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  • 1. Bellavia, Andrea
    et al.
    Tektonidis, Thanasis G
    Orsini, Nicola
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Quantifying the benefits of Mediterranean diet in terms of survival.2016In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 31, no 5, p. 527-30Article in journal (Refereed)
    Abstract [en]

    Beneficial effects of Mediterranean diet (MD) have been consistently documented. However, to fully understand the public health implications of MD adherence, an informative step is to quantify these effects in terms of survival time differences. The aim of this study was to evaluate the impact of MD on survival, presenting results in terms of differences in median age at death. We used data from 71,333 participants from a large population-based cohort of Swedish men and women, followed-up between January 1, 1998, and December 31, 2012. A total score of MD, ranging from 0 to 8, was calculated by including information on vegetables and fruits consumption, legumes and nuts, non-refined/high fiber grains, fermented dairy products, fish, red meat, use of olive oil/rapeseed oil, and moderate alcohol intake. Multivariable-adjusted differences in median age at death were estimated with Laplace regression and presented as a function of the MD score. During 15 years of follow-up we documented 14,697 deaths. We observed a linear dose-response association between the MD score and median age at death, with higher score associated with longer survival. The difference in median age at death between participants with the extreme scores (0 vs 8) of MD was up to 2 years (23 months, 95 % CI: 16-29). In this study we documented that adherence to MD may accrue benefits up to 2 years of longer survival.

  • 2. Bäck, Magnus
    et al.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bioactive lipids in aortic valve stenosis-a possible link to atherosclerosis?2017In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 113, no 11, p. 1276-1278Article in journal (Refereed)
  • 3. Carlström, Mattias
    et al.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Coffee consumption and reduced risk of developing type 2 diabetes: a systematic review with meta-analysis.2018In: Nutrition reviews, ISSN 0029-6643, E-ISSN 1753-4887, Vol. 76, no 6, p. 395-417Article in journal (Refereed)
    Abstract [en]

    Context: Type 2 diabetes (T2D) is a major health problem worldwide that is associated with increased morbidity and mortality. There is increased interest in the value of different nutrition-based strategies for preventing the development of T2D.

    Objective: This review aims to cover current knowledge regarding the effects of coffee consumption on development of T2D or modulation of adverse complications. A meta-analysis on coffee consumption and the risk of T2D was conducted. Moreover, bioactive components in coffee, polymorphisms, and potential underlying mechanism(s) in relation to T2D and adverse complications are discussed.

    Data sources: PubMed was searched up to December 1, 2017, and prospective cohort and nested case-control studies of the association between coffee consumption and T2D risk were selected.

    Data extraction: Two investigators independently extracted data from included studies.

    Results: A total of 30 prospective studies with 1 185 210 participants and 53 018 incident T2D cases were included in the meta-analysis. The pooled relative risk (RR) was 0.71 (95% confidence interval [CI], 0.67-0.76) for the highest category of coffee consumption (median consumption, 5 cups/d) vs the lowest category (median consumption, 0 cups/d). The risk of T2D decreased by 6% (RR = 0.94; 95%CI, 0.93-0.95) for each cup-per-day increase in coffee consumption. Results were similar for caffeinated coffee consumption (per additional cup of coffee per day: RR = 0.93; 95%CI, 0.90-0.96) and decaffeinated coffee consumption (corresponding RR = 0.94; 95%CI, 0.90-0.98).

    Conclusions: Available evidence indicates that coffee consumption is inversely associated with risk of T2D. Possible mechanisms behind this association include thermogenic, antioxidative, and anti-inflammatory effects; modulation of adenosine receptor signaling; and microbiome content and diversity.

  • 4. Drca, Nikola
    et al.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Jensen-Urstad, Mats
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Physical activity is associated with a reduced risk of atrial fibrillation in middle-aged and elderly women2015In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 101, no 20, p. 1627-1630Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Previous studies have found that regular participation in intense physical activity increases the risk of developing atrial fibrillation (AF) in men, but it remains unclear how physical activity influences the risk of AF in women. We aimed to examine whether physical activity of different types and at different ages influences the development of AF in women.

    METHODS: In the population-based Swedish Mammography Cohort, information about physical activity was obtained from 36 513 AF-free women (49-83 years old, median age 60 years) who had completed a questionnaire at study entry (1997). Participants reported their time spent on leisure-time exercise and on walking or bicycling throughout their lifetime (at study entry, and at 30 and 50 years of age). We used the Swedish National Inpatient Register (IPR) to determine whether the participants were diagnosed with AF. Cox proportional hazards regression models were used to estimate relative risks (RR) with 95% CI, adjusted for potential confounders.

    RESULTS: During a median follow-up of 12 years (10th percentile 7.5 years, 90th percentile 12.0 years), 2915 cases of AF were diagnosed. The risk of AF decreased with increasing levels of leisure-time exercise at study entry (RR 0.85, 95% CI 0.75 to 0.95 for ≥4 h/week vs <1 h/week) and walking/bicycling (RR 0.81, 95% CI 0.72 to 0.92, for ≥40 min/day vs almost never).

    CONCLUSIONS: Physical activity is associated with a reduced risk of AF in women. Moderate amount of physical activity was sufficient to significantly reduce AF risk.

  • 5.
    Helte, Emilie
    et al.
    Karolinska Inst, Inst Environm Med, Unit Nutr & Cardiovasc Epidemiol, Stockholm, Sweden.
    Akesson, Agneta
    Karolinska Inst, Inst Environm Med, Unit Nutr & Cardiovasc Epidemiol, Stockholm, Sweden.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Nutr & Cardiovasc Epidemiol, Stockholm, Sweden.
    Assessing Causality in Associations of Serum Calcium and Magnesium Levels With Heart Failure: A Two-Sample Mendelian Randomization Study2019In: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 10, article id 1069Article in journal (Refereed)
    Abstract [en]

    Evidence from observational studies suggests that increased exposure to calcium may increase the risk of coronary heart disease and stroke whereas magnesium might have a protective effect on disease risk. However, studies of the associations of these minerals with heart failure are scarce and limited by potential biases introduced by confounding and reverse causality. We applied a two-sample Mendelian randomization design using summary estimates to assess whether serum calcium and magnesium concentrations are causally associated with heart failure. Summary statistics data were collected for seven and six single-nucleotide polymorphisms associated with calcium and magnesium, respectively, from the hitherto largest genome-wide association studies on these minerals. Corresponding summary statistics for genetic associations with heart failure were available from publicly available data based on the UK Biobank study and based on participants of European ancestry. The findings showed that neither serum calcium nor magnesium concentrations were associated with heart failure. In the standard inverse-variance weighted analysis, the odds ratios of heart failure per genetically predicted one standard deviation increase in mineral concentrations were 0.89 (95% confidence interval 0.67-1.17; p = 0.41) for serum calcium and 0.89 (95% confidence interval 0.72-1.10; p = 0.28) for serum magnesium. Results were robust in sensitivity analyses, including the weighted median and Mendelian randomization Egger analyses. In conclusion, these findings do not support previous findings suggesting a link between serum calcium and magnesium and heart failure, but this study was underpowered to detect weak associations.

  • 6. Hindy, George
    et al.
    Engström, Gunnar
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Traylor, Matthew
    Markus, Hugh S
    Melander, Olle
    Orho-Melander, Marju
    Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study2018In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 49, no 4, p. 820-827Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR).

    METHODS: Summary data on 185 genome-wide lipids-associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance-weighted MR was used to obtain the causal estimates. Inverse-variance-weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias.

    RESULTS: A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04-1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10-1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67-0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes.

    CONCLUSIONS: LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes.

  • 7. Kaluza, Joanna
    et al.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Linden, Anders
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Consumption of Unprocessed and Processed Red Meat and the Risk of Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study of Men.2016In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 184, no 11, p. 829-836Article in journal (Refereed)
    Abstract [en]

    Consumption of both processed and unprocessed red meat has been associated with a higher risk of major chronic diseases. However, only processed meat consumption has been studied in relation to chronic obstructive pulmonary disease (COPD). Therefore, we endeavored to determine the association between the risk of COPD and consumption of processed and unprocessed red meat while taking into account smoking status. The population-based prospective Cohort of Swedish Men included 43,848 men who were 45-79 years of age and had no history of COPD or cancer at baseline. Meat consumption was assessed using a self-administered questionnaire in 1997. During 13.2 years of follow-up, 1,909 COPD cases were ascertained. Consumption of processed meat was associated with risk of COPD: Compared with men who consumed less than 25 g/day of processed meat, men who consumed 75 g/day or more had a multivariable-adjusted hazard ratio of 1.21 (95% confidence interval: 1.02, 1.44; P for trend = 0.03). The positive association was confined to current smokers (P for interaction = 0.003); among smokers who consumed 75 g/day or more of processed red meat, the hazard ratio was 1.26 (95% confidence interval: 1.00, 1.60) when compared with persons who consumed less than 25 g/day. Consumption of unprocessed red meat was not associated with COPD incidence. Findings from this prospective study indicate that high consumption of processed red meat is associated with an increased COPD risk among smokers.

