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1. Albuminuria Testing in Hypertension and Diabetes

Author: Jung-Im Shin, Alex R. Chang, Morgan E. Grams, Josef Coresh, Shoshana H. Ballew, Aditya Surapaneni, Kunihiro Matsushita, Henk J.G. Bilo, Juan J. Carrero, Gabriel Chodick, Kenn B. Daratha, Simerjot K. Jassal, Girish N. Nadkarni, Robert G. Nelson, Christoph Nowak, Nikita Stempniewicz, Keiichi Sumida, Jamie P. Traynor, Mark Woodward, Yingying Sang, Ron T. Gansevoort, John Chalmers, Katherine Tuttle, Radica Alicic, Sterling McPherson, Cami Jones, Gurmukteshwar Singh, Jamie Green, H. Lester Kirchner, Varda Shalev, Erwin P. Bottinger, Ruth J.F. Loos, Stephen B. Ellis, John Cuddeback, Elizabeth Ciemins, Emily Carbonara, Stephan Dunning, William C. Knowler, Helen C. Looker, Lyane M. Kieneker, Stephan J.L. Bakker, Hans L. Hillege, Pim van der Harst, Jacklyn Bergstrom, Joachim Ix, Csaba P. Kovesdy, Praveen Potukuchi, Marco Trevisan, Carl Gustaf Elinder, Björn Wettermark, Johan Ärnlöv, Patrick B. Mark, Peter C. Thomson, Colin C. Geddes, Gijs W.D. Landman, Kornelis J.J. van Hateren, Nanne Kleefstra, Orlando Gutierrez, Tsuneo Konta, Andrew S. Levey, Kevan Polkinghorne, Elke Schäffner, Jingsha Chen, Aditya Surapeneni, Groningen Kidney Center (GKC), and Cardiovascular Centre (CVC)
Subjects: Adult, medicine.medical_specialty, Article, Diabetes mellitus, Internal medicine, Internal Medicine, Diabetes Mellitus, Medicine, Albuminuria, Humans, Renal Insufficiency, Chronic, Aged, business.industry, Incidence (epidemiology), Odds ratio, Middle Aged, medicine.disease, Blood pressure, Meta-analysis, Creatinine, Cohort, Hypertension, medicine.symptom, business, Kidney disease, Glomerular Filtration Rate
Abstract: Albuminuria is an under-recognized component of chronic kidney disease definition, staging, and prognosis. Guidelines, particularly for hypertension, conflict on recommendations for urine albumin-to-creatinine ratio (ACR) measurement. Separately among 1 344 594 adults with diabetes and 2 334 461 nondiabetic adults with hypertension from the chronic kidney disease Prognosis Consortium, we assessed ACR testing, estimated the prevalence and incidence of ACR ≥30 mg/g and developed risk models for ACR ≥30 mg/g. The ACR screening rate (cohort range) was 35.1% (12.3%–74.5%) in diabetes and 4.1% (1.3%–20.7%) in hypertension. Screening was largely unrelated to the predicted risk of prevalent albuminuria. The median prevalence of ACR ≥30 mg/g across cohorts was 32.1% in diabetes and 21.8% in hypertension. Higher systolic blood pressure was associated with a higher prevalence of albuminuria (odds ratio [95% CI] per 20 mm Hg in diabetes, 1.50 [1.42–1.60]; in hypertension, 1.36 [1.28–1.45]). The ratio of undetected (due to lack of screening) to detected ACR ≥30 mg/g was estimated at 1.8 in diabetes and 19.5 in hypertension. Among those with ACR
Published: 2021

2. Plasma Protein Profile of Carotid Artery Atherosclerosis and Atherosclerotic Outcomes

Author: Elena Tremoli, Pär Hedberg, Tobias Feldreich, Bruna Gigante, Marju Orho-Melander, Jerzy Leppert, Lars Lind, Anders Hamsten, Johan Sundström, Carl Johan Östgren, Anders Mälarstig, Fabrizio Veglia, Christopher J. O'Donnell, Nora Franceschini, Fredrik H. Nystrom, Gunnar Engström, Johan Ärnlöv, Olle Melander, Yan Borné, Jan Nilsson, and Damiano Baldassarre
Subjects: Carotid Artery Diseases, Male, Proteomics, medicine.medical_specialty, Proteome, medicine.drug_class, Carotid Intima-Media Thickness, Risk Assessment, Risk Factors, Matrix Metalloproteinase 12, medicine.artery, Internal medicine, Mendelian randomization, medicine, Natriuretic peptide, Humans, Cardiac and Cardiovascular Systems, cardiovascular diseases, Common carotid artery, Myocardial infarction, Receptor, Aged, Sweden, Kardiologi, business.industry, Incidence, Genetic Variation, Mendelian Randomization Analysis, Blood Proteins, Middle Aged, Prognosis, medicine.disease, Blood proteins, Plaque, Atherosclerotic, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers, Lipoprotein
Abstract: Objective: To identify causal pathophysiological mechanisms for atherosclerosis and incident cardiovascular events using protein measurements. Approach and Results: Carotid artery atherosclerosis was assessed by ultrasound, and 86 cardiovascular-related proteins were measured using the Olink CVD-I panel in 7 Swedish prospective studies (11 754 individuals). The proteins were analyzed in relation to intima-media thickness in the common carotid artery (IMT-CCA), plaque occurrence, and incident cardiovascular events (composite end point of myocardial infarction or ischemic stroke) using a discovery/replication approach in different studies. After adjustments for traditional cardiovascular risk factors, 11 proteins remained significantly associated with IMT-CCA in the replication stage, whereas 9 proteins were replicated for plaque occurrence and 17 proteins for incident cardiovascular events. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and MMP (matrix metalloproteinase)-12 were associated with both IMT-CCA and incident events, but the overlap was considerably larger between plaque occurrence and incident events, including MMP-12, TIM-1 (T-cell immunoglobulin and mucin domain 1), GDF (growth/differentiation factor)-15, IL (interleukin)-6, U-PAR (urokinase plasminogen activator surface receptor), LOX-1 (lectin-like oxidized LDL [low-density lipoprotein] receptor 1), and TRAIL-R2 (TNF [tumor necrosis factor]-related apoptosis-inducing ligand receptor 2). Only MMP-12 was associated with IMT-CCA, plaque, and incident events with a positive and concordant direction of effect. However, a 2-sample Mendelian randomization analysis suggested that increased MMP-12 may be protective against ischemic stroke ( P =5.5×10 −7 ), which is in the opposite direction of the observational analyses. Conclusions: The present meta-analysis discovered several proteins related to carotid atherosclerosis that partly differed in their association with IMT-CCA, plaque, and incident atherosclerotic disease. Mendelian randomization analysis for the top finding, MMP-12, suggests that the increased levels of MMP-12 could be a consequence of atherosclerotic burden rather than the opposite chain of events.
Published: 2021

3. The relevance of geriatric assessments on the association between chronic kidney disease stages and mortality among older people

Author: Andrea, Corsonello, Luca, Soraci, Johan, Ärnlöv, Axel C, Carlsson, Regina, Roller-Wirnsberger, Gerhard, Wirnsberger, Francesco, Mattace-Raso, Lisanne, Tap, Francesc, Formiga, Rafael, Moreno-González, Tomasz, Kostka, Agnieszka, Guligowska, Rada, Artzi-Medvedik, Itshak, Melzer, Christian, Weingart, Cornell, Sieber, Fabrizia, Lattanzio, Tobias, Feldreich, and Internal Medicine
Subjects: Aging, glomerulus filtration rate, estimated glomerular filtration rate, very elderly, mortality rate, Persones grans, Cohort Studies, cognitive defect, Activities of Daily Living, eGFR, Renal Insufficiency, Prospective Studies, Chronic, Kidney diseases, Hand Strength, clinical trial, General Medicine, chronic kidney failure, cohort analysis, mild renal impairment, female, moderate renal impairment, prospective study, Glomerular Filtration Rate, ADL disability, albumin to creatinine ratio, Geriatrik, short physical performance battery, complication, malnutrition, Article, male, Mortalitat, Albuminuria, Humans, human, Renal Insufficiency, Chronic, Mortality, Geriatric Assessment, Aged, ACR, physical performance, daily life activity, major clinical study, multicenter study, disability, Geriatrics, grip strength, Malalties del ronyó, prognosis, Geriatrics and Gerontology, Older people, Geriatria
Abstract: Background age-adapted definition of chronic kidney disease (CKD) does not take individual risk factors into account. We aimed at investigating whether functional impairments influence CKD stage at which mortality increases among older people. Methods our series consisted of 2,372 outpatients aged 75 years or more enrolled in a multicentre international prospective cohort study. The study outcome was 24-month mortality. Kidney function was assessed by estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). Geriatric assessments included handgrip strength, short physical performance battery (SPPB), cognitive impairment, dependency in basic activities of daily living (BADL) and risk of malnutrition. Analysis was carried out by Cox regression, before and after stratification by individual functional impairments. Survival trees including kidney function and functional impairments were also investigated, and their predictivity assessed by C-index. Results overall, mortality was found to increase starting from eGFR = 30–44.9 ml/min/1.73 m2 (hazard ratio [HR] = 3.28, 95% confidence interval [CI] = 1.81–5.95) to ACR = 30–300 mg/g (HR = 1.96, 95%CI = 1.23–3.10). However, in survival trees, an increased risk of mortality was observed among patients with impaired handgrip and eGFR = 45–59.9 ml/min/1.73 m2, as well as patients with ACR Conclusions physical performance helps to identify a proportion of patients at an increased risk of mortality despite a mild–moderate impairment in kidney function and improves predictive accuracy of individual measures of kidney function.
Published: 2022

4. A longitudinal study over 40 years to study the metabolic syndrome as a risk factor for cardiovascular diseases

Author: Johan Ärnlöv, Lars Lind, Johan Sundström, Ulf Risérus, and Erik Lampa
Subjects: Adult, Male, medicine.medical_specialty, Longitudinal study, Epidemiology, Science, Myocardial Infarction, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Article, Healthy Aging, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genetics research, Prevalence, medicine, Humans, Cardiac and Cardiovascular Systems, Longitudinal Studies, Myocardial infarction, Risk factor, Aged, Ischemic Stroke, Aged, 80 and over, Heart Failure, Metabolic Syndrome, Multidisciplinary, Kardiologi, business.industry, Incidence, Cardiometabolic Risk Factors, Middle Aged, medicine.disease, Stroke, Risk factors, Ageing, Relative risk, Heart failure, Medicine, Observational study, Metabolic syndrome, business, Follow-Up Studies
Abstract: The impact of most, but not all, cardiovascular risk factors decline by age. We investigated how the metabolic syndrome (MetS) was related to cardiovascular disease (CVD) during 40 years follow-up in the Uppsala Longitudinal Study of Adult Men (ULSAM, 2,123 men all aged 50 at baseline with reinvestigations at age 60, 70, 77 and 82). The strength of MetS as a risk factor of incident combined end-point of three outcomes (CVD) declined with ageing, as well as for myocardial infarction, ischemic stroke and heart failure when analysed separately. For CVD, the risk ratio declined from 2.77 (95% CI 1.90–4.05) at age 50 to 1.30 (95% CI 1.05–1.60) at age 82. In conclusion, the strength of MetS as a risk factor of incident CVD declined with age. Since MetS was significantly related to incident CVD also at old age, our findings suggest that the occurrence of MetS in the elderly should not be regarded as innocent. However, since our data were derived in an observational study, any impact of MetS in the elderly needs to be verified in a randomized clinical intervention trial.
Published: 2021

5. Diabetes, sarcopenia and chronic kidney disease; the Screening for CKD among Older People across Europe (SCOPE) study

Author: Francesc, Formiga, Rafael, Moreno-González, Andrea, Corsonello, Axel, Carlsson, Johan, Ärnlöv, Francesco, Mattace-Raso, Tomasz, Kostka, Christian, Weingart, Regina, Roller-Wirnsberger, Lisanne, Tap, Agnieszka, Guligowska, Cornel, Sieber, Gerhard, Wirnsberger, Rada, Artzi-Medvedik, Ilan, Yehoshua, Cinzia, Giuli, Fabrizia, Lattanzio, Xavier, Corbella, Paul E, Stevens, Internal Medicine, Medical Informatics, ACS - Pulmonary hypertension & thrombosis, APH - Aging & Later Life, APH - Quality of Care, and APH - Global Health
Subjects: Male, Renal failure, Sarcopenia, Hand Strength, Diabetes, Cross-Sectional Studies, Elderly, SDG 3 - Good Health and Well-being, Chronic kidney disease, Diabetes Mellitus, Humans, Female, Prospective Studies, Renal Insufficiency, Chronic, Geriatrics and Gerontology, human activities, Aged
Abstract: Background Sarcopenia may be more present in older adults with diabetes (DM). Accordingly, we evaluated the prevalence of sarcopenia and its associated risk factors among community-dwelling older adults with DM. Methods A cross-sectional analysis of older people living in the community was carried out. Participants (aged 75 years and more) came from an European multicenter prospective cohort (SCOPE study). Global geriatric assessment including short physical performance battery, handgrip strength test and bioelectrical impedance analysis was performed. Sarcopenia was defined by the updated criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2). Estimated glomerular filtration rate (eGFR) was calculated using Berlin Initiative Study (BIS) to define the stages of chronic kidney disease (CKD). Previous known DM was defined as physician-diagnosed DM registered in the patient's medical record or the use of DM-related medications. Hemoglobin A1c levels and specific DM therapies administered were collected. Time elapsed from the first diagnosis of DM was not collected and, therefore, was not included in the analyses. Results A total of 1,420 subjects were evaluated with a median age of 79.0 (6.0) years, of which 804 (56.6%) were women and 615 (43.3%) men; 315 (22.2%) participants had prior DM diagnosis, with a median age of 80.0 (6.0), 146 (46.3%) were women. Using EWGSOP2 definition, 150 (10.6%) participants in the SCOPE study met diagnostic criteria for sarcopenia. Participants without diabetes had more often normal results in the 3 sarcopenia components than participants with diabetes [887 (80.31%) vs. 227 (72.1%), p = 0.002], highlighting higher percentages of severe sarcopenia in participants with diabetes [27 (8.6%) vs. 58 (5.2%), p = 0.028]. Confirmed or severe sarcopenia was detected in 41 (13%) participants with diabetes and 109 (9.8%) participants without diabetes (p = 0.108). According to BIS equation, sarcopenia was not significantly more prevalent in the more advanced stages of CKD (p = 0.845). In multivariate analyses, older age (odds ratios [OR], 1.17; 95% confidence interval [CI], 1.08–1.27), and lower body mass index (OR, 0.79; 95% CI, 0.71–0.89 were associated with the presence of sarcopenia. Conclusions One tenth of all older community-dwelling subjects have sarcopenia. Older age and being thinner, but not worse renal function, were associated with higher prevalence of sarcopenia in older older adults with diabetes.
Published: 2022

6. Targeted multiplex proteomics for prediction of all-cause mortality during long-term follow-up in outpatients with peripheral arterial disease

Author: Philippe Wagner, Emma Skau, Johan Ärnlöv, Jerzy Leppert, Pär Hedberg, and Egil Henriksen
Subjects: Male, Proteomics, 0301 basic medicine, Oncology, medicine.medical_specialty, Population, 030204 cardiovascular system & hematology, Risk Assessment, Peripheral Arterial Disease, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Outpatients, medicine, Humans, education, Aged, education.field_of_study, Framingham Risk Score, Receiver operating characteristic, business.industry, Proportional hazards model, Blood proteins, Confidence interval, 030104 developmental biology, Cohort, Female, GDF15, Cardiology and Cardiovascular Medicine, business, Biomarkers, Follow-Up Studies
Abstract: Background and aims Patients with peripheral arterial disease (PAD) are at high risk for fatal events. We aimed to investigate the ability among several serum proteins to predict all-cause mortality in outpatients with PAD. Methods Consecutive outpatients with carotid and/or lower extremity PAD were included in the discovery cohort (n = 436), and subjects with PAD from a population-based sample in the validation cohort (n = 129). Blood samples were analyzed for 81 proteins by a proximity extension assay. The proteins best predicting incident all-cause mortality were identified using L1-regularized Cox regression. The added value of the identified proteins to clinical risk markers was evaluated by Cox regression models and presented by the area under the receiver operator characteristics curves (AUC). Results In the discovery cohort (mean age 70 years; 59% men), 195 died (4.8 events per 100 person-years) during a 10.3 years median follow-up. The clinical risk markers generated an AUC of 0.70 (95% confidence interval [95%CI] 0.65–0.76). The two serum protein biomarkers with best prediction of all-cause mortality were growth differentiation factor 15 and tumor necrosis factor-related apoptosis-inducing ligand receptor 2. Adding these proteins to the clinical risk markers significantly improved prediction (p Conclusions In a large-sample targeted proteomics assay, we identified two proteins that improved risk prediction beyond the COPART risk score. The use of high-throughput proteomics assays may identify potential biomarkers for improved risk prediction in patients with PAD.
Published: 2020

7. Plant-based diets, insulin sensitivity and inflammation in elderly men with chronic kidney disease

Author: Ailema González-Ortiz, Tommy Cederholm, Ángeles Espinosa-Cuevas, Carla Maria Avesani, Ulf Risérus, Bengt Lindholm, Hong Xu, Juan Jesus Carrero, and Johan Ärnlöv
Subjects: Male, Nephrology, Protein-energy wasting, medicine.medical_specialty, Potasssium, Renal function, Disease, Vegetable, Lower risk, Gastroenterology, Internal medicine, Diabetes mellitus, Urologi och njurmedicin, Restriction, medicine, Animals, Humans, Urology and Nephrology, Renal Insufficiency, Chronic, Aged, Inflammation, business.industry, Diet, Vegetarian, Malnutrition, Klinisk medicin, Glucose clamp technique, medicine.disease, Cross-Sectional Studies, Fruit, Original Article, Insulin Resistance, Clinical Medicine, business, Glomerular Filtration Rate, Kidney disease
Abstract: Background In persons with CKD, adherence to plant-based diets is associated with lower risk of CKD progression and death, but underlying mechanisms are poorly characterized. We here explore associations between adherence to plant-based diets and measures of insulin sensitivity and inflammation in men with CKD stages 3–5. Methods Cross-sectional study including 418 men free from diabetes, aged 70–71 years and with cystatin-C estimated glomerular filtration rate (eGFR) 2 and not receiving kidney-specific dietetic advice. Information from 7-day food records was used to evaluate the adherence to a plant-based diet index (PBDi), which scores positively the intake of plant-foods and negatively animal-foods. Insulin sensitivity and glucose disposal rate were assessed with the gold-standard hyperinsulinemic euglycemic glucose clamp technique. Inflammation was evaluated by serum concentrations of C-reactive protein (CRP) and interleukin (IL)-6. Associations were explored through linear regression and restricted cubic splines. Results The majority of men had CKD stage 3a. Hypertension and cardiovascular disease were the most common comorbidities. The median PBDi was 38 (range 14–55). Across higher quintiles of PBDi (i.e. higher adherence), participants were less often smokers, consumed less alcohol, had lower BMI and higher eGFR (P for trend Conclusion In elderly men with non-dialysis CKD stages 3–5, adherence to a plant-based diet was associated with higher insulin sensitivity and lower inflammation, supporting a possible role of plant-based diets in the prevention of metabolic complications of CKD. Graphic abstract
Published: 2020

8. The plasma protein profile and cardiovascular risk differ between intima-media thickness of the common carotid artery and the bulb: A meta-analysis and a longitudinal evaluation

