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  • 101.
    Huang, Biying
    et al.
    Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr, Stanford, CA 94304 USA.;Karolinska Inst, Dept Med, S-17176 Stockholm, Sweden..
    Svensson, Per
    Karolinska Inst, Dept Med, S-17176 Stockholm, Sweden..
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Dalarna Univ, Sch Hlth & Social Studies, S-79188 Falun, Sweden..
    Sundstrom, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr, Stanford, CA 94304 USA.
    Effects of cigarette smoking on cardiovascular-related protein profiles in two community-based cohort studies2016Inngår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 254, s. 52-58Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and aims: Cardiovascular diseases account for the largest fraction of smoking-induced deaths. Studies of smoking in relation to cardiovascular-related protein markers can provide novel insights into the biological effects of smoking. We investigated the associations between cigarette smoking and 80 protein markers known to be related to cardiovascular diseases in two community-based cohorts, the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS, n = 969, 50% women, all aged 70 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 717, all men aged 77 years). Methods: Smoking status was self-reported and defined as current smoker, former smoker or never-smoker. Levels of the 80 proteins were measured using the proximity extension assay, a novel PCR-based proteomics technique. Results: We found 30 proteins to be significantly associated with current cigarette smoking in PIVUS (FDR<5%); and ten were replicated in ULSAM (p<0.05). Matrix metalloproteinase-12 (MMP-12), growth/differentiation factor 15 (GDF-15), urokinase plasminogen activator surface receptor (uPAR), TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), lectin-like oxidized LDL receptor 1 (LOX-1), hepatocyte growth factor (HGF), matrix metalloproteinase-10 (MMP-10) and matrix metalloproteinase-1 (MMP-1) were positively associated, while endothelial cell-specific molecule 1 (ESM-1) and interleukin-27 subunit alpha (IL27-A) showed inverse associations. All of them remained significant in a subset of individuals without manifest cardiovascular disease. Conclusions: The findings of the present study suggest that cigarette smoking may interfere with several essential parts of the atherosclerosis process, as evidenced by associations with protein markers representing endothelial dysfunction, inflammation, neointimal formation, foam cell formation and plaque instability. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

  • 102.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Arnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Metabolic syndrome and risk for heart failure in middle-aged men2006Inngår i: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 92, nr 10, s. 1409-1413Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To explore metabolic syndrome as a possible risk factor for development of heart failure (HF).

    Design: Community-based cohort study.

    Setting: Uppsala, Sweden.

    Participants: 2314 50-year-old men free from HF, myocardial infarction and valvular disease at baseline were enrolled between 1970 and 1974 and were followed up until the age of 70. A modified National Cholesterol Education Program definition of metabolic syndrome was used with body mass index in the place of waist circumference.

    Main outcome measure: First hospitalisation for HF.

    Results: In multivariable Cox proportional hazards models adjusted for established risk factors for HF (hypertension, diabetes, ECG left ventricular hypertrophy, smoking and body mass index), the presence at baseline of metabolic syndrome (hazard ratio 1.66, 95% confidence interval (CI) 1.02 to 2.70) was a predictor of subsequent HF. This relation was even stronger after adjustment for the presence of an acute myocardial infarction during follow up in addition to the other established risk factors for HF (hazard ratio 1.80, 95% CI 1.11 to 2.91).

    Conclusion: Metabolic syndrome was a significant predictor of HF, independent of established risk factors for HF including an interim myocardial infarction, during two decades of follow up in a community-based sample of middle-aged men. This implies that metabolic syndrome provides important risk information beyond that of established risk factors for HF.

  • 103.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Björklund-Bodegård, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Diurnal blood pressure pattern and risk of congestive heart failure2006Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 295, nr 24, s. 2859-2866Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: High blood pressure is the most important risk factor for congestive heart failure (CHF) at a population level, but the relationship of an altered diurnal blood pressure pattern to risk of subsequent CHF is unknown.

    OBJECTIVES: To explore 24-hour ambulatory blood pressure characteristics as predictors of CHF incidence and to investigate whether altered diurnal blood pressure patterns confer any additional risk information beyond that provided by conventional office blood pressure measurements.

    DESIGN, SETTING, AND PARTICIPANTS: Prospective, community-based, observational cohort in Uppsala, Sweden, including 951 elderly men free of CHF, valvular disease, and left ventricular hypertrophy at baseline between 1990 and 1995, followed up until the end of 2002. Twenty-four-hour ambulatory blood pressure monitoring was performed at baseline, and the blood pressure variables were analyzed as predictors of subsequent CHF.

    MAIN OUTCOME MEASURE: First hospitalization for CHF.

    RESULTS: Seventy men developed heart failure during follow-up, with an incidence rate of 8.6 per 1000 person-years at risk. In multivariable Cox proportional hazards models adjusted for antihypertensive treatment and established risk factors for CHF (myocardial infarction, diabetes, smoking, body mass index, and serum cholesterol level), a 1-SD (9-mm Hg) increase in nighttime ambulatory diastolic blood pressure (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.02-1.55) and the presence of "nondipping" blood pressure (night-day ambulatory blood pressure ratio > or =1; HR, 2.29; 95% CI, 1.16-4.52) were associated with an increased risk of CHF. After adjusting for office-measured systolic and diastolic blood pressures, nondipping blood pressure remained a significant predictor of CHF (HR, 2.21; 95% CI, 1.12-4.36 vs normal night-day pattern). Nighttime ambulatory diastolic blood pressure and nondipping blood pressure were also significant predictors of CHF after exclusion of all participants who had an acute myocardial infarction before baseline or during follow-up.

    CONCLUSIONS: Nighttime blood pressure appears to convey additional risk information about CHF beyond office-measured blood pressure and other established risk factors for CHF. The clinical value of this association remains to be established in future studies.

  • 104.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sleep disturbances independently predict heart failure in overweight middle-aged men2007Inngår i: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 9, nr 2, s. 184-190Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Sleep disturbances are associated with manifest heart failure (HF). However, the relationship between sleep disturbances and incident HF has been less studied. AIMS: To investigate self-reported sleep disturbances as predictors of HF in a longitudinal, community-based cohort of 2314 middle-aged men. METHODS AND RESULTS: Data on self-reported sleep disturbances, as well as established risk factors for HF were collected and analyzed using Cox proportional hazards analyses. In multivariable Cox proportional hazards models adjusted for established risk factors for HF, the presence at baseline of sleep disturbances (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.16-1.99; p=0.002) was an independent risk factor for HF. There was evidence of effect modification between BMI and sleep disturbances. In multivariable-adjusted models, sleep disturbance (HR, 1.58; 95% CI, 1.13-2.21; p=0.008) was an independent risk factor for HF in overweight participants (BMI>25), but not in normal-weight participants (BMI< or =25). All results remained similar in a sub-sample excluding all participants suffering from a myocardial infarction during follow-up. CONCLUSIONS: Self-reported sleep disturbances imply an increased risk of subsequent HF in overweight middle-aged men, via mechanisms largely independent of established risk factors for HF, including an interim myocardial infarction.

  • 105.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Socioeconomic factors as predictors of incident heart failure2006Inngår i: Journal of Cardiac Failure, ISSN 1071-9164, E-ISSN 1532-8414, Vol. 12, nr 7, s. 540-545Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Studies of socioeconomic factors as predictors of heart failure (HF) are few and have given opposing results. Further, it is unknown if these factors predict incident HF independently of myocardial infarction and other established risk factors for HF.

    METHODS AND RESULTS: In a community-based cohort of 2314 middle-age men free from HF, valvular disease, and previous myocardial infarction at baseline, socioeconomic factors were examined as predictors for HF using Cox proportional hazards analyses. In multivariable Cox proportional hazards models adjusted for established risk factors for HF (hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, serum cholesterol, and interim myocardial infarction), low occupational classification (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.03-2.35 for low vs. high occupational classification), low education level (HR 1.98, 95% CI 1.07-3.68 for elementary school vs. college exam) and being unmarried (HR 1.44, 95% CI 0.99-2.10 for being unmarried vs. being married) increased the risk of HF.

    CONCLUSION: High occupational classification and high education level decreased, and being unmarried increased, the risk of subsequent HF in middle-age men, via mechanisms largely independent of established risk factors for HF, including an interim myocardial infarction. Further studies are needed to understand the mechanisms behind these associations.

  • 106.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Basu, Samar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Low-grade albuminuria and the incidence of heart failure in a community-based cohort of elderly men2007Inngår i: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 28, nr 14, s. 1739-1745Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims To investigate associations of urinary albumin excretion rate (UAER) and heart failure (HF) incidence in a community-based sample.

    Methods and results In a prospective study of 70-year-old men free from HF at baseline (n = 1106), UAER (from timed overnight samples) was analysed with established risk factors for HF [acute MI before baseline, acute MI during follow-up (modelled as a time-dependent covariate), hypertension, diabetes, left ventricular hypertrophy, smoking, body mass index, and glomerular filtration rate] and more recently described risk factors [high-sensitive C-reactive protein and insulin sensitivity (clamp glucose disposal rate)] as predictors of HF incidence.

    Ninety-eight participants developed HF during a median follow-up of 9.0 years. In Cox proportional hazards models adjusted for established and novel risk factors for HF, a 1 SD increase in log UAER increased the risk of HF in individuals without anti-hypertensive treatment (hazard ratio 1.49; 95% CI 1.13–1.98; P = 0.005). Furthermore, UAER remained an independent predictor of HF, also in participants without diabetes at baseline or myocardial infarction at baseline or during follow-up. There were no significant associations between UAER and HF incidence in individuals with anti-hypertensive treatment.

    Conclusion Our observations support the notion that low-grade albuminuria is a marker for subclinical cardiovascular damage that predisposes to future HF in the community.

  • 107.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Berne, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Vasan, Ramachandran S.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Blomhoff, Rune
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Circulating retinol-binding protein 4, cardiovascular risk factors and prevalent cardiovascular disease in elderly2009Inngår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 206, nr 1, s. 239-244Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Our aim was to examine relations of serum retinol-binding protein 4 (RBP4) to cardiovascular risk factors, and prevalent metabolic syndrome (MetS) and cardiovascular disease (CVD) in a large community-based sample of elderly. METHODS: We evaluated cross-sectional relations of serum RBP4 to cardiovascular risk factors including anthropometrical measures, blood pressure, lipid measures, fasting glucose and insulin, body fat distribution including truncal fat by dual-energy x-ray absorptiometry (DXA), homeostasis model assessment insulin resistance (HOMA-IR) and prevalent MetS in one thousand eight 70-year old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), and in five hundred seven 82-year old men from Uppsala Longitudinal Study of Adult Men (ULSAM). In ULSAM, we also examined associations with prevalent CVD. RESULTS: RBP4 concentrations were positively correlated with serum triglycerides (r=0.30; P<0.0001 in both samples), whereas correlations with body mass index (BMI), waist circumference, sagittal abdominal diameter, total and truncal fat mass, total cholesterol, fasting glucose and HOMA-IR were weak. In multivariable-adjusted models, RBP-4 was associated with MetS (odds ratio (OR), 1.16 and 1.33; 95% confidence interval (CI), 0.99-1.37 and 1.05-1.67 per 1-standard deviation (SD) increase in PIVUS and ULSAM, respectively), and prior cerebrovascular disease (OR, 1.37; 95% CI, 1.00-1.88 per 1-SD increase in ULSAM), but not with prior myocardial infarction. CONCLUSION: In elderly, RBP4 concentrations were associated with MetS and its components in both sexes, and prior cerebrovascular disease in men. These findings are consistent with the hypothesis that circulating RBP4 could be a marker of metabolic complications and possibly also atherosclerosis and overt CVD.