  • 8. Kippler, Maria
    et al.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Berglund, Marika
    Glynn, Anders
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Åkesson, Agneta
    Associations of dietary polychlorinated biphenyls and long-chain omega-3 fatty acids with stroke risk.2016In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 94, p. 706-711, article id S0160-4120(16)30270-7Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Little is known about joint exposure to polychlorinated biphenyls (PCBs) and long-chain omega-3 fatty acids [eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)], through fish consumption, on cerebrovascular disease risk.

    OBJECTIVE: To explore associations of dietary PCB exposure and EPA-DHA intake with risk of different stroke subtypes.

    METHODS: This was assessed in the prospective population-based Cohort of Swedish Men including 39,948, middle-aged and elderly men, who were free of cardiovascular disease and cancer at baseline in 1997. Validated estimates of dietary PCBs and EPA-DHA were obtained via a food frequency questionnaire.

    RESULTS: During 12years of follow-up, 2286 and 474 incident cases of ischemic stroke and hemorrhagic stroke, respectively, were ascertained through register linkage. Dietary PCB exposure and EPA-DHA intake were associated with hemorrhagic stroke but not ischemic stroke. Men in the highest quartile of dietary PCB exposure (median 412ng/day) had a multivariable- and EPA-DHA-adjusted RR of hemorrhagic stroke of 2.77 [95% confidence interval (CI), 1.48-5.19] compared with men in the lowest quartile (median 128ng/day; p for trend <0.01). The corresponding RRs in men with and without hypertension were 5.45 (95% CI, 1.34-22.1) and 2.37 (95% CI 1.17-4.79), respectively. The multivariable- and PCB-adjusted RR of hemorrhagic stroke for the highest quartile of EPA-DHA intake (median 0.73g/day) versus the lowest quartile (median 0.18g/day) was 0.42 (95% CI, 0.22-0.79).

    CONCLUSION: Dietary PCB exposure was associated with an increased risk of hemorrhagic stroke, whereas a protective association was observed for dietary EPA-DHA intake.

  • 9.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Dietary Approaches for Stroke Prevention2017In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 48, no 10, p. 2905-2911Article in journal (Refereed)
    Abstract [en]

    Stroke is a leading cause of mortality and long-term disability. The consequences of stroke are often devastating and irreversible. Many stroke survivors experience mental and physical impairment and require assistance with daily life activities. Prevention of stroke through modifiable risk factors, such as diet, is, therefore, crucial to public health. Diet may influence stroke development through multiple pathways and mechanisms, including effects on blood pressure, blood lipids, thrombosis and coagulation, oxidative stress, systemic inflammation, endothelial function, glucose and insulin homeostasis, gut microbiome, and body weight. This review summarizes available data from prospective studies and randomized controlled trials (RCTs) of the associations of dietary patterns, foods, beverages, selected nutrients, and bioactive compounds with stroke risk.

  • 10.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Unit Cardiovasc & Nutr Epidemiol, Inst Environm Med, Stockholm, Sweden.
    Allara, Elias
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.
    Mason, Amy M.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Burgess, Stephen
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England;Univ Cambridge, MRC Biostat Unit, Cambridge, England.
    Thyroid Function and Dysfunction in Relation to 16 Cardiovascular Diseases: A Mendelian Randomization Study2019In: Circulation: Genomic and Precision Medicine, ISSN 2574-8300, Vol. 12, no 3, p. 121-126, article id e002468Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Subclinical thyroid dysfunction, defined as thyroidstimulating hormone levels outside the reference range with normal free thyroxine levels in asymptomatic patients, is associated with alterations in cardiac hemodynamics. We used Mendelian randomization to assess the role of thyroid dysfunction for cardiovascular disease (CVD).

    METHODS: Single-nucleotide polymorphisms associated with thyroid function were identified from a genome-wide association meta-analysis in up to 72 167 individuals. Data for genetic associations with CVD were obtained from meta-analyses of genome-wide association studies of atrial fibrillation (n= 537 409 individuals), coronary artery disease (n= 184 305 individuals), and ischemic stroke (n= 438 847) as well as from the UK Biobank (n= 367 703 individuals).

    RESULTS: Genetically predicted thyroid-stimulating hormone levels and hyperthyroidism were statistically significantly associated with atrial fibrillation but no other CVDs at the Bonferroni-corrected level of significance (P< 7.8x10-4). The odds ratios of atrial fibrillation were 1.15 (95% CI, 1.11-1.19; P= 2.4x10-14) per genetically predicted 1 SD decrease in thyroid-stimulating hormone levels and 1.05 (95% CI, 1.03-1.08; P= 5.4x10-5) for genetic predisposition to hyperthyroidism. Genetically predicted free thyroxin levels were not statistically significantly associated with any CVD.

    CONCLUSIONS: This Mendelian randomization study supports evidence for a causal association of decreased thyroid-stimulating hormone levels in the direction of a mild form of hyperthyroidism with an increased risk of atrial fibrillation but no other CVDs.

  • 11.
    Larsson, Susanna C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, S-17177 Stockholm, Sweden.
    Burgess, Stephen
    Univ Cambridge, MRC Biostat Unit, Cambridge, England;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Genetic association between adiposity and gout: a Mendelian randomization study2018In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 57, no 12, p. 2145-2148Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate whether overall obesity (as measured by BMI) and abdominal obesity (as measured by waist-to-hip ratio adjusted for BMI) are associated with gout risk and serum urate concentrations using Mendelian randomization.

    Methods: Single nucleotide polymorphisms associated with BMI (n = 97) and waist-to-hip ratio adjusted for BMI (n = 49) were analysed for association with gout risk in 2115 gout cases and 67 259 controls, and with serum urate concentrations in 110 347 individuals from the Global Urate Genetics Consortium.

    Results: Genetically higher BMI, but not waist-to-hip ratio adjusted for BMI, was positively associated with risk of gout and serum urate concentrations. Each standard deviation (about 4.6 kg/m(2)) increase in genetically predicted BMI was associated with an odds ratio of gout of 2.24 (95% CI 1.70, 2.95; P = 8.4 x 10(-9)) and with a 0.30 mg/dl (95% CI 0.25, 0.35; P = 1.6 x 10(-36)) increase in serum urate concentrations.

    Conclusion: These findings provide support that overall obesity may be a risk factor for gout and is associated with higher serum urate concentrations.

  • 12.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, S-17177 Stockholm, Sweden.
    Burgess, Stephen
    Univ Cambridge, Med Res Council, Biostat Unit, Cambridge, England;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Smoking and stroke: A mendelian randomization study2019In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 86, no 3, p. 468-471Article in journal (Refereed)
    Abstract [en]

    We used the Mendelian randomization design to explore the potential causal association of smoking with ischemic stroke and intracerebral hemorrhage using summary statistics data for 34,217 ischemic stroke cases and 404,630 noncases, and 1,545 cases of intracerebral hemorrhage and 1,481 noncases. Genetic predisposition to smoking initiation (ever smoking regularly), based on up to 372 single-nucleotide polymorphisms, was statistically significantly positively associated with any ischemic stroke, large artery stroke, and small vessel stroke but not cardioembolic stroke or intracerebral hemorrhage. This study provides genetic support for a causal association of smoking with ischemic stroke, particularly large artery and small vessel stroke. ANN NEUROL 2019;86:468-471

  • 13.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Carlström, Mattias
    Coffee consumption and gout: a Mendelian randomisation study2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 10, p. 1544-1546Article in journal (Refereed)
  • 14.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, SE-17177 Stockholm, Sweden.
    Drca, Nikola
    Karolinska Inst, Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden.
    Björck, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Bäck, Magnus
    Karolinska Univ Hosp, Div Valvular & Coronary Dis, Stockholm, Sweden;Karolinska Inst, Dept Med, Ctr Mol Med, Stockholm, Sweden.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, SE-17177 Stockholm, Sweden.
    Nut consumption and incidence of seven cardiovascular diseases2018In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 104, no 19, p. 1615-1620Article in journal (Refereed)
    Abstract [en]

    Background Nut consumption has been found to be inversely associated with cardiovascular disease mortality, but the association between nut consumption and incidence of specific cardiovascular diseases is unclear. We examined the association between nut consumption and incidence of seven cardiovascular diseases. Methods This prospective study included 61 364 Swedish adults who had completed a Food Frequency Questionnaire and were followed up for 17 years through linkage with the Swedish National Patient and Death Registers. Results Nut consumption was inversely associated with risk of myocardial infarction, heart failure, atrial fibrillation and abdominal aortic aneurysm in the age-adjusted and sex-adjusted analysis. However, adjustment for multiple risk factors attenuated these associations and only a linear, dose-response, association with atrial fibrillation (p(trend)=0.004) and a non-linear association (p(non-linearity)=0.003) with heart failure remained. Compared with no consumption of nuts, the multivariable HRs (95% CI) of atrial fibrillation across categories of nut consumption were 0.97 (0.93 to 1.02) for 1-3 times/month, 0.88 (0.79 to 0.99) for 1-2 times/week and 0.82 (0.68 to 0.99) for 3times/week. For heart failure, the corresponding HRs (95% CI) were 0.87 (0.80 to 0.94), 0.80 (0.67 to 0.97) and 0.98 (0.76 to 1.27). Nut consumption was not associated with risk of aortic valve stenosis, ischaemic stroke or intracerebral haemorrhage. Conclusions These findings suggest that nut consumption or factors associated with this nutritional behaviour may play a role in reducing the risk of atrial fibrillation and possibly heart failure. Trial registration number NCT01127711 and NCT01127698; Results.

