due to shock-refractory ventricular fibrillation (VF) is low. Clearly, there is a need for new pharmacological interventions in the setting of cardiopulmonary resuscitation (CPR) to improve outcome. Here, hemodynamic parameters and cardiac damage are compared between the treatment group (milrinone, esmolol and vasopressin) and controls (vasopressin only) during resuscitation from prolonged CA in piglets.

    Methods: Twenty-six immature male piglets were subjected to 12 min VF followed by 8 min CPR. The treatment group (n=13) received i.v. boluses vasopressin 0.4 U∙kg−1, esmolol 250 μg∙kg−1 and milrinone 25 μg∙kg−1 after 13 min, followed by i.v. boluses esmolol 375 μg∙kg−1 and milrinone 25 μg∙kg−1 after 18 min and continuous esmolol 15 μg∙kg−1∙h−1 infusion during 180 min reperfusion, while controls (n=13) received equal amounts of vasopressin and saline. A 200J monophasic counter-shock was delivered to achieve resumption of spontaneous circulation (ROSC) after 8 min CPR. If ROSC was not achieved, another 200J defibrillation and bolus vasopressin 0.4 U∙kg−1 were administered in both groups. DC shocks at 360J were applied as one shot min−1 over maximally 5 min. Hemodynamic variables and troponin I as a marker of cardiac injury were recorded.

    Results: Troponin I levels after 180 min reperfusion were lower in the treatment group than in controls (p<0.05). The treatment group received less norepinephrine (p<0.01) and had greater diuresis (p<0.01). There was no difference in survival between groups.

    Conclusions: The combination of milrinone, esmolol and vasopressin decreased cardiac injury compared with vasopressin alone. 

    Place, publisher, year, edition, pages
    Wiley, 2015
    Keywords
    Cardiac arrest, resumption of spontaneous circulation, ROSC, milrinone, vasopressin, esmolol, I/R injury, reperfusion injury, cardioprotection, myocardial ischemia, epinephrine, resuscitation
    National Category
    Anesthesiology and Intensive Care Medical and Health Sciences
    Research subject
    Anaesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-237869 (URN)10.1111/aas.12480 (DOI)000351537900008 ()
    Available from: 2014-12-06 Created: 2014-12-06 Last updated: 2024-04-18Bibliographically approved
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  • 2834. Zoghbi, William A
    et al.
    Levine, Robert A
    Flachskampf, Frank
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Grayburn, Paul
    Gillam, Linda
    Leipsic, Jonathon
    Thomas, James D
    Kwong, Raymond Y
    Vandervoort, Pieter
    Chandrashekhar, Y
    Atrial Functional Mitral Regurgitation: A JACC: Cardiovascular Imaging Expert Panel Viewpoint2022In: JACC Cardiovascular Imaging, ISSN 1936-878X, E-ISSN 1876-7591, Vol. 15, no 11, p. 1870-1882Article in journal (Refereed)
    Abstract [en]

    Functional or secondary mitral regurgitation (MR) is associated with increased cardiovascular morbidity and mortality. Mechanistically, secondary MR is attributable to an imbalance between mitral leaflet tethering and closure forces, leading to poor coaptation. The pathophysiology of functional MR is most often the result of abnormalities in left ventricular function and remodeling, seen in ischemic or nonischemic conditions. Less commonly and more recently recognized is the scenario in which left ventricular geometry and function are preserved, the culprit being mitral annular enlargement associated with left atrial dilatation, termed atrial functional mitral regurgitation (AFMR). This most commonly occurs in the setting of chronic atrial fibrillation or heart failure with preserved ejection fraction. There is variability in the published reports and in current investigations as to the definition of AFMR. This paper reviews the pathophysiology of AFMR and focus on the need for a collective definition of AFMR to facilitate consistency in reported data and enhance much-needed research into outcomes and treatment strategies in AFMR.

  • 2835. Zucchelli, Giulio
    et al.
    Di Cori, Andrea
    Segreti, Luca
    Laroche, Cécile
    Blomström-Lundqvist, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    Kutarski, Andrzej
    Regoli, François
    Butter, Christian
    Defaye, Pascal
    Pasquié, Jean Luc
    Auricchio, Angelo
    Maggioni, Aldo P
    Bongiorni, Maria Grazia
    Major cardiac and vascular complications after transvenous lead extraction: acute outcome and predictive factors from the ESC-EHRA ELECTRa (European Lead Extraction ConTRolled) registry2019In: Europace, ISSN 1099-5129, E-ISSN 1532-2092, Vol. 21, no 5, p. 771-780Article in journal (Refereed)
    Abstract [en]

    Aims: We aimed at describing outcomes and predictors of cardiac avulsion or tear (CA/T) with tamponade and vascular avulsion or tear (VA/T) after transvenous lead extraction (TLE) in the ESC-EHRA European Lead Extraction ConTRolled (ELECTRa) registry.

    Methods and results: A total of 3555 consecutive patients of whom 3510 underwent TLE at 73 centres in 19 European countries were enrolled. Among 58 patients (1.7%) with procedure-related major complications, 49 (84.5%) patients (30 CA/T and 19 VA/T) presented cardiovascular complications requiring pericardiocentesis, chest tube positioning and/or surgical repair. The mortality was 20% in patients with tamponade due to CA/T and 31.6% in patients with VA/T. Pericardiocentesis as first manoeuvre followed by rescue surgical repair was highly effective in case of CA/T (93.8%). At multivariate analysis, CA/T with tamponade was more common in RIATA lead extraction, female patients, leads with a mean dwelling time more than 10 years, and when ≥3 leads were extracted or multiple sheaths required. Occlusion or critical stenosis of superior venous access and the leads mean dwelling time more than 10 years were independent predictors for VA/T, while mechanical dilatation was an independent predictor of a lower incidence of this complication as compared to the use of powered sheaths.