  • 108.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Insulin resistance and risk of congestive heart failure2005Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 294, nr 3, s. 334-41Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Diabetes and obesity are established risk factors for congestive heart failure (CHF) and are both associated with insulin resistance. OBJECTIVE: To explore if insulin resistance may predict CHF and may provide the link between obesity and CHF. DESIGN, SETTING, AND PARTICIPANTS: The Uppsala Longitudinal Study of Adult Men, a prospective, community-based, observational cohort in Uppsala, Sweden. We investigated 1187 elderly (>or=70 years) men free from CHF and valvular disease at baseline between 1990 and 1995, with follow-up until the end of 2002. Variables reflecting insulin sensitivity (including euglycemic insulin clamp glucose disposal rate) and obesity were analyzed together with established risk factors (prior myocardial infarction, hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, and serum cholesterol level) as predictors of subsequent incidence of CHF, using Cox proportional hazards analyses. MAIN OUTCOME MEASURE: First hospitalization for heart failure. RESULTS: One hundred four men developed CHF during a median follow-up of 8.9 (range, 0.01-11.4) years. In multivariable Cox proportional hazards models adjusted for established risk factors for CHF, increased risk of CHF was associated with a 1-SD increase in the 2-hour glucose value of an oral glucose tolerance test (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.08-1.93), fasting serum proinsulin level (HR, 1.29; 95% CI, 1.02-1.64), body mass index (HR, 1.35; 95% CI, 1.11-1.65), and waist circumference (HR, 1.36; 95% CI, 1.10-1.69), whereas a 1-SD increase in clamp glucose disposal rate decreased the risk (HR, 0.66; 95% CI, 0.51-0.86). When adding clamp glucose disposal rate to these models as a covariate, the obesity variables were no longer significant predictors of subsequent CHF. CONCLUSIONS: Insulin resistance predicted CHF incidence independently of established risk factors including diabetes in our large community-based sample of elderly men. The previously described association between obesity and subsequent CHF may be mediated largely by insulin resistance.

  • 109.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Inflammation, as measured by the erythrocyte sedimentation rate, is an independent predictor for the development of heart failure2005Inngår i: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 45, nr 11, s. 1802-1806Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Our objective was to explore inflammation, measured as erythrocyte sedimentation rate (ESR), as a predictor for the development of heart failure (HF).

    BACKGROUND: In recent years, evidence of the importance of inflammation in the pathophysiology of HF has emerged, and various inflammatory markers have been found to predict future HF. Erythrocyte sedimentation rate is an inexpensive and easily accessible marker of systemic inflammation, but to this date it is unknown whether ESR predicts subsequent HF.

    METHODS: In a community-based prospective study of 2,314 middle-aged men free from HF, myocardial infarction, and valvular disease at baseline, ESR was analyzed in multivariable models together with established risk factors for HF (hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, obesity, and serum cholesterol) and hematocrit.

    RESULTS: A total of 282 men developed HF during a median follow-up time of 30 years. In Cox proportional hazards analyses, ESR was an independent predictor of HF (hazard ratio 1.46 for highest quartile vs. the lowest, 95% confidence interval 1.04 to 2.06). This observation remained significant when also adjusting for interim myocardial infarction during follow-up.

    CONCLUSIONS: Erythrocyte sedimentation rate was a significant predictor of HF, independent of established risk factors for HF, and interim myocardial infarction after three decades of follow-up in a population-based sample of middle-aged men. Our findings indicate that inflammation occurs early in the process leading to HF and that ESR could be used to evaluate this process.

  • 110.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    The validity of a diagnosis of heart failure in a hospital discharge register2005Inngår i: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 7, nr 5, s. 787-791Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND AIMS: The accuracy of a diagnosis of heart failure (HF) in hospital discharge registers is largely unknown. We aimed to determine the validity of such a diagnosis in the Swedish hospital discharge register.

    METHODS AND RESULTS: In a population-based study of 2322 middle-aged men (the ULSAM study), 321 participants were diagnosed with HF according to the Swedish hospital discharge register, during a median follow-up time of 29 years. A review board examined the validity of the diagnosis according to the European Society of Cardiology definition of HF. Eighty-two percent of the possible cases were classified as having definite HF. An echocardiographic examination increased the validity to 88%. For patients treated at an internal medicine or cardiology clinic the validity was 86% and 91%, respectively. If HF was the primary diagnosis, the validity was 95%, irrespective of clinic type.

    CONCLUSION: The HF diagnosis in the Swedish hospital discharge register appears slightly less precise than for acute myocardial infarction and stroke. For population-based research, only those with a primary diagnosis of HF in the hospital discharge register should be regarded as definite HF cases, or alternatively the cases should be validated individually.

  • 111.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Byberg, Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Relative importance and conjoint effects of obesity and physical inactivity for the development of insulin resistance2009Inngår i: European Journal of Cardiovascular Prevention & Rehabilitation, ISSN 1741-8267, E-ISSN 1741-8275, Vol. 16, nr 1, s. 28-33Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Obesity and physical inactivity are related to the development of insulin resistance, but their relative importance and conjoint effects are unclear. METHODS: We related body mass index (BMI) and self-reported leisure-time physical activity (PA) at the age of 50 years to insulin sensitivity measured with euglycemic insulin clamp technique and the presence of metabolic syndrome (MetS) at a subsequent examination, 20 years later, in 862 men free from diabetes and MetS at baseline. RESULTS: In a multivariable model including BMI, PA, homeostasis model assessment insulin resistance index, erythrocyte sedimentation rate, and all components of MetS at baseline, both BMI (beta, -0.19 mg/kg bodyweight/min per 1 kg/m; P<0.0001) and PA (adjusted least square means, 5.1, 5.2, 5.4, and 6.2 mg/kg bodyweight/min in individuals with sedentary, moderate, regular, and athletic PA, respectively; P=0.0035) were significant predictors of insulin sensitivity at age 70. When categorizing individuals into four groups by BMI and PA at baseline, insulin sensitivity at the age of 70 years decreased significantly over the following categories: multivariable-adjusted least square means, 5.8 (low BMI/high PA); 5.6 (low BMI/low PA); 5.1 (high BMI/high PA); and 4.6 (high BMI/low PA) mg/kg bodyweight/min, respectively; P value of less than 0.0001. CONCLUSION: In our community-based sample of middle-aged men, BMI and PA were independent predictors of insulin resistance after 20 years of follow-up. Our results imply that obesity and physical inactivity may increase insulin resistance and metabolic risk by partly independent pathways, and emphasize the importance of strategies that address both obesity and physical inactivity to achieve increased public health.

  • 112.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Vasan, Ramachandran S
    Flyvbjerg, Allan
    Frystyk, Jan
    Berne, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hänni, Arvo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Associations of serum adiponectin with skeletal muscle morphology and insulin sensitivity2009Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, nr 3, s. 953-957Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Skeletal muscle morphology and function are strongly associated with insulin sensitivity. OBJECTIVE: The objective of the study was to test the hypothesis that circulating adiponectin is associated with skeletal muscle morphology and that adiponectin mediates the relation of muscle morphology to insulin sensitivity. DESIGN, SETTINGS, AND PARTICIPANTS: This was a cross-sectional investigation of 461 men aged 71 yr, participants of the community-based Uppsala Longitudinal Study of Adult Men study. MAIN OUTCOME MEASURES: Measures included serum adiponectin, insulin sensitivity measured with euglycemic insulin clamp technique, and capillary density and muscle fiber composition determined from vastus lateralis muscle biopsies. RESULTS: In multivariable linear regression models (adjusting for age, physical activity, fasting glucose, and pharmacological treatment for diabetes), serum adiponectin levels rose with increasing capillary density (beta, 0.30 per 50 capillaries per square millimeter increase; P = 0.041) and higher proportion of type I muscle fibers (beta, 0.27 per 10% increase; P = 0.036) but declined with a higher proportion of type IIb fibers (beta, -0.39 per 10% increase; P = 0.014). Using bootstrap methods to examine the potential role of adiponectin in associations between muscle morphology and insulin sensitivity and the associations of capillary density (beta difference, 0.041; 95% confidence interval 0.001, 0.085) and proportion of type IIb muscle fibers (beta difference, -0.053; 95% confidence interval -0.107, -0.002) with insulin sensitivity were significantly attenuated when adiponectin was included in the models. CONCLUSIONS: Circulating adiponectin concentrations were higher with increasing skeletal muscle capillary density and in individuals with higher proportion of slow oxidative muscle fibers. Furthermore, our results indicate that adiponectin could be a partial mediator of the relations between skeletal muscle morphology and insulin sensitivity.

  • 113.
    James, Stefan K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Bellavia, Andrea
    Orsini, Nicola
    Wallentin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Cannon, Christopher
    Harrington, Robert
    Himmelmann, Anders
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Renlund, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Lytsy, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Time Based Measures Of Treatment Effect: Reassessment Of Ticagrelor Versus Clopidogrel In The Plato Study2016Inngår i: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 67, nr 13, s. 548-548Artikkel i tidsskrift (Annet vitenskapelig)
  • 114.
    Jobs, Elisabeth
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Nerpin, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Jobs, Magnus
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Basu, Samar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Oxidativ stress och inflammation.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Association Between Serum Cathepsin S and Mortality in Older Adults2011Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 306, nr 10, s. 1113-1121Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Experimental data suggest that cathepsin S, a cysteine protease, is involved in the complex pathways leading to cardiovascular disease and cancer. However, prospective data concerning a potential association between circulating cathepsin S levels and mortality are lacking.

    Objective: To investigate associations between circulating cathepsin S levels and mortality in 2 independent cohorts of elderly men and women.

