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  • 1. Bergström, Göran
    et al.
    Persson, Margaretha
    Adiels, Martin
    Björnson, Elias
    Bonander, Carl
    Ahlström, Håkan
    Alfredsson, Joakim
    Angerås, Oskar
    Berglund, Göran
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Brandberg, John
    Börjesson, Mats
    Cederlund, Kerstin
    de Faire, Ulf
    Duvernoy, Olov
    Ekblom, Örjan
    Engström, Gunnar
    Engvall, Jan E.
    Fagman, Erika
    Eriksson, Mats
    Erlinge, David
    Fagerberg, Björn
    Flinck, Agneta
    Gonçalves, Isabel
    Hagström, Emil
    Hjelmgren, Ola
    Lind, Lars
    Lindberg, Eva
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Ljungberg, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Magnusson, Martin
    Mannila, Maria
    Markstad, Hanna
    Mohammad, Moman A.
    Nystrom, Fredrik H.
    Ostenfeld, Ellen
    Persson, Anders
    Rosengren, Annika
    Sandström, Anette
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sköld, Magnus C.
    Sundström, Johan
    Swahn, Eva
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Torén, Kjell
    Östgren, Carl Johan
    Jernberg, Tomas
    Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population2021In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 144, no 12, p. 916-929Article in journal (Refereed)
    Abstract [en]

    Background: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population.

    Methods: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data.

    Results: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population.

    Conclusions: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.

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  • 2. Chen, Hao Yu
    et al.
    Cairns, Benjamin J.
    Small, Aeron M.
    Burr, Hannah A.
    Ambikkumar, Athithan
    Martinsson, Andreas
    Thériault, Sébastien
    Munter, Hans Markus
    Steffen, Brian
    Zhang, Richard
    Levinson, Rebecca T.
    Shaffer, Christian M.
    Rong, Jian
    Sonestedt, Emily
    Dufresne, Line
    Ljungberg, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Ranatunga, Dilrini K.
    Whitmer, Rachel A.
    Budoff, Matthew J.
    Nguyen, Albert
    Vasan, Ramachandran S.
    Larson, Martin G.
    Harris, William S.
    Damrauer, Scott M.
    Stark, Ken D.
    Boekholdt, S. Matthijs
    Wareham, Nicholas J.
    Pibarot, Philippe
    Arsenault, Benoit J.
    Mathieu, Patrick
    Gudnason, Vilmundur
    O'Donnell, Christopher J.
    Rotter, Jerome I.
    Tsai, Michael Y.
    Post, Wendy S.
    Clarke, Robert
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Bossé, Yohan
    Wells, Quinn S.
    Smith, J. Gustav
    Rader, Daniel J.
    Lathrop, Mark
    Engert, James C.
    Thanassoulis, George
    Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis2020In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 5, no 6, p. 694-702Article in journal (Refereed)
    Abstract [en]

    Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets.

    Objective: To identify novel genetic loci and pathways associated with AS.

    Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019.

    Exposures: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples.

    Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography.

    Results: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]).

    Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.

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  • 3.
    Hansén, Nike
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ljungberg, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Adipokines are possible risk markers for aortic stenosis requiring surgery2023In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 57, no 1, article id 2247193Article in journal (Refereed)
    Abstract [en]

    Objectives: Aortic stenosis (AS) is the most prevalent valvular heart disease among adults. The adipocyte-derived hormones, leptin and adiponectin, have profound metabolic actions. We examined whether these adipokines are independently associated with future aortic valve replacement (AVR).

    Design: In this longitudinal case-control study, we identified 336 cases who had undergone AVR due to AS, and who had previously participated in population-based health surveys. Two referents were matched to each case and leptin and adiponectin concentrations were analysed from stored baseline survey samples. Uni- and multivariable logistic regression analyses were used to estimate the risk of future AVR. An additional cohort was identified for validation including 106 cases with AVR and 212 matched referents.