    Conclusions: In the ELECTRa registry, RIATA lead extraction and superior venous access occlusion/thrombosis are two new independent predictors for cardiac tamponade and major vascular complications, respectively. The use of mechanical sheaths seems to be associated with a lower incidence of VA/T. A strategy of pericardiocentesis followed by a rescue surgical approach seems to be reasonable in order to treat a CA/T with tamponade.

  • 2836. Zuccon, Gianmarco
    et al.
    D'Oria, Mario
    Bastos Gonçalves, Frederico
    Fernandez-Prendes, Carlota
    Mani, Kevin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Caldeira, Daniel
    Koelemay, Mark
    Bissacco, Daniele
    Trimarchi, Santi
    Van Herzeele, Isabelle
    Wanhainen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery. Department of Peri-operative and Surgical Sciences, Surgery, Umeå University, Umeå, Sweden.
    Incidence, Risk Factors, and Prognostic Impact of Type Ib Endoleak Following Endovascular Repair for Abdominal Aortic Aneurysm: Scoping Review2023In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 66, no 3, p. 352-361Article, review/survey (Refereed)
    Abstract [en]

    OBJECTIVE: The primary objectives of this scoping review were to assess the rate of and risk factors for type Ib endoleak and to evaluate the extent of the evidence base that links type Ib endoleak to short and long term outcomes in patients undergoing endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA).

    METHODS: Potentially eligible studies were searched in the Cochrane Central Register of Controlled Trials, MEDLINE, Web of Science Core Collection, SciELO Citation Index, Russian Science Citation Index, and KCI-Korean Journal Database. A scoping review was performed according to PRISMA extension for Scoping Reviews.

    RESULTS: A total of 27 articles (four prospective registries and 23 retrospective cohort studies) dealing with type Ib endoleak were included in the final analysis. The number of patients reported on was 7 197, with follow up ranging between 12 months and 93 months. The reported frequency of type Ib endoleak in patients treated with EVAR ranged from 0% to 8%, Patient and or procedure related factors associated with risk of type Ib endoleak were (1) common iliac artery (CIA) diameter ˃ 18 mm requiring use of flared stent graft limbs (FLs) ˃ 20 mm, (2) length of CIA landing zone ˂ 20 mm, (3) marked iliac tortuosity, and (4) large initial AAA diameter. Depending on the study, 50 - 100% of type Ib endoleaks were corrected by endovascular means, with a reported immediate technical success of 100% in the studies providing this information.

    CONCLUSION: Type Ib endoleak after EVAR has been reported to occur in 0 - 8% of cases. Several anatomical features, including CIA diameter ˃ 18 mm or requiring the use of FLs ˃ 20 mm, length of CIA landing zone ˂ 20 mm, marked iliac tortuosity, and large initial AAA diameter, could increase the risk of type Ib endoleak and may require alternative therapeutic options and or more stringent follow up. Therefore, this updated scoping review provides a comprehensive summary of the frequency, risk factors, prognosis, and treatment of type Ib endoleaks, and has identified knowledge gaps in the literature to guide further studies.

  • 2837.
    Zvuloni, Eran
    et al.
    Technion IIT, Fac Biomed Engn, Haifa, Israel..
    Read, Jesse
    Ecole Polytech, Inst Polytech Paris, Comp Sci Lab LIX, Paris, France..
    Horta Ribeiro, Antônio
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology.
    Ribeiro, Antonio Luiz P.
    Univ Fed Minas Gerais, Hosp Clin, Fac Med, Telehlth Ctr,Dept Internal Med, Belo Horizonte, Brazil..
    Behar, Joachim A.
    Technion IIT, Fac Biomed Engn, IL-3200003 Haifa, Israel..
    On Merging Feature Engineering and Deep Learning for Diagnosis, Risk Prediction and Age Estimation Based on the 12-Lead ECG2023In: IEEE Transactions on Biomedical Engineering, ISSN 0018-9294, E-ISSN 1558-2531, Vol. 70, no 7, p. 2227-2236Article in journal (Refereed)
    Abstract [en]

    Objective: Over the past few years, deep learning (DL) has been used extensively in research for 12-lead electrocardiogram (ECG) analysis. However, it is unclear whether the explicit or implicit claims made on DL superiority to the more classical feature engineering (FE) approaches, based on domain knowledge, hold. In addition, it remains unclear whether combining DL with FE may improve performance over a single modality.

    Methods: To address these research gaps and in-line with recent major experiments, we revisited three tasks: cardiac arrhythmia diagnosis (multiclass-multilabel classification), atrial fibrillation risk prediction (binary classification), and age estimation (regression). We used an overall dataset of 2.3M 12-lead ECG recordings to train the following models for each task: i) a random forest taking FE as input; ii) an end-to-end DL model; and iii) a merged model of FE+DL.

    Results: FE yielded comparable results to DL while necessitating significantly less data for the two classification tasks. DL outperformed FE for the regression task. For all tasks, merging FE with DL did not improve performance over DL alone. These findings were confirmed on the additional PTB-XL dataset. Conclusion: We found that for traditional 12-lead ECG based diagnosis tasks, DL did not yield a meaningful improvement over FE, while it improved significantly the nontraditional regression task. We also found that combining FE with DL did not improve over DL alone, which suggests that the FE was redundant with the features learned by DL.