    Design, Setting, and Participants: Prospective study using 2 community-based cohorts, the Uppsala Longitudinal Study of Adult Men (ULSAM; n=1009; mean age: 71 years; baseline period: 1991-1995; median follow-up: 12.6 years; end of follow-up: 2006) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n=987; 50% women; mean age: 70 years; baseline period: 2001-2004; median follow-up: 7.9 years; end of follow-up: 2010). Serum samples were used to measure cathepsin S.

    Main Outcome Measure: Total mortality.

    Results: During follow-up, 413 participants died in the ULSAM cohort (incidence rate: 3.59/100 person-years at risk) and 100 participants died in the PIVUS cohort (incidence rate: 1.32/100 person-years at risk). In multivariable Cox regression models adjusted for age, systolic blood pressure, diabetes, smoking status, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease, higher serum cathepsin S was associated with an increased risk for mortality (ULSAM cohort: hazard ratio [HR] for 1-unit increase of cathepsin S, 1.04 [95% CI, 1.01-1.06], P=.009; PIVUS cohort: HR for 1-unit increase of cathepsin S, 1.03 [95% CI, 1.00-1.07], P=.04). In the ULSAM cohort, serum cathepsin S also was associated with cardiovascular mortality (131 deaths; HR for quintile 5 vs quintiles 1-4, 1.62 [95% CI, 1.11-2.37]; P=.01) and cancer mortality (148 deaths; HR for 1-unit increase of cathepsin S, 1.05 [95% CI, 1.01-1.10]; P=.01).

    Conclusions: Among elderly individuals in 2 independent cohorts, higher serum cathepsin S levels were associated with increased mortality risk. Additional research is needed to delineate the role of cathepsin S and whether its measurement might have clinical utility.

  • 115.
    Jobs, Elisabeth
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Helmersson, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Oxidativ stress och inflammation.
    Nerpin, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Jobs, M
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Basu, Samar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Oxidativ stress och inflammation.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Serum cathepsin S is associated with serum C-reactive protein and interleukin-6 independently of obesity in elderly men2010Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, nr 9, s. 4460-4464Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Cathepsin S has been suggested provide a mechanistic link between obesity and atherosclerosis, possibly mediated via adipose tissue-derived inflammation. Previous data have shown an association between circulating cathepsin S and inflammatory markers in the obese, but to date, community-based reports are lacking. Accordingly, we aimed to investigate the association between serum levels of cathepsin S and markers of cytokine-mediated inflammation in a community-based sample, with prespecified subgroup analyses in nonobese participants. METHODS: Serum cathepsin S, C-reactive protein (CRP), and IL-6 were measured in a community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men; mean age 71 years, n = 991). CRP and IL-6 were also measured at a reexamination after 7 yr. RESULTS: After adjustment for age, body mass index, fasting plasma glucose, diabetes treatment, systolic blood pressure, diastolic blood pressure, hypertension treatment, serum cholesterol, serum high-density lipoprotein cholesterol, prior cardiovascular disease, smoking, and leisure time physical activity, higher cathepsin S was associated with higher CRP (regression coefficient for 1 sd increase, 0.13; 95% confidence interval 0.07-0.19; P < 0.001) and higher serum IL-6 (regression coefficient for 1 sd increase, 0.08; 95% confidence interval 0.01-0.14; P = 0.02). These associations remained similar in normal-weight participants (body mass index <25 kg/m(2), n = 375). In longitudinal analyses, higher cathepsin S at baseline was associated with higher serum CRP and IL-6 after 7 yr. CONCLUSIONS: These results provide additional evidence for the interplay between cathepsin S and inflammatory activity and suggest that this association is present also in normal-weight individuals in the community.

  • 116.
    Jobs, Elisabeth
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Ingelsson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Jobs, Magnus
    University of Dalarna.
    Nerpin, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Iggman, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Basu, Samar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Oxidativ stress och inflammation.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Lars, Lind
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Serum cathepsin S is associated with decreased insulin sensitivity and the development of diabetes type 2 in a community-based cohort of elderly men2013Inngår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, nr 1, s. 163-165Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    To investigate associations between serum cathepsin S, impaired insulin sensitivity, defective insulin secretion, and diabetes risk in a community-based sample of elderly men without diabetes.

    RESEARCH DESIGN AND METHODS:

    Serum cathepsin S, insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin secretion (early insulin response during an oral glucose tolerance test) were measured in 905 participants of the Uppsala Longitudinal Study of Adult Men (mean age, 71 years). Thirty participants developed diabetes during 6 years of follow-up.

    RESULTS:

    After adjustment for age, anthropometric variables, and inflammatory markers, higher cathepsin S was associated with decreased insulin sensitivity (regression coefficient per SD increase -0.09 [95% CI -0.14 to -0.04], P = 0.001), but no association with early insulin response was found. Moreover, higher cathepsin S was associated with a higher risk for developing diabetes (odds ratio per SD increase 1.48 [1.08-2.01], P = 0.01).

    CONCLUSIONS:

    Cathepsin S activity appears to be involved in the early dysregulation of glucose and insulin metabolism.

  • 117.
    Johan, Sundström
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    L, Sullivan
    J, Selhub
    EJ, Benjamin
    RB, D'Agostino
    PF, Jacques
    Relations of plasma homocysteine to left ventricular structure and function: the Framingham heart study.2004Inngår i: Eur Heart J, Vol. 25, nr 6, s. 523-530Artikkel i tidsskrift (Fagfellevurdert)
  • 118.
    Johan, Sundström
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    L, Sullivan
    RB, D'Agostino
    PF, Jacques
    J, Selhub
    IH, Rosengren
    Plasma homocysteine, hypertension incidence and blood pressure trackning: the Framingham heart study.2003Inngår i: Hypertension, Vol. 42, s. 1100-1105Artikkel i tidsskrift (Fagfellevurdert)
  • 119.
    Järhult, Susann J
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Hansen, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Johansson, Lars
    Astra Zeneca, R&D, Mölndal.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Brachial artery hyperemic blood flow velocity in relation to established indices of vascular function and global atherosclerosis2012Inngår i: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 32, nr 3, s. 227-233Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Background

    Systolic to diastolic blood flow velocity (SDFV) ratio in the Brachial artery recently proved to be related to cardiovascular risk and Carotid atherosclerosis. We hypothesized that the SDFV ratio was related to established markers of vascular function and global atherosclerosis. 

     

    Methods

    Established markers of endothelial function in forearm resistance vessels, flow-mediated vasodilation and arterial stiffness were assessed in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study including 1016 individuals aged 70. Whole body magnetic resonance angiography was performed in a random 306 of the participants. Atherosclerotic lesions were summarized in a total atherosclerotic score (TAS). Before and during hyperemia of the Brachial artery, systolic and diastolic blood flow velocities were measured by Doppler.

     

    Results

    The SDFV ratio was positively related to endothelium-independent vasodilatation, while inverse relations to flow-mediated dilation, common carotid artery distensibility and the stroke volume to pulse pressure ratio were found. Endothelium-dependent vasodilatation and total peripheral resistance index were not significantly related to the SDFV ratio.

    The SDFV ratio (p=0.015) and the blood flow increase during hyperemia (p= 0.020) were both significantly related to TAS after gender adjustment. When adjusted for the Framingham risk score, both the SDFV ratio (p= 0.057) and blood flow increase (p= 0.078) lost somewhat in significance.

     

    Conclusion

    The SDFV ratio was related to established markers of both vasodilation and arterial compliance, and to global atherosclerosis. Future larger studies have to evaluate if the SDFV ratio is related to global atherosclerosis independently of traditional risk factors.

  • 120.
    Järhult, Susann J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Brachial artery hyperaemic blood flow velocity and left ventricular geometry2012Inngår i: Journal of Human Hypertension, ISSN 0950-9240, E-ISSN 1476-5527, Vol. 26, nr 4, s. 242-246Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cardiovascular risk factors and carotid atherosclerosis relate to blood flow velocity in the brachial artery during induced hyperaemia. This relation proved to be particularly strong when using the hyperaemic systolic to diastolic blood flow velocity (SDFV) ratio. In this study, we further investigated this ratio in relation to the left ventricular (LV) geometry in a cross-sectional analysis. In the Prospective Investigation of the Vasculature in Uppsala Seniors study, 1016 seventy-year-olds participated. Blood flow velocity during hyperaemia of the brachial artery by Doppler was analysed. Echocardiography was performed, allowing analysis of LV geometry, categorised into four different groups: normal, concentric remodelling, concentric and eccentric hypertrophy. The SDFV ratio increased in subjects with concentric LV-remodelling (P 0.006) or LV-hypertrophy (P=0.001), but not in those with eccentric hypertrophy (P=0.12) when compared with the group with normal LV geometry. These associations remained significant after adjustment for gender, blood pressure, blood glucose, body mass index and antihypertensive treatment. The SDFV ratio in the brachial artery was related to concentric geometry of the LV in an elderly population sample, suggesting this new hemodynamic variable as a marker of increased afterload. Future studies have to determine if the SDFV ratio is a powerful predictor of future CV events, in addition to LV geometry.

  • 121.
    Kalkan, A.
    et al.
    AstraZeneca, Sodertalje, Sweden..
    Bodegard, J.
    AstraZeneca, Sodertalje, Sweden..
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Svennblad, Bodil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Ostgren, C.
    Linkoping Univ, S-58183 Linkoping, Sweden..
    Nilsson, P. M.
    Lund Univ, Malmo, Sweden..
    Johansson, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Ekman, M.
    AstraZeneca, Sodertalje, Sweden..
    Healthcare utilisation and costs following initiation of insulin treatment in type 2 diabetes: a long-term follow-up in clinical practice2015Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr Suppl. 1, s. S482-S483Artikkel i tidsskrift (Annet vitenskapelig)
  • 122.
    Kalkan, Almina
    et al.
    AstraZeneca Nord Balt, Sodertalje, Sweden..
    Bodegard, Johan
    AstraZeneca Nord Balt, Sodertalje, Sweden..
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Svennblad, Bodil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Östgren, Carl Johan
    Linkoping Univ, Linkoping, Sweden..
    Nilsson, Peter Nilsson
    Lund Univ, Malmo, Sweden..
    Johansson, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Ekman, Manias
    AstraZeneca Nord Balt, Sodertalje, Sweden..
    Increased healthcare utilization costs following initiation of insulin treatment in type 2 diabetes: A long-term follow-up in clinical practice2017Inngår i: Primary Care Diabetes, ISSN 1751-9918, E-ISSN 1878-0210, Vol. 11, nr 2, s. 184-192Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: To compare long-term changes in healthcare utilization and costs for type 2 diabetes patients before and after insulin initiation, as well as healthcare costs after insulin versus non-insulin anti-diabetic (NIAD) initiation. Methods: Patients newly initiated on insulin (n = 2823) were identified in primary health care records from 84 Swedish primary care centers, between 1999 to 2009. First, healthcare costs per patient were evaluated for primary care, hospitalizations and secondary outpatient care, before and up to seven years after insulin initiation. Second, patients prescribed insulin in second line were matched to patients prescribed NIAD in second line, and the healthcare costs of the matched groups were compared. Results: The total mean annual healthcare cost increased from 1656 per patient 2 years before insulin initiation to 3814 seven years after insulin initiation. The total cumulative mean healthcare cost per patient at year 5 after second-line treatment was 13,823 in the insulin group compared to 9989 in the NIAD group. Conclusions: Initiation of insulin in type 2 diabetes patients was followed by increased healthcare costs. The increases in costs were larger than those seen in a matched patient population initiated on NIAD treatment in second-line. (C) 2016 The Author(s). Published by Elsevier Ltd on behalf of Primary Care Diabetes Europe. This is an open access article under the CC BY-NC-ND license.