    Results: Median age (interquartile range (IQR)) in years at survey was 59.9 (10.4) and at surgery 68.3 (12.7), and 48% were women. An elevated concentration of leptin was not associated with future AVR (odds ratio [95% confidence interval]) (1.10 [0.92–1.32]), although leptin was associated with a higher risk in patients with coronary artery disease (CAD) having more than 5 years between survey and AVR (1.41 [1.08–1.84]). Adiponectin was not associated with higher risk for future AVR (0.95 [0.82–1.11]), although after stratification for age, higher levels were associated with reduced risk for AVR in persons aged ≥60 years at surgery (0.79 [0.64–0.98]). In the validation study, leptin was associated with future AVR whereas adiponectin was not. None of the associations remained significant after adjustment for body mass index (BMI).

    Conclusions: The adipokine leptin may promote the development of AS.

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  • 4.
    Holmgren, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Ljungberg, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Troponin T but not C-reactive protein is associated with future surgery for aortic stenosis: a population based nested case-referent study2020In: Open heart, E-ISSN 2053-3624, Vol. 7, no 2, article id e001325Article in journal (Refereed)
    Abstract [en]

    Aims: High-sensitivity troponin T (hs-TnT) and high-sensitivity C reactive protein (hs-CRP) may convey prognostic information in patients with aortic stenosis (AS). This study evaluated if hs-TnT and hs-CRP associate with myocardial mass, and risk of future surgery for AS.

    Methods: In total, 336 patients (48% women) with surgery for AS with previous participation in large population surveys were identified. Preoperatively, myocardial mass and the presence of coronary artery disease (CAD) were assessed. Two matched referents were allocated for each case, and hs-TnT and hs-CRP were determined in stored plasma from the baseline survey. Conditional logistic regression analysis was used to estimate the risk (OR (95% CI)) related to one (natural logarithm) SD increase in hs-TnT and hs-CRP. Kaplan-Mayer and Cox regression analyses were used to evaluate time to surgery.

    Results: Median age (IQR) was 59.8 (10.3) years at survey, and median time between survey and surgery was 10.9 (9.3) years. Hs-TnT was independently associated with surgery for AS (1.24 (1.06–1.44)) irrespective of CAD, whereas Hs-CRP was not (1.05 (0.90–1.22)). Elevated hs-TnT levels at survey associated with shorter time to surgery (p<0.001), and with increased myocardial mass (p=0.002). Hs-CRP did not associate with time to surgery or with myocardial mass.

    Conclusions: Hs-TnT—but not hs-CRP—was associated with increased risk of—and shorter time to—future surgery for AS. Hs-TnT associated with myocardial mass at surgery which indicates that hs-TnT could be a potential biomarker for determining intervention.

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  • 5.
    Ljungberg, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Cardiovascular risk factors in aortic stenosis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Introduction: Aortic stenosis (AS) is the most common hemodynamic significant valvular heart disease and affects about 2% of the population. The incidence increases with age. When symptoms of the stenotic aortic valve disease eventually occur the 2-year mortality exceeds 50%. Aortic valve replacement (AVR) by surgery or by catheter intervention is the only known treatment. The causes of AS are only partly known, despite that the disease has been known since the beginning of 17th century. In younger individuals, a bicuspid valve is present in about 80% of the cases. The traditional cardiovascular risk-factors for ischemic heart disease have been linked to AS, and the histology of the stenotic aortic valve and the atherosclerotic plaques shares several features such as inflammation, lipid deposition and calcification. High levels of the lipoprotein Lp(a) has been linked to both atherosclerosis and AS, and a causal relation with AS is supported by Mandelian randomisation. End-stage renal disease is associated with increased risk of AS but if early impairment increases the risk is not known.