  • 15.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Drca, Nikola
    Jensen-Urstad, Mats
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Coffee consumption is not associated with increased risk of atrial fibrillation: results from two prospective cohorts and a meta-analysis2015In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 13, article id 207Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Whether coffee consumption affects the risk of developing atrial fibrillation (AF) remains unclear. We sought to investigate the association between coffee consumption and incidence of AF in two prospective cohorts, and to summarize available evidence using a meta-analysis.

    METHODS: Our study population comprised 41,881 men in the Cohort of Swedish Men and 34,594 women in the Swedish Mammography Cohort who had provided information on coffee consumption in 1997 and were followed up for 12 years. Incident cases of AF were ascertained by linkage with the Swedish Hospital Discharge Register. For the meta-analysis, prospective studies were identified by searching PubMed and Embase through 22 July 2015, and by reviewing the reference lists of retrieved articles. Study-specific relative risks were combined using a random effects model.

    RESULTS: We ascertained 4,311 and 2,730 incident AF cases in men and women, respectively, in the two cohorts. Coffee consumption was not associated with AF incidence in these cohort studies. The lack of association was confirmed in a meta-analysis, including six cohort studies with a total of 10,406 cases of AF diagnosed among 248,910 individuals. The overall relative risk (95% confidence interval) of AF was 0.96 (0.84-1.08) for the highest versus lowest category of coffee consumption, and 0.99 (0.94-1.03) per 2 cups/day increment of coffee consumption.

    CONCLUSIONS: We found no evidence that coffee consumption is associated with increased risk of AF.

  • 16.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Drca, Nikola
    Jensen-Urstad, Mats
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Combined impact of healthy lifestyle factors on risk of atrial fibrillation: Prospective study in men and women.2016In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 203, p. 46-9, article id S0167-5273(15)30664-1Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The combined impact of multiple lifestyle factors on risk of atrial fibrillation (AF) remains unclear. We investigated the joint association of four modifiable lifestyle factors on incidence of AF in a prospective study of men and women.

    METHODS: The study cohort comprised 39 300 men in the Cohort of Swedish Men and 33 090 women in the Swedish Mammography Cohort who were 45-83 years of age and free from atrial fibrillation at baseline. Healthy lifestyle was defined as body mass index <25 kg/m(2), regular exercise for ≥ 20 min/day, no or light-to-moderate alcohol consumption (≤ 2 drinks/day for men and ≤ 1 drink/day for women), and not smoking. Incident AF cases were identified through linkage with the Swedish National Inpatient Register.

    RESULTS: During a mean follow-up of 10.9 years, AF occurred in 4028 men and 2539 women. Compared with men and women with no healthy lifestyle factors, the multivariable relative risks (95% confidence interval) of AF were 0.83 (0.65-1.07) for one, 0.74 (0.58-0.94) for two, 0.62 (0.49-0.79) for three, and 0.50 (0.39-0.64) for four healthy lifestyle factors (P for trend <0.0001). The inverse association was similar in men and women.

    CONCLUSIONS: Four healthy lifestyle factors combined were associated with a halving of the risk of AF.

  • 17.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Drca, Nikola
    Jensen-Urstad, Mats
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Incidence of atrial fibrillation in relation to birth weight and preterm birth2015In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 178, p. 149-152, article id S0167-5273(14)02075-0Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hypertension, type 2 diabetes and other cardiovascular diseases, all risk factors for atrial fibrillation, are associated with birth weight. It remains unclear, however, whether risk of atrial fibrillation is also associated with birth weight. We investigated the associations of birth weight and preterm birth (i.e., born more than one month before term) with risk of atrial fibrillation (AF).

    METHODS: The study population comprised 29551 men and 23454 women who were free from AF at baseline. Information on birth weight, preterm birth, and risk factors for AF was obtained from a questionnaire. Incident AF cases were ascertained by linkage to the Swedish Inpatient Register.

    RESULTS: During 12years of follow-up, AF developed in 2711 men and 1491 women. High birth weight (≥5000g) was associated with an increased risk of AF after adjustment for age and other risk factors for AF, but the association did not persist after further adjustment for adult height. In men but not in women, low birth weight was associated with an increased risk of AF. Compared with men weighing 2500-3999g at birth, the multivariable RR was 1.86 (95% CI, 1.15 to 3.00) for those weighing <1500g. This association was stronger in men who were born full-term (RR 2.53; 95% CI, 1.35 to 4.73).

    CONCLUSIONS: Both high birth weight and low birth weight (in men), in particular in men born full-term, were associated with an increased risk of AF. The association with high birth weight appeared to be mediated through adult height.

  • 18.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, S-17177 Stockholm, Sweden.
    Drca, Nikola
    Karolinska Inst, Dept Med, Stockholm, Sweden;Karolinska Univ Hosp, Div Arrhythmia, Stockholm, Sweden.
    Mason, Amy M.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.
    Burgess, Stephen
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England;Univ Cambridge, MRC Biostat Unit, Cambridge, England.
    Resting Heart Rate and Cardiovascular Disease Mendelian Randomization Analysis2019In: CIRCULATION-GENOMIC AND PRECISION MEDICINE, ISSN 2574-8300, Vol. 12, no 3, p. 127-129Article in journal (Refereed)
  • 19.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Unit Cardiovasc & Nutrit Epidemiol, Inst Environm Med, S-17177 Stockholm, Sweden.
    Drca, Nikola
    Karolinska Inst, Dept Med, Stockholm, Sweden;Karolinska Univ Hosp, Div Arrhythmia, Stockholm, Sweden.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Serum Magnesium and Calcium Levels and Risk of Atrial Fibrillation: A Mendelian Randomization Study2019In: CIRCULATION: GENOMIC AND PRECISION MEDICINE, ISSN 2574-8300, Vol. 12, no 1, article id e002349Article in journal (Refereed)
  • 20.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden.
    Flicker, Leon
    Univ Western Australia, Med Sch, Perth, WA, Australia.
    Vitamin D: A novel protective factor for delirium?2019In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 92, no 12, p. 553-554Article in journal (Refereed)
    Abstract [en]

    Delirium is a state of acute brain dysfunction, affecting as many as 50% of older patients in hospital, and is associated with prolonged hospitalization, high health care costs, long-term cognitive decline and dementia, and a substantially increased risk of mortality.(1-3) One postulated mechanism is that delirium results from the breakdown of brain network dynamics triggered by a stressor (e.g., major surgery, general anesthesia, infections, or psychoactive drugs) in individuals with preexisting low brain resilience due to deficits in connectivity or plasticity.(2) Multiple lines of evidence support a strong relationship between delirium and dementia and that these conditions share some pathophysiologic mechanisms, including acetylcholine deficiency, inflammation, and reduced cerebral oxidative metabolism.

  • 21.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Giovannucci, Edward L
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Prospective Study of Glycemic Load, Glycemic Index, and Carbohydrate Intake in Relation to Risk of Biliary Tract Cancer2016In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 111, no 6, p. 891-6Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Diets that induce a high glycemic response might increase the risk of biliary tract cancer (BTC). We evaluated the hypothesis that diets with high glycemic load (GL) and high glycemic index (GI), which are measures of the glycemic effect of foods, are associated with an increased incidence of BTC.

    METHODS: We used data from a population-based prospective study of 76,014 Swedish adults (age 45-83 years; 57% men) who were free of cancer and had completed a food-frequency questionnaire in the autumn of 1997. Incident cancer cases were ascertained by linkage with the Swedish Cancer Registry. Data were analyzed using Cox proportional hazards regression models.

    RESULTS: During a mean follow-up of 13.3 years (1,010,777 person-years), we identified 140 extrahepatic BTC cases (including 77 gallbladder cancers) and 23 intrahepatic BTC cases. A high dietary GL was associated with an increased risk of BTC. The multivariable relative risks for the highest versus lowest quartile of dietary GL were 1.63 (95% confidence interval (95% CI), 1.01-2.63) for extrahepatic BTC, 2.14 (95% CI, 1.06-4.33) for gallbladder cancer, and 3.46 (95% CI, 1.22-9.84) for intrahepatic BTC. Dietary GI was statistically significantly positively associated with risk of extrahepatic BTC and gallbladder cancer. We observed no statistically significant association between carbohydrate intake and BTC risk, although all associations were positive.

    CONCLUSION: Although these data do not prove a causal relationship, they are consistent with the hypothesis that high-GL and high-GI diets are associated with an increased risk of BTC.

  • 22.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Giovannucci, Edward L
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sweetened Beverage Consumption and Risk of Biliary Tract and Gallbladder Cancer in a Prospective Study2016In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 108, no 10, article id djw125Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Sugar-sweetened beverage consumption raises blood glucose concentration and has been positively associated with weight gain and type 2 diabetes, all of which have been implicated in the development of biliary tract cancer (BTC). This study examined the hypothesis that sweetened beverage consumption is positively associated with risk of BTC in a prospective study.

    METHODS: The study population comprised 70 832 Swedish adults (55.9% men, age 45-83 years) from the Swedish Mammography Cohort and Cohort of Swedish Men who were free of cancer and diabetes and completed a food frequency questionnaire at baseline. Incident BTC case patients were ascertained through linkage with the Swedish Cancer Register. Cox proportional hazards regression model was used to analyze the data. All statistical tests were two-sided.