Author: Gunnar Engström, Johan Ärnlöv, Fabrizio Veglia, Marju Orho-Melander, Lars Lind, Anders Mälarstig, Bruna Gigante, Johan Sundström, Elena Tremoli, Jan Nilsson, Anders Hamsten, Yan Borné, Erik Ingelsson, Olle Melander, and Damiano Baldassarre
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Carotid Artery, Common, medicine.drug_class, 030204 cardiovascular system & hematology, Carotid Intima-Media Thickness, 03 medical and health sciences, 0302 clinical medicine, Osteoprotegerin, Internal medicine, medicine.artery, medicine, Natriuretic peptide, Humans, Longitudinal Studies, cardiovascular diseases, Common carotid artery, Myocardial infarction, Stroke, Aged, Sweden, business.industry, Incidence, Blood Proteins, Middle Aged, musculoskeletal system, medicine.disease, Blood proteins, 030104 developmental biology, Intima-media thickness, Cardiovascular Diseases, Meta-analysis, cardiovascular system, Cardiology, Intercellular Signaling Peptides and Proteins, Female, Cardiology and Cardiovascular Medicine, business, tissues
Abstract: Genetic loci associated with CHD show different relationships with intima-media thickness in the common carotid artery (IMT-CCA) and in the bulb (IMT-bulb). We evaluated if IMT-CCA and IMT-bulb differ also with respect to circulating protein profiles and risk of incident atherosclerotic disease.In three Swedish cohorts (MDC, IMPROVE, PIVUS, total n 7000), IMT-CCA and IMT-bulb were assessed by ultrasound at baseline, and 86 cardiovascular-related proteins were analyzed. In the PIVUS study only, IMT-CCA and IMT-bulb were investigated in relation to incident atherosclerotic disease over 10 years of follow-up.In a meta-analysis of the analysis performed separately in the cohorts, three proteins, matrix metalloproteinase-12 (MMP-12), hepatocyte growth factor (HGF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), were associated with IMT-CCA when adjusted for traditional cardiovascular risk factors. Five proteins were associated with IMT-bulb (MMP-12, growth/differentiation factor 15 (GDF-15), osteoprotegerin, growth hormone and renin). Following adjustment for cardiovascular risk factors, IMT-bulb was significantly more closely related to incident stroke or myocardial infarction (total number of cases, 111) than IMT-CCA in the PIVUS study (HR 1.51 for 1 SD, 95%CI 1.21-1.87, p 0.001 vs HR 1.17, 95%CI 0.93-1.47, p = 0.16). MMP-12 levels were related to this combined end-point (HR 1.30, 95%CI 1.08-1.56, p = 0.0061).Elevated levels of MMP-12 were associated with both IMT-CCA and IMT-bulb, but other proteins were significantly related to IMT in only one of these locations. The finding that IMT-bulb was more closely related to incident atherosclerotic disease than IMT-CCA emphasizes a difference between these measurements of IMT.
Published: 2020

9. Endostatin predicts mortality in patients with acute dyspnea – A cohort study of patients seeking care in emergency departments

Author: Rafid Tofik, Olle Melander, Johan Ärnlöv, Thoralph Ruge, Axel C. Carlsson, G Leijonberg, Torgny Wessman, and Anders Larsson
Subjects: Male, 030213 general clinical medicine, medicine.medical_specialty, Clinical Biochemistry, Population, macromolecular substances, 030204 cardiovascular system & hematology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Epidemiology, medicine, Humans, Hospital Mortality, education, Aged, Aged, 80 and over, education.field_of_study, business.industry, General Medicine, Emergency department, Middle Aged, Triage, Endostatins, Dyspnea, Acute Disease, Cohort, cardiovascular system, Female, Endostatin, Emergency Service, Hospital, business, Body mass index, Biomarkers, Cohort study
Abstract: Background: Increased levels of circulating endostatin predicts cardiovascular morbidity and impaired kidney function in the general population. The utility of endostatin as a risk marker for mortality in the emergency department (ED) has not been reported. Aim: Our main aim was to study the association between plasma endostatin and 90-day mortality in an unselected cohort of patients admitted to the ED for acute dyspnea. Design Circulating endostatin was analyzed in plasma from 1710 adults and related to 90-day mortality in Cox proportional hazard models adjusted for age, sex, body mass index, oxygen saturation, respiratory rate, body temperature, C-reactive protein, lactate, creatinine and medical priority according to the Medical Emergency Triage and Treatment System–Adult score (METTS-A). The predictive value of endostatin for mortality was evaluated with receiver operating characteristic (ROC) analysis and compared with the clinical triage scoring system and age. Results: Each one standard deviation increment of endostatin was associated with a HR of 2.12 (95% CI 1.31–3.44 p < 0.01) for 90-day mortality after full adjustment. Levels of endostatin were significantly increased in the group of patients with highest METTS-A (p < 0.001). When tested for the outcome 90-day mortality, the area under the ROC curve (AUC) was 0.616 for METTS-A, 0.701 for endostatin, 0.708 for METTS -A and age and 0.738 for METTS-A, age and levels of endostatin. Conclusions: In an unselected cohort of patients admitted to the ED with acute dyspnea, endostatin had a string association to 90-day mortality and improved prediction of 90-day mortality in the ED beyond the clinical triage scoring system and age with 3%. (Less)
Published: 2020

10. Effect of General Adiposity and Central Body Fat Distribution on the Circulating Metabolome : A Multi-Cohort Nontargeted Metabolomics Observational and Mendelian Randomization Study

Author: Susanna C. Larsson, Ulf Risérus, Johan Ärnlöv, Beatrice Kennedy, Andrea Ganna, Tove Fall, Christian Berne, Samira Salihovic, Patrik K. E. Magnusson, Ulf Hammar, Shafqat Ahmad, Lars Lind, and Johan Sundström
Subjects: Adult, Male, Endocrinology, Diabetes and Metabolism, Population, Physiology, Endocrinology and Diabetes, Creatine, Body Mass Index, Cohort Studies, chemistry.chemical_compound, Framingham Heart Study, Endocrinology, Risk Factors, Germany, Mendelian randomization, Metabolome, Internal Medicine, Body Fat Distribution, Humans, Metabolomics, Medicine, education, Adiposity, Aged, Aged, 80 and over, Sweden, education.field_of_study, Waist-Hip Ratio, business.industry, Mendelian Randomization Analysis, Middle Aged, medicine.disease, Obesity, United Kingdom, United States, Diabetes and Metabolism, chemistry, Obesity, Abdominal, Cohort, Endokrinologi och diabetes, Female, business, Body mass index
Abstract: Obesity is associated with adverse health outcomes, but the metabolic effects have not yet been fully elucidated. We aimed to investigate the association between adiposity with circulating metabolites and to address causality with Mendelian randomization (MR). Metabolomics data was generated by non-targeted ultra-performance liquid-chromatography coupled to time-of-flight mass-spectrometry in plasma and serum from three population-based Swedish cohorts: ULSAM (N=1,135), PIVUS (N=970), and TwinGene (N=2,059). We assessed associations between general adiposity measured as body mass index (BMI) and central body fat distribution measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI) with 210 annotated metabolites. We employed MR analysis to assess causal effects. Lastly, we attempted to replicate the MR findings in the KORA and TwinsUK cohorts (N=7,373), the CHARGE consortium (N=8,631), the Framingham Heart Study (N=2,076) and the DIRECT consortium (N=3,029). BMI was associated with 77 metabolites, while WHRadjBMI was associated with 11 and 3 metabolites in women and men, respectively. The MR analyses in the Swedish cohorts suggested a causal association (p-value P-16:0) as well as with increased creatine levels. The replication effort provided support for a causal association of adiposity on reduced levels of arachidonic acid (p-value 0.03). Adiposity is associated with variation of large parts of the circulating metabolome, however causality needs further investigation in well-powered cohorts.
Published: 2022

11. Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: a proteomics approach

Author: Christoph Nowak, Johan Ärnlöv, Ulf Risérus, Johan Sundström, Carl Johan Östgren, Fredrik H. Nystrom, Juan Jesus Carrero, Lars Lind, Tove Fall, Erik Ingelsson, and Axel C. Carlsson
Subjects: Oncology, Male, Proteomics, medicine.medical_specialty, Growth Differentiation Factor 15, Albumin-creatinine ratio, type 2 diabetes mellitus, Renal function, lcsh:Medicine, 030209 endocrinology & metabolism, Type 2 diabetes, Disease, Endocrinology and Diabetes, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, proteomics, Risk Factors, Diabetes mellitus, Internal medicine, Medicine, Humans, Diabetic Nephropathies, Risk factor, Aged, Sweden, glomerular filtration rate, 030219 obstetrics & reproductive medicine, business.industry, lcsh:R, Klinisk medicin, Type 2 Diabetes Mellitus, General Medicine, Articles, Middle Aged, medicine.disease, diabetic kidney disease, 3. Good health, risk factor, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Endokrinologi och diabetes, Biomarker (medicine), biomarker, Female, GDF15, Clinical Medicine, business, Biomarkers
Abstract: Background: Diabetic kidney disease (DKD) is a leading risk factor for end-stage renal disease and is one of the most important risk factors for cardiovascular disease in patients with diabetes. It is possible that novel markers portraying the pathophysiological underpinning processes may be useful. Aim: To investigate the associations between 80 circulating proteins, measured by a proximity extension assay, and prevalent DKD and major adverse cardiovascular events (MACE) in type 2 diabetes. Methods: We randomly divided individuals with type 2 diabetes from three cohorts into a two-thirds discovery and one-third replication set (total n = 813, of whom 231 had DKD defined by estimated glomerular filtration rate = 3 g/mol). Proteins associated with DKD were also assessed as predictors for incident major adverse cardiovascular events (MACE) in persons with DKD at baseline. Results: Four proteins were positively associated with DKD in models adjusted for age, sex, cardiovascular risk factors, glucose control, and diabetes medication: kidney injury molecule-1 (KIM-1, odds ratio [OR] per standard deviation increment, 1.65, 95% confidence interval [CI] 1.27-2.14); growth differentiation factor 15 (GDF-15, OR 1.40, 95% CI 1.16-1.69); myoglobin (OR 1.57, 95% CI 1.30-1.91), and matrix metalloproteinase 10 (MMP-10, OR 1.43, 95% CI 1.17-1.74). In patients with DKD, GDF-15 was significantly associated with increased risk of MACE after adjustments for baseline age, sex, microalbuminuria, and kidney function and (59 MACE events during 7 years follow-up, hazard ratio per standard deviation increase 1.43 [95% CI 1.03-1.98]) but not after further adjustments for cardiovascular risk factors. Conclusion: Our proteomics approach confirms and extends previous associations of higher circulating levels of GDF-15 with both micro- and macrovascular disease in patients with type 2 diabetes. Our data encourage additional studies evaluating the clinical utility of our findings.
Published: 2019

12. Global, regional, and national burden of stroke and its risk factors, 1990–2019 : a systematic analysis for the Global Burden of Disease Study 2019