    Material and methods: We identified 799 patients with surgery for valvular heart disease and/or disease of the ascending aorta with a prior participation in one of three large population based health surveys in northern Sweden (Västerbotten Intervention Program [VIP], MONItoring Of trends and Determinants in CArdivascular Disease survey [MONICA], and the Mammary Screening Project [MSP]). For each case, four referents matched by age, gender, type and date of survey, and geographical area were randomly selected. From the health surveys, data on cardiovascular risk-factors and health history as well as measurements of anthropometry, blood pressure, glucose and cholesterol levels were retrieved. Each case was carefully validated and data from pre- and perioperative assessments were collected. The presence of coronary artery disease (CAD) was determined from the preoperative coronary angiogram. Apolipoproteins B and A1, Lp(a), creatinine and cystatin C were analysed in samples obtained at the initial survey. As this is a matched case-referent study where cases and referents had the same follow-up duration within strata, logistic regression using the conditional maximum likelihood routine designed for matched analysis was used to estimate odds ratios (ORs) with 95% confidence intervals. Studied variables were tested in uni- and multivariable models.

    Results: Paper 1: Of the identified 799 cases with questionnaires, 322 were primarily operated for AS, 91 for aortic regurgitation, 181 for mitral regurgitation, 131 for disease of ascending aorta, 52 for CAD (and for concomitant valvular or aortic disease). The remaining 22 had various indications for valvular heart surgery and were excluded. Altogether 38% of patients were women. Aortic stenosis: Hypertension (OR 1.87 [1.37–2.54]), diabetes (OR 1.78 [1.01–3.11]) and total cholesterol (OR 1.64 [1.07–2.49]) were associated with future AVR. After exclusion of concomitant CAD, none of the these risk-factors remained significant. Aortic regurgitation: None of the cardiovascular risk-factors was associated with increased risk for aortic regurgitation demanding surgery, whereas high levels of cholesterol were associated with reduced risk for surgery (OR 0.29 [0.12–0.71]). Mitral regurgitation: High levels of cholesterol associated with surgery for mitral regurgitation (OR 1.74 [1.01–3.00]), but not in those without CAD. Disease of the ascending aorta: Hypertension (OR 2.42 [1.44–4.06]) and previous smoking (OR 1.97 (1.12–3.49]) related to increased risk for surgery of the ascending aorta, whereas diabetes was inversely associated with surgery (OR 0.09 [0.01–0.73]). Excluding CAD, only diabetes remained protective (OR 0.24 [0.07–0.81]). Paper 2: 322 patients underwent AVR, and 70 had surgery before the age of 60 years and 252 had surgery after 60 years of age. After exclusion of patients with CAD, 49 and 82 patients remained in these age groups. Arterial hypertension associated with future AVR in those operated before the age of 60 years regardless of concomitant CAD or not (OR 3.40 [1.45–7.93] and OR 5.88 [1.46–23.72]). In those older than 60 years at surgery and with concomitant CAD, all traditional cardiovascular risk factors associated with surgery, but in those without concomitant CAD, only impaired fasting glucose (IFG) was associated with surgery (OR 3.22 [1.19–8.76]). Paper 3: 336 patients having surgery for AS. Lipoprotein(a) [Lp(a)] was independently associated with surgery in those with concomitant CAD (OR 1.29 [1.07–1.55]), but not in those without CAD. A high Apo B/A1 ratio was associated with surgery in patients with CAD (OR 1.43 [1.16–1.76]), but not in those without. Paper 4: The same cohort as in paper 3 was examined. Renal function was estimated by the ratio between glomerular filtration rates (eGFR) obtained from cystatin C and creatinine, and a low ratio indicates early impairment of renal function (“shrunken pore syndrome”). A high ratio independently associated with lower risk for future AVR (OR 0.84 [0.73–0.97]). Protective effect was seen in women but not in men (0.74 [0.60–0.92] and 0.93 [0.76 [0.76–1.13], respectively). After stratification for CAD, the association remained significant in women with CAD but not in men with CAD (0.60 [0.44–0.83] and 0.96 [0.76 [0.75–1.23], respectively).