    RESULTS: During a mean follow-up of 13.4 years, 127 extrahepatic BTC case patients (including 71 gallbladder cancers) and 21 intrahepatic BTC case patients were ascertained. After adjustment for other risk factors, women and men in the highest category of combined sugar-sweetened and artificially sweetened beverage consumption had a statistically significantly increased risk of extrahepatic BTC and gallbladder cancer. The multivariable hazard ratios for two or more servings per day (200 mL/serving) of sweetened beverages compared with no consumption were 1.79 (95% confidence interval [CI] = 1.02 to 3.13) for extrahepatic BTC and 2.24 (95% CI = 1.02 to 4.89) for gallbladder cancer. The corresponding hazard ratio for intrahepatic BTC was 1.69 (95% CI = 0.41 to 7.03).

    CONCLUSIONS: These findings support the hypothesis that high consumption of sweetened beverages may increase the risk of BTC, particularly gallbladder cancer.

  • 23.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Håkansson, Niclas
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Dietary cysteine and other amino acids and stroke incidence in women2015In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 46, no 4, p. 922-926Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Cysteine could potentially lower the risk of stroke through antihypertensive and antioxidant effects. Our aim was to evaluate the hypothesis that cysteine intake is inversely associated with stroke incidence.

    METHODS: We used data from the Swedish Mammography Cohort, a population-based prospective cohort of 34 250 women who were free of cardiovascular disease and cancer and had completed a food-frequency questionnaire about diet and other risk factors for stroke in the autumn of 1997. Stroke cases were identified by linkage of the study population with the Swedish Inpatient Register and the Swedish Cause of Death Register. Relative risks (RR) with 95% confidence intervals, adjusted for potential confounders, were estimated by using Cox proportional hazards regression model.

    RESULTS: We ascertained 1751 incident cases of stroke during 10.4 years of follow-up. Dietary cysteine intake (mean, 635 mg/d) was inversely associated with stroke risk. The multivariable RR of total stroke comparing the highest with the lowest quintile of cysteine intake was 0.79 (95% confidence interval, 0.65-0.97; P for trend=0.04). The corresponding RR was 0.82 (95% confidence interval, 0.65-1.03; P for trend=0.12) for cerebral infarction and 0.54 (95% confidence interval, 0.29-1.03; P for trend=0.08) for intracerebral hemorrhage. Dietary intake of other amino acids showed no independent (after adjustment for cysteine intake) association with stroke risk.

    CONCLUSIONS: These findings suggest that dietary cysteine intake may be inversely associated with risk of stroke.

    CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01127698.

  • 24.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    King, Alice
    Madigan, Jeremy
    Levi, Christopher
    Norris, John W
    Markus, Hugh S
    Prognosis of carotid dissecting aneurysms: Results from CADISS and a systematic review2017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 88, no 7, p. 646-652Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine the natural history of dissecting aneurysm (DA) and whether DA is associated with an increased recurrent stroke risk and whether type of antithrombotic drugs (antiplatelets vs anticoagulants) modifies the persistence or development of DA.

    METHODS: We included 264 patients with extracranial cervical artery dissection (CAD) from the Cervical Artery Dissection in Stroke Study (CADISS), a multicenter prospective study that compared antiplatelet with anticoagulation therapy. Logistic regression was used to estimate age- and sex-adjusted odds ratios. We conducted a systematic review of published studies assessing the natural history of DA and stroke risk in patients with non-surgically-treated extracranial CAD with DA.

    RESULTS: In CADISS, DA was present in 24 of 264 patients at baseline. In 36 of 248 patients with follow-up neuroimaging at 3 months, 12 of the 24 baseline DAs persisted, and 24 new DA had developed. There was no association between treatment allocation (antiplatelets vs anticoagulants) and whether DA at baseline persisted at follow-up or whether new DA developed. During 12 months of follow-up, stroke occurred in 1 of 48 patients with DA and in 7 of 216 patients without DA (age- and sex-adjusted odds ratio 0.84; 95% confidence interval 0.10-7.31; p = 0.88). Published studies, mainly retrospective, showed a similarly low risk of stroke and no evidence of an increased stroke rate in patients with DA.

    CONCLUSIONS: The results of CADISS provide evidence suggesting that DAs may have benign prognosis and therefore medical treatment should be considered.

  • 25.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Markus, Hugh S
    Branched-chain amino acids and Alzheimer's disease: a Mendelian randomization analysis.2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 13604Article in journal (Refereed)
    Abstract [en]

    We conducted a two-sample Mendelian randomization study to test the hypothesis that raised plasma levels of the branched-chain amino acids isoleucine, leucine, and valine are associated with Alzheimer's disease (AD). From a genome-wide association study of 16,596 individuals of European ancestry, we obtained summary statistics for four independent single nucleotide polymorphisms (SNPs) associated with isoleucine levels and one SNP associated with both leucine and valine levels at genome-wide significance. Summary statistics of the associations of the five SNPs with AD were obtained from the International Genomics of Alzheimer's Project (17,008 AD cases and 37,154 controls). Based on four SNPs, the odds ratio of AD per genetically predicted one standard deviation higher isoleucine levels was 1.35 (95% CI, 1.08-1.69; p = 0.007). The leucine- and valine-raising allele was not associated with AD (p = 0.46). These data suggest that a genetic predisposition to raised plasma isoleucine levels is positively associated with AD.

  • 26.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Markus, Hugh S
    Does Treating Vascular Risk Factors Prevent Dementia and Alzheimer's Disease? A Systematic Review and Meta-Analysis.2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 64, no 2, p. 657-668Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Epidemiological evidence has associated Alzheimer's disease (AD) with vascular risk factors (VRFs), but whether treatment of VRFs reduces the incidence of dementia and AD is uncertain.

    OBJECTIVE: To conduct a systematic review and meta-analysis to summarize available data on the impact of treatment of VRFs on dementia and AD incidence.

    METHODS: Pertinent studies published until 1 January 2018 were identified from PubMed. Both randomized controlled trials (RCT) and prospective studies that investigated the impact of treatment of VRFs on dementia or AD incidence were included.

    RESULTS: Eight RCTs and 52 prospective studies were identified. Antihypertensive treatment was associated with a non-significant reduced risk of dementia in RCTs (n = 5; relative risk [RR], 0.84; 95% confidence interval [CI], 0.69-1.02) and prospective studies (n = 3; RR, 0.77; 95% CI, 0.58-1.01) and with reduced AD risk in prospective studies (n = 5; RR = 0.78; 95% CI, 0.66-0.91). In prospective studies, treatment of hyperlipidemia with statins, but not nonstatin lipid-lowering agents, was associated with reduced risk of dementia (n = 17; RR, 0.77; 95% CI, 0.63-0.95) and AD (n = 13; RR, 0.86; 95% CI, 0.80-0.92). The single RCT on statins and dementia incidence showed no association. Data from one RCT and six prospective studies did not support a beneficial impact of antidiabetic drugs or insulin therapy on dementia risk.

    CONCLUSION: Current evidence indicates that antihypertensives and statins might reduce the incidence of dementia and AD. Further trials to determine the effect of VRF on AD are needed.

  • 27.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Unit Cardiovasc & Nutr Epidemiol, Inst Environm Med, S-17177 Stockholm, Sweden.
    Markus, Hugh S.
    Univ Cambridge, Stroke Res Grp, Dept Clin Neurosci, Cambridge, England.
    Genetic Liability to Insomnia and Cardiovascular Disease Risk2019In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 140, no 9, p. 796-798Article in journal (Refereed)
  • 28.
    Larsson, Susanna C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, Stockholm, Sweden.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Circulating Serum 25-Hydroxyvitamin D Levels and Bone Mineral Density: Mendelian Randomization Study2018In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 33, no 5, p. 840-844Article in journal (Refereed)
    Abstract [en]

    There is considerable discussion of the importance for increased serum 25‐hydroxyvitamin D (S‐25OHD) concentration associated with adequacy for bone health. Accordingly, whether long‐term high S‐25OHD concentration in general positively affects bone mineral density (BMD) is uncertain. We used a Mendelian randomization design to determine the association between genetically increased S‐25OHD concentrations and BMD. Five single‐nucleotide polymorphisms (SNPs) in or near genes encoding enzymes and carrier proteins involved in vitamin D synthesis or metabolism were used as instrumental variables to genetically predict 1 standard deviation increase in S‐25OHD concentration. Summary statistics data for the associations of the S‐25OHD‐associated SNPs with dual‐energy X‐ray absorptiometry (DXA)‐derived femoral neck and lumbar spine BMD were obtained from the Genetic Factors for Osteoporosis (GEFOS) Consortium (32,965 individuals) and ultrasound‐derived heel estimated BMD from the UK Biobank (142,487 individuals). None of the SNPs were associated with BMD at Bonferroni‐corrected significance level, but there was a suggestive association between rs6013897 near CYP24A1 and femoral neck BMD (p = 0.01). In Mendelian randomization analysis, genetically predicted 1 standard deviation increment of S‐25OHD was not associated with higher femoral neck BMD (SD change in BMD 0.02; 95% confidence interval [CI] –0.03 to 0.07; p = 0.37), lumbar spine BMD (SD change in BMD 0.02; 95% CI –0.04 to 0.08; p = 0.49), or estimated BMD (g/cm2 change in BMD –0.03; 95% CI –0.05 to –0.01; p = 0.02). This study does not support a causal association between long‐term elevated S‐25OHD concentrations and higher BMD in generally healthy populations. These results suggest that more emphasis should be placed on the development of evidence‐based cut‐off points for vitamin D inadequacy rather than a general recommendation to increase S‐25OHD.