Author: Mosiur Rahman, Rehab Salah, Mario F P Peres, Licia Iacoviello, Benjamin A Stark, Mahalaqua Nazli Khatib, Amir Radfar, Kamarul Imran Musa, Yannick Béjot, Deanna Anderlini, Carlos Cantú-Brito, Feng Sha, V. E. Nwatah, Pradip Gyanwali, Boris Bikbov, Bartosz Miazgowski, Sindhura Lakshmi Koulmane Laxminarayana, Ali Bijani, Imteyaz A Khan, Yaser Mokhayeri, Bogdan Oancea, Tarang Parekh, Martin Dichgans, Linh Gia Vu, Naohiro Yonemoto, Ahmad Ghashghaee, Marcos Roberto Tovani-Palone, Gebiyaw Wudie Tsegaye, Mona Pathak, Maciej Banach, Marissa B Reitsma, Derrick A Bennett, Treska S Hassan, Allen Seylani, Gdiom Gebreheat Abady, Islam Y. Elgendy, Hassan Mehmood Lak, Ismael R. Campos-Nonato, Sorin Hostiuc, Sheikh Mohammed Shariful Islam, Alessandra C. Goulart, Silvia Schiavolin, Simona Sacco, Atif Amin Baig, Azeem Majeed, Sahar Eftekharzadeh, Badr Hasan Sobaih, Archith Boloor, Aimé Bonny, Graeme J. Hankey, Jiregna Darega Gela, Mohamed I Hegazy, Pedram Keshavarz, Segun Emmanuel Ibitoye, Maseer Khan, Hatem Abdelaziz Mohamed Wafa, Hualiang Lin, Enayet Karim Chowdhury, Simon I. Hay, Vanessa De la Cruz-Góngora, Xuefeng Liu, Arokiasamy Perianayagam, Maryam Zamanian, Sezer Kisa, Preetam Bhalchandra Mahajan, Junmei Miao Jonasson, Alberto Raggi, Shubha Jayaram, Tahira Ashraf, Ejaz Ahmad Khan, Matthias Endres, Masoumeh Sadeghi, Dominique Vervoort, Hanadi Al Hamad, Mowafa Househ, Elena V. Gnedovskaya, Johan Ärnlöv, Andrea Sylvia Winkler, Yousef Khader, Mikhail Sergeevich Zastrozhin, Yuming Guo, Yunquan Zhang, Sami Almustanyir, Lalit Dandona, Amir Masoud Rahmani, Chythra R Rao, Giancarlo Lucchetti, Irena Ilic, Suzanne Barker-Collo, Priya Rathi, Emerito Jose A. Faraon, Mohamad-Hani Temsah, Reza Ghanei Gheshlagh, Gyu Ri Kim, Carlos A Castañeda-Orjuela, Alaa Makki, Yun Jin Kim, Vida Abedi, Shanshan Li, Kewal Krishan, David Flood, Abdollah Mohammadian-Hafshejani, Michele Romoli, Gregory A. Roth, Jagdish Khubchandani, Isabela M. Benseñor, Rupak Desai, Mohammed Shannawaz, Aziz Sheikh, Claudiu Herteliu, Xiaoyue Xu, Santi Martini, Kenji Shibuya, Jasvinder A. Singh, Ravi Prakash Jha, Kairat Davletov, Mahya Beheshti, Rahmatollah Moradzadeh, Ismaeel Yunusa, Maria Inês Schmidt, Koustuv Dalal, Sohail Ahmad, Patrick D. M. C. Katoto, Oladimeji Adebayo, Nima Hafezi-Nejad, Ranil Jayawardena, Giampiero Mazzaglia, Mitra Abbasifard, Usman Iqbal, Hamid Yimam Hassen, Alireza Rafiei, Catherine O. Johnson, Mark Thomaz Ugliara Barone, Simona Giampaoli, Gaetano Isola, Ricardo Lutzky Saute, Mandira Lamichhane Dhimal, Vishnu Renjith, Farshad Farzadfar, Irina Filip, Daniel Diaz, André Karch, Samer Hamidi, Diego Augusto Santos Silva, David Colozza, Gbenga A. Kayode, Dinh-Toi Chu, Truong-Minh Pham, Arielle Wilder Bell, Aziz Rezapour, David Laith Rawaf, Anasthasia Zastrozhina, Yves Miel H Zuniga, Ivo Iavicoli, Adrian Pana, Salman Rawaf, Pankaj Bhardwaj, Omid Dadras, Anayat Ullah, Gina Agarwal, Shafiu Mohammed, Bing-Fang Hwang, Eyayou Girma Tadesse, Charles D.A. Wolfe, Sanjay Basu, Michael Brauer, Tanuj Kanchan, Ahmad Azam Malik, Brigid Unim, Min Seo Kim, Kia Vosoughi, Tomasz Miazgowski, Warren D. Lo, Vivek Podder, Dana Bryazka, Chuanhua Yu, Hassan Magdy Abd El Razek, Rufus Akinyemi, Zhi-Jiang Zhang, Ettore Beghi, Xiaochen Dai, Meghnath Dhimal, Mehrnoosh Samaei, Sathish Kumar Jayapal, Bay Vo, Amanual Getnet Mersha, Rajaa Al-Raddadi, Savita Lasrado, Jalal Arabloo, Pablo M. Lavados, Samaneh Akbarpour, Khezar Hayat, Ritesh G. Menezes, Vahid Alipour, Sowmya J. Rao, Mariam Molokhia, Trang Huyen Nguyen, Aletta E. Schutte, Zahra Kamiab, Lidia Morawska, Mohammad Ali Moni, Bo Norrving, Tommi Vasankari, Bruno Ramos Nascimento, Ai Koyanagi, Tissa Wijeratne, Rizwan Kalani, Chenwen Zhong, Bright Opoku Ahinkorah, Sepideh Ahmadi, Bruce Bartholow Duncan, Andrzej Rynkiewicz, Pradyumna Agasthi, Saeed Shahabi, Adnan Kisa, Fares Alahdab, Vafa Rahimi-Movaghar, Adnan Ansar, Matilde Leonardi, Ali Koolivand, Jefferson Antonio Buendia Rodriguez, Leonardo Roever, Daniel Asfaw Erku, Alok Atreya, Jean Jacques Noubiap, Dhaval Kolte, Shajedur Rahman Shawon, Michael Ekholuenetale, Navid Manafi, Narayanaswamy Venketasubramanian, Syed Amir Gilani, Mohamed M. Gad, Christopher J L Murray, Louis Jacob, Robert Ancuceanu, Simona Costanzo, Erkin M. Mirrakhimov, Seyed Hossein Yahyazadeh Jabbari, Nazanin Rajai, Muhammed Elhadi, Abdelrahman Ibrahim Abushouk, Alireza Zandifar, Walter Muruet, Jagadish Rao Padubidri, Promit Ananyo Chakraborty, Hans Orru, Mikk Jürisson, Rajeev Gupta, Kurnia Dwi Artanti, Till Bärnighausen, Mark Woodward, Masao Iwagami, Brijesh Sathian, Bingyu Li, Vijay Krishnamoorthy, Ahamarshan Jayaraman Nagarajan, Sherief Ghozy, Amanda G. Thrift, Michael A. Piradov, Florian Fischer, Mayowa O. Owolabi, Lorenzo G. Mantovani, Aman Yesuf Endries, Sara Sheikhbahaei, Stefan Lorkowski, Muhammed Shahriar Zaman, Ali Yadollahpour, Abdiwahab Hashi, Sreenivas Narasimha Swamy, Krittika Bhattacharyya, Hiroshi Yatsuya, Mika Kivimäki, Olayinka Stephen Ilesanmi, Irmina Maria Michalek, Ruxandra Irina Negoi, Alberico L. Catapano, Gholamreza Bazmandegan, Ahmed Al Montasir, Fakher Rahim, Amirhossein Sahebkar, Syed Mohamed Aljunid, Giang Thu Vu, G Anil Kumar, Juan Jesus Carrero, Hiroyasu Iso, Abdallah M. Samy, Stefan Stortecky, Reza Malekzadeh, Ashwin Kamath, Nevine El Nahas, Ayesha Humayun, Miguel A Barboza, Sheng-Chia Chung, Carlo La Vecchia, Oluwakemi Ololade Odukoya, Rita Krishnamurthi, Masood Ali Shaikh, Milena Ilic, Lalit Yadav, Nahlah Elkudssiah Ismail, Abdel Douiri, Yousef Mohammad, Jason H Y Wu, Sahar Saeedi Moghaddam, Ramesh Holla, Sadaf G. Sepanlou, Itamar S. Santos, Jost B. Jonas, Dian Kusuma, Atte Meretoja, Yasir Waheed, Ben Lacey, Zahra Aryan, Mulugeta Molla Birhanu, Moien Ab Khan, K. M. Saif-Ur-Rahman, Ramin Zand, Anna Aleksandrovna Skryabina, Sung In Jang, Rakhi Dandona, Emanuele D'Amico, Priyanga Ranasinghe, Jaykaran Charan, Bhaskaran Unnikrishnan, Davide Sattin, Akram Pourshams, Markus P. Schlaich, Arief Hargono, Samaneh Asgari, Ovidiu Baltatu, Ippazio Cosimo Antonazzo, Sandhya Neupane Kandel, Nizal Sarrafzadegan, Jakub Morze, Man Mohan Mehndiratta, Manjari Tripathi, Panniyammakal Jeemon, Rohollah Kalhor, Yogeshwar Kalkonde, Soraya Siabani, Sojib Bin Zaman, Seyed Sina Naghibi Irvani, Shilpa Gaidhane, Sahel Valadan Tahbaz, Yihienew Mequanint Bezabih, Samath D Dharmaratne, Ingan Ukur Tarigan, Vivek Gupta, Klara Dokova, Alireza Vakilian, Vardhmaan Jain, Akshaya Srikanth Bhagavathula, Sarah Wulf Hanson, Umar Farooque, Mohammad Ali Mansournia, Vera Marisa Costa, Alessandro Gialluisi, Valery L. Feigin, Himal Kandel, Suzanne Polinder, Nermin Ghith, Deepak Dhamnetiya, Michael H. Criqui, Asif Hanif, Ahmed Abualhasan, Veer Bala Gupta, Mahaveer Golechha, Bach Xuan Tran, Jason A. Anderson, Catherine Bisignano, Kazumasa Yamagishi, Zahid A Butt, Budi Aji, Baye Dagnew, Rasmus Havmoeller, Victor Volovici, Jitendra Singh, Paramjit Gill, Saverio Stranges, Eun Cheol Park, Andrew T Olagunju, Milena Santric-Milicevic, Woldesellassie M. Bezabhe, Sheikh M. Alif, Junjie Huang, Foad Abd-Allah, Yvonne Teuschl, Rajkumar Doshi, Nelson Alvis-Guzman, Marcel Ausloos, Mohsen Naghavi, Yusra Ahmed Salih, Mohsen Abbasi-Kangevari, Maarten J. Postma, Ghozali Ghozali, Yanzhong Wang, Ali H. Mokdad, Valentin Yurievich Skryabin, Nitin Joseph, Andre M. N. Renzaho, Muhammad Aziz Rahman, Mohammad Athar, Rustam Al-Shahi Salman, Albertino Damasceno, Fatemeh Pashazadeh Kan, Marcello Tonelli, Florentino Luciano Caetano dos Santos, Sonali G. Choudhari, Abdullah Hamid Feroze, Walter D. Johnson, Ro-Ting Lin, Francesca Giulia Magnani, Hermann Brenner, Shaimaa I. El-Jaafary, Tea Lallukka, Niveen M E Abu-Rmeileh, Jacek Jerzy Jozwiak, GBD 2019 Stroke Collaborators, Feigin, V. L., Stark, B. A., Johnson, C. O., Roth, G. A., Bisignano, C., Abady, G. G., Abbasifard, M., Abbasi-Kangevari, M., Abd-Allah, F., Abedi, V., Abualhasan, A., Abu-Rmeileh, N. M. E., Abushouk, A. I., Adebayo, O. M., Agarwal, G., Agasthi, P., Ahinkorah, B. O., Ahmad, S., Ahmadi, S., Salih, Y. A., Aji, B., Akbarpour, S., Akinyemi, R. O., Al Hamad, H., Alahdab, F., Alif, S. M., Alipour, V., Aljunid, S. M., Almustanyir, S., Al-Raddadi, R. M., Salman, R. A. -S., Alvis-Guzman, N., Ancuceanu, R., Anderlini, D., Anderson, J. A., Ansar, A., Antonazzo, I. C., Arabloo, J., Arnlov, J., Artanti, K. D., Aryan, Z., Asgari, S., Ashraf, T., Athar, M., Atreya, A., Ausloos, M., Baig, A. A., Baltatu, O. C., Banach, M., Barboza, M. A., Barker-Collo, S. L., Barnighausen, T. W., Barone, M. T. U., Basu, S., Bazmandegan, G., Beghi, E., Beheshti, M., Bejot, Y., Bell, A. W., Bennett, D. A., Bensenor, I. M., Bezabhe, W. M., Bezabih, Y. M., Bhagavathula, A. S., Bhardwaj, P., Bhattacharyya, K., Bijani, A., Bikbov, B., Birhanu, M. 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H, Lin, R, Liu, X, Lo, W, Lorkowski, S, Lucchetti, G, Saute, R, Abd El Razek, H, Magnani, F, Mahajan, P, Majeed, A, Makki, A, Malekzadeh, R, Malik, A, Manafi, N, Mansournia, M, Mantovani, L, Martini, S, Mazzaglia, G, Mehndiratta, M, Menezes, R, Meretoja, A, Mersha, A, Jonasson, J, Miazgowski, B, Miazgowski, T, Michalek, I, Mirrakhimov, E, Mohammad, Y, Mohammadian-Hafshejani, A, Mohammed, S, Mokdad, A, Mokhayeri, Y, Molokhia, M, Moni, M, Al Montasir, A, Moradzadeh, R, Morawska, L, Morze, J, Muruet, W, Musa, K, Nagarajan, A, Naghavi, M, Swamy, S, Nascimento, B, Negoi, R, Kandel, S, Nguyen, T, Norrving, B, Noubiap, J, Nwatah, V, Oancea, B, Odukoya, O, Olagunju, A, Orru, H, Owolabi, M, Padubidri, J, Pana, A, Parekh, T, Park, E, Kan, F, Pathak, M, Peres, M, Perianayagam, A, Pham, T, Piradov, M, Podder, V, Polinder, S, Postma, M, Pourshams, A, Radfar, A, Rafiei, A, Raggi, A, Rahim, F, Rahimi-Movaghar, V, Rahman, M, Rahmani, A, Rajai, N, Ranasinghe, P, Rao, C, Rao, S, Rathi, P, Rawaf, D, Rawaf, S, Reitsma, M, Renjith, V, Renzaho, A, Rezapour, A, Rodriguez, J, Roever, L, Romoli, M, Rynkiewicz, A, Sacco, S, Sadeghi, M, Moghaddam, S, Sahebkar, A, Saif-Ur-Rahman, K, Salah, R, Samaei, M, Samy, A, Santos, I, Santric-Milicevic, M, Sarrafzadegan, N, Sathian, B, Sattin, D, Schiavolin, S, Schlaich, M, Schmidt, M, Schutte, A, Sepanlou, S, Seylani, A, Sha, F, Shahabi, S, Shaikh, M, Shannawaz, M, Shawon, M, Sheikh, A, Sheikhbahaei, S, Shibuya, K, Siabani, S, Silva, D, Singh, J, Skryabin, V, Skryabina, A, Sobaih, B, Stortecky, S, Stranges, S, Tadesse, E, Tarigan, I, Temsah, M, Teuschl, Y, Thrift, A, Tonelli, M, Tovani-Palone, M, Tran, B, Tripathi, M, Tsegaye, G, Ullah, A, Unim, B, Unnikrishnan, B, Vakilian, A, Tahbaz, S, Vasankari, T, Venketasubramanian, N, Vervoort, D, Vo, B, Volovici, V, Vosoughi, K, Vu, G, Vu, L, Wafa, H, Waheed, Y, Wang, Y, Wijeratne, T, Winkler, A, Wolfe, C, Woodward, M, Wu, J, Hanson, S, Xu, X, Yadav, L, Yadollahpour, A, Jabbari, S, Yamagishi, K, Yatsuya, H, Yonemoto, N, Yu, C, Yunusa, I, Zaman, M, Zaman, S, Zamanian, M, Zand, R, Zandifar, A, Zastrozhin, M, Zastrozhina, A, Zhang, Y, Zhang, Z, Zhong, C, Zuniga, Y, Murray, C, Value, Affordability and Sustainability (VALUE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Microbes in Health and Disease (MHD)
Subjects: Male, Aging, 030204 cardiovascular system & hematology, Stroke data, GUIDELINES, 3124 Neurology and psychiatry, Body Mass Index, Global Burden of Disease, 0302 clinical medicine, RA0421, Risk Factors, Epidemiology, Strokes, YOUNG-ADULTS, Prevalence, 80 and over, Aetiology, 610 Medicine & health, Stroke, POPULATION, 1103 Clinical Sciences, 1109 Neurosciences, Cause of death, Aged, 80 and over, education.field_of_study, Mortality rate, Incidence (epidemiology), Incidence, 1. No poverty, Articles, Hälsovetenskaper, Middle Aged, Stroke types, ddc, 3. Good health, ISCHEMIC-STROKE, Income, Female, Quality-Adjusted Life Years, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, GBD, Population, Clinical Sciences, Clinical Neurology, 03 medical and health sciences, Clinical Research, MIDDLE-INCOME COUNTRIES, Health Sciences, medicine, Humans, Risk factor, education, GBD 2019 Stroke Collaborators, Cerebral Hemorrhage, Aged, Ischemic Stroke, Global burden, Science & Technology, Neurology & Neurosurgery, HYPERTENSION, business.industry, MORTALITY, Prevention, 3112 Neurosciences, Neurosciences, 1103 Clinical Sciences, SERVICES, Subarachnoid Hemorrhage, medicine.disease, PREVENTION, Brain Disorders, Good Health and Well Being, Attributable risk, Human medicine, Neurology (clinical), Neurosciences & Neurology, business, 1109 Neurosciences, 030217 neurology & neurosurgery, Demography, 2.4 Surveillance and distribution, RC
Abstract: Background Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings In 2019, there were 12·2 million (95% UI 11·0–13·6) incident cases of stroke, 101 million (93·2–111) prevalent cases of stroke, 143 million (133–153) DALYs due to stroke, and 6·55 million (6·00–7·02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11·6% [10·8–12·2] of total deaths) and the third-leading cause of death and disability combined (5·7% [5·1–6·2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70·0% (67·0–73·0), prevalent strokes increased by 85·0% (83·0–88·0), deaths from stroke increased by 43·0% (31·0–55·0), and DALYs due to stroke increased by 32·0% (22·0–42·0). During the same period, age-standardised rates of stroke incidence decreased by 17·0% (15·0–18·0), mortality decreased by 36·0% (31·0–42·0), prevalence decreased by 6·0% (5·0–7·0), and DALYs decreased by 36·0% (31·0–42·0). However, among people younger than 70 years, prevalence rates increased by 22·0% (21·0–24·0) and incidence rates increased by 15·0% (12·0–18·0). In 2019, the age-standardised stroke-related mortality rate was 3·6 (3·5–3·8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3·7 (3·5–3·9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62·4% of all incident strokes in 2019 (7·63 million [6·57–8·96]), while intracerebral haemorrhage constituted 27·9% (3·41 million [2·97–3·91]) and subarachnoid haemorrhage constituted 9·7% (1·18 million [1·01–1·39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79·6 million [67·7–90·8] DALYs or 55·5% [48·2–62·0] of total stroke DALYs), high body-mass index (34·9 million [22·3–48·6] DALYs or 24·3% [15·7–33·2]), high fasting plasma glucose (28·9 million [19·8–41·5] DALYs or 20·2% [13·8–29·1]), ambient particulate matter pollution (28·7 million [23·4–33·4] DALYs or 20·1% [16·6–23·0]), and smoking (25·3 million [22·6–28·2] DALYs or 17·6% [16·4–19·0]). Interpretation The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries. Funding Bill & Melinda Gates Foundation.
Published: 2021

13. Plasma calprotectin in the emergency department: a potential clinical biomarker for patients with infectious diseases

Author: Per Wändell, Toralph Ruge, Mari Rosenqvist, Torgny Wessman, Johan Ärnlöv, Anders Larsson, Olle Melander, and Martin Wollmer
Subjects: Male, medicine.medical_specialty, Infectious Medicine, Clinical Biochemistry, communicable diseases, Infektionsmedicin, leukocyte L1 antigen complex (calprotectin), Communicable Diseases, C-reactive protein, fluids and secretions, Risk Factors, Internal medicine, medicine, Leukocytes, Humans, Cardiac and Cardiovascular Systems, hospital, Aged, Aged, 80 and over, Kardiologi, biology, business.industry, General Medicine, Emergency department, Pneumonia, dyspnea, Middle Aged, medicine.disease, Triage, predictive value of tests, C-Reactive Protein, Predictive value of tests, Heart failure, biology.protein, Biomarker (medicine), Female, Calprotectin, business, Emergency Service, Hospital, Leukocyte L1 Antigen Complex, Emergency service, Biomarkers
Abstract: Increased levels of plasma calprotectin are reported in patients with infectious diseases. However, the clinical usefulness of calprotectin as a biomarker to identify patients with infectious diseases in the emergency department (ED) setting has not been investigated. To study the ability of calprotectin to discriminate patients with acute infectious diseases and dyspnea from patients with other causes of acute dyspnea in the ED setting. Patients aged ≥18 years seeking ED during daytime on weekdays between March 2013 and July 2018, with acute dyspnea, were included. Participants (n = 1287) were triaged according to Medical Emergency Triage and Treatment System-Adult score (METTS-A) or Rapid Emergency Triage and Treatment System (RETTS), and blood samples were collected. The association between calprotectin and other markers of infectious diseases, i.e. biomarkers (CRP, leucocytes) and body temperature, was studied. The predictive value of calprotectin for the outcome of acute infection was evaluated with receiver operating characteristic (ROC) analysis. Univariate cross-sectional regression showed significant associations between calprotectin and leucocytes, CRP and body temperature. Patients with severe infections including pneumonia (n = 119) had significantly higher concentrations of calprotectin compared to patients with heart failure (n = 162) or chronic obstructive pulmonary disease (n = 183). When tested for the outcome of acute infection (n = 109), the area under the ROC curve (AUROC) was for CRP 0.83 and for calprotectin 0.78. Plasma calprotectin identifies infectious diseases in ED patients with acute dyspnea, and the clinical usefulness of Calprotectin in the ED has to be further studied.
Published: 2021

14. The genomics of heart failure: design and rationale of the HERMES consortium

Author: Svati H. Shah, Olle Melander, Neneh Sallah, Quinn S. Wells, Jerome I. Rotter, Faye Zhao, Charlotte Andersson, Guðmundur Thorgeirsson, Ghazaleh Fatemifar, Alex S. F. Doney, Michael E. Dunn, David E. Lanfear, Ian Ford, Eric Boersma, Sonia Shah, Christopher Newton-Cheh, Douglas L. Mann, Niek Verweij, Carolina Roselli, Laura M. Yerges-Armstrong, Jian Yang, Christian Torp-Pedersen, Veikko Salomaa, Mary L. Biggs, Alaa Shalaby, Christoph Nowak, Stefan Gross, Patrick T. Ellinor, Mari Liis Tammesoo, Diane T. Smelser, Peter M. Visscher, Hans L. Hillege, Ruth C. Lovering, Honghuang Lin, Colin N. A. Palmer, Louis Philippe Lemieux Perreault, Jeffrey Brandimarto, Uwe Völker, Perttu Salo, Andrea Koekemoer, Rebecca Gutmann, Åsa K. Hedman, Nilesh J. Samani, Heming Xing, Faiez Zannad, Jaison Jacob, Harry Hemingway, Michael R. Brown, Franco Giulianini, Anubha Mahajan, Xing Chen, Alexander Niessner, Peter Almgren, Daniel I. Swerdlow, Gunnar Engström, Lars Lind, Tõnu Esko, Tomasz Czuba, Anna Helgadottir, Harvey D. White, David J. Stott, Johan Ärnlöv, Lars Køber, Chim C. Lang, Krishna G. Aragam, Kent D. Taylor, Anders Mälarstig, Frederick K. Kamanu, Kenneth B. Margulies, Michelle L. O'Donoghue, Andrew D. Morris, Sahar Ghasemi, J. Wouter Jukema, Jessica van Setten, Abbas Dehghan, Guillaume Paré, Luca A. Lotta, Giorgio E. M. Melloni, Albert Henry, Bruce M. Psaty, Paul M. Ridker, David J. Carey, Marie-Pierre Dubé, John S. Gottdiener, Xiaosong Wang, Per H. Svensson, Xu Chen, Patrik K. E. Magnusson, Claudia Langenberg, Alexander Teumer, Vilmantas Giedraitis, Simon de Denus, Michael W. Nagle, Marcus Dörr, Thomas P. Cappola, André G. Uitterlinden, Michael Morley, Eliana Portilla-Fernandez, J. Gustav Smith, Abirami Veluchamy, Peter Weeke, Ify R. Mordi, Unnur Thorsteinsdottir, Naveed Sattar, Folkert W. Asselbergs, Daniel I. Chasman, Daníel F. Guðbjartsson, Jonathan H. Chung, Marcus E. Kleber, Raul Weiss, Christopher P. Nelson, Spiros Denaxas, Bing Yu, Simon P. R. Romaine, Nicholas A Marston, Anjali T. Owens, Cecilia M. Lindgren, John J.V. McMurray, Joshua D. Backman, Michael V. Holmes, Stella Trompet, Hilma Holm, Kerri L. Wiggins, Jian'an Luan, Stephan B. Felix, Yifan Yang, Jemma B. Wilk, Maryam Kavousi, Markus Perola, Christian T. Ruff, Jean-Claude Tardif, G Sveinbjörnsson, Samuel C. Dudley, Nicholas J. Wareham, Teemu J. Niiranen, Andrew P. Morris, Danny Tuckwell, Maris Teder-Laving, R. Thomas Lumbers, James P. Cook, Géraldine Asselin, William A. Chutkow, Winfried März, Steven A. Lubitz, John G.F. Cleland, Bill Kraus, Ramachandran S. Vasan, Christopher M. Haggerty, Olympe Chazara, Chris Finan, Heather L. Bloom, Hans-Peter Brunner-La Rocca, Francoise Fougerousse, Kenneth Rice, Craig L. Hyde, Graciela E. Delgado, Mark Chaffin, Marc S. Sabatine, Alanna C. Morrison, Kay-Tee Khaw, Kari Stefansson, Felix Vaura, Barry London, Isabella Kardys, Aroon D. Hingorani, Hongsheng Gui, Steen Stender, René Fouodjio, Mohsen Ghanbari, Pim van der Harst, Nicholas L. Smith, Karoline Kuchenbaecker, Adriaan A. Voors, Benoit Tyl, University College of London [London] (UCL), University College London Hospitals (UCLH), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Lund University [Lund], Pfizer, Karolinska Institutet [Stockholm], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Groningen [Groningen], University of Oxford [Oxford], Dalarna University, Massachusetts General Hospital [Boston], Montreal Heart Institute - Institut de Cardiologie de Montréal, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, University of Washington [Seattle], Emory University [Atlanta, GA], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Pennsylvania [Philadelphia], The University of Texas Health Science Center at Houston (UTHealth), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), AstraZeneca, Novartis Institutes for BioMedical Research (NIBR), University of Glasgow, University of Liverpool, Université de Montréal (UdeM), Imperial College London, University of Heidelberg, Medical Faculty, University of Dundee, Universität Greifswald - University of Greifswald, University of Minnesota Medical School, University of Minnesota System, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Uppsala University, University of Maryland School of Medicine, University of Maryland System, University of Iceland [Reykjavik], deCODE genetics [Reykjavik], Henry Ford Hospital, Carver College of Medicine, University of Iowa, Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), ICIN - Netherlands Heart Institute, Leiden University Medical Center (LUMC), Netherlands Heart Institute, Partenaires INRAE, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, University of Leicester, Duke University [Durham], University of Iowa [Iowa City], Genentech, Inc., Genentech, Inc. [San Francisco], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Skane University Hospital [Malmo], University of Edinburgh, Medizinische Universität Wien = Medical University of Vienna, University of Turku, National Institute for Health and Welfare [Helsinki], McMaster University [Hamilton, Ontario], Kaiser Permanente Washington Health Research Institute [Seattle] (KPWHRI), Harbor UCLA Medical Center [Torrance, Ca.], University Medical Center [Utrecht], University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), University of Tartu, Aalborg University [Denmark] (AAU), Leiden University, University of Queensland [Brisbane], Ohio State University [Columbus] (OSU), Auckland City Hospital, GlaxoSmithKline, Glaxo Smith Kline, University of Texas Health Science Center, Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Duke University Medical Center, Regeneron Pharmaceuticals [Tarrytown], Vanderbilt University [Nashville], European Project, Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Cardiology, University of Oxford, University of Pennsylvania, Universiteit Leiden, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Epidemiology, and Internal Medicine
Subjects: Male, Study Designs, Cardiomyopathy, Disease, 030204 cardiovascular system & hematology, 0302 clinical medicine, AFRICAN ANCESTRY, Epidemiology, 80 and over, WIDE ASSOCIATION, EPIDEMIOLOGY, Cardiac and Cardiovascular Systems, AGING RESEARCH, RISK, Aged, 80 and over, 0303 health sciences, Kardiologi, Genomics, Middle Aged, Prognosis, 3. Good health, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Heart failure, CLASSIFICATION, Heart Failure/genetics, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Genetic model, medicine, Genetics, Diseases of the circulatory (Cardiovascular) system, Humans, Allele frequency, Genotyping, METAANALYSIS, 030304 developmental biology, Aged, Association studies, Study Design, business.industry, Odds ratio, ADULTS, COHORTS, medicine.disease, RC666-701, REPLICATION, business, Biomarkers, Genome-Wide Association Study
Abstract: Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
Published: 2021