    Conclusion: The traditional cardiovascular risk-factors associated with future surgery for valvular heart disease and for surgery of the ascending aorta, however with a clear difference if there was concomitant CAD or not. Arterial hypertension was a major risk factor for surgery for AS in younger patients without CAD, whereas impaired fasting glucose (IFG) associated with surgery in elderly patients without CAD. High levels of Lp(a) and a high Apo B/A1 ratio were associated with future AVR only in patients with concomitant CAD. Similarly, early renal impairment expressed as low ratio of eGFR by cystatin C and by creatinine (“shrunken pore”) associated with future AVR.

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  • 6.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease2017In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 6, no 12, article id e007160Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Aortic stenosis (AS) has different clinical phenotypes, including AS with or without concomitant coronary artery disease (CAD). It is unknown whether these phenotypes share the same risk factors. In particular, lipoprotein(a) [Lp(a)] and apolipoproteins (Apo) are associated with AS, but it is unknown whether these associations differ among phenotypes. In this prospective analysis we examined the impact of Lp(a) and Apo in subgroups of patients with AS.

    METHODS AND RESULTS: We identified 336 patients (mean age at survey 56.7 years, 48% female) who underwent surgery for AS after a median 10.9 years (interquartile range 9.3 years), participants in 1 of 3 large population surveys. For each patient, 2 matched referents were allocated. Lp(a) and Apo were analyzed in the baseline samples. Uni- and multivariable logistic regression analyses were used to estimate risks related to a 1 (ln) standard deviation increase in Lp(a) and the ratio of Apo B to Apo A1 (Apo B/A1 ratio). High levels of Lp(a) predicted surgery for AS in 203 patients with concomitant CAD (odds ratio [95% confidence intervals]) (1.29 [1.07-1.55]), but not in 132 patients without CAD (1.04 [0.83-1.29]) in the fully adjusted model. Similarly, a high Apo B/A1 ratio predicted surgery in patients with concomitant CAD (1.43 [1.16-1.76]) but not in those without CAD (0.87 [0.69-1.10]).

    CONCLUSIONS: High levels of Lp(a) and a high Apo B/A1 ratio were associated with surgery for AS in patients with concomitant CAD but not in those with isolated AS. This finding may lead to a new avenue of research for targeted risk factor interventions in this population.

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  • 7.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Janiec, Mikael
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Siegbahn, Agneta
    Fall, Tove
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement2018In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 138, no 6Article in journal (Refereed)
    Abstract [en]

    Background: Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights. Methods: Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study. Results: Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease. Conclusions: We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.

  • 8.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mild impairment of renal function (shrunken pore syndrome) is associated with increased risk for future surgery for aortic stenosis2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 7, p. 524-530Article in journal (Refereed)
    Abstract [en]

    Recently, a new approach was proposed to detect mild impairment in renal function: a reduced ratio between estimated glomerular filtration rate (eGFR) calculated by cystatin C and eGFR calculated by creatinine. We aimed to evaluate if this ratio is associated with aortic stenosis (AS) requiring surgery. We identified 336 patients that first participated in population surveys and later underwent surgery for AS (median age [interquartile range] 59.8 [10.3] years at survey and 68.3 [12.7] at surgery, 48% females). For each patient, two matched referents were allocated. Cystatin C and creatinine were determined in stored plasma. eGFR(cystatin C) and eGFR(creatinine) and their ratio were estimated. Conditional logistic regression analyses were used to estimate the risk (odds ratio (OR) with [95% confidence interval (CI)]) related to one (ln) standard deviation increase in the ratio between eGFR(cystatin C) and eGFR(creatinine). A high ratio was associated with lower risk for AS requiring surgery (OR [95% CI]) (OR 0.84 [0.73-0.97]), especially in women (0.74 [0.60-0.92] vs. 0.93 [0.76-1.13] in men). After further stratification for coronary artery disease (CAD), the association remained in women with CAD but not in women without CAD (0.60 [0.44-0.83] and 0.89 [0.65-1.23], respectively). In conclusion, a high ratio between eGFR(cystatin C) and eGFR(creatinine) was associated with lower risk for surgery for AS, especially in women. Mild impairment of renal function is thus associated with future risk for AS requiring surgery.