  • 123.
    Kanukula, Raju
    et al.
    George Inst Global Hlth, Hyderabad, India.
    Esam, Hariprasad
    George Inst Global Hlth, Hyderabad, India.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Rodgers, Anthony
    Univ New South Wales, George Inst Global Hlth, Sydney, NSW, Australia.
    Salam, Abdul
    Univ New South Wales, George Inst Global Hlth, Hyderabad, India.
    Does Co-administration of Antihypertensive Drugs and Statins Alter Their Efficacy and Safety?: A Systematic Review and Meta-analysis of Randomized Controlled Trials2019Inngår i: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 73, nr 6, s. 352-358Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Antihypertensive drugs (AHTDs) and statins are frequently administered together, but there is uncertainty on whether the presence of one affects the main effects of the other. This systematic review and meta-analysis assessed the effects of coadministered AHTDs and statins on blood pressure (BP) and cholesterol. MEDLINE, Cochrane Central Register of Controlled Trials and drug regulatory agency websites were searched, until January 2018. Twelve double-blind randomized controlled trials that allocated adults with or without hypertension and/or hyperlipidemia (n = 4434) to fixed doses of AHTD alone, statin alone and both drugs together, for >= 4 weeks, were included. BP lowering was similar with AHTD + statin compared with AHTD alone [systolic BP -0.1 mm Hg, 95% confidence interval (CI), -1.0 to 0.8, and diastolic BP -1.0 mm Hg, 95% CI, -2.3 to -0.2]. AHTD + statin compared with statin alone resulted in small reduction in low-density lipoprotein cholesterol (-3.9 mg/dL, 95% CI, -6.1 to -1.7), and this effect was largely associated with co-administration of amlodipine and atorvastatin or rosuvastatin. There was no difference in safety outcomes. Overall, it can be concluded that there is no clinically important difference in the effects of AHTDs and statins whether used separately or together for reduction in BP and lowdensity lipoprotein cholesterol.

  • 124.
    Kaptoge, Stephen
    et al.
    Univ Cambridge, Sch Clin Med, Dept Publ Hlth & Primary Care, Cambridge, England.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Di Angelantonio, Emanuele
    Univ Cambridge, Sch Clin Med, Dept Publ Hlth & Primary Care, Cambridge, England.
    World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions2019Inngår i: The Lancet Global Health, E-ISSN 2214-109X, Vol. 7, nr 10, s. E1332-E1345Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: To help adapt cardiovascular disease risk prediction approaches to low-income and middle-income countries, WHO has convened an effort to develop, evaluate, and illustrate revised risk models. Here, we report the derivation, validation, and illustration of the revised WHO cardiovascular disease risk prediction charts that have been adapted to the circumstances of 21 global regions.

    Methods: In this model revision initiative, we derived 10-year risk prediction models for fatal and non-fatal cardiovascular disease (ie, myocardial infarction and stroke) using individual participant data from the Emerging Risk Factors Collaboration. Models included information on age, smoking status, systolic blood pressure, history of diabetes, and total cholesterol. For derivation, we included participants aged 40–80 years without a known baseline history of cardiovascular disease, who were followed up until the first myocardial infarction, fatal coronary heart disease, or stroke event. We recalibrated models using age-specific and sex-specific incidences and risk factor values available from 21 global regions. For external validation, we analysed individual participant data from studies distinct from those used in model derivation. We illustrated models by analysing data on a further 123 743 individuals from surveys in 79 countries collected with the WHO STEPwise Approach to Surveillance.

    Findings: Our risk model derivation involved 376 177 individuals from 85 cohorts, and 19 333 incident cardiovascular events recorded during 10 years of follow-up. The derived risk prediction models discriminated well in external validation cohorts (19 cohorts, 1 096 061 individuals, 25 950 cardiovascular disease events), with Harrell's C indices ranging from 0·685 (95% CI 0·629–0·741) to 0·833 (0·783–0·882). For a given risk factor profile, we found substantial variation across global regions in the estimated 10-year predicted risk. For example, estimated cardiovascular disease risk for a 60-year-old male smoker without diabetes and with systolic blood pressure of 140 mm Hg and total cholesterol of 5 mmol/L ranged from 11% in Andean Latin America to 30% in central Asia. When applied to data from 79 countries (mostly low-income and middle-income countries), the proportion of individuals aged 40–64 years estimated to be at greater than 20% risk ranged from less than 1% in Uganda to more than 16% in Egypt.

    Interpretation: We have derived, calibrated, and validated new WHO risk prediction models to estimate cardiovascular disease risk in 21 Global Burden of Disease regions. The widespread use of these models could enhance the accuracy, practicability, and sustainability of efforts to reduce the burden of cardiovascular disease worldwide.

    Funding: World Health Organization, British Heart Foundation (BHF), BHF Cambridge Centre for Research Excellence, UK Medical Research Council, and National Institute for Health Research.

  • 125.
    Karmali, Kunal N.
    et al.
    Northwestern Univ, Dept Med, Chicago, IL 60611 USA..
    Lloyd-Jones, Donald M.
    Northwestern Univ, Dept Med, Chicago, IL 60611 USA..
    van der Leeuw, Joep
    Univ Med Ctr Utrecht, Dept Vasc Med, Utrecht, Netherlands..
    Goff, David C., Jr.
    NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA..
    Yusuf, Salim
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada..
    Zanchetti, Alberto
    Ist Auxol Italiano, Milan, Italy..
    Glasziou, Paul
    Bond Univ, Ctr Res Evidence Based Practice, Robina, Australia..
    Jackson, Rodney
    Univ Auckland, Sch Populat Hlth, Fac Med & Hlth Sci, Auckland, New Zealand..
    Woodward, Mark
    Univ Oxford, George Inst Global Hlth, Oxford, England.;George Inst Global Hlth, Sydney, NSW, Australia..
    Rodgers, Anthony
    George Inst Global Hlth, Sydney, NSW, Australia..
    Neal, Bruce C.
    George Inst Global Hlth, Sydney, NSW, Australia..
    Berge, Eivind
    Oslo Univ Hosp, Dept Cardiol, Oslo, Norway..
    Teo, Koon
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada..
    Davis, Barry R.
    Univ Texas Dallas, Sch Publ Hlth, Dallas, TX USA..
    Chalmers, John
    George Inst Global Hlth, Sydney, NSW, Australia..
    Pepine, Carl
    Univ Florida, Div Cardiovasc Med, Gainesville, FL USA..
    Rahimi, Kazem
    Univ Oxford, George Inst Global Hlth, Oxford, England..
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Blood pressure-lowering treatment strategies based on cardiovascular risk versus blood pressure: A meta-analysis of individual participant data2018Inngår i: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, nr 3, artikkel-id e1002538Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Clinical practice guidelines have traditionally recommended blood pressure treatment based primarily on blood pressure thresholds. In contrast, using predicted cardiovascular risk has been advocated as a more effective strategy to guide treatment decisions for cardiovascular disease (CVD) prevention. We aimed to compare outcomes from a blood pressure-lowering treatment strategy based on predicted cardiovascular risk with one based on systolic blood pressure (SBP) level.

    Methods and findings: We used individual participant data from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) from 1995 to 2013. Trials randomly assigned participants to either blood pressure-lowering drugs versus placebo or more intensive versus less intensive blood pressure-lowering regimens. We estimated 5-y risk of CVD events using a multivariable Weibull model previously developed in this dataset. We compared the two strategies at specific SBP thresholds and across the spectrum of risk and blood pressure levels studied in BPLTTC trials. The primary outcome was number of CVD events avoided per persons treated. We included data from 11 trials (47,872 participants). During a median of 4.0 y of follow-up, 3,566 participants (7.5%) experienced a major cardiovascular event. Areas under the curve comparing the two treatment strategies throughout the range of possible thresholds for CVD risk and SBP demonstrated that, on average, a greater number of CVD events would be avoided for a given number of persons treated with the CVD risk strategy compared with the SBP strategy (area under the curve 0.71 [95% confidence interval (CI) 0.70-0.72] for the CVD risk strategy versus 0.54 [95% CI 0.53-0.55] for the SBP strategy). Compared with treating everyone with SBP >= 150 mmHg, a CVD risk strategy would require treatment of 29% (95% CI 26%-31%) fewer persons to prevent the same number of events or would prevent 16% (95% CI 14%-18%) more events for the same number of persons treated. Compared with treating everyone with SBP >= 140 mmHg, a CVD risk strategy would require treatment of 3.8% (95% CI 12.5% fewer to 7.2% more) fewer persons to prevent the same number of events or would prevent 3.1% (95% CI 1.5%-5.0%) more events for the same number of persons treated, although the former estimate was not statistically significant. In subgroup analyses, the CVD risk strategy did not appear to be more beneficial than the SBP strategy in patients with diabetes mellitus or established CVD.

    Conclusions: A blood pressure-lowering treatment strategy based on predicted cardiovascular risk is more effective than one based on blood pressure levels alone across a range of thresholds. These results support using cardiovascular risk assessment to guide blood pressure treatment decision-making in moderate- to high-risk individuals, particularly for primary prevention.