  • 29.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Orsini, Nicola
    Coffee Consumption and Risk of Dementia and Alzheimer's Disease: A Dose-Response Meta-Analysis of Prospective Studies.2018In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 10, no 10, article id E1501Article in journal (Refereed)
    Abstract [en]

    Coffee consumption is associated with a reduced risk of several diseases but uncertainty remains about the influence of coffee consumption on the risk of dementia. We performed a dose-response meta-analysis to summarize the prospective data on coffee consumption and associated risk of dementia and Alzheimer's disease. We identified studies by searching PubMed (from January 1966) and Web of Science (from January 1945) through 4 October 2018 and by scrutinizing the reference lists of pertinent publications. Two researchers independently reviewed the literature. Results were combined using a restricted cubic spline random-effects dose-response meta-analysis based on a one-stage approach. Eight relevant prospective studies were identified. These studies included 7486 dementia cases diagnosed among 328,885 individuals during an average follow-up of 4.9⁻25 years. Meta-analysis of all eight studies indicated no statistically significant association between coffee consumption and the risk of dementia and no deviations from a linear trend (p = 0.08). The relative risk of dementia per 1 cup/day increment of coffee consumption was 1.01 (95% confidence interval (CI) 0.98⁻1.05; p = 0.37). Meta-analysis of five studies that focused on Alzheimer's disease revealed no association between coffee consumption and Alzheimer's disease and no deviations from a linear trend (p = 0.79). The relative risk of Alzheimer's disease per 1 cup/day increment of coffee consumption was 1.01 (95% confidence interval 0.95⁻1.07; p = 0.80). These results do not support an association between coffee consumption and an increased risk of overall dementia or Alzheimer's disease specifically, but further research on the association of coffee consumption with dementia risk is needed.

  • 30.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Orsini, Nicola
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Alcohol consumption and risk of heart failure: a dose-response meta-analysis of prospective studies2015In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 17, no 4, p. 367-373Article in journal (Refereed)
    Abstract [en]

    AIMS: The aim of this study was to conduct a meta-analysis of prospective studies assessing the relationship between alcohol consumption and risk of heart failure (HF).

    METHODS AND RESULTS: We searched the PubMed database from inception to September 2014 and reviewed the reference list of relevant articles to identify prospective studies assessing the association between alcohol consumption and risk of HF. Study-specific relative risk (RR) estimates were combined using a random-effects meta-analysis. The meta-analysis included eight prospective studies, with a total of 202 378 participants and 6211 cases of HF. The pooled adjusted RRs of HF were 0.85 [95% confidence interval (CI) 0.78-0.93] for light to moderate alcohol consumption (<14 drinks/week) and 0.90 (95% CI 0.72-1.13) for high alcohol consumption (≥14 drinks/week) compared with non-drinkers. In a dose-response meta-analysis, we observed a non-linear relationship between alcohol consumption and risk of HF (P for non-linearity = 0.001). Compared with non-drinkers, the RRs (95% CI) across levels of alcohol consumption were 0.90 (0.84-0.96) for 3 drinks/week, 0.83 (0.73-0.95) for 7 drinks/week, 0.84 (0.72-0.98) for 10 drinks/week, 0.90 (0.73-1.10) for 14 drinks/week, and 1.07 (0.77-1.48) for 21 drinks/week.

    CONCLUSION: Alcohol consumption in moderation is associated with a reduced risk of HF.

  • 31.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Orsini, Nicola
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Urinary cadmium concentration and risk of breast cancer: a systematic review and dose-response meta-analysis2015In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 182, no 5, p. 375-380Article in journal (Refereed)
    Abstract [en]

    Cadmium is a toxic and persistent heavy metal with estrogenic activities. We conducted a systematic review and meta-analysis of cohort, case-control, and cross-sectional studies of the association between urinary cadmium concentration, a biomarker of cadmium exposure, and breast cancer risk. Studies were identified by searching PubMed and Embase (to March 15, 2015) and by reviewing the reference lists of pertinent articles. Study-specific risk estimates were combined by using a random-effects model. We identified 2 cohort studies (with 67 breast cancer deaths) and 5 case-control studies and 1 cross-sectional study (with 1,416 cases and 5,083 controls) on urinary cadmium concentration in relation to breast cancer risk. The studies were published during the past 10 years (2006-2015). There was no consistent association between urinary cadmium and breast cancer mortality in the cohort studies. In case-control and cross-sectional studies, the pooled odds ratios were 2.24 (95% confidence interval: 1.50, 3.34; I(2) = 63.4%) for the highest versus lowest category of cadmium concentration and 1.66 (95% confidence interval: 1.23, 2.25) for each 0.5-µg/g creatinine increase of cadmium concentration. This meta-analysis suggests that a high cadmium exposure may be a risk factor for breast cancer, but large prospective studies are needed to confirm this finding.

  • 32.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Scott, Robert A
    Traylor, Matthew
    Langenberg, Claudia C
    Hindy, George
    Melander, Olle
    Orho-Melander, Marju
    Seshadri, Sudha
    Wareham, Nicholas J
    Markus, Hugh S
    Type 2 diabetes, glucose, insulin, BMI, and ischemic stroke subtypes: Mendelian randomization study2017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 89, no 5, p. 454-460Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To implement a mendelian randomization (MR) approach to determine whether type 2 diabetes mellitus (T2D), fasting glucose, fasting insulin, and body mass index (BMI) are causally associated with specific ischemic stroke subtypes.

    METHODS: MR estimates of the association between each possible risk factor and ischemic stroke subtypes were calculated with inverse-variance weighted (conventional) and weighted median approaches, and MR-Egger regression was used to explore pleiotropy. The number of single nucleotide polymorphisms (SNPs) used as instrumental variables was 49 for T2D, 36 for fasting glucose, 18 for fasting insulin, and 77 for BMI. Genome-wide association study data of SNP-stroke associations were derived from METASTROKE and the Stroke Genetics Network (n = 18,476 ischemic stroke cases and 37,296 controls).

    RESULTS: Conventional MR analysis showed associations between genetically predicted T2D and large artery stroke (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.16-1.40, p = 3.3 × 10-7) and small vessel stroke (OR 1.21, 95% CI 1.10-1.33, p = 8.9 × 10-5) but not cardioembolic stroke (OR 1.06, 95% CI 0.97-1.15, p = 0.17). The association of T2D with large artery stroke but not small vessel stroke was consistent in a sensitivity analysis using the weighted median method, and there was no evidence of pleiotropy. Genetically predicted fasting glucose and fasting insulin levels and BMI were not statistically significantly associated with any ischemic stroke subtype.

    CONCLUSIONS: This study provides support that T2D may be causally associated with large artery stroke.

  • 33.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Singleton, Andrew B
    Nalls, Mike A
    Richards, J Brent
    No clear support for a role for vitamin D in Parkinson's disease: A Mendelian randomization study.2017In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 32, no 8, p. 1249-1252Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Observational studies have found that relative to healthy controls, patients with Parkinson's disease have lower circulating concentrations of 25-hydroxyvitamin D, a clinical biomarker of vitamin D status. However, the causality of this association is uncertain. We undertook a Mendelian randomization study to investigate whether genetically decreased 25-hydroxyvitamin D concentrations are associated with PD to minimize confounding and prevent bias because of reverse causation.

    METHODS: As instrumental variables for the Mendelian randomization analysis, we used 4 single-nucleotide polymorphisms that affect 25-hydroxyvitamin D concentrations (rs2282679 in GC, rs12785878 near DHCR7, rs10741657 near CYP2R1, and rs6013897 near CYP24A1). Summary effect size estimates of the 4 single-nucleotide polymorphisms on PD were obtained from the International Parkinson's Disease Genomics Consortium (including 5333 PD cases and 12,019 controls). The estimates of the 4 single-nucleotide polymorphisms were combined using an inverse-variance weighted meta-analysis.

    RESULTS: Of the 4 single-nucleotide polymorphisms associated with 25-hydroxyvitamin D concentrations, one (rs6013897 in CYP24A1) was associated with PD (odds ratio per 25-hydroxyvitamin D-decreasing allele, 1.09; 95% confidence interval, 1.02-1.16; P = 0.008), whereas no association was observed with the other 3 single-nucleotide polymorphisms (P > 0.23). The odds ratio of PD per genetically predicted 10% lower 25-hydroxyvitamin D concentration, based on the 4 single-nucleotide polymorphisms, was 0.98 (95% confidence interval, 0.93-1.04; P = 0.56).

    CONCLUSIONS: This Mendelian randomization study provides no clear support that lowered 25-hydroxyvitamin D concentration is causally associated with risk of PD. © 2017 International Parkinson and Movement Disorder Society.