    Significance: Our findings provides important recommendations on 12-lead ECG based machine learning strategy and data regime to choose for a given task. When looking at maximizing performance as the end goal, if the task is nontraditional and a large dataset is available then DL is preferable. If the task is a classical one and/or a small dataset is available then a FE approach may be the better choice.

  • 2838.
    Zwackman, Sammy
    et al.
    Linköping Univ, Dept Hlth Med & Caring Sci, Div Diagnost & Specialist Med, Unit Cardiovasc Sci, Linköping, Sweden..
    Leosdottir, Margret
    Skane Univ Hosp, Dept Cardiol, Malmö, Sweden.;Lund Univ, Fac Med, Dept Clin Sci, Malmö, Sweden..
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).
    Jernberg, Tomas
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden..
    Karlsson, Jan-Erik
    Linköping Univ, Dept Hlth Med & Caring Sci, Div Diagnost & Specialist Med, Unit Cardiovasc Sci, Linköping, Sweden.;Cty Hosp Ryhov, Dept Internal Med, Jönköping, Sweden..
    Lawesson, Sofia Sederholm
    Linköping Univ, Dept Hlth Med & Caring Sci, Div Diagnost & Specialist Med, Unit Cardiovasc Sci, Linköping, Sweden..
    Michelsen, Halldora Ögmundsdottir
    Ravn-Fischer, Annica
    Gothenburg Univ, Sahlgrenska Univ Hosp, Inst Med, Sahlgrenska Acad,Dept Mol & Clin Med,Dept Cardiol, Gothenburg, Sweden..
    Wallert, John
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden.;Stockholm HealthCare Serv, Huddinge, Region Stockhol, Sweden..
    Alfredsson, Joakim
    Linköping Univ, Dept Hlth Med & Caring Sci, Div Diagnost & Specialist Med, Unit Cardiovasc Sci, Linköping, Sweden..
    Provision of professional interpreters and Heart School attendance for foreign-born compared with native-born myocardial infarction patients in Sweden2024In: IJC Heart & Vasculature, E-ISSN 2352-9067, Vol. 51, article id 101392Article in journal (Refereed)
    Abstract [en]

    Objective:

    Interactive patient education, referred to as Heart School (HS), is an important part of cardiac rehabilitation (CR) after myocardial infarction (MI), which has been associated with improved outcomes. Little is known about HS attendance among foreign-born patients. The aims were to assess; 1) HS attendance in foreign-born versus native-born patients, 2) the association between the provision of professional interpreters and HS attendance, and 3) secondary prevention goal attainment after MI based on HS attendance.

    Methods:

    The provision of professional interpreters during post-MI follow-up was assessed by a questionnaire sent to all 78 Swedish CR sites. Patient-specific data was retrieved from the SWEDEHEART registry. The association between the provision of professional interpreters and HS attendance was estimated with logistic regression models. HS attendance and attainment of secondary prevention goals by country of birth were investigated.

    Results:

    In total, 8377 patients < 75 years (78 % male) were included. Foreign-born (19.8 %) had a higher prevalence of cardiovascular risk factors and were less likely to attend HS (33.7 vs 51.3 %, p < 0.001), adjusted odds ratio (OR) 0.59 (95 % confidence interval (CI) 0.52-0.68), compared with native-born patients. CR centers providing professional interpreters had higher HS attendance among foreign-born (adjusted OR 1.55, 95 % CI 1.20-2.01) but not among native-born patients. Attending HS was similarly associated with improved secondary prevention goal attainment in both groups.

    Conclusions:

    Despite similar positive association between HS attendance and attainment of secondary prevention goals, foreign-born patients attended HS less often. With the provision of professional interpreters, HS attendance increased in foreign-born patients.

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  • 2839.
    Ärnlöv, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Carlsson, Axel C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ingelsson, Erik
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Tobias E
    Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community2013In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 83, no 1, p. 160-166Article in journal (Refereed)
    Abstract [en]

    Fibroblast growth factor-23 (FGF23), a regulator of mineral metabolism, has been linked to cardiovascular disease in chronic kidney disease. As community-based data of the longitudinal association between FGF23 and cardiovascular events are lacking, we investigated a possible relationship in 727 men of the Uppsala Longitudinal Study of Adult Men population-based cohort (mean age 77 years). During a median follow-up of 9.7 years, 110 participants died of cardiovascular causes. In Cox regression models adjusted for age and established cardiovascular risk factors, higher serum FGF23 was associated with a significantly increased risk for cardiovascular mortality (hazard ratio (HR) per increased s.d. of 1.36). This relationship remained significant, albeit attenuated, after adjustment for glomerular filtration rate (GFR) (HR 1.21). FGF23 was also associated with all-cause mortality, although the association was weaker than that with cardiovascular mortality, and it was nonsignificant in fully adjusted multivariate models. Spline analysis suggested a log-linear relationship between FGF23 and outcome. Participants with a combination of high FGF23 (>60 pg/ml), low GFR (<60 ml/min), and micro-/macro-albuminuria (albumin/creatinine ratio above 3 mg/ml) had an almost eightfold increased risk compared with participants without these abnormalities. Thus, a higher FGF23 level is associated with an increased cardiovascular mortality risk in the community. Clinical trials are needed to determine whether FGF23 is a modifiable risk factor.