  • 126. Khalili, Payam
    et al.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Franklin, Stanley S.
    Jendle, Johan
    Lundin, Fredrik
    Jungner, Ingmar
    Nilsson, Peter M.
    Combined effects of brachial pulse pressure and sialic acid for risk of cardiovascular events during 40 years of follow-up in 37 843 individuals2012Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 30, nr 9, s. 1718-1724Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Pulse pressure (PP) is a risk marker for cardiovascular disease (CVD) in individuals 50 years and older. Inflammation is suggested to influence atherosclerosis, but could also increase PP. We aimed to examine the combined effects of PP and the inflammatory marker sialic acid, and their independent roles on CVD risk. Methods: From a population-based study in Sweden between 1962 and 1965, 18 429 men and 19 414 women at the age of 50 or older were selected and followed for first CVD event until 2005. We investigated the biological interactions between sialic acid and PP. The associations of PP and sialic acid with risk of CVD were calculated by using Cox proportional hazards model. Adjustments were made for conventional risk factors, mean arterial pressure (MAP) and socioeconomic status. Results: The mean age was 59.5 (SD 6.5) years and the number of incident CVD events in men and women were 3641 and 3227, respectively. No biological interaction was seen between PP and sialic acid. In men, the adjusted hazard ratio for PP was 0.92 [95% confidence interval (CI) 0.88-0.96, P < 0.0001) for 1 SD of PP, and 1.09 (95% CI 1.05-1.13, P < 0.0001) for 1 SD of sialic acid. In women, the corresponding figures were 1.02 (95% CI 0.97-1.07, P = 0.48) and 1.09 (95% CI 1.05-1.13, P < 0.0001). Conclusions: Sialic acid but not PP was an independent risk factor for CVD. The risk induced by PP is highly affected by MAP. This suggests that both estimated arterial stiffness and inflammation contribute through different pathways to risk of CVD.

  • 127. Khalili, Payam
    et al.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Jendle, Johan
    Lundin, Fredrik
    Jungner, Ingmar
    Nilsson, Peter M.
    Sialic acid and incidence of hospitalization for diabetes and its complications during 40-years of follow-up in a large cohort: The Varmland survey2014Inngår i: Primary Care Diabetes, ISSN 1751-9918, E-ISSN 1878-0210, Vol. 8, nr 4, s. 352-357Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: To examine the association of sialic acid (SA) with first recorded diabetes mellitus-related hospitalization. Methods: From a population-based study in Varmland, Sweden, between 1962 and 1965, 87,035 men and women were selected and followed for first recorded diabetes-related hospitalization until 2005. The association of SA was calculated and stratified for gender by Cox's proportional hazards models. Adjustments were made for conventional risk factors and socioeconomic status. Association analyses were made for comparisons between SA-levels above and below median. Results: The mean age was 47.2 (SD 13.0) years and the total numbers of incident diabetes-related hospitalizations in men and women were 3445 and 3273, respectively. Hazard ratios per one standard deviation of SA were 1.12 (95% CI: 1.08-1.17, p < 0.0001) in men and 1.17 (95% CI: 1.13-1.22, p < 0.0001) in women. Interaction analyses indicated a relatively higher SA-associated risk in women than in men with above median SA levels. Conclusions: In this large population-based cohort followed for more than 40 years, elevated SA, as a marker of systemic inflammation, was independently associated with risk of diabetes and diabetes-related hospitalizations.

  • 128. Khan, Tauseef A.
    et al.
    Shah, Tina
    Prieto, David
    Zhang, Weili
    Price, Jackie
    Fowkes, Gerald R.
    Cooper, Jackie
    Talmud, Philippa J.
    Humphries, Steve E.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Hubacek, Jaroslav A.
    Ebrahim, Shah
    Lawlor, Debbie A.
    Ben-Shlomo, Yoav
    Abdollahi, Mohammad R.
    Slooter, Arjen J. C.
    Szolnoki, Zoltan
    Sandhu, Manjinder
    Wareham, Nicholas
    Frikke-Schmidt, Ruth
    Tybjaerg-Hansen, Anne
    Fillenbaum, Gerda
    Heijmans, Bastiaan T.
    Katsuya, Tomohiro
    Gromadzka, Grazyna
    Singleton, Andrew
    Ferrucci, Luigi
    Hardy, John
    Worrall, Bradford
    Rich, Stephen S.
    Matarin, Mar
    Whittaker, John
    Gaunt, Tom R.
    Whincup, Peter
    Morris, Richard
    Deanfield, John
    Donald, Ann
    Smith, George Davey
    Kivimaki, Mika
    Kumari, Meena
    Smeeth, Liam
    Khaw, Kay-Tee
    Nalls, Michael
    Meschia, James
    Sun, Kai
    Hui, Rutai
    Day, Ian
    Hingorani, Aroon D.
    Casas, Juan P.
    Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals2013Inngår i: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 42, nr 2, s. 475-492Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background At the APOE gene, encoding apolipoprotein E, genotypes of the epsilon 2/epsilon 3/epsilon 4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk. Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT). Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84-1.43) for epsilon 2/epsilon 2; 0.85 (95% CrI: 0.78-0.92) for epsilon 2/epsilon 3; 1.05 (95% CrI: 0.89-1.24) for epsilon 2/epsilon 4; 1.05 (95% CrI: 0.99-1.12) for epsilon 3/epsilon 4; and 1.12 (95% CrI: 0.94-1.33) for epsilon 4/epsilon 4 using the epsilon 3/epsilon 3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 x 10(-152)), apolipoprotein B (P-trend: 8.7 x 10(-06)) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 x 10(-26)) and HDL-C (P-trend: 1.6 x 10(-12)). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear. Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE epsilon 2/epsilon 2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.

  • 129.
    Kuhlmann, Antje
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Olafsdottir, Inga Sif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Janson, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Association of biomarkers of inflammation and cell adhesion with lung function in the elderly: a population-based study2013Inngår i: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 13, s. 82-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Low lung function is associated with increased morbidity and mortality. It is therefore of interest to identify biomarkers that are associated with impaired lung function. The aim of the study was to analyse associations of biomarkers and combinations of biomarkers with lung function in an elderly general population. Methods: Lung function (FEV1 and FVC) and a panel of 15 inflammatory markers from blood samples were analysed in 888 subjects aged 70 years. Biomarkers included cytokines, chemokines, adhesion molecules, C-reactive protein (CRP) and leukocyte count. Results: Leukocyte count and CRP were independently associated with FEV1 after adjustments for other inflammatory markers, sex, BMI, current smoking and pack-years of smoking. In a similar model, leukocyte count and vascular cell adhesion protein 1 (VCAM-1) were the biomarkers that were significantly associated with FVC. Subjects that had both leukocyte count and CRP in the lowest tertile had a FEV1 that was 9% of predicted higher than subjects with leukocyte count and CRP in the highest tertile (103 +/- 16 vs. 94 +/- 21% of predicted, p=0.0002) (mean +/- SD). A difference of 8% of predicted in FVC was found between subjects with leukocyte count and VCAM-1 in the lowest and highest tertiles, respectively (106 +/- 18 vs. 98 +/- 19% of predicted, p=0.002). Conclusion: Leucocyte count, CRP and VCAM-1 were found to relate to poorer lung function. A dose related association was found for the combination leukocyte count and CRP towards FEV1 and leukocyte and VCAM-1 towards FVC. This indicates that combination of two biomarkers yielded more information than assessing them one by one when analysing the association between systemic inflammation and lung function.

  • 130.
    Lampa, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Arnlöv, J.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Diabetes increases the mortality in myocardial infarction, heart failure and stroke: results from a longitudinal study over 40 years2018Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, s. S178-S178Artikkel i tidsskrift (Annet vitenskapelig)
  • 131. Larsson, Tobias E
    et al.
    Olauson, Hannes
    Hagström, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Conjoint effects of serum calcium and phosphate on risk of total, cardiovascular, and noncardiovascular mortality in the community2010Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 30, nr 2, s. 333-339Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Hyperphosphatemia is a cardiovascular risk factor in patients with chronic kidney disease. Relations of circulating calcium (Ca) and phosphorus (Pi) to long-term mortality risk in the community require further investigation. METHODS AND RESULTS: Associations of serum Ca and Pi to mortality were evaluated in a community-based cohort of 2176 men (mean age, 50.1 years). During follow-up (median, 29.8 years), 1009 men died, and 466 of these deaths resulted from cardiovascular causes. In Cox proportional hazards models, serum Pi and [CaxPi] were independent predictors of total mortality (hazard ratio per SD, 1.06; 95% CI, 1.01-1.12; P=0.03; 1.07; 95% CI, 1.01-1.12; P=0.01) and cardiovascular mortality (1.10; 95% CI, 1.02-1.18; P=0.01; 1.10; 95% CI, 1.03-1.19; P=0.008). Serum Ca was associated with risk of total mortality (1.08; 95% CI, 1.01-1.16; P=0.02) and noncardiovascular mortality (1.10; 95% CI, 1.01-1.21; P=0.04). Results were consistent after multivariate adjustments in subsamples of individuals with estimated glomerular filtration rate >90 mL/min and low-to-normal serum Ca and Pi. CONCLUSIONS: Circulating Ca and Pi levels are associated with risks of total, cardiovascular, and noncardiovascular mortality in the community, and their conjoint effects are additive. Additional studies are warranted to evaluate whether Ca and Pi are modifiable risk factors in the general population.

  • 132.
    Laszkowska, M.
    et al.
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY USA.
    Mahadev, S.
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY USA.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Lebwohl, B.
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY USA.
    Green, P. H. R.
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY USA.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Ludvigsson, J. F.
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY USA;Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden;Orebro Univ Hosp, Dept Paediat, Orebro, Sweden;Univ Nottingham, Sch Med, Div Epidemiol & Publ Hlth, Nottingham, England.
    Systematic review with meta-analysis: the prevalence of coeliac disease in patients with osteoporosis2018Inngår i: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 48, nr 6, s. 590-597Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Earlier studies have produced highly varying risk estimates for the prevalence of coeliac disease (CD) in osteoporosis.

    AIMS: To investigate the prevalence of CD among individuals with osteoporosis.

    METHODS: We conducted a systematic review of articles published in PubMed, Medline or EMBASE through May 2017 to identify studies looking at prevalence of CD in patients with osteoporosis. Search terms included "coeliac disease" combined with "fractures", "bone disease", "bone density", "densitometry", "osteoporos*", "osteomal*", "osteodys" or "dexa" or "dxa" or "skelet". Non-English papers with English-language abstracts were included. We used fixed-effects inverse variance-weighted models, and tested heterogeneity through subgroup analysis as well as through meta-regression.

    RESULTS:  = 40.1%), and influenced by the underlying CD prevalence in the general population. After adding four studies (n = 814) with CD defined as positive tissue transglutaminase or endomysial antibodies, the pooled prevalence was comparable (1.6%; 95% CI = 1.2%-2.0%).

    CONCLUSIONS: About 1 in 62 individuals with osteoporosis, or 1.6%, have biopsy-verified CD. This prevalence is comparable to that in the general population. These findings argue against routinely screening patients with osteoporosis for CD, which is contrary to current guideline recommendations. Additional studies are needed to determine the true utility of such screening programs.