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  • 9.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Engström, Karl Gunnar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Albertsson, Elin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Holmer, Paul
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Traditional Cardiovascular Risk Factors and Their Relation to Future Surgery for Valvular Heart Disease or Ascending Aortic Disease: A Case-Referent Study2017In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 6, no 5, article id e005133Article in journal (Refereed)
    Abstract [en]

    Background: Risk factors for developing heart valve and ascending aortic disease are based mainly on retrospective data. To elucidate these factors in a prospective manner, we have performed a nested case-referent study using data from large, population-based surveys. Methods and Results: A total of 777 patients operated for heart valve disease or disease of the ascending aorta had previously participated in population-based health surveys in Northern Sweden. Median time (interquartile range) from survey to surgery was 10.5 (9.0) years. Primary indications for surgery were aortic stenosis (41%), aortic regurgitation (12%), mitral regurgitation (23%), and dilatation/dissection of the ascending aorta (17%). For each case, referents were allocated, matched for age, sex, and geographical area. In multivariable models, surgery for aortic stenosis was predicted by hypertension, high cholesterol levels, diabetes mellitus, and active smoking. Surgery for aortic regurgitation was associated with a low cholesterol level, whereas a high cholesterol level predicted surgery for mitral regurgitation. Hypertension, blood pressure, and previous smoking predicted surgery for disease of the ascending aorta whereas diabetes mellitus was associated with reduced risk. After exclusion of cases with coronary atherosclerosis, only the inverse associations between cholesterol and aortic regurgitation and between diabetes mellitus and disease of the ascending aorta remained. Conclusions: This is the first truly prospective study of traditional cardiovascular risk factors and their association with valvular heart disease and disease of the ascending aorta. We confirm the strong association between traditional risk factors and aortic stenosis, but only in patients with concomitant coronary artery disease. In isolated valvular heart disease, the impact of traditional risk factors is varying.

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  • 10.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Engström, Karl Gunnar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Arterial hypertension and diastolic blood pressure associate with aortic stenosis2019In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 53, no 2, p. 91-97Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Due to age-related differences in aortic valve structure, it is likely that the pathophysiology of aortic stenosis (AS) and associated risk factors differ between age groups. Here we prospectively studied the influence of traditional cardiovascular risk factors on AS development requiring surgery among patients without concomitant coronary artery disease (CAD) and stratified for age.

    DESIGN: This study included 322 patients, who had prior to surgery for AS participated in population-based surveys, and 131 of them had no visible CAD upon preoperative coronary angiogram. For each case, we selected four referents matched for age, gender, and geographic area. To identify predictors for surgery, we used multivariable conditional logistic regression with a model including arterial hypertension (or measured blood pressure and antihypertensive medication), cholesterol levels, diabetes, body mass index (BMI), and smoking.

    RESULTS: In patients without CAD, future surgery for AS was associated with arterial hypertension and elevated levels of diastolic blood pressure in patients younger than 60 years at surgery (odds ratio [95% confidence interval]), (3.40 [1.45-7.93] and 1.60 [1.09-2.37], respectively), and with only impaired fasting glucose tolerance in patients 60 years or older at surgery (3.22 [1.19-8.76]).

    CONCLUSION: Arterial hypertension and elevated diastolic blood pressure are associated with a risk for AS requiring surgery in subjects below 60 years of age. Strict blood pressure control in this group is strongly advocated to avoid other cardiovascular diseases correlated to hypertension. If hypertension and elevated diastolic blood pressure are risk factors for developing AS requiring surgery need further investigations. Notably, elevated fasting glucose levels were related to AS requiring surgery in older adults without concomitant CAD.