  • 2840.
    Ärnlöv, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Carrero, J. J.
    Karolinska Inst, Stockholm, Sweden..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stenemo, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Larsson, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Carlsson, A. C.
    Karolinska Inst, Stockholm, Sweden..
    Discovery and replication of new risk markers for 5-year kidney function decline using a targeted multiplex proteomics chip2016Conference paper (Refereed)
  • 2841.
    Åberg, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Björklund, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Platelet-leukocyte aggregate formation and inflammation in patients with pulmonary arterial hypertension and CTEPH2022In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 33, no 8, p. 1199-1207Article in journal (Refereed)
    Abstract [en]

    Pulmonary hypertension (PH) is defined by increased mean pulmonary artery pressure, and the clinical classification includes five etiologies, of which we investigated subgroup 1, pulmonary arterial hypertension (PAH) and subgroup 4, chronic thrombotic and/or embolic disease (CTEPH). Platelets participate in both innate and adaptive immune responses and could possibly contribute to the suggested systemic inflammation associated with PAH. In this study, we utilized flow cytometry to analyze platelet activation and platelet-monocyte (PMA) and granulocyte (PGA) aggregates in PAH and CTEPH patients and healthy control subjects. The plasma concentration of proinflammatory cytokines was measured by multiplex electrochemiluminescence. Our main finding is that circulating platelets are activated in the circulation and form aggregates with both monocytes and granulocytes in patients with idiopathic PAH (IPAH), associated PAH (APAH) and pulmonary hypertension due to CTEPH. There was a strong correlation between the platelet activation, assessed as P-selectin, and the number of aggregates formed. IL-6, IL-8, IL-10 and TNF-alpha were increased in all PH subgroups as compared to healthy controls, and PMAs were associated with circulating IL-6, IL-8 and IL-10, whereas PGAs were associated with IL-6. The increased concentrations of platelet-leukocyte aggregates found in PAH/CTEPH patients might thus contribute to the inflammatory state in PH.

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  • 2842.
    Åberg, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Edén, Desireé
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Activation of beta1-integrins and caveolin-1 by TF/FVIIa promotes cell survival2018In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 114, p. S88-S88Article in journal (Other academic)
  • 2843.
    Åberg, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Tissue factor/FVIIa transactivates the IGF-1R by a Src-dependent phosphorylation of caveolin-12016In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 111, p. S99-S99Article in journal (Other academic)
  • 2844.
    Åkerblom, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Biomarkers of Renal Function in Acute Coronary Syndromes2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The thesis aimed to investigate cystatin C and creatinine-based estimates of glomerular filtration rate (eGFR), both at admission and during follow-up, on the combined endpoint of cardiovascular death and myocardial infarction in patients with acute coronary syndrome (ACS). We also evaluated two cystatin C assays and assessed genetic determinants of cystatin C concentrations.

    We used the PLATelet inhibition and Patient Outcomes study, where all types of ACS patients (n=18624) were randomized to ticagrelor or clopidogrel treatment. Multivariable Cox regression models, including clinical variables and biomarkers (troponin and NT-proBNP), and c-statistics were calculated.

    Cystatin C and the creatinine-based CKD-EPI equation exhibited similar significant prognostic impact on the combined endpoint, with Area Under Curves (AUC) 0.6923 and 0.6941, respectively. Follow-up samples of renal biomarkers did not improve risk prediction.

    Patients randomized to ticagrelor treatment were associated with a non-sustained larger increase in renal markers at discharge, but neither the change nor the difference between the randomized groups affected cardiovascular risk.

    Two different cystatin C assays exhibited good correlation 0.86 (95% confidence interval 0.85-0.86), however moderate level of agreement. Risk prediction with a combination of creatinine and cystatin C did not outperform the creatinine-based CKD-EPI equation, AUC: 0.6913 and 0.6924, respectively (n=13050).

    The genetic polymorphism rs6048952 independently affected the cystatin C concentration with mean levels of 0.85mg/L, 0.80mg/L and 0.73mg/L for the A/A, A/G, and G/G genotypes, respectively.

    The genetic polymorphism did not affect outcome overall, however in the non-ST-elevation ACS subgroup a signal that genetic polymorphism may be associated with cardiovascular death was observed (p=0.002).

    In conclusion: cystatin C or eGFR, irrespective of equation or assay, are important cardiovascular risk factors in ACS patients. Nonetheless, the incremental value of adding any renal variable, to a multivariable risk model, is small. Further research on the impact of cystatin C genetic polymorphism is warranted.

    List of papers
    1. Cystatin C and Estimated Glomerular Filtration Rate as Predictors for Adverse Outcome in Patients with ST-Elevation and Non-ST-Elevation Acute Coronary Syndromes: Results from the Platelet Inhibition and Patient Outcomes Study
    Open this publication in new window or tab >>Cystatin C and Estimated Glomerular Filtration Rate as Predictors for Adverse Outcome in Patients with ST-Elevation and Non-ST-Elevation Acute Coronary Syndromes: Results from the Platelet Inhibition and Patient Outcomes Study
    Show others...
    2012 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 58, no 1, p. 190-199Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    We evaluated the predictive ability of cystatin C and creatinine-based estimations of glomerular filtration rate (eGFR), including the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation, in acute coronary syndrome (ACS) patients with (STE-ACS) or without (NSTE-ACS) ST elevation in a large contemporary ACS population.

    METHODS:

    Concentrations of cystatin C and creatinine, as well as eGFR at randomization, were measured in 16 401 patients in the Platelet Inhibition and Patient Outcomes (PLATO) study and evaluated as predictors of the composite end point of cardiovascular death or myocardial infarction within 1 year. Two Cox proportional hazards models were used, the first adjusting for clinical characteristics and the second for clinical characteristics plus the biomarkers N-terminal pro-B-type natriuretic peptide, troponin I, and C-reactive protein.