  • 133.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Andrén, Bertil
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Klinisk fysiologi Hj-lung, G H.
    Sundström, Johan
    Institutionen för folkhälso- och vårdvetenskap.
    The stroke volume/pulse pressure ratio predicts coronary heart disease mortality in a population of elderly men.2004Inngår i: J Hypertens, ISSN 0263-6352, Vol. 22, nr 5, s. 899-905Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The stroke volume to pulse pressure ratio (SV/PP), a measure of total arterial compliance, predicts adverse cardiovascular events in hypertensive subjects. The relations to cardiovascular risk factors and its predictive capacity in the general population are not known. METHOD AND RESULTS: In 1970-73, all 50-year-old men living in Uppsala County, Sweden, were invited to a health survey assessing cardiovascular risk factors. At a reinvestigation 20 years later, 470 subjects underwent an echocardiographic examination, hyperinsulinaemic euglycaemic clamp, oral glucose tolerance test and measurements of blood pressure and lipids. They were thereafter followed for a median of 7.2 years. Serum triglycerides and post-load glucose and insulin levels at age 50 were predictors of SV/PP ratio measured 20 years later (P < 0.05-0.001). At age 70, SV/PP was related to serum non-esterified fatty acids, post-load glucose and insulin levels and insulin sensitivity (P < 0.05-0.001). SV/PP was reduced in subjects with concentric left ventricular hypertrophy (LVH, P < 0.01), and in subjects with a low E-wave to A-wave (E/A) ratio (P < 0.001). The SV/PP ratio predicted mortality from coronary heart disease [hazard ratio 0.54, 95% confidence interval 0.30-0.97 for a one standard deviation (1SD) increase in ln(SV/PP)] independently of left ventricular mass and other major cardiovascular risk factors. Pulse pressure or total peripheral resistance were not significant predictors for future mortality from coronary heart disease. CONCLUSION: The SV/PP ratio was related to main components of the insulin resistance syndrome, concentric LVH and a low E/A ratio. Furthermore, the SV/PP ratio was an independent predictor of mortality from coronary heart disease in a community-based sample of men aged 70.

  • 134.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Berglund, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Endothelial Function in Resistance and Conduit Arteries and 5-Year Risk of Cardiovascular Disease2011Inngår i: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 123, nr 14, s. 1545-1551Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background-Impaired endothelial function has been implicated as a cause of cardiovascular disease. Little is known of the relations of measures of endothelial function in resistance and conduit arteries to incident cardiovascular disease in the general population, and available techniques have not been compared. Methods and Results-In 1016 participants (70 years of age) of the population-based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (52% women), we measured endothelium-dependent vasodilation using the invasive forearm technique with acetylcholine given in the brachial artery, the brachial artery ultrasound technique with measurement of flow-mediated dilatation, and the pulse-wave analysis-based method with beta-2-agonist terbutaline provocation. During 5 years of follow-up, 101 participants experienced a composite end point of myocardial infarction, stroke, or death, excluding the 85 persons with a history of myocardial infarction or stroke at baseline. In logistic regression models adjusted for several established and novel cardiovascular disease risk factors and medications, endothelium-dependent vasodilation by the invasive forearm technique with acetylcholine was associated with risk of the end point (odds ratio, 0.72 per SD; 95% confidence interval, 0.56 to 0.93; P = 0.01). Endothelial function by the other 2 methods was not related to risk of the end point. Addition of endothelium-dependent vasodilation to the Framingham risk score improved discrimination of risk of the end point. Conclusions-Endothelium-dependent vasodilation in resistance arteries, but not in the brachial conduit artery (flow-mediated dilatation), was associated with 5-year risk of a composite end point of death, myocardial infarction, or stroke independently of major cardiovascular disease risk factors. This vascular measurement improved risk discrimination when added to an established risk score in an elderly population.

  • 135.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Carlsson, Axel C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Alfred Nobels Alle 23, S-14152 Huddinge, Sweden..
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Dalarna Univ, Dept Hlth & Social Sci, S-79188 Falun, Sweden..
    Impact of physical activity on cardiovascular status in obesity2017Inngår i: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 47, nr 2, s. 167-175Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background We have recently shown that being physically active (PA) counteracts, but not eliminates the increased risk of future cardiovascular disease in overweight and obese subjects. To investigate this further, we studied the impact of being normal weight, overweight and obese on multiple markers of subclinical cardiovascular disease in relation to physical activity. Materials and methods At age 70, 1016 subjects were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Being PA was defined as performing regular heavy exercise (self-reported). According to body mass index (BMI)/PA groups, the participants were categorized as PA/normal weight (BMI < 25 kg/m(2), n = 104), non-PA/normal weight (n = 234), PA/overweight (BMI 25-29.9 kg/m(2), n = 133), non-PA/overweight (n = 295), PA/obese (BMI = 30 kg/m(2), n = 54) and non-PA/obese (n = 169). Several different measurements of endothelial reactivity and arterial compliance (plethysmography and ultrasound), cartotid artery atherosclerosis and echocardiography were performed, and seven markers of coagulation/ fibrinolysis were measured. Results Physically active subjects with obesity showed impaired vasoreactivity in the forearm resistance vessels, increased left ventricular mass and impaired left ventricular systolic and diastolic functions, together with impaired coagulation/fibrinolysis when compared to PA/normal-weight subjects (P < 0.05 to < 0.001). The majority of these disturbances were seen also in PA/overweight subjects when compared to PA/normal-weight subjects (P < 0.05 to < 0.001). Conclusions Our data provide additional support for the notion that an increased level of self-reported physical activity does not fully eliminate the deleterious cardiovascular consequences associated with overweight and obesity.

  • 136.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Elmstahl, Solve
    Bergman, Ebba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Englund, Martin
    Lindberg, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Nilsson, Peter M.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    EpiHealth: a large population-based cohort study for investigation of gene-lifestyle interactions in the pathogenesis of common diseases2013Inngår i: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 28, nr 2, s. 189-197Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The most common diseases affecting middle-aged and elderly subjects in industrialized countries are multigenetic and lifestyle related. Several attempts have been made to study interactions between genes and lifestyle factors, but most such studies lack the power to examine interactions between several genes and several lifestyle components. The primary objective of the EpiHealth cohort study is to provide a resource to study interactions between several genotypes and lifestyle factors in a large cohort (the aim is 300,000 individuals) derived from the Swedish population in the age range of 45-75 years regarding development of common degenerative disorders, such as cardiovascular diseases, cancer, dementia, joint pain, obstructive lung disease, depression, and osteoporotic fractures. The study consists of three parts. First, a collection of data on lifestyle factors by self-assessment using an internet-based questionnaire. Second, a visit to a test center where blood samples are collected and physiological parameters recorded. Third, the sample is followed for occurrence of outcomes using nationwide medical registers. This overview presents the study design and some baseline characteristics from the first year of data collection in the EpiHealth study.

  • 137.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Gigante, Bruna
    Karolinska Inst, Dept Med, Bruna Gigante Unit Cardiovasc Med, Huddinge, Sweden.
    Borne, Yan
    Lund Univ, Yan Borne Dept Clin Sci Malmo, Lund, Sweden.
    Mälarstig, Anders
    Karolinska Inst, Dept Med, Bruna Gigante Unit Cardiovasc Med, Huddinge, Sweden.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi. Univ New South Wales, George Inst Global Hlth, Sydney, NSW, Australia.
    Ärnlöv, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Huddinge, Sweden;Dalarna Univ, Sch Hlth & Social Sci, Falun, Sweden.
    Ingelsson, Erik
    Stanford Univ, Stanford Diabet Res Ctr, Stanford Cardiovasc Inst, Dept Med,Div Cardiovasc Med, Stanford, CA 94305 USA.
    Baldassarre, Damiano
    Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy;IRCCS, Ctr Cardiol Monzino, Milan, Italy.
    Tremoli, Elena
    IRCCS, Ctr Cardiol Monzino, Milan, Italy.
    Veglia, Fabrizio
    IRCCS, Ctr Cardiol Monzino, Milan, Italy.
    Hamsten, Anders
    Karolinska Inst, Dept Med, Bruna Gigante Unit Cardiovasc Med, Huddinge, Sweden.
    Orho-Melander, Marju
    Lund Univ, Yan Borne Dept Clin Sci Malmo, Lund, Sweden.
    Nilsson, Jan
    Lund Univ, Yan Borne Dept Clin Sci Malmo, Lund, Sweden.
    Melander, Olle
    Lund Univ, Yan Borne Dept Clin Sci Malmo, Lund, Sweden.
    Engström, Gunnar
    Lund Univ, Yan Borne Dept Clin Sci Malmo, Lund, Sweden.
    The plasma protein profile and cardiovascular risk differ between intima-media thickness of the common carotid artery and the bulb: A meta-analysis and a longitudinal evaluation2020Inngår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 295, s. 25-30Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and aims: Genetic loci associated with CHD show different relationships with intima-media thickness in the common carotid artery (IMT-CCA) and in the bulb (IMT-bulb). We evaluated if IMT-CCA and IMT-bulb differ also with respect to circulating protein profiles and risk of incident atherosclerotic disease.

    Methods: In three Swedish cohorts (MDC, IMPROVE, PIVUS, total n > 7000), IMT-CCA and IMT-bulb were assessed by ultrasound at baseline, and 86 cardiovascular-related proteins were analyzed. In the PIVUS study only, IMT-CCA and IMT-bulb were investigated in relation to incident atherosclerotic disease over 10 years of follow-up.

    Results: In a meta-analysis of the analysis performed separately in the cohorts, three proteins, matrix metalloproteinase-12 (MMP-12), hepatocyte growth factor (HGF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), were associated with IMT-CCA when adjusted for traditional cardiovascular risk factors. Five proteins were associated with IMT-bulb (MMP-12, growth/differentiation factor 15 (GDF-15), osteoprotegerin, growth hormone and renin). Following adjustment for cardiovascular risk factors, IMT-bulb was significantly more closely related to incident stroke or myocardial infarction (total number of cases, 111) than IMT-CCA in the PIVUS study (HR 1.51 for 1 SD, 95%CI 1.21-1.87, p < 0.001 vs HR 1.17, 95%CI 0.93-1.47, p = 0.16). MMP-12 levels were related to this combined end-point (HR 1.30, 95%CI 1.08-1.56, p = 0.0061).

    Conclusions: Elevated levels of MMP-12 were associated with both IMT-CCA and IMT-bulb, but other proteins were significantly related to IMT in only one of these locations. The finding that IMT-bulb was more closely related to incident atherosclerotic disease than IMT-CCA emphasizes a difference between these measurements of IMT.

  • 138.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Lampa, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Methylation-based estimated biological age and cardiovascular disease2018Inngår i: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, nr 2, artikkel-id e12872Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: DNA methylation changes over life at specific sites in the genome, which can be used to estimate "biological age." The aim of this population-based longitudinal cohort study was to investigate the association between estimated biological age and incident cardiovascular disease (CVD).