15. Strong Associations Between Early Tubular Damage and Urinary Cytokine, Chemokine, and Growth Factor Levels in Elderly Males and Females

Author: Lars Lind, Johan Ärnlöv, Johanna Helmersson-Karlqvist, Måns Thulin, Anders Larsson, Kim Kultima, Bengt Fellström, and Inga Soveri
Subjects: Male, medicine.medical_specialty, Chemokine, Urinary system, medicine.medical_treatment, Immunology, Renal function, Inflammation, Lipocalin, Virology, Internal medicine, Medicine, Humans, Prospective Studies, Acute tubular necrosis, Aged, Sweden, biology, business.industry, Cell Biology, medicine.disease, Endocrinology, Cytokine, Kidney Tubules, Cystatin C, biology.protein, Cytokines, Intercellular Signaling Peptides and Proteins, Female, medicine.symptom, Chemokines, business
Abstract: Acute tubular necrosis is associated with high mortality rates and it is important to develop new biomarkers for tubular damage. The aim of this study was to investigate the effect of early tubular damage on a large number of urinary cytokines, chemokines, and growth factors. We selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The tubular damage markers cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) were analyzed in the urine samples and urinary cytokine levels were analyzed with 2 multiplex assays (proximity extension assay). After adjustment for sex, body mass index, estimated glomerular filtration rate, smoking, and multiplicity testing using the false discovery rate approach, there remained 26 cytokines that correlated significantly with urine cystatin C, 27 cytokines that correlated with NGAL, and 66 cytokines that correlated with KIM-1. Tubular damage shows a strong association with urinary cytokines, chemokines, and growth factors. Our findings indicate that multiplex proteomics could be a promising new approach to explore the complex effects of tubular damage.
Published: 2021

16. Development of Risk Prediction Equations for Incident Chronic Kidney Disease

Author: Robert G, Nelson Morgan, E Grams, Shoshana H, Ballew, Yingying, Sang, Fereidoun, Azizi, Steven J, Chadban, Layal, Chaker, Stephan C, Dunning, Caroline, Fox, Yoshihisa, Hirakawa, Kunitoshi, Iseki, Joachim, Ix, Tazeen H, Jafar, Anna, Köttgen, David M, J Naimark, Takayoshi, Ohkubo, Gordon J, Prescott Casey, M Rebholz, Charumathi, Sabanayagam, Toshimi, Sairenchi, Ben, Schöttker, Yugo, Shibagaki, Marcello, Tonelli, Luxia, Zhang, Ron T, Gansevoort, Kunihiro, Matsushita, Mark, Woodward, Josef, Coresh, Varda, Shalev, CKD Prognosis Consortium, John, Chalmers, Hisatomi, Arima, Vlado, Perkovic, Morgan, Grams, Kevan, Polkinghorne, Robert, Atkins, Steven, Chadban, Ming-Hui, Zhao, Fang, Wang, Jinwei, Wang, Frank, Sacks, Gary, Curhan, Michael, Shlipak, Mark, Sarnak, Ronit, Katz, Jade, Hiramoto, Hiroyasu, Iso, Isao, Muraki, Kazumasa, Yamagishi, Mitsumasa, Umesawa, Hermann, Brenner, Kai-Uwe, Saum, Dietrich, Rothenbacher, Shih-Jen, Hwang, Alex, Chang, Jamie, Green, Gurmukteshwar, Singh, H Lester, Kirchner, Corri, Black, Angharad, Marks, Gordon, Prescott, Laura, Clark, Nick, Fluck, Cirillo, Massimo, Stein, Hallan, Marius, Øvrehus, Knut, Langlo, Solfrid, Romundstad, Fujiko, Irie, Adolfo, Correa, Casey, Rebholz, Bessie, Young, L Ebony, Boulware, Stanford, Mwasongwe, Tsuyoshi, Watanabe, Kunihiro, Yamagata, Koichi, Asahi, Gabriel, Chodick, Carmen, Peralta, Erwin, Bottinger, Girish, Nadkarni, Stephen, Ellis, Rajiv, Nadukuru, Timothy, Kenealy, C Raina, Elley, John, Collins, Paul, Drury, Kei, Asayama, Masahiro, Kikuya, Hirohito, Metoki, Masaaki, Nakayama, Chiho, Iseki, Robert, Nelson, Helen, Looker, William, Knowler, Ron, Gansevoort, Stephan, Bakker, Hiddo, Heerspink, Simerjot, Jassal, Jaclyn, Bergstrom, Elizabeth, Barrett-Connor, Csaba, Kovesdy, Keiichi, Sumida, Kamyar, Kalantar-Zadeh, Sanaz, Sedaghat, Arfan, Ikram, Ewout, Hoorn, Abbas, Dehghan, Juan, Carrero, Marie, Evans, Carl-Gustaf, Elinder, Tien, Wong, Ching-Yu, Cheng, Chi-Pang, Wen, Chwen-Keng, Tsao, Min-Kuang, Tsai, Chien-Hua, Chen, Farhad, Hosseinpanah, Farzad, Hadaegh, Mohammadhassan, Mirbolouk, Marit, Solbu, Bjørn, Eriksen, Trond, Jenssen, Anne, Eggen, Lars, Lannfelt, Anders, Larsson, Johan, Ärnlöv, Henk, Bilo, Gijs, Landman, Kornelis, Hateren, Nanne, Kleefstra, Stephan, Dunning, Nikita, Stempniewicz, John, Cuddeback, Elizabeth, Ciemins, Shoshana, Ballew, Andrew, Levey, Jingsha, Chen, Lucia, Kwak, Aditya, Surapeneni, Mark, Woodward., Robert, G, Nelson, Morgan, E, Gram, Shoshana, H, Ballew, Yingying, Sang, Fereidoun, Azizi, Steven, J, Chadban, Layal, Chaker, Stephan, C, Dunning, Caroline, Fox, Yoshihisa, Hirakawa, Kunitoshi, Iseki, Joachim, Ix, Tazeen, H, Jafar, Anna, Köttgen, David, M, J, Naimark, Takayoshi, Ohkubo, Gordon, J, Prescott, Casey, M, Rebholz, Charumathi, Sabanayagam, Toshimi, Sairenchi, Ben, Schöttker, Yugo, Shibagaki, Marcello, Tonelli, Luxia, Zhang, Ron, T, Gansevoort, Kunihiro, Matsushita, Mark, Woodward, Josef, Coresh, Varda, Shalev, CKD Prognosis, Consortium, John, Chalmer, Hisatomi, Arima, Vlado, Perkovic, Morgan, Gram, Kevan, Polkinghorne, Robert, Atkin, Steven, Chadban, Ming-Hui, Zhao, Fang, Wang, Jinwei, Wang, Frank, Sack, Gary, Curhan, Michael, Shlipak, Mark, Sarnak, Ronit, Katz, Jade, Hiramoto, Hiroyasu, Iso, Isao, Muraki, Kazumasa, Yamagishi, Mitsumasa, Umesawa, Hermann, Brenner, Kai-Uwe, Saum, Dietrich, Rothenbacher, Shih-Jen, Hwang, Alex, Chang, Jamie, Green, Gurmukteshwar, Singh, H, Lester, Kirchner, Corri, Black, Angharad, Mark, Gordon, Prescott, Laura, Clark, Nick, Fluck, Cirillo, Massimo, Stein, Hallan, Marius, Øvrehu, Knut, Langlo, Solfrid, Romundstad, Fujiko, Irie, Adolfo, Correa, Casey, Rebholz, Bessie, Young, L, Ebony, Boulware, Stanford, Mwasongwe, Tsuyoshi, Watanabe, Kunihiro, Yamagata, Koichi, Asahi, Gabriel, Chodick, Carmen, Peralta, Erwin, Bottinger, Girish, Nadkarni, Stephen, Elli, Rajiv, Nadukuru, Timothy, Kenealy, C, Raina, Elley, John, Collin, Paul, Drury, Kei, Asayama, Masahiro, Kikuya, Hirohito, Metoki, Masaaki, Nakayama, Chiho, Iseki, Robert, Nelson, Helen, Looker, William, Knowler, Ron, Gansevoort, Stephan, Bakker, Hiddo, Heerspink, Simerjot, Jassal, Jaclyn, Bergstrom, Elizabeth, Barrett-Connor, Csaba, Kovesdy, Keiichi, Sumida, Kamyar, Kalantar-Zadeh, Sanaz, Sedaghat, Arfan, Ikram, Ewout, Hoorn, Abbas, Dehghan, Juan, Carrero, Marie, Evan, Carl-Gustaf, Elinder, Tien, Wong, Ching-Yu, Cheng, Chi-Pang, Wen, Chwen-Keng, Tsao, Min-Kuang, Tsai, Chien-Hua, Chen, Farhad, Hosseinpanah, Farzad, Hadaegh, Mohammadhassan, Mirbolouk, Marit, Solbu, Bjørn, Eriksen, Trond, Jenssen, Anne, Eggen, Lars, Lannfelt, Anders, Larsson, Johan, Ärnlöv, Henk, Bilo, Gijs, Landman, Kornelis, Hateren, Nanne, Kleefstra, Stephan, Dunning, Nikita, Stempniewicz, John, Cuddeback, Elizabeth, Ciemin, Shoshana, Ballew, Andrew, Levey, Jingsha, Chen, Lucia, Kwak, Aditya, Surapeneni, Mark, Woodward., Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Epidemiology, and Internal Medicine
Subjects: Male, medicine.medical_specialty, Renal function, Disease, Risk Assessment, 01 natural sciences, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Interquartile range, Internal medicine, Diabetes mellitus, medicine, CKD, Humans, 030212 general & internal medicine, 0101 mathematics, Renal Insufficiency, Chronic, Statistic, Aged, Original Investigation, business.industry, 010102 general mathematics, General Medicine, Middle Aged, Models, Theoretical, medicine.disease, MODEL, RENAL-DISEASE, Albuminuria, Female, medicine.symptom, business, Body mass index, Glomerular Filtration Rate, Kidney disease
Abstract: IMPORTANCE Early identification of individuals at elevated risk of developing chronic kidney disease (CKD) could improve clinical care through enhanced surveillance and better management of underlying health conditions.OBJECTIVE To develop assessment tools to identify individuals at increased risk of CKD, defined by reduced estimated glomerular filtration rate (eGFR).DESIGN, SETTING, AND PARTICIPANTS Individual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium including 5 222 711 individuals from 28 countries. Data were collected from April 1970 through January 2017. A 2-stage analysis was performed, with each study first analyzed individually and summarized overall using a weighted average. Because clinical variables were often differentially available by diabetes status, models were developed separately for participants with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external cohorts (n = 2 253 540).EXPOSURES Demographic and clinical factors.MAIN OUTCOMES AND MEASURES Incident eGFR of less than 60 mL/min/1.73 m(2).RESULTS Among 4 441 084 participants without diabetes (mean age, 54 years, 38% women), 660 856 incident cases (14.9%) of reduced eGFR occurred during a mean follow-up of 4.2 years. Of 781 627 participants with diabetes (mean age, 62 years, 13% women), 313 646 incident cases (40%) occurred during a mean follow-up of 3.9 years. Equations for the 5-year risk of reduced eGFR included age, sex, race/ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, body mass index, and albuminuria concentration. For participants with diabetes, the models also included diabetes medications, hemoglobin A(1c), and the interaction between the 2. The risk equations had a median C statistic for the 5-year predicted probability of 0.845 (interquartile range [IQR], 0.789-0.890) in the cohorts without diabetes and 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes. Calibration analysis showed that 9 of 13 study populations (69%) had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25.CONCLUSIONS AND RELEVANCE Equations for predicting risk of incident chronic kidney disease developed from more than 5 million individuals from 34 multinational cohorts demonstrated high discrimination and variable calibration in diverse populations. Further study is needed to determine whether use of these equations to identify individuals at risk of developing chronic kidney disease will improve clinical care and patient outcomes.
Published: 2019

17. Socioeconomic factors and mortality in patients with atrial fibrillation-a cohort study in Swedish primary care

Author: Johan Ärnlöv, Axel C. Carlsson, Kristina Sundquist, Danijela Gasevic, Martin J. Holzmann, Jan Sundquist, and Per Wändell
Subjects: Male, medicine.medical_specialty, Databases, Factual, 030204 cardiovascular system & hematology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Atrial Fibrillation, medicine, Single person, Electronic Health Records, Humans, cardiovascular diseases, 030212 general & internal medicine, Myocardial infarction, Socioeconomic status, Aged, Proportional Hazards Models, Socioeconomic Determinants, Aged, 80 and over, Sweden, Primary Health Care, Proportional hazards model, business.industry, Public Health, Environmental and Occupational Health, Klinisk medicin, Atrial fibrillation, Middle Aged, medicine.disease, Comorbidity, Social Class, Marital status, Female, Clinical Medicine, business, Cohort study
Abstract: Background:Preventing ischaemic stroke attracts significant focus in atrial fibrillation (AF) cases. Less is known on the association between socioeconomic factors and mortality and cardiovascular outcomes in patients with AF.Methods:Our study population included adults (n=12 283) ≥45 years diagnosed with AF at 75 primary care centres in Sweden 2001-07. Cox regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between the exposures educational level, marital status, neighbourhood socioeconomic status and the outcomes all-cause mortality, after adjustment for age, and comorbid cardiovascular conditions.Results:During a mean of 5.8 years (SD 2.4) of follow-up, 3954 (32.3%) patients had died; 1971 were women (35.0%) and 1983 were men (29.8%). Higher educational level was associated with a reduced mortality in fully adjusted models: HR 0.85 (95% CI 0.77-0.96) for secondary school in men, HR 0.73 (95% CI 0.60-0.88) for college/university in women, and HR 0.82 (95% CI 0.71-0.94) for college/university in men, compared to primary school. Unmarried men and divorced men had an increased risk of death, compared with married men: HR 1.25 (95% CI 1.05-1.50), and HR 1.23 (95% CI 1.07-1.42), respectively. College/university education level was also associated with lower risk of myocardial infarction in men and women, and lower risk of congestive heart failure in women.Conclusion:More attention could be paid to individuals of lower levels of formal education, and unmarried men, in order to provide timely management for AF and prevent its debilitating complications.
Published: 2018

18. Circulating proteins as predictors of cardiovascular mortality in end-stage renal disease

Author: Darren Green, Nicolas Vuilleumier, Tove Fall, Abdul Rashid Qureshi, Peter Stenvinkel, Johan Ärnlöv, Peter Bárány, Tobias Feldreich, Jonas Ripsweden, Axel C. Carlsson, Olof Heimbürger, Christoph Nowak, Juan Jesus Carrero, and Philip A. Kalra
Subjects: Nephrology, Proteomics, Male, Time Factors, medicine.medical_treatment, 030232 urology & nephrology, 030204 cardiovascular system & hematology, Gastroenterology, 0302 clinical medicine, Risk Factors, Urologi och njurmedicin, Prevalence, Medicine, Hepatitis A Virus Cellular Receptor 1, ddc:616, Incidence, Hazard ratio, Middle Aged, CVD, Prognosis, 3. Good health, Cardiovascular Diseases, Cohort, Original Article, Female, Hemodialysis, Adult, medicine.medical_specialty, Risk Assessment, End stage renal disease, 03 medical and health sciences, Renal Dialysis, Internal medicine, Urology and Nephrology, Humans, ESRD, Dialysis, Aged, Sweden, business.industry, Proportional hazards model, Klinisk medicin, medicine.disease, Kidney Transplantation, Kidney Failure, Chronic, Clinical Medicine, business, Biomarkers, Kidney disease
Abstract: Introduction Proteomic profiling of end-stage renal disease (ESRD) patients could lead to improved risk prediction and novel insights into cardiovascular disease mechanisms. Plasma levels of 92 cardiovascular disease-associated proteins were assessed by proximity extension assay (Proseek Multiplex CVD-1, Olink Bioscience, Uppsala, Sweden) in a discovery cohort of dialysis patients, the Mapping of Inflammatory Markers in Chronic Kidney disease cohort [MIMICK; n = 183, 55% women, mean age 63 years, 46 cardiovascular deaths during follow-up (mean 43 months)]. Significant results were replicated in the incident and prevalent hemodialysis arm of the Salford Kidney Study [SKS dialysis study, n = 186, 73% women, mean age 62 years, 45 cardiovascular deaths during follow-up (mean 12 months)], and in the CKD5-LD-RTxcohort with assessments of coronary artery calcium (CAC)-score by cardiac computed tomography (n = 89, 37% women, mean age 46 years). Results In age and sex-adjusted Cox regression in MIMICK, 11 plasma proteins were nominally associated with cardiovascular mortality (in order of significance: Kidney injury molecule-1 (KIM-1), Matrix metalloproteinase-7, Tumour necrosis factor receptor 2, Interleukin-6, Matrix metalloproteinase-1, Brain-natriuretic peptide, ST2 protein, Hepatocyte growth factor, TNF-related apoptosis inducing ligand receptor-2, Spondin-1, and Fibroblast growth factor 25). Only plasma KIM-1 was associated with cardiovascular mortality after correction for multiple testing, but also after adjustment for dialysis vintage, cardiovascular risk factors and inflammation (hazard ratio) per standard deviation (SD) increase 1.84, 95% CI 1.26–2.69, p = 0.002. Addition of KIM-1, or nine of the most informative proteins to an established risk-score (modified AROii CVM-score) improved discrimination of cardiovascular mortality risk from C = 0.777 to C = 0.799 and C = 0.823, respectively. In the SKS dialysis study, KIM-1 predicted cardiovascular mortality in age and sex adjusted models (hazard ratio per SD increase 1.45, 95% CI 1.03–2.05, p = 0.034) and higher KIM-1 was associated with higher CACscores in the CKD5-LD-RTx-cohort. Conclusions Our proteomics approach identified plasma KIM-1 as a risk marker for cardiovascular mortality and coronary artery calcification in three independent ESRD-cohorts. The improved risk prediction for cardiovascular mortality by plasma proteomics merit further studies. Electronic supplementary material The online version of this article (10.1007/s40620-018-0556-5) contains supplementary material, which is available to authorized users.
Published: 2018

19. Cathepsin B and S as markers for cardiovascular risk and all-cause mortality in patients with stable coronary heart disease during 10 years: a CLARICOR trial sub-study

Author: Jørgen Hilden, Jonas Wuopio, Johan Ärnlöv, Janus Christian Jakobsen, Hans Jørn Kolmos, Erik Kjøller, Anders Larsson, Ahmad Sajadieh, Jens Kastrup, Carl Bring, Axel C. Carlsson, Christian Gluud, Gorm B. Jensen, and Per Winkel
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Proteases, Denmark, Ischemic heart disease, Cardiovascular biomarkers, Myocardial Infarction, Coronary Disease, 030204 cardiovascular system & hematology, Gastroenterology, Cathepsin B, Cathepsin, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Clarithromycin, Internal medicine, medicine, Humans, In patient, Angina, Unstable, Registries, Mortality, Aged, Proportional Hazards Models, Peripheral Vascular Diseases, business.industry, Middle Aged, Atherosclerosis, Cardiovascular risk, Cathepsins, Cardiovascular biomarker, Coronary heart disease, Cerebrovascular Disorders, Treatment Outcome, 030104 developmental biology, Cardiovascular Diseases, Female, Lysosomes, Cardiology and Cardiovascular Medicine, business, All cause mortality, Follow-Up Studies, Glomerular Filtration Rate
Abstract: Background and aims: The lysosomal cysteine proteases cathepsin B and S have been implicated in the atherosclerotic process. The present paper investigates the association between serum levels of cathepsin B and S and cardiovascular events and mortality in patients with stable coronary heart disease. Methods: The CLARICOR trial is a randomised, placebo-controlled trial investigating the effect of clarithromycin versus placebo in patients with stable coronary heart disease. The outcome was time to either a cardiovascular event or all-cause mortality. The placebo group was used as discovery sample and the clarithromycin group as replication sample: n = 1998, n = 1979; mean age (years) 65, 65; 31%, 30% women; follow-up for 10 years; number of composite outcomes n = 1204, n = 1220; respectively. We used a pre-defined multivariable Cox regression model adjusting for inflammation, established cardiovascular risk factors, kidney function, and use of cardiovascular drugs. Results: Cathepsin B was associated with an increased risk of the composite outcome in both samples after multivariable adjustment (discovery: multivariable ratio (HR) per standard deviation increase 1.12, 95% confidence interval (CI) 1.05–1.19, p < 0.001, replication; HR 1.14, 95% CI 1.07–1.21, p < 0.001). There was no significant association between cathepsin S and the composite outcome in either the discovery or replication sample after multivariable adjustment (p>0.45). Secondary analyses suggest that cathepsin B was predominantly associated with mortality rather than specific cardiovascular events. Conclusions: Cathepsin B, but not serum cathepsin S, was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease. The clinical implications of our findings remain to be established.
Published: 2018