    RESULTS:

    The median cystatin C value was 0.83 mg/L. Increasing quartiles of cystatin C were strongly associated with poor outcome (6.9%, 7.1%, 9.5%, and 16.2%). The fully adjusted hazard ratios per SD of cystatin C in the NSTE-ACS and STE-ACS populations were 1.12 (95% CI 1.04-1.20) (n = 8053) and 1.06 (95% CI 0.97-1.17) (n = 5278), respectively. There was no significant relationship of cystatin C with type of ACS (STE or NSTE). c Statistics ranged from 0.6923 (cystatin C) to 0.6941 (CKD-EPI).

    CONCLUSIONS:

    Cystatin C concentration contributes independently in predicting the risk of cardiovascular death or myocardial infarction in NSTE-ACS, with no interaction by type of ACS. CKD-EPI exhibited the largest predictive value of all renal markers. Nevertheless, the additive predictive value of cystatin C or creatinine-based eGFR measures in the unselected ACS patient is small.

    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-165398 (URN)10.1373/clinchem.2011.171520 (DOI)000299052700032 ()22126936 (PubMedID)
    Available from: 2012-01-05 Created: 2012-01-05 Last updated: 2017-12-08Bibliographically approved
    2. Outcome and causes of renal deterioration evaluated by serial cystatin C measurements in acute coronary syndrome patients: Results from the PLATelet inhibition and patient Outcomes (PLATO) study
    Open this publication in new window or tab >>Outcome and causes of renal deterioration evaluated by serial cystatin C measurements in acute coronary syndrome patients: Results from the PLATelet inhibition and patient Outcomes (PLATO) study
    Show others...
    2012 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 164, no 5, p. 728-734Article in journal (Refereed) Published
    Abstract [en]

    Background: To investigate if ticagrelor treatment and other clinical characteristics were associated with increased cystatin C concentrations and if a deterioration in estimated renal function was associated with worse outcome in patients with acute coronary syndromes (ACS). Methods: Plasma cystatin C concentrations were determined within 24 hours of admission (baseline), at discharge, 1 month, and 6 months in the PLATO trial. The changes over time in relation to randomized treatment were analyzed by analysis of covariance. C-statistics and the relative Integrated Discrimination Improvement of the cystatin C concentrations regarding the primary outcome (cardiovascular death or myocardial infarction) was evaluated by multivariable analysis including background characteristics and biomarkers: N-terminal-pro-B-type natriuretic peptide and Troponin I. Results: Mean cystatin C concentrations in 2133 ticagrelor- and 2162 clopidogrel-treated patients were at baseline (0.86 mg/L and 0.86 mg/L), discharge (1.01 mg/L and 0.98 mg/L) (P <.0005), 1 month (1.00 mg/L and 0.98 mg/L) (P =.12), and 6 months (1.00 mg/L and 0.99 mg/L) (P =.17), respectively. Age, heart failure, and type of ACS were major determinants of the cystatin C concentration. c Statistics and the relative Integrated Discrimination Improvement of the primary outcome for the baseline cystatin C concentration were 0.687 and 5.2%, compared to 0.684 and 4.5% at discharge (n = 4034) and 0.693 and 5.1% at one month (n = 3096), respectively. Conclusions: Mean cystatin C concentrations increased in ACS patients, most importantly determined by age. The initial greater increase in ticagrelor-treated patients was not sustained over time. Risk prediction did not improve with serial measurements of renal markers.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-186226 (URN)10.1016/j.ahj.2012.08.017 (DOI)000310783100015 ()
    Available from: 2012-11-28 Created: 2012-11-28 Last updated: 2022-01-28Bibliographically approved
    3. Cystatin C- and Creatinine-based Estimates of Renal Function and Their Value for Risk Prediction in Patients with Acute Coronary Syndrome: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
    Open this publication in new window or tab >>Cystatin C- and Creatinine-based Estimates of Renal Function and Their Value for Risk Prediction in Patients with Acute Coronary Syndrome: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
    Show others...
    2013 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 9, p. 1369-1375Article in journal (Refereed) Published
    Abstract [en]

    Background: The estimated glomerular filtration rate (eGFR) independently predicts cardiovascular (CV) death or myocardial infarction (MI), and can be estimated by creatinine and cystatin C concentrations. We evaluated two different cystatin C assays, alone or combined with creatinine, in patients with acute coronary syndromes.

    Methods: Plasma cystatin C, measured with assays from Gentian and Roche, and serum creatinine was analyzed in 16279 patients from the PLATelet inhibition and patient Outcomes trial. Pearson’s correlation and agreement (Bland–Altman) between methods was evaluated. Prognostic value in relation to CV death or MI during one year of follow up was evaluated by multivariable logistic regression analysis including clinical variables and biomarkers, c-statistics and relative Integrated Discrimination Improvement (IDI).

    Results: Median cystatin C concentrations (interquartile intervals) were 0.83 (0.68 - 1.01) mg/L (Gentian) and 0.94 (0.80 - 1.14) mg/L (Roche). Overall correlation was 0.86 (95% confidence interval 0.85-0.86). The level of agreement was ±0.39mg/L (±2 standard deviations) (n=16279).