  • 34.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Tektonidis, Thanasis G
    Gigante, Bruna
    Åkesson, Agneta
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Healthy Lifestyle and Risk of Heart Failure: Results From 2 Prospective Cohort Studies2016In: Circulation Heart Failure, ISSN 1941-3289, E-ISSN 1941-3297, Vol. 9, no 4, article id e002855Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The joint impact of multiple healthy lifestyle factors on heart failure (HF) risk is unclear. We investigated the separate and collective associations of healthy lifestyle factors with HF incidence in 2 population-based prospective cohort studies.

    METHODS AND RESULTS: This study consisted of 33,966 men (Cohort of Swedish Men) and 30,713 women (Swedish Mammography Cohort) who were 45 to 83 years of age and free of HF and ischemic heart disease at baseline. A healthy lifestyle was defined as being a nonsmoker and physically active (≥150 min/wk), and having body mass index between 18.5 and 25 kg/m(2) and a healthy diet (defined as adherence to a modified Mediterranean diet). Incident HF cases were ascertained by linkage with the Swedish National Patient Register and the Swedish Cause of Death Register. Cox proportional hazards regression was used to analyze the data. During 13 years of follow-up, HF was diagnosed in 1488 men and 1096 women. Each healthy lifestyle factor was associated with a statistically significant lower risk of HF in both men and women, and the risk decreased with increasing number of healthy behaviors. The greatest reduction in HF risk was observed for combinations that included nonsmoking. Compared with men and women with none of the healthy lifestyle factors, the multivariable relative risks (95% confidence interval) of HF for those with all 4 healthy behaviors were 0.38 (0.28-0.53) in men and 0.28 (0.19-0.41) in women.

    CONCLUSIONS: Adhering to a healthy lifestyle is associated with a substantially lower HF risk.

    CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01127698 and NCT01127711.

  • 35.
    Larsson, Susanna C.
    et al.
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden.
    Traylor, Matthew
    Univ Cambridge, Stroke Res Grp, Dept Clin Neurosci, Cambridge, England.
    Burgess, Stephen
    Univ Cambridge, MRC Biostat Unit, Cambridge, England;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.
    Boncoraglio, Giorgio B.
    Fdn IRCCS Ist Neurol Carlo Besta, Dept Cerebrovasc Dis, Milan, Italy.
    Jern, Christina
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Clin Pathol & Genet, Gothenburg, Sweden.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Markus, Hugh S.
    Univ Cambridge, Stroke Res Grp, Dept Clin Neurosci, Cambridge, England.
    Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study2019In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 92, no 9, p. E944-E950Article in journal (Refereed)
    Abstract [en]

    Objective To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.

    Methods Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).

    Results In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI-] 0.69-0.89; p = 1.3 x 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 x 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.

    Conclusions This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

  • 36.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Traylor, Matthew
    Burgess, Stephen
    Markus, Hugh S
    Genetically-Predicted Adult Height and Alzheimer's Disease2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 60, no 2, p. 691-698Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Observational studies have linked increased adult height with better cognitive performance and reduced risk of Alzheimer's disease (AD). It is unclear whether the associations are due to shared biological processes that influence height and AD or due to confounding by early life exposures or environmental factors.

    OBJECTIVE: To use a genetic approach to investigate the association between adult height and AD.

    METHODS: We selected 682 single nucleotide polymorphisms (SNPs) associated with height at genome-wide significance (p < 5×10-8) in the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary statistics for each of these SNPs on AD were obtained from the International Genomics of Alzheimer's Project (IGAP) of 17,008 individuals with AD and 37,154 controls. The estimate of the association between genetically predicted height and AD was calculated using the inverse-variance weighted method.

    RESULTS: The odds ratio of AD was 0.91 (95% confidence interval, 0.86-0.95; p = 9.8×10-5) per one standard deviation increase (about 6.5 cm) in genetically predicted height based on 682 SNPs, which were clustered in 419 loci. In an analysis restricted to one SNP from each height-associated locus (n = 419 SNPs), the corresponding OR was 0.92 (95% confidence interval, 0.86-0.97; p = 4.8×10-3).

    CONCLUSIONS: This finding suggests that biological processes that influence adult height may have a role in the etiology of AD.

  • 37.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Traylor, Matthew
    Malik, Rainer
    Dichgans, Martin
    Burgess, Stephen
    Markus, Hugh S
    Modifiable pathways in Alzheimer's disease: Mendelian randomisation analysis.2017In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 359, article id j5375Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine which potentially modifiable risk factors, including socioeconomic, lifestyle/dietary, cardiometabolic, and inflammatory factors, are associated with Alzheimer's disease.

    DESIGN: Mendelian randomisation study using genetic variants associated with the modifiable risk factors as instrumental variables.

    SETTING: International Genomics of Alzheimer's Project.

    PARTICIPANTS: 17 008 cases of Alzheimer's disease and 37 154 controls.

    MAIN OUTCOME MEASURES: Odds ratio of Alzheimer's per genetically predicted increase in each modifiable risk factor estimated with Mendelian randomisation analysis.

    RESULTS: This study included analyses of 24 potentially modifiable risk factors. A Bonferroni corrected threshold of P=0.002 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. Genetically predicted educational attainment was significantly associated with Alzheimer's. The odds ratios were 0.89 (95% confidence interval 0.84 to 0.93; P=2.4×10-6) per year of education completed and 0.74 (0.63 to 0.86; P=8.0×10-5) per unit increase in log odds of having completed college/university. The correlated trait intelligence had a suggestive association with Alzheimer's (per genetically predicted 1 SD higher intelligence: 0.73, 0.57 to 0.93; P=0.01). There was suggestive evidence for potential associations between genetically predicted higher quantity of smoking (per 10 cigarettes a day: 0.69, 0.49 to 0.99; P=0.04) and 25-hydroxyvitamin D concentrations (per 20% higher levels: 0.92, 0.85 to 0.98; P=0.01) and lower odds of Alzheimer's and between higher coffee consumption (per one cup a day: 1.26, 1.05 to 1.51; P=0.01) and higher odds of Alzheimer's. Genetically predicted alcohol consumption, serum folate, serum vitamin B12, homocysteine, cardiometabolic factors, and C reactive protein were not associated with Alzheimer's disease.

    CONCLUSION: These results provide support that higher educational attainment is associated with a reduced risk of Alzheimer's disease.

  • 38.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Traylor, Matthew
    Markus, Hugh S
    Circulating Vitamin K₁ Levels in Relation to Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study.2018In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 10, no 11, article id E1575Article in journal (Refereed)
    Abstract [en]

    Vitamin K plays a crucial role in blood coagulation, and hypercoagulability has been linked to atherosclerosis-related vascular disease. We used the Mendelian randomization study design to examine whether circulating vitamin K₁ (phylloquinone) levels are associated with ischemic stroke. Four single-nucleotide polymorphisms associated with vitamin K₁ levels were used as instrumental variables. Summary-level data for large artery atherosclerotic stroke (n = 4373 cases), small vessel stroke (n = 5386 cases), cardioembolic stroke (n = 7193 cases), and any ischemic stroke (n = 34,217 cases and 404,630 non-cases) were available from the MEGASTROKE consortium. Genetically-predicted circulating vitamin K₁ levels were associated with large artery atherosclerotic stroke but not with any other subtypes or ischemic stroke as a whole. The odds ratios per genetically predicted one nmol/L increase in natural log-transformed vitamin K₁ levels were 1.31 (95% confidence interval (CI) 1.12⁻1.53; p = 7.0 × 10-4) for large artery atherosclerotic stroke, 0.98 (95% CI 0.85⁻1.12; p = 0.73) for small vessel stroke, 1.01 (95% CI 0.90⁻1.14; p = 0.84) for cardioembolic stroke, and 1.05 (95% CI 0.99⁻1.11; p = 0.11) for any ischemic stroke. These findings indicate that genetic predisposition to higher circulating vitamin K₁ levels is associated with an increased risk of large artery atherosclerotic stroke.

  • 39.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Nobels Vag 13, Stockholm, Sweden.
    Traylor, Matthew
    Univ Cambridge, Dept Clin Neurosci, Stroke Res Grp, Cambridge, England.
    Markus, Hugh S.
    Univ Cambridge, Dept Clin Neurosci, Stroke Res Grp, Cambridge, England.
    Homocysteine and small vessel stroke: A mendelian randomization analysis2019In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 85, no 4, p. 495-501Article in journal (Refereed)
    Abstract [en]

    Objective

    Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization.

    Methods

    We used summary statistics data for single-nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B-6 (n = 1), and vitamin B-12 (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases).

    Results

    Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13-1.58; p = 6.7 x 10(-4)) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B-6 levels were 0.49 (95% CI, 0.34-0.71; p = 1.3 x 10(-4)) and 0.70 (95% CI, 0.52-0.94; p = 0.02), respectively. Genetically higher vitamin B-12 levels were not associated with any stroke subtype.