    MATERIALS AND METHODS: Based on formulas published by Hannum et al and Horvath et al, "biological age" was calculated using data from the Illumina 450k Bead Methylation chip in 832 participants free from cardiovascular disease in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70 years at the examination). The difference between estimated biological and chronological age was calculated (DiffAge).

    RESULTS: During 10 years of follow-up, 153 incident cases of cardiovascular disease occurred. In the sex-adjusted analyses, the Horvath estimation of DiffAge was significantly related to incident cardiovascular disease (HR 1.040, 95% CI 1.010-1.071, P = .0079). Thus, for each year of increased biological age, a 4% increased risk of future cardiovascular disease was observed. This relationship was still significant following adjustment for the traditional risk factors sex, BMI, diabetes, HDL and LDL-cholesterol, systolic blood pressure and smoking (HR 1.033, 95% CI 1.004-1.063, P = .024). No such significant association was found using the Hannum formula.

    CONCLUSIONS: DNA methylation-based estimation of "biological age" per Horvath was associated with incident cardiovascular disease.

  • 139.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ingelsson, Erik
    Stanford Univ, Dept Med, Stanford, CA 94305 USA.
    Ärnlöv, Johan
    Dalarna Univ, Sch Hlth & Social Sci, Falun, Sweden;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Huddinge, Sweden.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Swedish Med Prod Agcy, Uppsala, Sweden.
    Reaven, Gerald M.
    Stanford Univ, Dept Med, Stanford, CA 94305 USA.
    Can the Plasma Concentration Ratio of Triglyceride/High-Density Lipoprotein Cholesterol Identify Individuals at High Risk of Cardiovascular Disease During 40-Year Follow-Up?2018Inngår i: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 16, nr 8, s. 433-439Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The plasma concentration ratio of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) is a simple way to estimate insulin resistance. We aimed to evaluate the TG/HDL-C ratio as a simple clinical way to identify apparently healthy individuals with insulin resistance and enhanced risk of future cardiovascular disease (CVD).

    Methods: One thousand seven hundred twenty men, aged 50 years, free from diabetes and CVD when evaluated at baseline in 1970-1974 were followed for 40 years regarding incident CVD (myocardial infarction and/or ischemic stroke, n=576).

    Results: Participants with a high TG/HDL-C ratio (highest quartile >1.8) at baseline were more insulin resistant, with a significantly more adverse cardiometabolic risk profile (P<0.001) at baseline, compared with those with a lower ratio. This group also showed an increased risk of CVD [hazard ratio, HR 1.47 (95% confidence interval 1.26-1.93) P<0.001]. Fourteen percent of subjects with metabolic syndrome, in whom insulin resistance is increased, were also at enhanced CVD risk [HR 1.75 (1.42-2.16) P<0.001].

    Conclusions: Twenty-five percent of apparently healthy 50-year-old men with the highest TG/HDL-C plasma concentration ratio had a significantly more adverse cardiometabolic profile at baseline, and developed more CVD over the next 40 years, compared with those not meeting this cut point. Determining the TG/HDL-C ratio in middle-aged men provided a simple and potentially clinically useful way to identify increased risk of developing CVD in persons free of diabetes or manifest CVD.

  • 140.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Söderberg, Stefan
    Department of Public Health and Clinical Medicine, Umeå University, Umeå.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Johansson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    On the association between body fat and left ventricular mass2019Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 37, nr 8, s. 1699-1704Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: As intervention studies have shown a reduction in body weight to be paralleled with a reduction in left ventricular mass (LVM), we quantified a hypothesized causal relationship between fat mass and LVM, and how much of these effects that was mediated by blood pressure (BP), diabetes and adipokines. Also visceral and subcutaneous adipose tissue (VAT and SAT) were explored in the same fashion.

    METHODS: In the Prospective Study of the Vasculature in Uppsala Seniors study (n = 1016, 50% women, all aged 70 years), LVM was measured by echocardiography (indexed for lean mass, LVMI), fat and lean mass by dual-energy X-ray. VAT and SAT were measured by abdominal MRI (in n = 275).

    RESULTS: In a structural equation model adjusting for sex, the total effect of fat mass on LVMI was large (standardized coefficient 0.280, P = 3.2 × 10, 95% confidence interval 0.210-0.349). Out of the total effect of fat mass on LVMI, 29.0% was mediated by BP and glucose (P = 2.4 × 10). The BP pathway was most important, mediating 24.4% of the total effect of fat mass on LVMI (P = 4.6 × 10), while the glucose pathway accounted for 4.6% (P = 0.033). The association of VAT with LVMI (0.202, P = 2.4 × 10) was slightly weaker than that of SAT with LVMI (0.283, P = 1.0 × 10). Of several measured adipokines, leptin was a significant mediator of the effect of fat mass on LVMI (P = 3.0 × 10).

    CONCLUSION: One-third of the hypothesized association between body fat and LVMI was mediated by BP and glucose in this population-based cohort. Leptin was also an important mediator. Visceral adipose tissue was not more closely related to LVMI than subcutaneous abdominal fat.

  • 141.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Salihovic, Samira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ganna, Andrea
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA;Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Broeckling, Corey D.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA.
    Magnusson, Patrik K.
    Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden.
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap.
    Prenni, Jessica
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, Erik
    Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA;Stanford Cardiovasc Inst, Stanford, CA USA.
    Arnlov, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Huddinge, Sweden;Dalarna Univ, Sch Hlth & Social Sci, Falun, Sweden.
    A Multi-Cohort Metabolomics Analysis Discloses Sphingomyelin (32:1) Levels to be Inversely Related to Incident Ischemic Stroke2020Inngår i: Journal of Stroke & Cerebrovascular Diseases, ISSN 1052-3057, E-ISSN 1532-8511, Vol. 29, nr 2, artikkel-id 104476Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and Purpose:

    To search for novel pathophysiological pathways related to ischemic stroke using a metabolomics approach.

    Methods:

    We identified 204 metabolites in plasma by liquid chromatography mass spectrometry in 3 independent population-based samples (TwinGene, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) and Uppsala Longitudinal Study of Adult Men). TwinGene was used for discovery and the other 2 samples were meta-analyzed as replication. In PIVUS, traditional cardiovascular (CV) risk factors, multiple markers of subclinical CV disease, markers of coagulation/fibrinolysis were measured and analyzed in relation to top metabolites.

    Results:

    In TwinGene (177 incident cases, median follow-up 4.3 years), levels of 28 metabolites were associated with incident ischemic stroke at a false discover rate (FDR) of 5%. In the replication (together 194 incident cases, follow-up 10 and 12 years, respectively), only sphingomyelin (32:1) was significantly associated (HR.69 per SD change, 95% CI.57-0.83, P value = .00014; FDR <5%) when adjusted for systolic blood pressure, diabetes, smoking, low density lipoportein (LDL)- and high density lipoprotein (HDL), body mass index (BMI) and atrial fibrillation. In PIVUS, sphingomyelin (32:1) levels were significantly related to both LDL- and HDL-cholesterol in a positive fashion, and to serum triglycerides, BMI and diabetes in a negative fashion. Furthermore, sphingomyelin (32:1) levels were related to vasodilation in the forearm resistance vessels, and inversely to leukocyte count (P < .0069 and .0026, respectively).

    Conclusions:

    An inverse relationship between sphingomyelin (32:1) and incident ischemic stroke was identified, replicated, and characterized. A possible protective role for sphingomyelins in stroke development has to be further investigated in additional experimental and clinical studies.

  • 142.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    A Detailed Cardiovascular Characterization of Obesity Without the Metabolic Syndrome2011Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 31, nr 8, s. e27-e34Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Although obesity without metabolic disturbances has been regarded as harmless, we have recently shown that obese subjects without the metabolic syndrome (MetS) has an increased risk of cardiovascular (CV) disorders and mortality during long-term follow-up. To investigate the basis for that increased risk, we studied the impact of obesity without MetS on multiple markers of subclinical CV disease.

    Methods and Results: At age 70, 1016 subjects were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors study. According to body mass index (BMI)/MetS status, they were categorized as normal weight (BMI = 30 kg/m(2)) without MetS (n = 102), and obese with MetS (n = 118). Several different measurements of endothelial reactivity, arterial compliance (plethysmography and ultrasound), carotid artery atherosclerosis, and echocardiography were performed, and 7 markers of coagulation/fibrinolysis were measured. Subjects with obesity without MetS showed impaired vasoreactivity, a more echolucent carotid artery wall, increased left ventricular mass and function together with impaired coagulation/fibrinolysis compared with normal-weight subjects without the MetS (P < 0.05 to 0.001). The majority of these disturbances were also seen in overweight subjects without the MetS.

    Conclusion: In contrast to some previous studies, our data do not support that obesity without MetS is a benign condition, because obesity without MetS was associated with impairments in multiple markers of subclinical CV disease. This was also the case for overweight subjects without the MetS.

  • 143.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap.
    Lindahl, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Stenemo, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Discovery of New Risk Markers for Ischemic Stroke Using a Novel Targeted Proteomics Chip2015Inngår i: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 46, nr 12, s. 3340-3347Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and Purpose-Emerging technologies have made it possible to simultaneously evaluate a large number of circulating proteins as potential new stroke risk markers. Methods-We explored associations between 85 cardiovascular proteins, assessed by a proteomics chip, and incident ischemic stroke in 2 independent cohorts of elderly (Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS]: n=977; 50% women, mean age=70.1 years, 71 fatal/nonfatal ischemic stroke events during 10.0 years; and Uppsala Longitudinal Study in Adult Men [ULSAM]: n=720, mean age=77.5 years, 75 ischemic stroke events during 9.5 years). The proteomics chip uses 2 antibodies for each protein and a polymerase chain reaction step to achieve a high-specific binding and the possibility to measure multiple proteins in parallel, but gives no absolute concentrations. Results-In PIVUS, 16 proteins were related to incident ischemic stroke using a false discovery rate of 5%. Of these, N-terminal pro-B-type natriuretic peptide (P=0.0032), adrenomedullin (P=0.018), and eosinophil cationic protein (P=0.0071) were replicated in ULSAM after adjustment for established stroke risk factors. In predefined secondary meta-analyses of individual data, interleukin-27 subunit , growth/differentiation factor 15, urokinase plasminogen activator surface receptor, tumor necrosis factor receptor superfamily member 6, macrophage colony-stimulating factor 1, and matrix metalloproteinase-7 were also potential risk markers for ischemic stroke after adjustment for multiple comparisons (P<0.0006). The addition of N-terminal pro-B-type natriuretic peptide, adrenomedullin, and eosinophil cationic protein to a model with established risk factors increased the C-statistic from 0.629 to 0.689 (P=0.001). Conclusions-Our data suggest that large-scale proteomics analysis is a promising way of discovering novel biomarkers that could substantially improve the prediction of ischemic stroke.