20. Cystatin C predicts long term mortality better than creatinine in a nationwide study of intensive care patients

Author: Johanna Helmersson-Karlqvist, Miklos Lipcsey, Johan Ärnlöv, Bo Ravn, Alain Dardashti, Max Bell, and Anders Larsson
Subjects: Male, medicine.medical_specialty, Anestesi och intensivvård, Time Factors, Critical Care, Science, Urology, Renal function, 030204 cardiovascular system & hematology, urologic and male genital diseases, Article, 03 medical and health sciences, chemistry.chemical_compound, Prognostic markers, 0302 clinical medicine, Intensive care, Urologi och njurmedicin, Urology and Nephrology, Medicine, Humans, 030212 general & internal medicine, Cystatin C, Mortality, reproductive and urinary physiology, Aged, Creatinine, Multidisciplinary, Kidney diseases, Anesthesiology and Intensive Care, biology, business.industry, Proportional hazards model, Middle Aged, female genital diseases and pregnancy complications, chemistry, Decreased glomerular filtration rate, Risk factors, biology.protein, Long term mortality, Female, Cystatin, business, Glomerular Filtration Rate
Abstract: Decreased glomerular filtration rate (GFR) is linked to poor survival. The predictive value of creatinine estimated GFR (eGFR) and cystatin C eGFR in critically ill patients may differ substantially, but has been less studied. This study compares long-term mortality risk prediction by eGFR using a creatinine equation (CKD-EPI), a cystatin C equation (CAPA) and a combined creatinine/cystatin C equation (CKD-EPI), in 22,488 patients treated in intensive care at three University Hospitals in Sweden, between 2004 and 2015. Patients were analysed for both creatinine and cystatin C on the same blood sample tube at admission, using accredited laboratory methods. During follow-up (median 5.1 years) 8401 (37%) patients died. Reduced eGFR was significantly associated with death by all eGFR-equations in Cox regression models. However, patients reclassified to a lower GFR-category by using the cystatin C-based equation, as compared to the creatinine-based equation, had significantly higher mortality risk compared to the referent patients not reclassified. The cystatin C equation increased C-statistics for death prediction (p p = 0.013 vs. combined equation). In conclusion, this data favours the sole cystatin C equation rather than the creatinine or combined equations when estimating GFR for risk prediction purposes in critically ill patients.
Published: 2021

21. Large-Scale Plasma Protein Profiling of Incident Myocardial Infarction, Ischemic Stroke, and Heart Failure

Author: Themistocles L. Assimes, Daniela Zanetti, Lars Lind, Johan Ärnlöv, Stefan Gustafsson, and Martin Ingelsson
Subjects: Male, medicine.medical_specialty, medicine.drug_class, Myocardial Infarction, heart failure, Disease, proteomics, cardiovascular disease, Internal medicine, medicine, Natriuretic peptide, Diseases of the circulatory (Cardiovascular) system, Humans, Cardiac and Cardiovascular Systems, Myocardial infarction, Longitudinal Studies, Stroke, Aged, Ischemic Stroke, Proportional Hazards Models, Heart Failure, Kardiologi, business.industry, Proportional hazards model, Incidence, Blood Proteins, medicine.disease, Blood proteins, stroke, myocardial infarction, Heart Disease Risk Factors, RC666-701, Heart failure, Cardiology, GDF15, Cardiology and Cardiovascular Medicine, business
Abstract: Background We recently reported a link between plasma levels of 2 of 84 cardiovascular disease (CVD)–related proteins and the 3 major CVDs, myocardial infarction, ischemic stroke, and heart failure. The present study investigated whether measurement of almost 10 times the number of proteins could lead to discovery of additional risk markers for CVD. Methods and Results We measured 742 proteins using the proximity extension assay in 826 male participants of ULSAM (Uppsala Longitudinal Study of Adult Men) who were free from CVD at the age of 70 years. Cox proportional hazards models were adjusted for age only, as well as all traditional risk factors. During a 12.5‐year median follow‐up (maximal, 22.0 years), 283 incident CVDs occurred. Forty‐one proteins were significantly (false discovery rate P =0.0038). Conclusions Large‐scale proteomics seem useful for the discovery of new risk markers for CVD and to improve risk prediction in an elderly population of men. Further studies are needed to replicate the findings in independent samples of both men and women of different ages.
Published: 2021

22. Plasma proteomics and lung function in four community-based cohorts

Author: P. Hedberg, Andreas Rydell, Karin Lisspers, Johan Ärnlöv, David Iggman, Christer Janson, Björn Ställberg, Erik Ingelsson, Christoph Nowak, Lars Lind, Johan Sundström, and Jerzy Leppert
Subjects: Lung Diseases, Male, Pulmonary and Respiratory Medicine, Proteomics, Growth Differentiation Factor 15, Respiratory Medicine and Allergy, Computational biology, FEV(1), Protein expression, 03 medical and health sciences, FEV1, 0302 clinical medicine, Mendelian randomization, Humans, Medicine, Cardiac and Cardiovascular Systems, Longitudinal Studies, 030212 general & internal medicine, Lung function, Aged, Maximal Expiratory Flow Rate, Lungmedicin och allergi, Community based, Kardiologi, Interleukin-6, Mechanism (biology), business.industry, Klinisk medicin, food and beverages, Mendelian Randomization Analysis, Middle Aged, Protein profiling, Cross-Sectional Studies, 030228 respiratory system, Linear Models, Female, Plasma proteomics, Clinical Medicine, business, Biomarkers, Genome-Wide Association Study
Abstract: BACKGROUND: Underlying mechanism leading to impaired lung function are incompletely understood. OBJECTIVES: To investigate whether protein profiling can provide novel insights into mechanisms leading to impaired lung function. METHODS: We used four community-based studies (n = 2552) to investigate associations between 79 cardiovascular/inflammatory proteins and forced expiratory volume in 1 s percent predicted (FEV1%) assessed by spirometry. We divided the cohorts into discovery and replication samples and used risk factor-adjusted linear regression corrected for multiple comparison (false discovery rate of 5%). We performed Mendelian randomization analyses using genetic and spirometry data from the UK Biobank (n = 421,986) to assess causality. MEASUREMENTS AND MAIN RESULTS: In cross-sectional analysis, 22 proteins were associated with lower FEV1% in both the discovery and replication sample, regardless of stratification by smoking status. The combined proteomic data cumulatively explained 5% of the variation in FEV1%. In longitudinal analyses (n = 681), higher plasma levels of growth differentiation factor 15 (GDF-15) and interleukin 6 (IL-6) predicted a more rapid 5-year decline in lung function (change in FEV1% per standard deviation of protein level -1.4, (95% CI, -2.5 to -0.3) for GDF-15, and -0.8, (95% CI, -1.5 to -0.2) for IL-6. Mendelian randomization analysis in UK-biobank provided support for a causal effect of increased GDF-15 levels and reduced FEV1%. CONCLUSIONS: Our combined approach identified GDF-15 as a potential causal factor in the development of impaired lung function in the general population. These findings encourage additional studies evaluating the role of GDF-15 as a causal factor for impaired lung function.
Published: 2021

23. Multicohort Metabolomics Analysis Discloses 9-Decenoylcarnitine to Be Associated With Incident Atrial Fibrillation

Author: Lars Lind, Tove Fall, Johan Sundström, Jessica E. Prenni, Corey D. Broeckling, Samira Salihovic, Patrik K. E. Magnusson, and Johan Ärnlöv
Subjects: Male, medicine.medical_specialty, Epidemiology, 030204 cardiovascular system & hematology, Bioinformatics, Risk Assessment, Mass Spectrometry, 03 medical and health sciences, 0302 clinical medicine, Metabolomics, Atrial Fibrillation, medicine, Humans, Cardiac and Cardiovascular Systems, atrial fibrillation, Carnitine, gene, Aged, Original Research, 030304 developmental biology, 0303 health sciences, Kardiologi, business.industry, Decenoylcarnitine, carnitine, Klinisk medicin, Atrial fibrillation, Mendelian Randomization Analysis, medicine.disease, metabolomics, Metabolism, Echocardiography, Female, epidemiology, Clinical Medicine, Cardiology and Cardiovascular Medicine, business, Biomarkers, Chromatography, Liquid, Genome-Wide Association Study, medicine.drug
Abstract: Background The molecular mechanisms involved in atrial fibrillation are not well known. We used plasma metabolomics to investigate if we could identify novel biomarkers and pathophysiological pathways of incident atrial fibrillation. Methods and Results We identified 200 endogenous metabolites in plasma/serum by nontargeted ultra‐performance liquid chromatography coupled to time‐of‐flight mass spectrometry in 3 independent population‐based samples (TwinGene, n=1935, mean age 68, 43% females; PIVUS [Prospective Investigation of the Vasculature in Uppsala Seniors], n=897, mean age 70, 51% females; and ULSAM [Uppsala Longitudinal Study of Adult Men], n=1118, mean age 71, all males), with available data on incident atrial fibrillation during 10 to 12 years of follow‐up. A meta‐analysis of ULSAM and PIVUS was used as a discovery sample and TwinGene was used for validation. In PIVUS, we also investigated associations between metabolites of interest and echocardiographic indices of myocardial geometry and function. Genome‐wide association studies were performed in all 3 cohorts for metabolites of interest. In the meta‐analysis of PIVUS and ULSAM with 430 incident cases, 4 metabolites were associated with incident atrial fibrillation at a false discovery rate P =0.0061). A meta‐analysis of all 3 cohorts disclosed another 4 significant metabolites. In PIVUS, 9‐decenoylcarnitine was related to left atrium size and left ventricular mass. A Mendelian randomization analysis did not suggest a causal role of 9‐decenoylcarnitine in atrial fibrillation. Conclusions A nontargeted metabolomics analysis disclosed 1 novel replicated biomarker for atrial fibrillation, 9‐Decenoylcarnitine, but this acetylcarnitine is likely not causally related to atrial fibrillation.
Published: 2021

24. Plasma Protein Profile of Incident Myocardial Infarction, Ischemic Stroke, and Heart Failure in 2 Cohorts

Author: Johan Sundström, Lars Lind, and Johan Ärnlöv
Subjects: Male, Proteomics, Time Factors, Proteome, Epidemiology, Myocardial Infarction, heart failure, 030204 cardiovascular system & hematology, 0302 clinical medicine, Risk Factors, Cardiovascular Disease, Medicine, Cardiac and Cardiovascular Systems, Myocardial infarction, Longitudinal Studies, Prospective Studies, Stroke, Original Research, Aged, 80 and over, 0303 health sciences, Kardiologi, Incidence, Blood Proteins, Prognosis, Blood proteins, stroke, myocardial infarction, Cardiology, Female, epidemiology, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Risk Assessment, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, Humans, 030304 developmental biology, Aged, Ischemic Stroke, Sweden, business.industry, medicine.disease, Heart failure, Ischemic stroke, Etiology, business, protein, Biomarkers
Abstract: Background The aim is to study common etiological pathways for 3 major cardiovascular diseases (CVD), as reflected in multiple proteins. Methods and Results Eighty‐four proteins were measured using the proximity extension technique in 870 participants in the PIVUS (Prospective Investigation of Uppsala Seniors Study) cohort on 3 occasions (age 70, 75, and 80 years). The sample was followed for incident myocardial infarction, ischemic stroke or heart failure. The same proteins were measured in an independent validation sample, the ULSAM (Uppsala Longitudinal Study of Adult Men) cohort in 595 participants at age 77. During a follow‐up of up to 15 years in PIVUS and 9 years in ULSAM, 222 and 167 individuals experienced a CVD. Examining associations with the 3 outcomes separately in a meta‐analysis of the 2 cohorts, 6 proteins were related to incident myocardial infarction, 25 to heart failure, and 8 proteins to ischemic stroke following adjustment for traditional risk factors. Growth differentiation factor 15 and tumor necrosis factor‐related apoptosis‐inducing ligand receptor 2 were related to all 3 CVDs. Including estimated glomerular filtration rate in the models attenuated some of these relationships. Fifteen proteins were related to a composite of all 3 CVDs using a discovery/validation approach when adjusting for traditional risk factors. A selection of 7 proteins by lasso in PIVUS improved discrimination of incident CVD by 7.3% compared with traditional risk factors in ULSAM. Conclusions We discovered and validated associations of multiple proteins with incident CVD. Only a few proteins were associated with all 3 diseases: myocardial infarction, ischemic stroke, and heart failure.
Published: 2021

25. Estimated salt intake and risk of atrial fibrillation in a prospective community-based cohort

Author: Johan Ärnlöv, Marju Orho-Melander, Christoph Nowak, and Jonas Wuopio
Subjects: dietary salt, 0301 basic medicine, Adult, Male, medicine.medical_specialty, hypertension, 030204 cardiovascular system & hematology, Excretion, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Risk Factors, Internal medicine, Atrial Fibrillation, Internal Medicine, medicine, Humans, atrial fibrillation, Cardiac and Cardiovascular Systems, Prospective Studies, Risk factor, Salt intake, Sodium Chloride, Dietary, Aged, Proportional Hazards Models, Kardiologi, Proportional hazards model, business.industry, Hazard ratio, Klinisk medicin, blood pressure, Public Health, Global Health, Social Medicine and Epidemiology, Atrial fibrillation, Original Articles, Middle Aged, medicine.disease, Kawasaki formulae, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 030104 developmental biology, Blood pressure, Cohort, Hypertension, Original Article, Female, Clinical Medicine, sodium excretion, business, Follow-Up Studies
Abstract: Introduction: Hypertension predisposes to atrial fibrillation (AF) – a major risk factor for ischaemic stroke. Since a high dietary salt consumption is associated with hypertension, we investigated the association between urinary sodium excretion as a marker for dietary sodium intake and risk of new-onset AF in community-dwelling adults. Method: The UK Biobank includes 40- to 69-year-old British residents recruited 2006–2010. Participants were divided into sex-specific quintiles according to 24-hour sodium excretion estimated based on spot samples with the Kawasaki equation. We excluded participants with AF at baseline. Cox regression adjusted for cardiovascular risk factors was used to assess associations with risk of AF, using the third quintile as reference. Results: A total of 257 545 women and 215 535 men were included. During up to 10 years' follow-up, 2221 women and 3751 men were diagnosed with AF. There was a tendency for an increased risk of AF in the lowest and highest quintiles of estimated daily salt intake in both women and men. In the fully adjusted model, significant associations were seen amongst men in the lowest and highest quintiles of sodium excretion (hazard ratio, HRQv1, 1.20; 95% CI, 1.08–1.32, P < 0.001, and HRQv5 1.15, 95% CI, 1.03–1.27, P = 0.011). Conclusion: We found evidence for a U-shaped association between estimated daily salt intake and AF risk amongst men. A suggestive J-shaped association in women was not statistically confirmed, but analyses were likely underpowered. Our results suggest that above a certain physiological minimum level progressively higher salt intake is associated with increasing risk of AF. (Less)
Published: 2020

26. Kidney Disease Biomarkers Improve Heart Failure Risk Prediction in the General Population

Author: Johan Ärnlöv and Christoph Nowak
Subjects: Adult, Male, medicine.medical_specialty, Population, Renal function, 030204 cardiovascular system & hematology, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Risk Factors, Internal medicine, Medicine, Albuminuria, Humans, 030212 general & internal medicine, Cystatin C, education, Renal biomarkers, Aged, Heart Failure, education.field_of_study, Kidney, business.industry, Incidence, Middle Aged, medicine.disease, medicine.anatomical_structure, Heart failure, Creatinine, Cardiology, Female, Kidney Diseases, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Biomarkers, Kidney disease, Glomerular Filtration Rate
Abstract: Background: The kidneys play an important role in heart failure (HF), but it is unclear if renal biomarkers improve HF risk prediction beyond established risk factors. We aimed to assess whether adding biomarkers of kidney disease to conventional risk factors improved 10-year risk prediction for incident HF in a contemporary community sample. Methods: We included 450 212 participants in the UK Biobank aged 39 to 70 years without HF who had been assessed in 2006 to 2010 with the urine albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C. There were 1701 incident cases of HF during up to 10.3 years of follow-up (mean 8.2±0.7 years). We used the Atherosclerosis Risk in Communities study heart failure risk score excluding natriuretic peptides as the base model to which we added eGFR and urine albumin-to-creatinine ratio. Harrell’s C-statistic of ARIC-HF was 0.845 (95% CI, 0.831–0.859). Results: Each combination of added kidney measures (creat-eGFR, cysC-eGFR, and urine albumin-to-creatinine ratio) led to significant improvement in risk discrimination, calibration, and reclassification. The optimal pair of added kidney measures was cysC-eGFR and urine albumin-to-creatinine ratio (ΔC=0.019 [95% CI, 0.015–0.022]). Addition of cysC-eGFR made the largest contribution to reclassification improvement (continuous net reclassification improvement 0.323 [95% CI, 0.278–0.360]). Conclusions: In a large community sample, the addition of kidney disease markers to conventional risk factors improved prediction of 10-year HF risk. Our results support including kidney disease markers in the identification of persons at highest risk of HF and demonstrate a possible role of impaired kidney function in HF development in asymptomatic persons.
Published: 2020

27. Impaired kidney function is associated with lower quality of life among community-dwelling older adults : The screening for CKD among older people across Europe (SCOPE) study

Author: Fabrizia Lattanzio, Rafael Moreno-Gonzalez, Yehudit Melzer, Johan Ärnlöv, Gerhard Wirnsberger, Andrea Corsonello, Axel C. Carlsson, Robert Kob, Francesco U.S. Mattace-Raso, Regina Roller-Wirnsberger, Francesc Formiga, Tomasz Kostka, Agnieszka Guligowska, Paolo Fabbietti, Pedro Gil, Lisanne Tap, Itshak Melzer, Rada Artzi-Medvedik, Ellen Freiberger, Sara Lainez Martinez, and Internal Medicine
Subjects: Quality of life, medicine.medical_specialty, Old adults, Geriatrik, 030232 urology & nephrology, Kidney, Persones grans, 03 medical and health sciences, 0302 clinical medicine, Lower urinary tract symptoms, Internal medicine, Diabetes mellitus, Chronic kidney disease, Chronic renal failure, medicine, Humans, Gerontologi, medicinsk/hälsovetenskaplig inriktning, 030212 general & internal medicine, Gerontology, specialising in Medical and Health Sciences, Renal Insufficiency, Chronic, Aged, Geriatrics, Polypharmacy, Aged, 80 and over, COPD, business.industry, Klinisk medicin, medicine.disease, 3. Good health, Europe, Qualitat de vida, Insuficiència renal crònica, Quality of Life, Geriatric Depression Scale, Female, Independent Living, Older people, Clinical Medicine, Geriatrics and Gerontology, business, Kidney disease, Glomerular Filtration Rate
Abstract: Background Quality of life (QoL) refers to the physical, psychological, social and medical aspects of life that are influenced by health status and function. The purpose of this study was to measure the self-perceived health status among the elderly population across Europe in different stages of Chronic Kidney Disease (CKD). Methods Our series consisted of 2255 community-dwelling older adults enrolled in the Screening for Chronic Kidney Disease (CKD) among Older People across Europe (SCOPE) study. All patients underwent a comprehensive geriatric assessment (CGA), including included demographics, clinical and physical assessment, number of medications taken, family arrangement, Geriatric Depression Scale (GDS), Cumulative Illness Rating Scale, History of falls, Lower urinary tract symptoms, and Short Physical Performance Battery (SPPB). Estimated glomerular filtration rate (eGFR) was calculated by Berlin Initiative Study (BIS) equation. Quality of life was assessed by Euro Qol questionnaire (Euro-Qol 5D) and EQ-Visual Analogue Scale (EQ-VAS). The association between CKD (eGFR 2) and low EQoL-VAS was investigated by multivariable logistic regression models. Results CKD was found to be significantly associated with low EQoL-VAS in crude analysis (OR = 1.47, 95%CI = 1.16–1.85 for eGFR Conclusions CKD may significantly affect QoL in community-dwelling older adults. Physical performance, polypharmacy, diabetes, hypertension and COPD may affect such association, which suggests that the impact of CKD on QoL is likely multifactorial and partly mediated by co-occurrent conditions/risk factors.
Published: 2020