    Interpretation

    These findings suggest that any effect of homocysteine-lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495-501

  • 40.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, S-17177 Stockholm, Sweden.
    Wallin, Alice
    Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, S-17177 Stockholm, Sweden.
    Håkansson, Niclas
    Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, S-17177 Stockholm, Sweden.
    Stackelberg, Otto
    Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, S-17177 Stockholm, Sweden;Stockholm South Gen Hosp, Dept Surg, Stockholm, Sweden.
    Bäck, Magnus
    Karolinska Univ Hosp, Div Valvular & Coronary Dis, Stockholm, Sweden;Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, S-17177 Stockholm, Sweden.
    Type 1 and type 2 diabetes mellitus and incidence of seven cardiovascular diseases2018In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 262, p. 66-70Article in journal (Refereed)
    Abstract [en]

    Background: The association between type 1 diabetes mellitus (T1DM) and specific cardiovascular diseases (CVD) is uncertain. Furthermore, data on type 2 diabetes mellitus (T2DM) in relation to risk of aortic valve stenosis, atrial fibrillation, abdominal aortic aneurysm, and intracerebral hemorrhage are scarce and inconclusive. We examined the associations of T1DM and T2DM with incidence of seven CVD outcomes.

    Methods: This study comprised 71,483 Swedish adults from two population-based prospective cohorts. T1DM and T2DM diagnosis and incident CVD cases were ascertained through linkage with the population-based registers.

    Results: T1DM was associated with myocardial infarction (hazard ratio [HR] 3.26; 95% confidence interval [CI] 2.47-4.30), heart failure (HR 2.68; 95% CI 1.76-4.09), and ischemic stroke (HR 2.61; 95% CI 1.80-3.79). Increased risk of myocardial infarction, ischemic stroke, and heart failure was also observed in T2DM patients and the magnitude of the associations increased with longer T2DM duration. T2DM was also associated with an increased risk of aortic valve stenosis (HR 1.34; 95% CI 1.05-1.71) and with lower risk of abdominal aortic aneurysm (HR 0.57; 95% CI 0.40-0.82) and intracerebral hemorrhage (HR 0.51; 95% CI 0.30-0.88). Only long-term T2DM(>= 20 years) was associated with an increased risk of atrial fibrillation (HR 1.44; 95% CI 1.02-2.04).

    Conclusion: T1DM and T2DM are associated with increased risk of major CVD outcomes. Trial registration: The Cohort of Swedish Men and the Swedish Mammography Cohort are registered at clinicaltrials.gov as NCT01127711 and NCT01127698, respectively.

  • 41.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wallin, Alice
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Dietary Approaches to Stop Hypertension Diet and Incidence of Stroke: Results From 2 Prospective Cohorts2016In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 47, no 4, p. 986-990Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: High adherence to the Dietary Approaches to Stop Hypertension (DASH) diet is associated with lower risk of hypertension, the major risk factor for stroke. We examined whether adherence to the DASH diet is inversely associated with the incidence of stroke.

    METHODS: The study population comprised 74 404 men and women (45-83 years of age), without stroke at baseline, from the Cohort of Swedish Men and the Swedish Mammography Cohort. Diet was assessed with a food-frequency questionnaire. A modified DASH diet score was created based on consumption of vegetables, fruits, legumes and nuts, whole grains, low-fat dairy, red meat and processed meat, and sweetened beverages. Stroke cases were identified through linkage to the Swedish National Patient and Cause of Death Registers. Relative risks and 95% confidence intervals were estimated using Cox proportional hazards regression model.

    RESULTS: During 882 727 person-years (mean, 11.9 years) of follow-up, 3896 ischemic strokes, 560 intracerebral hemorrhages, and 176 subarachnoid hemorrhages were ascertained. The modified DASH diet score was statistically significantly inversely associated with the risk of ischemic stroke (P for trend=0.002), with a multivariable relative risk of 0.86 (95% confidence interval, 0.78-0.94) for the highest versus the lowest quartile of the score. The modified DASH diet score was nonsignificantly inversely associated with intracerebral hemorrhage (corresponding relative risk=0.81; 95% confidence interval, 0.63-1.05) but was not associated with subarachnoid hemorrhage.

    CONCLUSIONS: These findings indicate that high adherence to the DASH diet is associated with a reduced risk of ischemic stroke.

    CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01127698 and NCT01127711 for the Swedish Mammography Cohort and the Cohort of Swedish Men, respectively.

  • 42.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wallin, Alice
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Markus, Hugh S
    Differing association of alcohol consumption with different stroke types: a systematic review and meta-analysis.2016In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 14, no 1, article id 178Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Whether light-to-moderate alcohol consumption is protective against stroke, and whether any association differs by stroke type, is controversial. We conducted a meta-analysis to summarize the evidence from prospective studies on alcohol drinking and stroke types.

    METHODS: Studies were identified by searching PubMed to September 1, 2016, and reference lists of retrieved articles. Additional data from 73,587 Swedish adults in two prospective studies were included. Study-specific results were combined in a random-effects model.

    RESULTS: The meta-analysis included 27 prospective studies with data on ischemic stroke (25 studies), intracerebral hemorrhage (11 studies), and/or subarachnoid hemorrhage (11 studies). Light and moderate alcohol consumption was associated with a lower risk of ischemic stroke, whereas high and heavy drinking was associated with an increased risk; the overall RRs were 0.90 (95 % CI, 0.85-0.95) for less than 1 drink/day, 0.92 (95 % CI, 0.87-0.97) for 1-2 drinks/day, 1.08 (95 % CI, 1.01-1.15) for more than 2-4 drinks/day, and 1.14 (95 % CI, 1.02-1.28) for more than 4 drinks/day. Light and moderate alcohol drinking was not associated with any hemorrhagic stroke subtype. High alcohol consumption (>2-4 drinks/day) was associated with a non-significant increased risk of both hemorrhagic stroke subtypes, and the relative risk for heavy drinking (>4 drinks/day) were 1.67 (95 % CI, 1.25-2.23) for intracerebral hemorrhage and 1.82 (95 % CI, 1.18-2.82) for subarachnoid hemorrhage.

    CONCLUSION: Light and moderate alcohol consumption was inversely associated only with ischemic stroke, whereas heavy drinking was associated with increased risk of all stroke types with a stronger association for hemorrhagic strokes.

  • 43.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Potato consumption and risk of cardiovascular disease: 2 prospective cohort studies2016In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 104, no 5, p. 1245-1252Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Whether consumption of potatoes, which are rich in potassium and have a high glycemic index and glycemic load, is associated with the risk of cardiovascular disease (CVD) is unknown.

    OBJECTIVE: The aim was to examine the association between potato consumption and risk of total and specific CVD events as well as mortality from CVD in 2 prospective cohorts of Swedish adults, a population with a high consumption of potatoes.

    DESIGN: Information on potato consumption was available from 69,313 men and women, free of CVD and diabetes, in the Cohort of Swedish Men and the Swedish Mammography Cohort. Nonfatal and fatal cases of CVD diagnosed over 13 y of follow-up were identified by linkage with the Swedish National Patient and Cause of Death Registers. Analyses were conducted by using a Cox proportional hazards regression model, controlled for potential confounders.

    RESULTS: We ascertained 10,147 major CVD events [myocardial infarction (MI), heart failure (HF), and stroke] and 4003 deaths due to CVD. Total potato consumption was not associated with the risk of major CVD events, specific CVD endpoints, or CVD mortality in either men or women. Multivariable HRs (95% CIs) per an increment of 3 servings/wk of total potato consumption (boiled potatoes, fried potatoes, and French fries) were 1.00 (0.97, 1.02) for major CVD events, 1.01 (0.97, 1.04) for MI, 0.97 (0.93, 1.02) for HF, 1.01 (0.97, 1.05) for stroke, and 0.99 (0.95, 1.03) for CVD mortality. There were no significant trends between the consumption of boiled potatoes, fried potatoes, or French fries and risk of any CVD outcome.

    CONCLUSION: Potato consumption was not associated with the risk of CVD in this population. The Swedish Mammography Cohort and the Cohort of Swedish Men are registered at clinicaltrials.gov as NCT01127698 and NCT01127711, respectively.

  • 44.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, Stockholm, Sweden.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, Stockholm, Sweden.
    Sedentary leisure-time in relation to mortality and survival time2019In: Journal of Science and Medicine in Sport, ISSN 1440-2440, E-ISSN 1878-1861, Vol. 22, no 5, p. 562-567Article in journal (Refereed)
    Abstract [en]

    Objective: To examine the association between sedentary leisure-time and all-cause mortality and differences in survival time.

    Design: Prospective cohort study.

    Methods: Information on sedentary leisure-time, defined as TV viewing and/or sitting reading, was collected from 72 003 Swedish adults who were 45-83 (median 60) years of age and completed a self-administered questionnaire at baseline and were followed up for 17 years through linkage with the Swedish Death Register.

    Results: The association between sedentary leisure-time and all-cause mortality was modified by age with a more pronounced association in middle-aged (<60 years of age) than in older adults (>= 60 years of age) (p-interaction <0.001). During follow-up, 3358 and 15 217 deaths occurred in the middle-aged and older age group, respectively. The multivariable-adjusted hazard ratios for the highest (>6 h/day) versus lowest category (<1 h/day) of sedentary leisure-time were 1.72 (95% confidence interval [CI] 1.29-2.30) in middle-aged adults and 1.19 (95% CI 1.05-1.36) in older adults. This corresponded to a difference in survival time of respectively 2.4 (95% CI -4.1 to -0.8) years and 1.5 (95% CI -2.2 to -0.7) years.

    Conclusions: Prolonged sedentary leisure-time was associated with a significantly decreased survival time up to 2.4 years in middle-aged adults. 