  • 144.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Change in left ventricular geometry over 10 years in the elderly and risk of incident cardiovascular disease2019Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 37, nr 2, s. 325-330Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Left ventricular hypertrophy (LVH) is related to a poor prognosis. We aimed to determine how left ventricular (LV) geometry changes over time, and how this relates to future cardiovascular disease.

    Methods: In the Prospective Study of the Vasculature in Uppsala Seniors study, 1016 individuals were investigated with echocardiography at age 70. This was repeated after 5 and 10 years. Incident cardiovascular disease (myocardial infarction, stroke, and heart failure, n = 163) was recorded over 10 years.

    Results: LV mass index (LVMI) and LV end-diastolic diameter (LVEDD) progressively increased over 10 years, while LV thickness declined (P< 0.0001 for all). Adjusting for traditional cardiovascular risk factors, LVMI at baseline, but not LVEDD, was significantly associated with incident cardiovascular disease [hazard ratio (HR) 1.02, 95% confidence interval 1.003-1.03, P = 0.019]. When adding the change in LVMI, or change in LVEDD, between ages 70 and 75 years to the models and using the time between 75 and 80 as follow-up (in total 82 incident cases), neither the change in LVMI nor the change in LVEDD were significant. Using updated information on LV geometric groups, an increased risk was seen for concentric LVH as compared with the normal group following adjustment for traditional risk factors (HR 2.29, P = 0.0014, 95% confidence interval 1.38-3.82). Eccentric LVH and concentric remodeling were not associated with a statistically significant increased risk of cardiovascular disease.

    Conclusion: In elderly individuals without myocardial infarction, a progressive dilatation of the LV was seen over 10 years. However, the LV dilation seen over time in this age group was not associated with a major increase in risk of future cardiovascular disease.

  • 145.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet.
    Lampa, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Ärnlov, Johan
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden;Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA;Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA 94305 USA.
    Longitudinal effects of aging on plasma proteins levels in older adults - associations with kidney function and hemoglobin levels2019Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 2, artikkel-id e0212060Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background A targeted proteomics chip has been shown to be useful to discover novel associations of proteins with cardiovascular disease. We investigated how these proteins change with aging, and whether this change is related to a decline in kidney function, or to a change in hemoglobin levels. Material and methods In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, including 1,016 participants from the general population aged 70 at baseline, 84 proteins were measured at ages 70, 75, 80. At these occasions, glomerular filtration rate (eGFR) was estimated and the hemoglobin levels were measured. Results Sixty-one of the 84 evaluated proteins changed significantly during the 10-year follow-up (multiple testing-adjusted alpha = 0.00059), most showing an increase. The change in eGFR was inversely related to changes of protein levels for the vast majority of proteins (74%). The change in hemoglobin was significantly related to the change in 40% of the evaluated proteins, with no obvious preference of the direction of these relationships. Conclusion The majority of evaluated proteins increased with aging in adults. Therefore, normal ranges for proteins might be given in age-strata. The increase in protein levels was associated with the degree of reduction in eGFR for the majority of proteins, while no clear pattern was seen for the relationships between the proteins and the change in hemoglobin levels. Studies on changes in urinary proteins are warranted to understand the association between the reduction in eGFR and increase in plasma protein levels.

  • 146.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sundström, Johan
    Institutionen för folkhälso- och vårdvetenskap. Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lithell, Hans
    Institutionen för folkhälso- och vårdvetenskap.
    Cardiovascular risk factors and electrographical characteristics and abnormalities in middle-aged males.1997Inngår i: J Intern Med, ISSN 0954-6820, Vol. 241, nr 2, s. 109-13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: To evaluate if characteristics and abnormalities found at the electrocardiogram (ECG) are related to common cardiovascular risk factors included in the insulin-resistance metabolic syndrome. DESIGN: Cross-sectional. SETTING: Tertiary university hospital. SUBJECTS: Over 2000 middle-aged males in whom ECG abnormalities were recorded, together with ECG characteristics measured in a random sample of men with no ECG abnormalities (n = 113). INTERVENTIONS: None. RESULTS: All three components of the metabolic syndrome; elevated blood pressure, dyslipidaemia and hyperinsulinaemia were found to be related to the heart rate (P < 0.002) and the QRS-duration (P < 0.01) and inversely to the QoT-interval (P < 0.05), the early diastolic phase (P < 0.05) and the T-wave amplitude (P < 0.02). The components of the metabolic syndrome was furthermore found to be associated with the occurrence of T-wave abnormalities (n = 64, P < 0.01) and to a lesser degree also to the occurrence of Q-waves (n = 21). CONCLUSIONS: The components of the insulin-resistance metabolic syndrome were related both to certain ECG characteristics in subjects with a normal ECG and to some ECG abnormalities. A raised sympathetic activity is likely to be the link between some of the described associations, whilst coronary heart diseases may explain others.

  • 147.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Stenemo, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Hagström, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Dalarna Univ, Dept Hlth & Social Sci, Falun, Sweden..
    Discovery of new biomarkers for atrial fibrillation using a custom-made proteomics chip2017Inngår i: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 103, nr 5, s. 379-384Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Apart from several established clinical risk factors for atrial fibrillation (AF), a number of biomarkers have also been identified as potential risk factors for AF. None of these have so far been adopted in clinical practice. Objective To use a novel custom-made proteomics chip to discover new prognostic biomarkers for AF risk. Methods In two independent community-based cohorts (Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (978 participants without AF, mean age 70.1 years, 50% women, median followup 10.0 years) and Uppsala Longitudinal Study of Adult Men (ULSAM) (n= 725, mean age 77.5 years, median follow-up 7.9 years)), ninety-two plasma proteins were assessed at baseline by a proximity extension assay (PEA) chip. Of those, 85 proteins showed a call rate > 70% in both cohorts. Results Thirteen proteins were related to incident AF in PIVUS (148 events) using a false discovery rate of 5%. Of those, five were replicated in ULSAM at nominal multivariable p value (123 events, N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), fibroblast growth factor 23 (FGF-23), fatty acid-binding protein 4 (FABP4), growth differentiation factor 15 (GDF-15) and interleukin-6 (IL-6)). Of those, NT-pro-BNP and FGF-23 were also associated with AF after adjusting for established AF risk factors. In a prespecified secondary analysis pooling the two data sets, T-cell immunoglobulin and mucin domain 1 (TIM-1) and adrenomedullin (AM) were also significantly related to incident AF in addition to the aforementioned five proteins (Bonferroni-adjustment). The addition of NT-proBNP to a model with established risk factors increased the C-statistic from 0.605 to 0.676 (p< 0.0001). Conclusions Using a novel proteomics approach, we confirmed the previously reported association between NT-pro-BNP, FGF-23, GDF-15 and incident AF, and also discovered four proteins (FABP4, IL-6, TIM-1 and AM) that could be of importance in the development of AF.

  • 148.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Ärnlöv, Johan
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med, Stockholm, Sweden.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
    Proteomic profiling of endothelium-dependent vasodilation2019Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 37, nr 1, s. 216-222Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: As endothelial dysfunction is an early event in atherosclerosis formation, we investigated if proteins previously related to cardiovascular disease also were related to endothelial function using a novel targeted proteomics approach.

    Methods: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 850970, all aged 70 years), endothelium-dependent vasodilation (EDV) in the forearm was assessed by intraarterial infusion of acetylcholine. Flow-mediated vasodilation (FMD) was investigated in the brachial artery by ultrasound. The same investigations were carried out in the Prospective investigation of Obesity, Energy and Metabolism (POEM) study (n = 375-461, all aged 50 years). After strict quality control, 84 cardiovascular-related proteins measured by the proximity extension assay were studied in relation to EDV and FMD in PIVUS (discovery sample) and POEM (validation sample).

    Results: Of the 15 proteins being significantly related to EDV in PIVUS (false discovery rate < 0.025), seven could be replicated in POEM at nominal significance and same effect direction when adjusted for sex and storage time. Of those, only cathepsin D remained significant following further adjustment for traditional cardiovascular risk factors (beta, -0.08; 95% confidence interval, -0.16, -0.01; P = 0.033; change in ln-transformed EDV per 1-SD increase in protein level). No protein was significantly related to FMD.

    Conclusion: Using a discovery/validation approach in two samples, our results indicate an inverse association between plasma cathepsin D levels and endothelial-dependent vasodilation.

  • 149.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lampa, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Impact of Aging on the Strength of Cardiovascular Risk Factors: A Longitudinal Study Over 40 Years2018Inngår i: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 7, nr 1, artikkel-id e007061Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background-The knowledge of the impact of cardiovascular risk factors at different ages has mainly been based on different studies performed at different ages. This study aimed to investigate the change in impact of traditional cardiovascular risk factors over the aging process in subjects followed for 4 decades. Methods and Results-In the ULSAM (Uppsala Longitudinal Study of Adult Men) study, 2322 men originally investigated in 1970 to 1974 have been followed regarding cardiovascular diseases until the end of 2013. This cohort has been investigated physically at ages 50, 60, 70, 77, and 82 years regarding body mass index, low-density lipoprotein-and high-density lipoprotein-cholesterol, triglycerides, systolic blood pressure and diastolic blood pressure, fasting glucose, and smoking. These data were used to model the interactions between risk factors and age regarding incident myocardial infarction (n=540), ischemic stroke (n=343), or heart failure (n=397). Significant interactions were observed between age and the set of traditional risk factors regarding all 3 outcomes (P<0.05 for all). Generally, a decline in the rate ratios was seen with aging for most risk factors, being most pronounced for body mass index regarding myocardial infarction and for systolic blood pressure regarding ischemic stroke and heart failure. However, low-density lipoprotein-cholesterol was significantly related to incident myocardial infarction, whereas both body mass index and fasting glucose were significantly related to incident heart failure also at a high age. Conclusions-Using a longitudinal design in middle-aged men spanning 4 decades showed that the impact of traditional cardiovascular risk factors generally declined with aging. However, some of the risk factors remained significantly associated with incident cardiovascular disease also at old age.

  • 150.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Vessby, Bengt
    Institutionen för folkhälso- och vårdvetenskap.
    Sundström, Johan
    Institutionen för folkhälso- och vårdvetenskap. Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    The apolipoprotein B/AI ratio and the metabolic syndrome independently predict risk for myocardial infarction in middle-aged men.2006Inngår i: Arterioscler Thromb Vasc Biol, ISSN 1524-4636, Vol. 26, nr 2, s. 406-10Artikkel i tidsskrift (Fagfellevurdert)
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