28. Global Plasma Metabolomics to Identify Potential Biomarkers of Blood Pressure Progression

Author: Tove Fall, Samira Salihovic, Johan Sundström, Lars Lind, Johan Ärnlöv, Yi-Ting Lin, Erik Ingelsson, and Ulf Hammar
Subjects: Male, 0301 basic medicine, hypertension, body mass index, Blood Pressure, 030204 cardiovascular system & hematology, Ceramides, Bioinformatics, Article, 03 medical and health sciences, 0302 clinical medicine, Metabolomics, Humans, Medicine, Triglycerides, Aged, Aged, 80 and over, glomerular filtration rate, business.industry, Klinisk medicin, blood pressure, Middle Aged, medicine.disease, 030104 developmental biology, Blood pressure, oleic acid, Potential biomarkers, Pathophysiology of hypertension, Hypertension, Clinical Medicine, Cardiology and Cardiovascular Medicine, business, Biomarkers, Oleic Acid
Abstract: Objective: The pathophysiology of hypertension remains incompletely understood. We investigated associations of circulating metabolites with longitudinal blood pressure (BP) changes in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort and validated the findings in the Uppsala Longitudinal Study of Adult Men cohort. Approach and Results: Circulating metabolite levels were assessed with liquid- and gas-chromatography coupled to mass spectrometry among persons without BP-lowering medication at baseline. We studied associations of baseline levels of metabolites with changes in BP levels and the clinical BP stage between baseline and a follow-up examination 5 years later. In the discovery cohort, we investigated 504 individuals that contributed with 757 observations of paired BP measurements. The mean baseline systolic and diastolic BPs were 144 (19.7)/76 (9.7) mm Hg, and change in systolic and diastolic BPs were 3.7 (15.8)/−0.5 (8.6) mm Hg over 5 years. The metabolites associated with diastolic BP change were ceramide, triacylglycerol, total glycerolipids, oleic acid, and cholesterylester. No associations with longitudinal changes in systolic BP or BP stage were observed. Metabolites with similar structures to the 5 top findings in the discovery cohort were investigated in the validation cohort. Diacylglycerol (36:2) and monoacylglycerol (18:0), 2 glycerolipids, were associated with diastolic BP change in the validation cohort. Conclusions: Circulating baseline levels of ceramide, triacylglycerol, total glycerolipids, and oleic acid were positively associated with longitudinal diastolic BP change, whereas cholesterylester levels were inversely associated with longitudinal diastolic BP change. Two glycerolipids were validated in an independent cohort. These metabolites may point towards pathophysiological pathways of hypertension.
Published: 2020

29. Kidney function and other factors and their association with falls updates The screening for CKD among older people across Europe (SCOPE) study

Author: Paolo Fabbietti, Ellen Freiberger, Pedro Gil, Andrea Corsonello, Axel C. Carlsson, Rada Artzi-Medvedik, Fabrizia Lattanzio, Tomasz Kostka, Agnieszka Guligowska, Itshak Melzer, Robert Kob, Regina Roller-Wirnsberger, Francesc Formiga, Johan Ärnlöv, Sara Lainez Martinez, Gerhard Wirnsberger, Lisanne Tap, Francesco U.S. Mattace-Raso, Rafael Moreno-Gonzalez, Sabine Britting, and Internal Medicine
Subjects: Male, Urinary incontinence, 030232 urology & nephrology, Poison control, Kidney, Fear of falling, Persones grans, 0302 clinical medicine, Activities of Daily Living, Medicine, Gerontologi, medicinsk/hälsovetenskaplig inriktning, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Aged, 80 and over, Geriatrics, Kidney diseases, Fear, 16. Peace & justice, 3. Good health, Europe, Female, Falls, medicine.symptom, medicine.medical_specialty, Geriatrik, End stage renal disease, 03 medical and health sciences, Kidney function, Lower urinary tract symptoms, Internal medicine, Injury prevention, Humans, Gerontology, specialising in Medical and Health Sciences, Renal Insufficiency, Chronic, Aged, Retrospective Studies, business.industry, Research, Klinisk medicin, Injurious falls, medicine.disease, Cross-Sectional Studies, Malalties del ronyó, Clinical Medicine, Older people, Geriatrics and Gerontology, business, Kidney disease
Abstract: Background Reduced kidney function has become a major public health concern, especially among older people, as Chronic Kidney Disease (CKD) is associated with increased risk of end stage renal disease and mortality. Falls are a serious negative health outcome in older persons with one third of people aged 65 years experiencing a fall per year and increasing fall rates with increasing age. The impact of CKD on falls in older community-dwelling persons is not well investigated. Additionally, lower urinary tract symptoms (LUTS) may also increase the risk of falls. Therefore, our aim was to investigate the impact of CKD and LUTS on falls as well as on injurious falls. Methods The SCOPE study is an observational, multinational, multicenter, prospective cohort study involving community-dwelling older persons aged 75 years and more recruited from August 2016 to March 2018 in seven European countries. The main outcomes of the present study were any falls and any injurious falls during the 12 months before enrolment. The cross-sectional association of estimated glomerular filtration rate (eGFR) and LUTS with study outcomes was investigated by logistic regression analysis adjusted for baseline characteristics of enrolled subjects. Results Our series consisted of 2256 SCOPE participants (median age = 79.5 years, 55.7% female). Of them, 746 participants experienced a fall and 484 reported an injurious fall in the 12 months prior to baseline assessment. CKD was not significantly associated with falls (OR = 0.95, 95%CI = 0.79–1.14 for eGFROR = 1.02, 95%CI = 0.81–1.28 for eGFROR = 1.08, 95%CI = 0.74–1.57 for eGFROR = 0.91, 95%CI = 0.67–1.24 for eGFROR = 0.93, 95%CI = 0.63–1.37 for eGFROR = 1.19, 95%CI = 0.62–2.29 for eGFROR = 1.56, 95%CI = 1.29–1.89) and injurious falls (OR = 1.58, 95%CI = 1.14–2.19), and such associations were confirmed in all multivariable models. Conclusions Cross-sectional data suggest that CKD may not be associated with history of falls or injurious falls, whereas LUTS is significantly associated with the outcomes. Trial registration This study was registered on 25th February 2016 at clinicaltrials.gov (NCT02691546).
Published: 2020

30. Prevalence of sarcopenia in community-dwelling older adults using the updated EWGSOP2 definition according to kidney function and albuminuria : The Screening for CKD among Older People across Europe (SCOPE) study

Author: Regina Roller-Wirnsberger, Johan Ärnlöv, Cornel C. Sieber, Sara Lainez Martinez, Lisanne Tap, Gerhard Wirnsberger, Paolo Fabbietti, Pedro Gil, Tomasz Kostka, Agnieszka Guligowska, Rafael Moreno-Gonzalez, Xavier Corbella, Ellen Freiberger, Andrea Corsonello, Fabrizia Lattanzio, Itshak Melzer, Axel C. Carlsson, Yehudit Melzer, Francesc Formiga, Francesco U.S. Mattace-Raso, and Internal Medicine
Subjects: Male, Proteïnúria, Sarcopenia, 030232 urology & nephrology, Kidney, EWGSOP2, 0302 clinical medicine, Chronic kidney disease, Epidemiology, Activities of Daily Living, Prevalence, 030212 general & internal medicine, Prospective Studies, Estimated glomerular filtration rate, Prospective cohort study, Geriatrics, Aged, 80 and over, Kidney diseases, Hand Strength, 3. Good health, Europe, Proteinuria, Older adults, Female, Independent Living, medicine.symptom, Bioelectrical impedance analysis, Glomerular Filtration Rate, medicine.medical_specialty, Geriatrik, Renal function, 03 medical and health sciences, Internal medicine, medicine, Humans, Albuminuria, Renal Insufficiency, Chronic, Aged, business.industry, Research, Klinisk medicin, medicine.disease, Cross-Sectional Studies, Malalties del ronyó, Geriatrics and Gerontology, Clinical Medicine, business, human activities, Kidney disease
Abstract: Background Loss of muscle mass and function may be more pronounced in older adults with chronic kidney disease (CKD) and with albuminuria. Thus, we investigated the prevalence of sarcopenia among community-dwelling older adults according to kidney function and grade of albuminuria. We also explored differences in the prevalence of sarcopenia according to three different equations for the estimation of glomerular filtration rate (eGFR). Methods A cross-sectional analysis of 1420 community-dwelling older adults (≥75 years old) included in the SCOPE study, a multicenter prospective cohort study, was conducted. Comprehensive geriatric assessment including short physical performance battery (SPPB), handgrip strength test and bioelectrical impedance analysis (BIA) was performed. Sarcopenia was defined using the updated criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2). eGFR was calculated using Berlin Initiative Study (BIS), Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) and Full Age Spectrum (FAS) equations, and urinary albumin-to-creatinine ratio (ACR) was collected to categorize CKD according to Kidney Disease Improving Global Outcomes guidelines. Results Median age was 79.5 years (77.0–83.0), 804 (56.6%) were women. Using EWGSOP2 definition, 150 (10.6%) participants met diagnostic criteria for sarcopenia. Moreover, 85 (6%) participants had severe sarcopenia. Sarcopenia was more prevalent in participants with more advanced stages of CKD according to BIS eq. (9.6% in stages 1 and 2 and 13.9% in stages 3a, 3b and 4, p = 0.042), and also according to CKD-EPI (9.8% vs. 14.2%, p = 0.042) and FAS although not reaching statistical signification (9.8% vs. 12.7%, p = 0.119). Thus, differences in prevalence are observed among CKD categories as estimated by different equations. Prevalence of sarcopenia was also higher with increasing albuminuria categories: 9.3% in normoalbuminuric, 13.2% in microalbuminuric and 16.8% in macroalbuminuric participants, (p = 0.019). Conclusions Sarcopenia is common among community-dwelling older adults, especially among those with more advanced CKD categories, with prevalence estimates differing slightly depending on the equation used for the estimation of eGFR; as well as among those with higher albuminuria categories.
Published: 2020

31. Non-targeted urine metabolomics and associations with prevalent and incident type 2 diabetes

Author: Corey D. Broeckling, Andrea Ganna, Johan Ärnlöv, Tove Fall, Lars Lind, Jessica E. Prenni, Erik Ingelsson, Samira Salihovic, Christian Berne, Christoph Nowak, Johan Sundström, Institute for Molecular Medicine Finland, Data Science Genetic Epidemiology Lab, and University of Helsinki
Subjects: 0301 basic medicine, Oncology, Male, BLOOD, endocrine system diseases, Metabolic disorders, lcsh:Medicine, Urine, Type 2 diabetes, ANNOTATION, MELLITUS, 0302 clinical medicine, Endocrinology, Risk Factors, Tandem Mass Spectrometry, Prevalence, lcsh:Science, RISK, Multidisciplinary, PLASMA, Incidence, Endocrine system and metabolic diseases, 3. Good health, Endokrinologi och diabetes, Metabolome, Biomarker (medicine), Female, medicine.medical_specialty, Urinary system, 030209 endocrinology & metabolism, Endocrinology and Diabetes, Article, 03 medical and health sciences, Metabolomics, Internal medicine, Diabetes mellitus, Carnitine, medicine, Humans, Aged, business.industry, lcsh:R, Case-control study, Klinisk medicin, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 2, 3121 General medicine, internal medicine and other clinical medicine, Case-Control Studies, lcsh:Q, Clinical Medicine, business, Biomarkers, Chromatography, Liquid
Abstract: Better risk prediction and new molecular targets are key priorities in type 2 diabetes (T2D) research. Little is known about the role of the urine metabolome in predicting the risk of T2D. We aimed to use non-targeted urine metabolomics to discover biomarkers and improve risk prediction for T2D. Urine samples from two community cohorts of 1,424 adults were analyzed by ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). In a discovery/replication design, three out of 62 annotated metabolites were associated with prevalent T2D, notably lower urine levels of 3-hydroxyundecanoyl-carnitine. In participants without diabetes at baseline, LASSO regression in the training set selected six metabolites that improved prediction of T2D beyond established risk factors risk over up to 12 years' follow-up in the test sample, from C-statistic 0.866 to 0.892. Our results in one of the largest non-targeted urinary metabolomics study to date demonstrate the role of the urine metabolome in identifying at-risk persons for T2D and suggest urine 3-hydroxyundecanoyl-carnitine as a biomarker candidate.
Published: 2020

32. TNFR1 is associated with short-term mortality in patients with diabetes and acute dyspnea seeking care at the emergency department

Author: Anders Larsson, Johan Ärnlöv, Torgny Wessman, Olle Melander, Axel C. Carlsson, Thoralph Ruge, and Per Wändell
Subjects: Male, Time Factors, Endocrinology, Diabetes and Metabolism, Short term mortality, 030204 cardiovascular system & hematology, 0302 clinical medicine, Endocrinology, Cardiac and Cardiovascular Systems, Hospital Mortality, Aged, 80 and over, Kardiologi, Diabetes, General Medicine, Middle Aged, Hälsovetenskaper, respiratory system, Prognosis, Triage level, Receptors, Tumor Necrosis Factor, Type I, Acute Disease, Endokrinologi och diabetes, Female, Original Article, Emergency Service, Hospital, Acute dyspnea, Tumor necrosis factor receptor, Adult, medicine.medical_specialty, Soluble tumor necrosis factor alpha (TNFR), Renal function, Endocrinology and Diabetes, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Health Sciences, Diabetes Mellitus, Internal Medicine, medicine, Humans, In patient, Mortality, Aged, business.industry, 030208 emergency & critical care medicine, Emergency department, medicine.disease, Cross-Sectional Studies, Dyspnea, business, Biomarkers, Biomedical sciences
Abstract: Background Circulating levels of TNF alpha receptor 1 (TNFR1) and 2 (TNFR2) are associated with increased long-term mortality and impaired kidney function. Aim To study association between circulating levels of TNFR1 and TNFR2 and short-term mortality in patients with diabetes and dyspnea. Population and methods Patients aged ≥ 18 years seeking at emergency department (ED) during daytime on weekdays between December 2013 and July 2018, with diabetes and acute dyspnea, identified at the triage process, were included. Participants (n = 291) were triaged according to Medical Emergency Triage and Treatment System-Adult score, and blood samples were collected. Association between TNFR1 and TNFR2, respectively, and 90-day mortality were estimated by Cox regression models adjusted for age, sex, BMI, creatinine and CRP. Results Univariate models showed significant associations between TNFR1 and TNFR2, respectively, and CRP, age and creatinine. TNFR1 and TNFR2 tended to be elevated in patients with the highest triage level, compared to patients with lower triage levels (ns). In longitudinal analyses, TNFR1 but not TNFR2 was associated with increased short-term mortality, HR adjusted for age, BMI and creatinine 1.43 (95% CI 1.07–1.91), but not in the model also adjusted for CRP, HR 1.29 (95% CI 0.94–1.77). In secondary analysis for quartile 4 versus quartiles 1–3 of TNFR1, corresponding HRs were 2.46 (95% CI 1.27–5.15) and 2.21 (95% CI 1.07–2.56). Conclusions We found a trend for the association between circulating TNFR1 levels and short-term mortality in patients with diabetes and acute dyspnea at the ED, possibly suggesting an inflammatory pathway for the association.
Published: 2020

33. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Author: Sorin Hostiuc, Shaun Wen Huey Lee, Jorge R. Ledesma, Carsten Flohr, Masoumeh Sadeghi, João Mauricio Castaldelli-Maia, Behzad Karami Matin, Cyrus Alinia, Mehdi Bohluli, Félix Carvalho, Yun Jin Kim, Catalina Liliana Andrei, Seyyed Meysam Mousavi, Bernhard T. Baune, Ehsan Ahmadpour, Dinh-Toi Chu, Beatrix Haddock, Gianfranco Alicandro, Vasily Vlassov, Mohammad Taghi Khodayari, Gianna Gayle Herrera Amul, Arash Tehrani-Banihashemi, Govinda Prasad Dhungana, Fereshteh Ansari, Michael K. Hole, Azeem Majeed, Iman Halvaei, Saqib Ali, Arianna Maever L. Amit, Tomas Y. Yeheyis, John S. Ji, Martin McKee, Jamileh Shadid, Leonardo Roever, Peng Jia, Ettore Beghi, Pablo M. Lavados, Young Eun Kim, Vahid Alipour, Sowmya J. Rao, Ahmad Daryani, Cathleen Keller, Ibrahim Abdollahpour, Nicole K. DeCleene, Ebrahim Babaee, Saman Esmaeilnejad, Boris Bikbov, William M. Gardner, Lydia M. Haile, Luca Ronfani, Azalea M. Thomson, Irena Ilic, Ruth W. Kimokoti, Yingxi Zhao, Guoqing Hu, Mehran Shams-Beyranvand, Ilais Moreno Velásquez, Nathaniel J. Henry, Brijesh Sathian, Daniel Kim, Peter Memiah, Mohammad Hadi Abbasi, Andrea Farioli, Zahra Kamiab, Bolajoko O. Olusanya, Matthew C. Doxey, Tommi Vasankari, Hamideh Salimzadeh, Luisa Sorio Flor, Priya Rathi, Shanshan Li, Tanvir M. Huda, Dillon O Sylte, Rosario Cárdenas, Agegnehu Bante, Helen Ippolito, Alyssa Acebedo, Jeffrey D. Stanaway, Anwar Faraj, João Pedro Silva, Amin Mousavi Khaneghah, Pushpendra Kumar, Sangram Kishor Patel, Josephine W. Ngunjiri, Holly E. Erskine, Eugene Sobngwi, Filippo Ariani, Shane D. Morrison, Mohammad Aghaali, Meghan D. Mooney, Vera Marisa Costa, Palash Chandra Banik, Rupak Desai, Ken Takahashi, Maigeng Zhou, Morteza Oladnabi, Bogdan Oancea, Daniela Ribeiro, Mohammad Farahmand, Irmina Maria Michalek, Yetunde O. John-Akinola, Khem Narayan Pokhrel, Emilie R Maddison, Syed Mohamed Aljunid, Damian G. Hoy, Hosni Salem, V. Prakash, Shuhei Nomura, Inga Dora Sigfusdottir, Anders Larsson, Sharareh Eskandarieh, Abdollah Mohammadian-Hafshejani, Somayeh Bohlouli, Joana Morgado-da-Costa, Siamak Sabour, Theo Vos, Han Yong Wunrow, Khaled Khatab, Alireza Zangeneh, Ann Kristin Knudsen, Marissa B Reitsma, Hannah J. Henrikson, Randah R. Hamadeh, Tuomo J. Meretoja, Ireneous N. Soyiri, Giuseppe Grosso, Ziyad Al-Aly, Taraneh Yousefinezhadi, Joseph L Ward, Roba Khundkar, Ricardo Santiago Gomez, Reza Malekzadeh, John J. McGrath, Sandra B. Munro, Shahin Soltani, Amy E. Peden, Rufus Akinyemi, Marcel Ausloos, Naohiro Yonemoto, Bogdan Wojtyniak, Ahmad Ghashghaee, Guilherme Borges, Sadia Bibi, Farhad Islami, Hamed Mirzaei, Mohammad Ali Sahraian, M. Ashworth Dirac, Hosna Janjani, Kairat Davletov, Hermann Brenner, Yuichiro Yano, Elissa M. Abrams, Ana Vukovic, Bartosz Miazgowski, Jobert Richie Nansseu, Jennifer O Lam, Mona Pathak, Leeberk Raja Inbaraj, Thirunavukkarasu Sathish, Asadollah Gholamian, Carlos A Castañeda-Orjuela, Babak Eshrati, Edgar Denova-Gutiérrez, Atte Meretoja, Lorenzo Monasta, Ronan A. Lyons, Neda Kianipour, Desalegn Getnet Demsie, Yasir Waheed, Desta Debalkie Atnafu, Davide Sattin, Kevin S Ikuta, Ghobad Moradi, Srinivas Goli, Krittika Bhattacharyya, Mika Kivimäki, Christopher Troeger, Jordi Alonso, Alireza Ahmadi, Navid Manafi, Caroline Stein, Songhomitra Panda-Jonas, Jason Nguyen, Moses K. Muriithi, Aziz Rezapour, Ismael R. Campos-Nonato, Adrian Pana, H. Dean Hosgood, Noore Alam, James L. Fisher, Mariam Molokhia, Susan F. Rumisha, Ernoiz Antriyandarti, Ayman Grada, Emma Nichols, Babak Asghari, André Luiz Sena Guimarães, Ferrán Catalá-López, Aletta E. Schutte, Fiona B. Bennitt, Maciej Banach, Antonio Biondi, Donal Bisanzio, Josip Car, Ronny Westerman, Shafiu Mohammed, Biniyam Sahiledengle Geberemariyam, Kenji Shibuya, Meghdad Pirsaheb, Milena Santric-Milicevic, Karen M. Tabb, Paula Moraga, Soheil Hassanipour, Hasan Yusefzadeh, Avina Vongpradith, Dara K. Mohammad, Ralph Maddison, Babak Moazen, Getachew Mullu Kassa, Rahman Shiri, Fernando Neves Hugo, Hmwe H Kyu, Zachary V Dingels, Florian Fischer, Valentin Yurievich Skryabin, Rafael Tabarés-Seisdedos, Massimo Cirillo, Nikita Otstavnov, Robert C. Reiner, Van C. Lansingh, Rodrigo Sarmiento-Suarez, Ashkan Afshin, Benjamin A Stark, Mohsen Abbasi-Kangevari, Natalie C. Galles, Behnam Heidari, Eun-Kee Park, Mohammad Ali Jahani, Suzanne Polinder, Mahalaqua Nazli Khatib, Farhad Jadidi-Niaragh, Amir Radfar, Mowafa Househ, Derrick A Bennett, Gaorui Guo, Hesam Ghiasvand, Taweewat Wiangkham, Tamás Joó, Cristiana Abbafati, Kathryn Mei Ming Lau, Anita K. Nandi, Miklós Szócska, Manasi Kumar, Eduardo A. Undurraga, Oladimeji M. Adebayo, Simon Yadgir, Victor Aboyans, Justin J. Lang, Catherine O. Johnson, Soewarta Kosen, Carla Sofia e.Sá Farinha, Marcos Roberto Tovani-Palone, Kamarul Imran Musa, Farshad Pourmalek, Kiomars Sharafi, Heather Orpana, Samuel B. Albertson, Mahdi Afshari, Nicholas J K Breitborde, Nelson J. Alvis-Zakzuk, Adrian Oţoiu, Iván Landires, Robert G. Weintraub, Kidanemaryam Berhe, André Faro, Sophia Emmons-Bell, Lauren E. Schaeffer, Alexandre C. Pereira, Mehdi Naderi, Yordanos Gizachew Yeshitila, Mehdi Hosseinzadeh, Arash Etemadi, Oleguer Plana-Ripoll, Theodore Patrick Younker, Joemer C. Maravilla, Alireza Ansari-Moghaddam, Borhan Mansouri, Narayanaswamy Venketasubramanian, Seyed Mohammad Kazem Aghamir, Linda Morales, Amanda Deen, Noushin Mohammadifard, Obinna Onwujekwe, Ai Koyanagi, Michele Nguyen, Chieh Han, Kiana Ramezanzadeh, Mika Shigematsu, Mohammed Shannawaz, Khurshid Alam, Javad Nazari, Bryan L. Sykes, Rajat Das Gupta, Stephen S Lim, Lingkan Barua, Zubair Kabir, Michael Brauer, Afarin Rahimi-Movaghar, Deepa Jahagirdar, Kaja Abbas, Gholamreza Bazmandegan, Mark A. Stokes, Rajaa Al-Raddadi, Kanyin L. Ong, Kate Causey, Ahmed Omar Bali, Matilde Leonardi, Jeffrey V. Lazarus, Wondimeneh Shibabaw Shiferaw, André Karch, Blair R. Bumgarner, Nelson Alvis-Guzman, Jennifer H MacLachlan, Saeed Amini, Parvaiz A Koul, Blessing J. Akombi, Ro Ting Lin, Dabere Nigatu, Alaa Badawi, Flavia M. Cicuttini, Deanna Anderlini, Claudio Alberto Dávila-Cervantes, Rupert R A Bourne, Tanuj Kanchan, Catherine P. Benziger, Tahiya Alam, M. Mofizul Islam, Muktar Omer Omer, Leila Zaki, Mehdi Mirzaei-Alavijeh, Inbal Salz, Katharine J Looker, Shiwei Liu, Fatemeh Amiri, Christopher R. Cederroth, Mitra Abbasifard, Hamidreza Pazoki Toroudi, Gbenga A. Kayode, Antonio Luiz Pinho Ribeiro, Krishna Kumar Aryal, Mu'awiyyah Babale Sufiyan, Mohamed M. Gad, Assefa Desalew, Lidia Morawska, Davood Anvari, Mohammad Reza Salahshoor, Hadi Pourjafar, Abdu A. Adamu, Maryam Adabi, Zulfiqar A. Bhutta, Jessica A. Cruz, Foad Abd-Allah, Amir Hasanzadeh, Jordan Weiss, Maryam Ghadimi, Seyed-Mohammad Fereshtehnejad, Serge Resnikoff, Joanna L Whisnant, Kelly Compton, Priya Parmar, Sanjay Basu, Leila R Kalankesh, Nickolas Reinig, Ana Maria Mantilla Herrera, Fatemeh Rajati, Damian Santomauro, Mojisola Oluwasanu, Sheikh Mohammed Shariful Islam, David M. Pereira, Joht Singh Chandan, Deepak Kumar Pasupula, Aristidis Tsatsakis, Hoa Thi Do, Whitney L. Teagle, Hans W. Hoek, James Leigh, Morteza Arab-Zozani, Yasser Vasseghian, Stephanie R M Zimsen, Charlie Ashbaugh, Fariba Dorostkar, Abdelrahman Ibrahim Abushouk, Mikk Jürisson, Golnaz Heidari, Kala M. Mehta, Saeed Shahabi, Sarah Wulf Hanson, Nizal Sarrafzadegan, Dharmesh Kumar Lal, Hai Quang Pham, Aleksandr Y. Aravkin, Joshua A. Salomon, David C. Schwebel, Milena Ilic, Kareha M Agesa, Jost B. 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L., Department of Public Health, Clinicum, Department of Neurosciences, HUS Comprehensive Cancer Center, Environmental Sciences, Public Health, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Value, Affordability and Sustainability (VALUE), Microbes in Health and Disease (MHD), Sálfræðideild (HR), Department of Psychology (RU), Samfélagssvið (HR), School of Social Sciences (RU), Háskólinn í Reykjavík, Reykjavik University, GBD 2019 Diseases and Injuries Collaborator, Violante FS, Department of Earth Observation Science, Faculty of Geo-Information Science and Earth Observation, and UT-I-ITC-ACQUAL
Subjects: Male, Life expectancy, Disability-Adjusted Life Year, Diseases, Disease, communicable disease, systematic analysis, Global Burden of Disease, 0302 clinical medicine, 80 and over, Medicine, 10. No inequality, Child, 11 Medical and Health Sciences, injuries, Aged, 80 and over, education.field_of_study, Sjúkdómar, DEMENTIA, FALLS, General Medicine, Forvarnir, 3. Good health, Child, Preschool, Human, GBD, Population health, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Humans, Global Burden of Disease Study, education, Aged, Spatial Analysis, Global burden, Disability, Prevention, DISABILITY, Infant, Spatial Analysi, Mortality rate, Global Burden of Disease, Diseases, Injuries, Systematic analysis, PREVENTION, Years of potential life lost, Risk factors, Disease study, ITC-ISI-JOURNAL-ARTICLE, RISK-FACTORS, Clinical Medicine, RA, Demography, Fötlun, Dánartíðni, Áhættuþættir, 030204 cardiovascular system & hematology, Risk Factors, Cause of Death, Global health, 030212 general & internal medicine, 1. No poverty, Disability-Adjusted Life Years, Public Health, Global Health, Social Medicine and Epidemiology, Middle Aged, 3142 Public health care science, environmental and occupational health, Adolescent, Adult, Age Distribution, Female, Infant, Newborn, Young Adult, Lýðheilsa, CLINICAL-TRIALS, Population, Settore MED/01 - Statistica Medica, diseases, ITC-HYBRID, Heilbrigðisvísindi, General & Internal Medicine, Mortality, Preschool, Disease burden, business.industry, Risk Factor, Klinisk medicin, Newborn, purl.org/pe-repo/ocde/ford#3.02.00 [https], Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Áverkar, Systematic analysis, NA, business
Abstract: Publisher's version (útgefin grein), Background In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990-2010 time period, with the greatest annualised rate of decline occurring in the 0-9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10-24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10-24 years were also in the top ten in the 25-49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50-74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and development investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd., Research reported in this publication was supported by the Bill & Melinda Gates Foundation; the University of Melbourne; Queensland Department of Health, Australia; the National Health and Medical Research Council, Australia; Public Health England; the Norwegian Institute of Public Health; St Jude Children's Research Hospital; the Cardiovascular Medical Research and Education Fund; the National Institute on Ageing of the National Institutes of Health (award P30AG047845); and the National Institute of Mental Health of the National Institutes of Health (award R01MH110163). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders. The authors alone are responsible for the views expressed in this Article and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated, the National Health Service (NHS), the National Institute for Health Research (NIHR), the UK Department of Health and Social Care, or Public Health England; the United States Agency for International Development (USAID), the US Government, or MEASURE Evaluation; or the European Centre for Disease Prevention and Control (ECDC). This research used data from the Chile National Health Survey 2003, 2009-10, and 2016-17. The authors are grateful to the Ministry of Health, the survey copyright owner, for allowing them to have the database. All results of the study are those of the authors and in no way committed to the Ministry. The Costa Rican Longevity and Healthy Aging Study project is a longitudinal study by the University of Costa Rica's Centro Centroamericano de Poblacion and Instituto de Investigaciones en Salud, in collaboration with the University of California at Berkeley. The original pre-1945 cohort was funded by the Wellcome Trust (grant 072406), and the 1945-55 Retirement Cohort was funded by the US National Institute on Aging (grant R01AG031716). The principal investigators are Luis Rosero-Bixby and William H Dow and co-principal investigators are Xinia Fernandez and Gilbert Brenes. The accuracy of the authors' statistical analysis and the findings they report are not the responsibility of ECDC. ECDC is not responsible for conclusions or opinions drawn from the data provided. ECDC is not responsible for the correctness of the data and for data management, data merging and data collation after provision of the data. ECDC shall not be held liable for improper or incorrect use of the data. The Health Behaviour in School-Aged Children (HBSC) study is an international study carried out in collaboration with WHO/EURO. The international coordinator of the 1997-98, 2001-02, 2005-06, and 2009-10 surveys was Candace Currie and the databank manager for the 1997-98 survey was Bente Wold, whereas for the following surveys Oddrun Samdal was the databank manager. A list of principal investigators in each country can be found on the HBSC website. Data used in this paper come from the 2009-10 Ghana Socioeconomic Panel Study Survey, which is a nationally representative survey of more than 5000 households in Ghana. The survey is a joint effort undertaken by the Institute of Statistical, Social and Economic Research (ISSER) at the University of Ghana and the Economic Growth Centre (EGC) at Yale University. It was funded by EGC. ISSER and the EGC are not responsible for the estimations reported by the analysts. The Palestinian Central Bureau of Statistics granted the researchers access to relevant data in accordance with license number SLN2014-3-170, after subjecting data to processing aiming to preserve the confidentiality of individual data in accordance with the General Statistics Law, 2000. The researchers are solely responsible for the conclusions and inferences drawn upon available data. Data for this research was provided by MEASURE Evaluation, funded by USAID. The authors thank the Russia Longitudinal Monitoring Survey, conducted by the National Research University Higher School of Economics and ZAO Demoscope together with Carolina Population Center, University of North Carolina at Chapel Hill and the Institute of Sociology, Russia Academy of Sciences for making data available. This paper uses data from the Bhutan 2014 STEPS survey, implemented by the Ministry of Health with the support of WHO; the Kuwait 2006 and 2014 STEPS surveys, implemented by the Ministry of Health with the support of WHO; the Libya 2009 STEPS survey, implemented by the Secretariat of Health and Environment with the support of WHO; the Malawi 2009 STEPS survey, implemented by Ministry of Health with the support of WHO; and the Moldova 2013 STEPS survey, implemented by the Ministry of Health, the National Bureau of Statistics, and the National Center of Public Health with the support of WHO. This paper uses data from Survey of Health, Ageing and Retirement in Europe (SHARE) Waves 1 (DOI:10.6103/SHARE. w1.700), 2 (10.6103/SHARE.w2.700), 3 (10.6103/SHARE.w3.700), 4 (10.6103/SHARE.w4.700), 5 (10.6103/SHARE.w5.700), 6 (10.6103/SHARE.w6.700), and 7 (10.6103/SHARE.w7.700); see Borsch-Supan and colleagues (2013) for methodological details. The SHARE data collection has been funded by the European Commission through FP5 (QLK6-CT-2001-00360), FP6 (SHARE-I3: RII-CT-2006-062193, COMPARE: CIT5-CT-2005-028857, SHARELIFE: CIT4-CT-2006-028812), FP7 (SHARE-PREP: GA N degrees 211909, SHARE-LEAP: GA N degrees 227822, SHARE M4: GA N degrees 261982) and Horizon 2020 (SHARE-DEV3: GA N degrees 676536, SERISS: GA N degrees 654221) and by DG Employment, Social Affairs & Inclusion. Additional funding from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, the US National Institute on Aging (U01_AG09740-13S2, P01_AG005842, P01_AG08291, P30_AG12815, R21_AG025169, Y1-AG-4553-01, IAG_BSR06-11, OGHA_04-064, HHSN271201300071C), and from various national funding sources is gratefully acknowledged. This study has been realised using the data collected by the Swiss Household Panel, which is based at the Swiss Centre of Expertise in the Social Sciences. The project is financed by the Swiss National Science Foundation. The United States Aging, Demographics, and Memory Study is a supplement to the Health and Retirement Study (HRS), which is sponsored by the National Institute of Aging (grant number NIA U01AG009740). It was conducted jointly by Duke University and the University of Michigan. The HRS is sponsored by the National Institute on Aging (grant number NIA U01AG009740) and is conducted by the University of Michigan. This paper uses data from Add Health, a program project designed by J Richard Udry, Peter S Bearman, and Kathleen Mullan Harris, and funded by a grant P01-HD31921 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with cooperative funding from 17 other agencies. Special acknowledgment is due to Ronald R Rindfuss and Barbara Entwisle for assistance in the original design. Information on how to obtain the Add Health data files is available on the Add Health website. No direct support was received from grant P01-HD31921 for this analysis. The data reported here have been supplied by the United States Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US Government. Collection of data for the Mozambique National Survey on the Causes of Death 2007-08 was made possible by USAID under the terms of cooperative agreement GPO-A-00-08-000_D3-00. This manuscript is based on data collected and shared by the International Vaccine Institute (IVI) from an original study IVI conducted. L G Abreu acknowledges support from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (Brazil; finance code 001) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, a Brazilian funding agency). I N Ackerman was supported by a Victorian Health and Medical Research Fellowship awarded by the Victorian Government. O O Adetokunboh acknowledges the South African Department of Science and Innovation and the National Research Foundation. A Agrawal acknowledges the Wellcome Trust DBT India Alliance Senior Fellowship. S M Aljunid acknowledges the Department of Health Policy and Management, Faculty of Public Health, Kuwait University and International Centre for Casemix and Clinical Coding, Faculty of Medicine, National University of Malaysia for the approval and support to participate in this research project. M Ausloos, C Herteliu, and A Pana acknowledge partial support by a grant of the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084. A Badawi is supported by the Public Health Agency of Canada. D A Bennett was supported by the NIHR Oxford Biomedical Research Centre. R Bourne acknowledges the Brien Holden Vision Institute, University of Heidelberg, Sightsavers, Fred Hollows Foundation, and Thea Foundation. G B Britton and I Moreno Velasquez were supported by the Sistema Nacional de Investigacion, SNI-SENACYT, Panama. R Buchbinder was supported by an Australian National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship. J J Carrero was supported by the Swedish Research Council (2019-01059). F Carvalho acknowledges UID/MULTI/04378/2019 and UID/QUI/50006/2019 support with funding from FCT/MCTES through national funds. A R Chang was supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant K23 DK106515. V M Costa acknowledges the grant SFRH/BHD/110001/2015, received by Portuguese national funds through Fundacao para a Ciencia e Tecnologia, IP, under the Norma Transitaria DL57/2016/CP1334/CT0006. A Douiri acknowledges support and funding from the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care South London at King's College Hospital NHS Foundation Trust and the Royal College of Physicians, and support from the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. B B Duncan acknowledges grants from the Foundation for the Support of Research of the State of Rio Grande do Sul (IATS and PrInt) and the Brazilian Ministry of Health. H E Erskine is the recipient of an Australian NHMRC Early Career Fellowship grant (APP1137969). A J Ferrari was supported by a NHMRC Early Career Fellowship grant (APP1121516). H E Erskine and A J Ferrari are employed by and A M Mantilla-Herrera and D F Santomauro affiliated with the Queensland Centre for Mental Health Research, which receives core funding from the Queensland Department of Health. M L Ferreira holds an NHMRC Research Fellowship. C Flohr was supported by the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust. M Freitas acknowledges financial support from the EU (European Regional Development Fund [FEDER] funds through COMPETE POCI-01-0145-FEDER-029248) and National Funds (Fundacao para a Ciencia e Tecnologia) through project PTDC/NAN-MAT/29248/2017. A L S Guimaraes acknowledges support from CNPq. C Herteliu was partially supported by a grant co-funded by FEDER through Operational Competitiveness Program (project ID P_40_382). P Hoogar acknowledges Centre for Bio Cultural Studies, Directorate of Research, Manipal Academy of Higher Education and Centre for Holistic Development and Research, Kalaghatagi. F N Hugo acknowledges the Visiting Professorship, PRINT Program, CAPES Foundation, Brazil. B-F Hwang was supported by China Medical University (CMU107-Z-04), Taichung, Taiwan. S M S Islam was funded by a National Heart Foundation Senior Research Fellowship and supported by Deakin University. R Q Ivers was supported by a research fellowship from the National Health and Medical Research Council of Australia. M Jakovljevic acknowledges the Serbian part of this GBD-related contribution was co-funded through Grant OI175014 of the Ministry of Education Science and Technological Development of the Republic of Serbia. P Jeemon was supported by a Clinical and Public Health intermediate fellowship (grant number IA/CPHI/14/1/501497) from the Wellcome Trust-Department of Biotechnology, India Alliance (2015-20). O John is a recipient of UIPA scholarship from University of New South Wales, Sydney. S V Katikireddi acknowledges funding from a NRS Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_12017/13, MC_UU_12017/15), and the Scottish Government Chief Scientist Office (SPHSU13, SPHSU15). C Kieling is a CNPq researcher and a UK Academy of Medical Sciences Newton Advanced Fellow. Y J Kim was supported by Research Management Office, Xiamen University Malaysia (XMUMRF/2018-C2/ITCM/00010). K Krishan is supported by UGC Centre of Advanced Study awarded to the Department of Anthropology, Panjab University, Chandigarh, India. M Kumar was supported by K43 TW 010716 FIC/NIMH. B Lacey acknowledges support from the NIHR Oxford Biomedical Research Centre and the BHF Centre of Research Excellence, Oxford. J V Lazarus was supported by a Spanish Ministry of Science, Innovation and Universities Miguel Servet grant (Instituto de Salud Carlos III [ISCIII]/ESF, the EU [CP18/00074]). K J Looker thanks the NIHR Health Protection Research Unit in Evaluation of Interventions at the University of Bristol, in partnership with Public Health England, for research support. S Lorkowski was funded by the German Federal Ministry of Education and Research (nutriCARD, grant agreement number 01EA1808A). R A Lyons is supported by Health Data Research UK (HDR-9006), which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, NIHR (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. J J McGrath is supported by the Danish National Research Foundation (Niels Bohr Professorship), and the Queensland Health Department (via West Moreton HHS). P T N Memiah acknowledges support from CODESRIA. U O Mueller gratefully acknowledges funding by the German National Cohort Study BMBF grant number 01ER1801D. S Nomura acknowledges the Ministry of Education, Culture, Sports, Science, and Technology of Japan (18K10082). A Ortiz was supported by ISCIII PI19/00815, DTS18/00032, ISCIII-RETIC REDinREN RD016/0009 Fondos FEDER, FRIAT, Comunidad de Madrid B2017/BMD-3686 CIFRA2-CM. These funding sources had no role in the writing of the manuscript or the decision to submit it for publication. S B Patten was supported by the Cuthbertson & Fischer Chair in Pediatric Mental Health at the University of Calgary. G C Patton was supported by an aNHMRC Senior Principal Research Fellowship. M R Phillips was supported in part by the National Natural Science Foundation of China (NSFC, number 81371502 and 81761128031). A Raggi, D Sattin, and S Schiavolin were supported by grants from the Italian Ministry of Health (Ricerca Corrente, Fondazione Istituto Neurologico C Besta, Linea 4-Outcome Research: dagli Indicatori alle Raccomandazioni Cliniche). P Rathi and B Unnikrishnan acknowledge Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal. A L P Ribeiro was supported by Brazilian National Research Council, CNPq, and the Minas Gerais State Research Agency, FAPEMIG. D C Ribeiro was supported by The Sir Charles Hercus Health Research Fellowship (#18/111) Health Research Council of New Zealand. D Ribeiro acknowledges financial support from the EU (FEDER funds through the Operational Competitiveness Program; POCI-01-0145-FEDER-029253). P S Sachdev acknowledges funding from the NHMRC of Australia Program Grant. A M Samy was supported by a fellowship from the Egyptian Fulbright Mission Program. M M Santric-Milicevic acknowledges the Ministry of Education, Science and Technological Development of the Republic of Serbia (contract number 175087). R Sarmiento-Suarez received institutional support from Applied and Environmental Sciences University (Bogota, Colombia) and ISCIII (Madrid, Spain). A E Schutte received support from the South African National Research Foundation SARChI Initiative (GUN 86895) and Medical Research Council. S T S Skou is currently funded by a grant from Region Zealand (Exercise First) and a grant from the European Research Council under the EU's Horizon 2020 research and innovation program (grant agreement number 801790). J B Soriano is funded by Centro de Investigacion en Red de Enfermedades Respiratorias, ISCIII. R Tabares-Seisdedos was supported in part by the national grant PI17/00719 from ISCIII-FEDER. N Taveira was partially supported by the European & Developing Countries Clinical Trials Partnership, the EU (LIFE project, reference RIA2016MC-1615). S Tyrovolas was supported by the Foundation for Education and European Culture, the Sara Borrell postdoctoral programme (reference number CD15/00019 from ISCIII-FEDER). S B Zaman received a scholarship from the Australian Government research training programme in support of his academic career., "Peer Reviewed"
Published: 2020