    The area under curve (AUC) in the multivariable risk prediction model with cystatin C (Gentian, Roche) or Chronic Kidney Disease - Epidemiology (CKD-EPI) added was 0.6914, 0.6913 and 0.6932. Corresponding relative IDIs were 2.96%, 3.86% and 4.68%, respectively (n=13050). Addition of eGFR by the combined creatinine-cystatin C equation yielded AUC of 0.6923(Gentian) and 0.6924(Roche) with relative IDIs of 3.54% and 3.24% respectively.

    Conclusions: Despite differences in cystatin C concentrations, overall correlation between the Gentian and Roche assays was good while agreement was moderate.  The combined creatinine-cystatin C equation did not outperform risk prediction compared to CKD-EPI.

    Keywords
    cystatin C, creatinine, glomerular filtration rate, myocardial infarction, acute coronary, syndrome, death, assay
    National Category
    Cardiac and Cardiovascular Systems
    Research subject
    Cardiology
    Identifiers
    urn:nbn:se:uu:diva-197704 (URN)10.1373/clinchem.2012.200709 (DOI)000325398600015 ()
    Available from: 2013-04-04 Created: 2013-04-02 Last updated: 2022-01-28Bibliographically approved
    4. Polymorphism of the cystatin C gene in patients with acute coronary syndromes: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
    Open this publication in new window or tab >>Polymorphism of the cystatin C gene in patients with acute coronary syndromes: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
    Show others...
    2014 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 168, no 1, p. 96-102Article in journal (Other academic) Published
    Abstract [en]

    Purpose: Plasma cystatin C is independently associated with cardiovascular (CV) risk in non-ST-elevation acute coronary syndromes (NSTE-ACS). The effect of genetic variability on cystatin C concentrations and outcome is unclear.

    Methods: Plasma cystatin C concentrations were measured in blood, obtained within 24 hours of admission, in 16279 ACS patients from the PLATelet inhibition and patient Outcomes trial. 9978 patients were genome-wide genotyped with up to 2.5 million SNPs. The first occurrence of CV death or myocardial infarction (MI) within one year was evaluated by multivariable (clinical variables and biomarkers) Cox regression analysis and c-statistics both overall (all ACS) and in NSTE-ACS.

    Results: We observed SNPs association with cystatin C levels (up to p=7.82 x 10-16). The most significant SNP (rs6048952) was adjacent the CST3 gene with additive effect on cystatin C concentrations: 0.85mg/L, 0.80mg/L and 0.73mg/L for the A/A, A/G and G/G genotypes respectively. Multivariable c-statistics regarding the combined endpoint (CV death or MI) was 0.6619. Adding cystatin C concentrations or genetically adjusted cystatin C levels, exhibited c-statistics of 0.6705 and 0.6703, respectively.

    The overall hazard ratio for rs6048952 was 0.93 (95%CI 0.82-1.04) regarding the CV death or MI while 0.85 (95%CI 0.70-1.03) regarding CV death in all ACS patients. In the NSTE-ACS subgroup, the hazard ratio for rs6048952 was 0.72 (95%CI 0.54-0.95).

    Conclusions: Genetic polymorphism, independently of kidney function, affects cystatin C concentrations, but does not appear to influence ischemic outcome in an overall ACS population. However, genetic variation appears to affect cardiovascular mortality in moderate-to-high risk NSTE-ACS patients.

    Keywords
    genetics, rs6048952, CST3, CST, cystatin C, acute coronary syndrome, mortality, death, myocardial infarction
    National Category
    Cardiac and Cardiovascular Systems
    Research subject
    Cardiology
    Identifiers
    urn:nbn:se:uu:diva-197712 (URN)10.1016/j.ahj.2014.03.010 (DOI)000338748800014 ()
    Note

    Published as Manuscript with the title: Genetic Polymorphism and Relationship to Cystatin C Concentrations and Outcome - Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study

    Available from: 2013-04-04 Created: 2013-04-02 Last updated: 2022-01-28Bibliographically approved
    Download full text (pdf)
    fulltext
  • 2845.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Duke Clin Res Inst, Durham, NC USA..
    Clare, Robert M.
    Duke Clin Res Inst, Durham, NC USA..
    Lokhnygina, Yuliya
    Duke Clin Res Inst, Durham, NC USA..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Van de Werf, Frans
    Univ Leuven, Dept Cardiol, Leuven, Sweden..
    Moliterno, David J.
    Univ Kentucky, Gill Heart Inst, Lexington, KY USA.;Univ Kentucky, Div Cardiovasc Med, Lexington, KY USA..
    Patel, Uptal D.
    Duke Clin Res Inst, Durham, NC USA..
    Leonardi, Sergio
    Fdn IRCCS Policlin San Matteo, Pavia, Italy..
    Armstrong, Paul W.
    Univ Alberta, Div Cardiol, Edmonton, AB, Canada..
    Harrington, Robert A.
    Stanford Univ, Dept Med, Stanford, CA 94305 USA..
    White, Harvey D.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand..
    Aylward, Philip E.
    Flinders Univ & Med Ctr, South Australian Hlth & Med Res Inst, Adelaide, SA, Australia..
    Mahaffey, Kenneth W.
    Stanford Univ, Dept Med, Stanford, CA 94305 USA..
    Tricoci, Pierluigi
    Duke Clin Res Inst, Durham, NC USA..
    Albuminuria and cardiovascular events in patients with acute coronary syndromes: Results from the TRACER trial2016In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 178, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Background Albuminuria is associated with cardiovascular (CV) outcomes. We evaluated albuminuria, alone and in combination with estimated glomerular filtration rate (eGFR), as a predictor of mortality and CV morbidity in 12,944 patients with non-ST-segment elevation acute coronary syndromes. Methods Baseline serum creatinine and urinary dipsticks were obtained, with albuminuria stratified into no/trace albuminuria, microalbuminuria (>= 30 but <300 mg/dL), or macroalbuminuria (>= 300 mg/dL). Kaplan-Meier rates and proportional Cox hazards models of CV death, overall mortality, CV death or myocardial infarction (MI), and bleeding were calculated. Incidence of acute kidney injury, identified by adverse event reporting and creatinine increase (absolute >= 0.3 mg/dL or relative >= 50%), was descriptively reported. Results Both dipstick albuminuria and creatinine values were available in 9473 patients (73.2%). More patients with macroalbuminuria, versus no/trace albuminuria, had diabetes (66% vs 27%) or hypertension (86% vs 68%). Rates for CV death and overall mortality per strata were 3.1% and 4.8% (no/trace albuminuria); 5.8% and 9.0% (microalbuminuria); and 7.7% and 12.6% (macroalbuminuria) at 2 years of follow-up. Corresponding rates for CV death or MI were 12.2%, 16.9%, and 23.5%, respectively. Observed acute kidney injury rates were 0.6%, 1.2%, and 2.9% (n = 79), respectively. Adjusted HRs for macroalbuminuria on CV mortality were 1.65 (95% CI 1.15-2.37), and after adjustment with eGFR, 1.37 (95% CI 0.93-2.01). Corresponding HRs for overall mortality were 1.82 (95% CI 1.37-2.42) and 1.47 (95% CI 1.08-1.98). Conclusions High-risk patients with non-ST-segment elevation acute coronary syndromes and albuminuria have increased morbidity and increased overall mortality independent of eGFR.