  • 45.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Urinary cadmium and mortality from all causes, cancer and cardiovascular disease in the general population: systematic review and meta-analysis of cohort studies2016In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 45, no 3, p. 782-791Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cadmium is a toxic heavy metal distributed in the environment. We conducted a systematic review and meta-analysis to examine the association between urinary cadmium concentration and mortality from all causes, cancer and cardiovascular disease (CVD) in the general population.

    METHODS: Studies were identified by searching PubMed and Embase (to 30 March 2015) and the reference lists of retrieved articles. We included prospective studies that reported hazard ratios (HR) with 95% confidence intervals (CI) for the association between urinary cadmium concentration and all-cause, cancer or CVD mortality. A random-effects model was used to combine study-specific results.

    RESULTS: Nine cohort studies, including 5600 deaths from all causes, 1332 deaths from cancer and 1715 deaths from CVD, were eligible for inclusion in the meta-analysis. The overall HRs for the highest vs lowest category of urinary cadmium were1.44 (95% CI, 1.25-1.64; I(2 )= 40.5%) for all-cause mortality (six studies), 1.39 (95% CI, 0.96-1.99; I(2 )= 75.9%) for cancer mortality (four studies) and 1.57 (95% CI, 1.27-1.95; I(2 )= 34.0%) for CVD mortality (five studies). In an analysis restricted to six cohort studies conducted in populations with a mean urinary cadmium concentration of ≤1 µg/g creatinine, the HRs were 1.38 (95% CI, 1.17-1.63; I(2 )= 48.3%) for all-cause mortality, 1.56 (95% CI, 0.98-2.47; I(2 )= 81.0%) for cancer mortality and 1.50 (95% CI, 1.18-1.91; I(2 )= 38.2%) for CVD mortality.

    CONCLUSIONS: Even at low-level exposure, cadmium appears to be associated with increased mortality. Further large prospective studies of cadmium exposure and mortality are warranted.

  • 46.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Åkesson, Agneta
    Author Response2015In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 84, no 22, article id 2293Article in journal (Refereed)
  • 47.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Åkesson, Agneta
    Gigante, Bruna
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Chocolate consumption and risk of myocardial infarction: a prospective study and meta-analysis.2016In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 102, no 13, p. 1017-22Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine whether chocolate consumption is associated with a reduced risk of ischaemic heart disease, we used data from a prospective study of Swedish adults and we performed a meta-analysis of available prospective data.

    METHODS AND RESULTS: The Swedish prospective study included 67 640 women and men from the Cohort of Swedish Men and the Swedish Mammography Cohort who had completed a food-frequency questionnaire and were free of cardiovascular disease at baseline. Myocardial infarction (MI) cases were ascertained through linkage with the Swedish National Patient and Cause of Death Registers. PubMed and EMBASE databases were searched from inception until 4 February 2016 to identify prospective studies on chocolate consumption and risk of ischaemic heart disease.

    RESULTS: The results from eligible studies were combined using a random-effects model. During follow-up (1998-2010), 4417 MI cases were ascertained in the Swedish study. Chocolate consumption was inversely associated with MI risk. Compared with non-consumers, the multivariable relative risk for those who consumed ≥3-4 servings/week of chocolate was 0.87 (95% CI 0.77 to 0.98; p for trend =0.04). Five prospective studies on chocolate consumption and ischaemic heart disease were identified. Together with the Swedish study, the meta-analysis included six studies with a total of 6851 ischaemic heart disease cases. The overall relative risk for the highest versus lowest category of chocolate consumption was 0.90 (95% CI 0.82 to 0.97), with little heterogeneity among studies (I(2)=24.3%).

    CONCLUSIONS: Chocolate consumption is associated with lower risk of MI and ischaemic heart disease.

  • 48.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Åkesson, Agneta
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Egg consumption and risk of heart failure, myocardial infarction, and stroke: results from 2 prospective cohorts.2015In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 102, no 5, p. 1007-1013Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Some studies have found that egg consumption is associated with a higher risk of ischemic heart disease in patients with diabetes. Epidemiologic studies of egg consumption in relation to risk of heart failure (HF) and stroke types are scarce.

    OBJECTIVE: The aim of this study was to examine whether egg consumption is associated with incidence of HF, myocardial infarction (MI), or stroke types.

    DESIGN: In prospective cohorts of 37,766 men (Cohort of Swedish Men) and 32,805 women (Swedish Mammography Cohort) who were free of cardiovascular disease (CVD), egg consumption was assessed at baseline with a food-frequency questionnaire. Incident CVD cases were identified through linkage with the Swedish National Patient and Cause of Death Registers. The data were analyzed with the use of a Cox proportional hazards regression model.

    RESULTS: During 13 y of follow-up, we ascertained 1628 HFs, 3262 MIs, 2039 ischemic strokes, and 405 hemorrhagic strokes in men and 1207 HFs, 1504 MIs, 1561 ischemic strokes, and 294 hemorrhagic strokes in women. There was no statistically significant association between egg consumption and risk of MI or any stroke type in either men or women or HF in women. In men, consumption of ≤6 eggs/wk was not associated with HF risk; however, daily egg consumption (≥1/d) was associated with a 30% higher risk of HF (RR: 1.30; 95% CI: 1.01, 1.67). Egg consumption was not associated with any CVD outcome in individuals with diabetes.

    CONCLUSIONS: Daily egg consumption was not associated with risk of MI or any stroke type in either men or women or with HF in women. Consumption of eggs ≥1 time/d, but not less frequent consumption, was associated with an elevated risk of HF in men.

  • 49.
    Larsson, Susanna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Åkesson, Agneta
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Primary prevention of stroke by a healthy lifestyle in a high-risk group2015In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 84, no 22, p. 2224-2228Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine the impact of a healthy lifestyle on stroke risk in men at higher risk of stroke because of other cardiovascular diseases or conditions.

    METHODS: Our study population comprised 11,450 men in the Cohort of Swedish Men who had a history of hypertension, high cholesterol levels, diabetes, heart failure, or atrial fibrillation. Participants had completed a questionnaire about diet and lifestyle and were free from stroke and ischemic heart disease at baseline (January 1, 1998). We defined a healthy lifestyle as a low-risk diet (≥5 servings/d of fruits and vegetables and <30 g/d of processed meat), not smoking, ≥150 min/wk of physical activity, body mass index of 18.5 to 25 kg/m(2), and low to moderate alcohol consumption (>0 to ≤30 g/d). Ascertainment of stroke cases was accomplished through linkage with the National Inpatient Register and the Swedish Cause of Death Register.

    RESULTS: During a mean follow-up of 9.8 years, we ascertained 1,062 incident stroke cases. The risk of total stroke and stroke types decreased with increasing number of healthy lifestyle factors. The multivariable relative risk of total stroke for men who achieved all 5 healthy lifestyle factors compared with men who achieved 0 or 1 factor was 0.28 (95% confidence interval 0.14-0.55). The corresponding relative risks (95% confidence interval) were 0.31 (0.15-0.66) for ischemic stroke and 0.32 (0.04-2.51) for hemorrhagic stroke.

    CONCLUSIONS: A healthy lifestyle is associated with a substantially reduced risk of stroke in men at higher risk of stroke.

  • 50. Markus, Hugh S
    et al.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kuker, Wilhelm
    Schulz, Ursula G
    Ford, Ian
    Rothwell, Peter M
    Clifton, Andrew
    Stenting for symptomatic vertebral artery stenosis: The Vertebral Artery Ischaemia Stenting Trial.2017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 89, no 12, p. 1229-1236Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To compare in the Vertebral Artery Ischaemia Stenting Trial (VIST) the risks and benefits of vertebral angioplasty and stenting with best medical treatment (BMT) alone for symptomatic vertebral artery stenosis.

    METHODS: VIST was a prospective, randomized, open-blinded endpoint clinical trial performed in 14 hospitals in the United Kingdom. Participants with symptomatic vertebral stenosis ≥50% were randomly assigned (1:1) to vertebral angioplasty/stenting plus BMT or to BMT alone with randomization stratified by site of stenosis (extracranial vs intracranial). Because of slow recruitment and cessation of funding, recruitment was stopped after 182 participants. Follow-up was a minimum of ≥1 year for each participant.

    RESULTS: Three patients did not contribute any follow-up data and were excluded, leaving 91 patients in the stent group and 88 in the medical group. Mean follow-up was 3.5 (interquartile range 2.1-4.7) years. Of 61 patients who were stented, stenosis was extracranial in 48 (78.7%) and intracranial in 13 (21.3%). No periprocedural complications occurred with extracranial stenting; 2 strokes occurred during intracranial stenting. The primary endpoint of fatal or nonfatal stroke occurred in 5 patients in the stent group vs 12 in the medical group (hazard ratio 0.40, 95% confidence interval 0.14-1.13, p = 0.08), with an absolute risk reduction of 25 strokes per 1,000 person-years. The hazard ratio for stroke or TIA was 0.50 (p = 0.05).

    CONCLUSIONS: Stenting in extracranial stenosis appears safe with low complication rates. Large phase 3 trials are required to determine whether stenting reduces stroke risk.

    ISRCTNCOM IDENTIFIER: ISRCTN95212240.

    CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with symptomatic vertebral stenosis, angioplasty with stenting does not reduce the risk of stroke. However, the study lacked the precision to exclude a benefit from stenting.

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