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  • 11.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Engström, Karl Gunnar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Arterial hypertension and elevated diastolic blood pressure is associated with developing aortic stenosis requiring surgery in persons less than 60 years of ageManuscript (preprint) (Other academic)
    Abstract [en]

    Background:  Due to age-related differences in aortic valve structure, it is likely that the pathophysiology of aortic stenosis and associated risk factors differ between age groups. Here we prospectively studied the influence of traditional cardiovascular risk factors on aortic stenosis development among patients without concomitant coronary artery disease, and stratified for age. 

    Methods: This study included 131 patients from previous population-based surveys, who underwent surgery for aortic stenosis and had no visible coronary arteriosclerosis upon preoperative coronary angiogram. The younger group included 49 patients of <60 years old at surgery: median age, 54.4 years; median follow-up, 8.7 years. The older group included 82 patients of ≥60 years old at surgery: median age, 71.3 years; median follow-up, 11.0 years. For each case, we selected four referents matched for age, gender, and geographic area. To identify predictors for surgery, we used multivariable conditional logistic regression with a model including arterial hypertension, cholesterol levels, diabetes, BMI, and smoking. 

    Results:  Future surgery for aortic stenosis was associated with arterial hypertension and elevated levels of diastolic blood pressure in the younger group (odds ratio, 3.40; 95% confidence interval, 1.45–7.93, and odds ratio 1,60; 95% confidence interval, 1.09–2.37, respectively), and with only impaired fasting glucose tolerance in the older group (odds ratio, 3.22; 95% confidence interval, 1.19–8.76). 

    Conclusion: Arterial hypertension and elevated diastolic blood pressure are associated with a risk for aortic stenosis development in subjects below 60 years of age. Strict blood pressure control in this group are strongly advocated to avoid other cardiovascular diseases correlated to hypertension. If hypertension and elevated diastolic blood pressure are risk for developing aortic stenosis need further investigations. Notably, elevated fasting glucose levels were related to aortic stenosis in older adults without concomitant coronary artery disease. 

  • 12.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Early impairment of renal function (shrunken pore syndrome) is associated with increased risk for future surgery for aortic stenosisManuscript (preprint) (Other academic)
    Abstract [en]

    Introduction 

    Renal insufficiency is a known risk factor for cardiovascular disease. However, it is unknown if early impairment in renal function is associated with increased risk for aortic stenosis (AS). Recently a new approach was proposed to detect early impairment in renal function by using the ratio between glomerular filtration rate (GFR) calculated by cystatin C and GFR calculated by creatinine. 

    Purpose 

    To evaluate if the ratio between GFR cystatin C and GFR creatinine is associated with increased risk for AS requiring surgery and further, to evaluate if the ratio associates with survival. 

    Methods 

    We identified 334 patients that underwent surgery for AS after participation in population surveys (median age (interquartile range) 59.4 (10.3) years at survey and 68.3 (12.7) at surgery, 48% females). For each patient, two matched referents were allocated. Circulating levels of cystatin C and creatinine were determined at baseline (survey). Estimated glomerular filtration rates (eGFR) were calculated using the CAPA and Lund-Malmö-Revised formulas. Uni- and multivariable conditional logistic regression analyses were used to estimate the risk (odds ratio (OR) with [95% confidence interval]) related to one (ln) standard deviation increase in cystatin C, creatinine, eGFR cystatin C, eGFR creatinine, and in the ratio between eGFR cystatin C and eGFR creatinine, respectively. 

    Results 

    A high ratio was associated with lower risk for AS requiring surgery (OR 0.84 [0.73–0.97]). After stratification for sex, this effect was seen in women but not in men (0.74 [0.60–0.92] and 0.93 [0.76 [0.76–1.13], respectively). After further stratification for CAD, the association remained in women with CAD, but the effect was not seen in men with CAD (0.60 [0.44–0.83] and 0.96 [0.76 [0.75–1.23]). A high ratio was associated with longer survival in the entire cohort (HR 0.84 [0.75–0.95]). 