  • 2846.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C.
    Duke Clinical Research Institute, Durham, NC, USA.
    Budaj, Andrzej
    Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland.
    Himmelmann, Anders
    AstraZeneca Research and Development, Mölndal, Sweden.
    Husted, Steen
    Department of Cardiology, Århus University Hospital, Århus, Denmark.
    Storey, Robert F.
    Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Polymorphism of the cystatin C gene in patients with acute coronary syndromes: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study2014In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 168, no 1, p. 96-102Article in journal (Other academic)
    Abstract [en]

    Purpose: Plasma cystatin C is independently associated with cardiovascular (CV) risk in non-ST-elevation acute coronary syndromes (NSTE-ACS). The effect of genetic variability on cystatin C concentrations and outcome is unclear.

    Methods: Plasma cystatin C concentrations were measured in blood, obtained within 24 hours of admission, in 16279 ACS patients from the PLATelet inhibition and patient Outcomes trial. 9978 patients were genome-wide genotyped with up to 2.5 million SNPs. The first occurrence of CV death or myocardial infarction (MI) within one year was evaluated by multivariable (clinical variables and biomarkers) Cox regression analysis and c-statistics both overall (all ACS) and in NSTE-ACS.

    Results: We observed SNPs association with cystatin C levels (up to p=7.82 x 10-16). The most significant SNP (rs6048952) was adjacent the CST3 gene with additive effect on cystatin C concentrations: 0.85mg/L, 0.80mg/L and 0.73mg/L for the A/A, A/G and G/G genotypes respectively. Multivariable c-statistics regarding the combined endpoint (CV death or MI) was 0.6619. Adding cystatin C concentrations or genetically adjusted cystatin C levels, exhibited c-statistics of 0.6705 and 0.6703, respectively.

    The overall hazard ratio for rs6048952 was 0.93 (95%CI 0.82-1.04) regarding the CV death or MI while 0.85 (95%CI 0.70-1.03) regarding CV death in all ACS patients. In the NSTE-ACS subgroup, the hazard ratio for rs6048952 was 0.72 (95%CI 0.54-0.95).

    Conclusions: Genetic polymorphism, independently of kidney function, affects cystatin C concentrations, but does not appear to influence ischemic outcome in an overall ACS population. However, genetic variation appears to affect cardiovascular mortality in moderate-to-high risk NSTE-ACS patients.

  • 2847.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Flodin, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Comparison between cystatin C and creatinine estimated GFR in cardiology patients2015In: Cardiorenal medicine, ISSN 1664-5502, Vol. 5, no 4, p. 289-296Article in journal (Refereed)
    Abstract [en]

    Objective: Estimation of the glomerular filtration rate (GFR) is essential for identification, evaluation and risk prediction in patients with kidney disease. Estimated GFR (eGFR) is also needed for the correct dosing of drugs eliminated by the kidneys and to identify high-risk individuals in whom coronary angiography or other procedures may lead to kidney failure. Both cystatin C and creatinine are used for the determination of GFR, and we aimed to investigate if eGFR by the two methods differ in cardiology patients.

     Methods: We compared cystatin C and creatinine (CKD-EPI) eGFR calculated from the same request from a cardiology outpatient unit (n = 2,716), a cardiology ward (n = 980), a coronary care unit (n = 1,464), and an advanced coronary care unit (n = 518) in an observational, cross-sectional study. 

    Results: The median creatinine eGFR results are approximately 10 ml/min/1.73 m2 higher than the median cystatin C eGFR that is up to 90 ml/min/1.73 m2, irrespective of the level of care. Creatinine eGFR resulted in a less advanced eGFR category in the majority of patients with a cystatin C eGFR <60 ml/min/1.73 m2.