    Conclusion 

    A high ratio between eGFR based on cystatin C and eGFR based on creatinine was associated with lower risk for surgery for AS in those with CAD with a clear sex-difference. Early renal impairment is thus associated with future risk for AS requiring surgery. Further, a high ratio relates to longer survival. 

  • 13.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Prospective analysis of risk factors for valvular heart disease and disease of the ascending aorta: a nested population based case-control study2016In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 37, p. 796-796Article in journal (Other academic)
  • 14.
    Skoglund Larsson, Linn
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Ljungberg, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Brunström, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Survival after surgery of the ascending aorta: a matched cohort study2022In: European Journal of Cardio-Thoracic Surgery, ISSN 1010-7940, E-ISSN 1873-734X, Vol. 62, no 3Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Surgery of ascending aortic aneurysms is performed prophylactically or acute. The expected survival after surgery is uncertain. The goal of this study was to compare mortality in people with aortic surgery with matched controls.

    METHODS: All patients undergoing ascending aortic surgery at Umeå University Hospital from 1988 to 2012, who previously participated in 1 of 3 population-based health surveys, were matched to 2 randomly selected controls from the same health survey and followed until death or until censoring on 24 August 2017, whichever came first. Mortality was calculated using the Kaplan-Meier method and the log-rank test. Cox regression analyses were made for all-cause mortality, adjusted for traditional cardiovascular risk factors. Deaths during the first 90 days after surgery and at >90 days postoperatively were studied separately.

    RESULTS: The median follow-up time was 9.2 years. A total of 61 of 189 patients and 51 of 370 controls died [hazard ratio (HR) 2.77, 95% confidence interval (CI) 1.91-4.01]. Mortality was increased during the first 90 days post-surgery (HR 43.4, 95% CI 5.83-323), as well as after the first 90 days (HR 1.90, 95% CI 1.25-2.88) and after acute surgery (HR 6.05, 95% CI 2.92-12.56) as well as after elective surgery (HR 2.10, 95% CI 1.35-3.27). Among 57 surgical patients with information about cause of death, 23 (40%) died of aortic disease.

    CONCLUSIONS: During follow-up, more patients died than matched controls. Findings were consistent when adjusting for traditional cardiovascular risk factors and across subgroups. Both short-term and long-term postoperative deaths were increased as well.