    Conclusions: Our study demonstrates a difference between creatinine and cystatin C eGFR in cardiology patients. It is important to be aware of which marker is used for the reported eGFR to minimize erroneous interpretations of the test results, as this could lead to under- or overmedication. Further studies are needed to determine the best method of estimating the GFR in cardiology units.

  • 2848.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Himmelmann, Anders
    Huhn, Monika
    Pieper, Karen
    Husted, Steen
    Storey, Robert
    Becker, Richard
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Serum Uric Acid Is Associated With Cardiovascular Outcomes In Patients With Acute Coronary Syndromes: Results From The Platelet Inhibition And Patient Outcomes (Plato) Trial2016In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 67, no 13, p. 556-556Article in journal (Other academic)
  • 2849.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Becker, Richard C.
    Duke Clinical Research Institute, Durham, NC, USA.
    Budaj, Andrzej
    Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland.
    Himmelmann, Anders
    AstraZeneca Research and Development, Mölndal, Sweden.
    Horrow, Jay
    AstraZeneca Research and Development, Wilmington, USA.
    Husted, Steen
    Department of Cardiology, Århus University Hospital, Århus, Denmark.
    Storey, Robert F.
    Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
    Åsenblad, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Cystatin C- and Creatinine-based Estimates of Renal Function and Their Value for Risk Prediction in Patients with Acute Coronary Syndrome: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study2013In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 9, p. 1369-1375Article in journal (Refereed)
    Abstract [en]

    Background: The estimated glomerular filtration rate (eGFR) independently predicts cardiovascular (CV) death or myocardial infarction (MI), and can be estimated by creatinine and cystatin C concentrations. We evaluated two different cystatin C assays, alone or combined with creatinine, in patients with acute coronary syndromes.

    Methods: Plasma cystatin C, measured with assays from Gentian and Roche, and serum creatinine was analyzed in 16279 patients from the PLATelet inhibition and patient Outcomes trial. Pearson’s correlation and agreement (Bland–Altman) between methods was evaluated. Prognostic value in relation to CV death or MI during one year of follow up was evaluated by multivariable logistic regression analysis including clinical variables and biomarkers, c-statistics and relative Integrated Discrimination Improvement (IDI).

    Results: Median cystatin C concentrations (interquartile intervals) were 0.83 (0.68 - 1.01) mg/L (Gentian) and 0.94 (0.80 - 1.14) mg/L (Roche). Overall correlation was 0.86 (95% confidence interval 0.85-0.86). The level of agreement was ±0.39mg/L (±2 standard deviations) (n=16279).

    The area under curve (AUC) in the multivariable risk prediction model with cystatin C (Gentian, Roche) or Chronic Kidney Disease - Epidemiology (CKD-EPI) added was 0.6914, 0.6913 and 0.6932. Corresponding relative IDIs were 2.96%, 3.86% and 4.68%, respectively (n=13050). Addition of eGFR by the combined creatinine-cystatin C equation yielded AUC of 0.6923(Gentian) and 0.6924(Roche) with relative IDIs of 3.54% and 3.24% respectively.

    Conclusions: Despite differences in cystatin C concentrations, overall correlation between the Gentian and Roche assays was good while agreement was moderate.  The combined creatinine-cystatin C equation did not outperform risk prediction compared to CKD-EPI.

  • 2850.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Becker, Richard C
    Budaj, Andrzej
    Buck, Kristen
    Giannitsis, Evangelos
    Horrow, Jay
    Husted, Steen
    Katus, Hugo A
    Steg, Philippe Gabriel
    Storey, Robert F
    Åsenblad, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    James, Stefan K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Cystatin C and Estimated Glomerular Filtration Rate as Predictors for Adverse Outcome in Patients with ST-Elevation and Non-ST-Elevation Acute Coronary Syndromes: Results from the Platelet Inhibition and Patient Outcomes Study2012In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 58, no 1, p. 190-199Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    We evaluated the predictive ability of cystatin C and creatinine-based estimations of glomerular filtration rate (eGFR), including the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation, in acute coronary syndrome (ACS) patients with (STE-ACS) or without (NSTE-ACS) ST elevation in a large contemporary ACS population.

    METHODS:

    Concentrations of cystatin C and creatinine, as well as eGFR at randomization, were measured in 16 401 patients in the Platelet Inhibition and Patient Outcomes (PLATO) study and evaluated as predictors of the composite end point of cardiovascular death or myocardial infarction within 1 year. Two Cox proportional hazards models were used, the first adjusting for clinical characteristics and the second for clinical characteristics plus the biomarkers N-terminal pro-B-type natriuretic peptide, troponin I, and C-reactive protein.

    RESULTS:

    The median cystatin C value was 0.83 mg/L. Increasing quartiles of cystatin C were strongly associated with poor outcome (6.9%, 7.1%, 9.5%, and 16.2%). The fully adjusted hazard ratios per SD of cystatin C in the NSTE-ACS and STE-ACS populations were 1.12 (95% CI 1.04-1.20) (n = 8053) and 1.06 (95% CI 0.97-1.17) (n = 5278), respectively. There was no significant relationship of cystatin C with type of ACS (STE or NSTE). c Statistics ranged from 0.6923 (cystatin C) to 0.6941 (CKD-EPI).

    CONCLUSIONS:

    Cystatin C concentration contributes independently in predicting the risk of cardiovascular death or myocardial infarction in NSTE-ACS, with no interaction by type of ACS. CKD-EPI exhibited the largest predictive value of all renal markers. Nevertheless, the additive predictive value of cystatin C or creatinine-based eGFR measures in the unselected ACS patient is small.

5455565758 2801 - 2850 of 2864
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