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  • 15.
    Söderberg, Stefan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ljungberg, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Troponin T but not C-reactive protein is associated with myocardial mass and risk for, and time to future surgery for aortic stenosis: a population-based study2020In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 41, p. 1884-1884Article in journal (Other academic)
  • 16.
    Yu Chen, Hao
    et al.
    Division of Experimental Medicine, McGill University, Montreal, Canada; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Room D05.5120, 1001 Decarie Blvd., QC, Montreal, Canada.
    Dina, Christian
    CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F, France.
    Small, Aeron M.
    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
    Shaffer, Christian M.
    Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, USA.
    Levinson, Rebecca T.
    Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, USA.
    Helgadóttir, Anna
    deCODE genetics/Amgen Inc., Reykjavik, Iceland.
    Capoulade, Romain
    CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F, France.
    Munter, Hans Markus
    McGill University and Genome Quebec Innovation Centre, Montreal, Canada.
    Martinsson, Andreas
    Department of Cardiology, Clinical Sciences, Lund University, Sweden; Skåne University Hospital, Lund, Sweden; Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Cairns, Benjamin J.
    MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
    Trudsø, Linea C.
    Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Hoekstra, Mary
    Division of Experimental Medicine, McGill University, Room EM1.2218, 1001 Decarie Blvd., QC, Montreal, Canada; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada.
    Burr, Hannah A.
    Division of Experimental Medicine, McGill University, Room EM1.2218, 1001 Decarie Blvd., QC, Montreal, Canada; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada.
    Marsh, Thomas W.
    Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Room D05.5120, 1001 Decarie Blvd., QC, Montreal, Canada; Department of Human Genetics, McGill University, Montreal, Canada.
    Damrauer, Scott M.
    Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
    Dufresne, Line
    Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada.
    Le Scouarnec, Solena
    CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F, France.
    Messika-Zeitoun, David
    Department of Cardiology, Bichat Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; Division of Cardiology, University of Ottawa Heart Institute, ON, Ottawa, Canada.
    Ranatunga, Dilrini K.
    Division of Research, Kaiser Permanente of Northern California, Oakland, USA.
    Whitmer, Rachel A.
    Department of Public Health Sciences, University of California Davis, Davis, USA.
    Bonnefond, Amélie
    University Lille, Inserm, CNRS, Institut Pasteur de Lille, CHU Lille, Lille, France; Department of Metabolism, Imperial College London, London, UK.
    Sveinbjornsson, Garðar
    deCODE genetics/Amgen Inc., Reykjavik, Iceland.
    Daníelsen, Ragnar
    Internal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
    Arnar, David O.
    deCODE genetics/Amgen Inc., Reykjavik, Iceland; Internal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland; School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
    Thorgeirsson, Gudmundur
    deCODE genetics/Amgen Inc., Reykjavik, Iceland; School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
    Thorsteinsdottir, Unnur
    deCODE genetics/Amgen Inc., Reykjavik, Iceland; School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
    Gudbjartsson, Daníel F
    deCODE genetics/Amgen Inc., Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
    Hólm, Hilma
    deCODE genetics/Amgen Inc., Reykjavik, Iceland.
    Ghouse, Jonas
    Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Olesen, Morten Salling
    Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Christensen, Alex H.
    Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen, Denmark.
    Mikkelsen, Susan
    Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
    Jacobsen, Rikke Louise
    Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Dowsett, Joseph
    Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Pedersen, Ole Birger Vesterager
    Department of Clinical Immunology, Zealand University Hospital, Naestved, Denmark.
    Erikstrup, Christian
    Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
    Ostrowski, Sisse R.
    Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
    O'Donnell, Christopher J.
    National Heart, Lung, Blood Institute's and Boston University's Framingham Heart Study, Boston, USA.
    Budoff, Matthew J.
    Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, USA.
    Gudnason, Vilmundur
    Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
    Post, Wendy S.
    Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA.
    Rotter, Jerome I.
    Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, USA.
    Lathrop, Mark
    McGill University and Genome Quebec Innovation Centre, Montreal, Canada; Department of Human Genetics, McGill University, Montreal, Canada.
    Bundgaard, Henning
    Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ljungberg, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Le Tourneau, Thierry
    CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F, France.
    Smith, J Gustav
    Department of Cardiology, Clinical Sciences, Lund University, Sweden and Skåne University Hospital, Lund, Sweden; Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University and the Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Wallenberg Center for Molecular Medicine and Lund University Diabetes Center, Lund, Sweden.
    Wells, Quinn S.
    Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, USA.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Stefánsson, Kári
    deCODE genetics/Amgen Inc., Reykjavik, Iceland; School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
    Schott, Jean-Jacques
    CHU Nantes, CNRS, INSERM, l'institut du thorax, 8 Quai Moncousu, Nantes F, France.
    Rader, Daniel J.
    Departments of Genetics and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
    Clarke, Robert
    MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
    Engert, James C.
    Division of Experimental Medicine, McGill University, Montreal, Canada; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Room D05.5120, 1001 Decarie Blvd., QC, Montreal, Canada; Department of Human Genetics, McGill University, Montreal, Canada.
    Thanassoulis, George
    Division of Experimental Medicine, McGill University, Montreal, Canada; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Room D05.5120, 1001 Decarie Blvd., QC, Montreal, Canada.
    Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study2023In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 44, no 21, p. 1927-1939Article in journal (Refereed)
    Abstract [en]

    AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

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