34. A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

Author: Diana A van der Plaat, Lars Lind, Jingyuan Fu, Bruno H. Stricker, Veikko Salomaa, Judith M. Vonk, Guy Brusselle, Jun Liu, Aki S. Havulinna, Cleo C. van Diemen, Ivana Prokic, Marita Kalaoja, Cornelia M. van Duijn, Maaike de Vries, Alexandra Zhernakova, Lies Lahousse, Ashley van der Spek, Markus Perola, Johannes Kettunen, Najaf Amin, Johan Ärnlöv, Mika Ala-Korpela, Mohsen Ghanbari, H. Marike Boezen, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Faculty of Medicine, University of Helsinki, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Epidemiology, Pulmonary Medicine, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Life Course Epidemiology (LCE), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: Male, BIOMARKER, Respiratory Medicine and Allergy, Respiratory System, LOCI, ACUTE-PHASE PROTEINS, Cohort Studies, Pulmonary Disease, Chronic Obstructive, Rotterdam Study, 0302 clinical medicine, Risk Factors, Glycoprotein acetyls, Medicine and Health Sciences, 030212 general & internal medicine, 1102 Cardiorespiratory Medicine and Haematology, Lung, Netherlands, Lungmedicin och allergi, Aged, 80 and over, 0303 health sciences, COPD, Incidence (epidemiology), GLYCOPROTEIN, Mendelian Randomization Analysis, IDENTIFY, Middle Aged, Prognosis, 3. Good health, Survival Rate, LUNG-FUNCTION, TESTS, Biomarker (medicine), Female, Research Article, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Lung Disorder, 03 medical and health sciences, Internal medicine, Mendelian randomization, medicine, Humans, Metabolomics, Aged, Glycoproteins, 030304 developmental biology, lcsh:RC705-779, business.industry, MORTALITY, Klinisk medicin, lcsh:Diseases of the respiratory system, Omics, medicine.disease, respiratory tract diseases, Logistic Models, GLYCA, 3121 General medicine, internal medicine and other clinical medicine, RISK-FACTORS, Clinical Medicine, business, Biomarkers
Abstract: Background Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis. Methods We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach. Results There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10− 4 in the discovery and OR = 1.30, P = 1.8 × 10− 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52–2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94–1.20). Conclusions Our study shows that circulating blood GlycA is a biomarker of early COPD pathology.
Published: 2020

35. Using proximity extension proteomics assay to discover novel biomarkers associated with circulating leptin levels in patients with type 2 diabetes

Author: Tobias Feldreich, Johan Sundström, Lars Lind, Camilla Vavruch, Fredrik H. Nystrom, Stefan Söderberg, Johan Ärnlöv, Carl Johan Östgren, and Christoph Nowak
Subjects: 0301 basic medicine, False discovery rate, Leptin, Male, Proteomics, medicine.medical_specialty, lcsh:Medicine, Disease, Type 2 diabetes, Endocrinology and Diabetes, Predictive markers, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Cardiac and Cardiovascular Systems, lcsh:Science, Aged, Multidisciplinary, Kardiologi, business.industry, Incidence (epidemiology), lcsh:R, Diabetes, Middle Aged, medicine.disease, Blood proteins, 030104 developmental biology, Endocrinology, Cardiovascular diseases, Diabetes Mellitus, Type 2, Cohort, Endokrinologi och diabetes, lcsh:Q, Female, business, 030217 neurology & neurosurgery, Mace, Biomarkers
Abstract: We aimed to discover novel associations between leptin and circulating proteins which could link leptin to the development of cardiovascular disease in patients with type 2 diabetes (T2DM). In a discovery phase, we investigated associations between 88 plasma proteins, assessed with a proximity extension assay, and plasma leptin in a cohort of middle-aged patients with T2DM. Associations passing the significance threshold of a False discovery rate of 5% (corresponding to pFunding Agencies|FORSS, the Research Council of Southeastern Sweden; Swedish Heart-Lung foundationSwedish Heart-Lung Foundation; King Gustaf V and Queen Victoria Freemason Foundation, Sweden; Linkoping University; Uppsala University Hospital
Published: 2020

36. Prognosis and Reclassification by YKL-40 in Stable Coronary Artery Disease

Author: Julia S. Johansen, Jakob Schroder, Christian Gluud, Jens Kastrup, Gorm Boje Jensen, Jørgen Hilden, Janus Christian Jakobsen, Ahmad Sajadieh, Per Winkel, Johan Ärnlöv, Anders Larsson, Marina Harutyunyan, and Erik Kjøller
Subjects: Male, musculoskeletal diseases, medicine.medical_specialty, YKL-40, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, CHI3L1, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Risk Factors, Internal medicine, Clarithromycin, medicine, cohort study, Humans, Coronary Heart Disease, Cardiac and Cardiovascular Systems, 030212 general & internal medicine, Chitinase-3-Like Protein 1, Coronary atherosclerosis, Aged, Proportional Hazards Models, Original Research, Quality and Outcomes, Kardiologi, Potential risk, business.industry, coronary atherosclerosis, YKL‐40, Middle Aged, medicine.disease, Prognosis, Anti-Bacterial Agents, Survival Rate, C-Reactive Protein, Cardiology, Female, Cardiology and Cardiovascular Medicine, Inflammatory biomarker, business, Biomarkers, Cohort study, Follow-Up Studies
Abstract: Background The inflammatory biomarker YKL‐40 has previously been studied as a potential risk marker in cardiovascular disease. We aimed to assess the prognostic reclassification potential of serum YKL‐40 in patients with stable coronary artery disease. Methods and Results The main study population was the placebo group of the CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) trial. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all‐cause mortality. We used Cox proportional hazards regression models adjusted for C‐reactive protein level and baseline cardiovascular risk factors. Improvement in prediction by adding serum YKL‐40 to the risk factors was calculated using the Cox‐Breslow method and c‐statistic. A total of 2200 patients were randomized to placebo, with a follow‐up duration of 10 years. YKL‐40 was associated with an increased risk of the composite outcome (hazard ratio per unit increase in (YKL‐40) 1.13, 95% CI 1.03–1.24, P =0.013) and all‐cause mortality (hazard ratio 1.32, 95% CI 1.17–1.49, P Conclusions Higher serum YKL‐40 was independently associated with an increased risk of adverse cardiovascular outcomes and mortality. Addition of YKL‐40 did not improve risk prediction in patients with stable coronary artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT00121550.
Published: 2020

37. Associations of Circulating Protein Levels With Lipid Fractions in the General Population

Author: Johan Ärnlöv, Johan Sundström, Sylwia M. Figarska, Anders Mälarstig, Sölve Elmståhl, Erik Ingelsson, Tove Fall, Lars Lind, and Stefan Gustafsson
Subjects: Male, Proteomics, 0301 basic medicine, medicine.medical_specialty, Genotype, Population, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, chemistry.chemical_compound, Diabetes mellitus, Internal medicine, medicine, Humans, Protein Interaction Maps, education, Triglycerides, Aged, Aged, 80 and over, Sweden, education.field_of_study, Triglyceride, business.industry, Cholesterol, Cholesterol, HDL, Lipid metabolism, Blood Proteins, Cholesterol, LDL, Mendelian Randomization Analysis, Middle Aged, Lipid Metabolism, medicine.disease, Blood proteins, Phenotype, 030104 developmental biology, Endocrinology, chemistry, Female, lipids (amino acids, peptides, and proteins), Resistin, Cardiology and Cardiovascular Medicine, business, Biomarkers, Lipoprotein
Abstract: Objective— Revealing patterns of associations between circulating protein and lipid levels could improve biological understanding of cardiovascular disease (CVD). In this study, we investigated the associations between proteins related to CVD and triglyceride (TG), total cholesterol, LDL (low-density lipoprotein), and HDL (high-density lipoprotein) cholesterol levels in individuals from the general population. Approach and Results— We measured plasma protein levels using the Olink ProSeek CVD I or II+III arrays and analyzed 57 proteins available in 3 population-based cohorts: EpiHealth (n=2029; 52% women; median age, 61 years), PIVUS (Prospective Study of the Vasculature in Uppsala Seniors; n=790; 51% women; all aged 70 years), and ULSAM (Uppsala Longitudinal Study of Adult Men; n=551; all men aged 77 years). A discovery analysis was performed in EpiHealth in a regression framework (adjusted for sex, age, body mass index, smoking, glucose levels, systolic blood pressure, blood pressure medication, diabetes mellitus medication, and CVD history), and associations with false discovery rate P value of 0.05 was considered a successful replication (validation false discovery rate of 0.1%). We used summary statistics from a genome-wide association study on each protein biomarker (meta-analysis of EpiHealth, PIVUS, ULSAM, and IMPROVE [Carotid Intima–Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population]) and publicly available data from Global Lipids Genetics Consortium to perform Mendelian randomization analyses to address possible causality of protein levels. Of 57 tested proteins, 42 demonstrated an association with at least 1 lipid fraction; 35 were associated with TG, 15 with total cholesterol, 9 with LDL cholesterol, and 24 with HDL cholesterol. Among these associations, we found KIM-1 (kidney injury molecule-1), TNFR (TNF [tumor necrosis factor] receptor) 1 and 2, TRAIL-R2 (TRAIL [TNF-related apoptosis-inducing ligand] receptor 2), and RETN (resistin) to be associated with all 4 lipid fractions. Further, 15 proteins were related to both TG and HDL cholesterol in a consistent and biologically expected manner, that is, higher TG and lower HDL cholesterol or vice versa. Another common pattern of associations was concomitantly higher TG, total cholesterol, and LDL cholesterol, which is associated with higher CVD risk. We did not find evidence of causal links for protein levels. Conclusions— Our comprehensive analysis of plasma proteins and lipid fractions of 3370 individuals from the general population provides new information about lipid metabolism.
Published: 2018

38. Plasma potassium ranges associated with mortality across stages of chronic kidney disease: the Stockholm CREAtinine Measurements (SCREAM) project

Author: Lars H. Lund, Juan Jesus Carrero, Johan Ärnlöv, Peter Bárány, Tomas Jernberg, Hairong Xu, Marie Evans, and Alessandro Gasparini
Subjects: Adult, Male, medicine.medical_specialty, Hyperkalemia, 030232 urology & nephrology, Renal function, Comorbidity, 030204 cardiovascular system & hematology, Gastroenterology, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, hyperkalaemia, Clinical Research, chronic renal failure, Internal medicine, Epidemiology, CKD, medicine, Humans, Renal Insufficiency, Chronic, Aged, Transplantation, Creatinine, business.industry, potassium, Middle Aged, Prognosis, medicine.disease, Cross-Sectional Studies, Serum potassium, chemistry, Nephrology, Cohort, epidemiology, Female, ORIGINAL ARTICLES, medicine.symptom, business, Glomerular Filtration Rate, Kidney disease
Abstract: BackgroundSmall-scale studies suggest that hyperkalaemia is a less threatening condition in chronic kidney disease (CKD), arguing adaptation/tolerance to potassium (K+) retention. This study formally evaluates this hypothesis by estimating the distribution of plasma K+ and its association with mortality across CKD stages.MethodsThis observational study included all patients undergoing plasma K+ testing in Stockholm during 2006–11. We randomly selected one K+ measurement per patient and constructed a cross-sectional cohort with mortality follow-up. Covariates included demographics, comorbidities, medications and estimated glomerular filtration rate (eGFR). We estimated K+ distribution and defined K+ ranges associated with 90-, 180- and 365-day mortality.ResultsIncluded were 831 760 participants, of which 70 403 (8.5%) had CKD G3 (eGFR 90 to 4.43 (3.22–5.65) mmol/L for eGFR ≤15 mL/min/1.73 m2. The association between K+ and mortality was U-shaped, but it flattened at lower eGFR strata and shifted upwards. For instance, the range where the 90-day mortality risk increased by no more than 100% was 3.45–4.94 mmol/L in eGFR >60 mL/min, but was 3.36–5.18 in G3 and 3.26–5.53 mmol/L in G4–G5. In conclusion, CKD stage modifies K+ distribution and the ranges that predict mortality in the community.ConclusionAlthough this study supports the view that hyperkalaemia is better tolerated with worse CKD, it challenges the current use of a single optimal K+ range for all patients.
Published: 2018

39. Circulating endostatin and the incidence of heart failure

Author: Johan Ärnlöv, Ulf Risérus, Erik Ingelsson, Johan Sundström, Toralph Ruge, Lars Lind, Anders Larsson, and Axel C. Carlsson
Subjects: Male, Time Factors, Angiogenesis, Disease, Heart failure, angiogenesis, anti-angiogenesis, epidemiology, left ventricular systolic function, population based studies, remodelling of extracellular matrix, 030204 cardiovascular system & hematology, Ventricular Function, Left, Ventricular Dysfunction, Left, 0302 clinical medicine, Diastole, Risk Factors, Epidemiology, Cardiac and Cardiovascular Systems, Longitudinal Studies, Prospective Studies, 030212 general & internal medicine, Kardiologi, Incidence, Incidence (epidemiology), Prognosis, Echocardiography, Doppler, Endostatins, Up-Regulation, cardiovascular system, Cardiology, Female, Endostatin, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Systole, 03 medical and health sciences, Internal medicine, Diabetes mellitus, medicine, Humans, Aged, Heart Failure, Sweden, business.industry, Klinisk medicin, medicine.disease, Cross-Sectional Studies, Clinical Medicine, business, Biomarkers, Kidney disease
Abstract: Objective: Circulating levels of endostatin are elevated in many underlying conditions leading to heart failure such as hypertension, diabetes, chronic kidney disease and ischemic heart disease. Yet, the association between endostatin and the incidence of heart failure has not been reported previously in the community. Design: We investigated the longitudinal association between serum endostatin levels and incident heart failure in two community-based cohorts of elderly: Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n = 966; mean age 70 years, 51% women, 81 events, mean follow-up 10 years) and Uppsala Longitudinal Study of Adult Men (ULSAM, n = 747 men; mean age 78 years, 98 heart failure events, mean follow-up 8 years). We also investigated the cross-sectional association between endostatin and echocardiographic left ventricular systolic function and diastolic function (ejection fraction and E/A-ratio, respectively). Results: Higher serum endostatin was associated with an increased risk for heart failure in both cohorts after adjustment for established heart failure risk factors, glomerular filtration rate and N-terminal pro-brain natriuretic peptide (NT-proBNP) (PIVUS: multivariable hazard ratio (HR) per 1-standard deviation (SD) increase, HR 1.46 (95%CI, 1.17-1.82, p
Published: 2018

40. Heart failure in immigrant groups: a cohort study of adults aged 45 years and over in Sweden

Author: Jan Sundquist, Axel C. Carlsson, Per Wändell, Xinjun Li, Kristina Sundquist, Danijela Gasevic, Johan Ärnlöv, and Martin J. Holzmann
Subjects: Congestive heart failure, Male, Pediatrics, Time Factors, Immigration, Segmented assimilation, 030204 cardiovascular system & hematology, 0302 clinical medicine, gender, 030212 general & internal medicine, Registries, media_common, Aged, 80 and over, Refugees, Incidence, Atrial fibrillation, Emigration and Immigration, Middle Aged, humanities, Female, Cardiology and Cardiovascular Medicine, Cohort study, medicine.medical_specialty, socio-economic status, media_common.quotation_subject, Emigrants and Immigrants, Article, first generation immigrants, neighborhood, second generation immigrants, 03 medical and health sciences, Age Distribution, medicine, Humans, cardiovascular diseases, Sex Distribution, Socioeconomic status, Aged, Heart Failure, Sweden, business.industry, Klinisk medicin, medicine.disease, Coronary heart disease, Increased risk, Socioeconomic Factors, Heart failure, Clinical Medicine, business
Abstract: OBJECTIVE:An increased risk of being diagnosed with coronary heart disease or atrial fibrillation has been shown among different immigrant groups. However, less is known on the risk of being diagnosed with congestive heart failure (CHF).DESIGN:We studied CHF in immigrants including all adults ≥45 years in Sweden (n = 3,274,119) from 1998 to 2012. CHF was defined as at the first event registered in the National Patient Register. Risk of incident CHF in immigrant groups compared to the Swedish-born population was assessed by Cox regression, stratified by sex, adjusting for age, socio-demographic status, and co-morbidities.RESULTS:During a mean follow-up of 14 years in total, a total of 302,340 (9.2%) events of CHF were registered. We found the following: higher incidence in men from Bosnia, Iraq, Lebanon, Russia and Africa; among women from Bosnia, Iraq, Lebanon, Turkey, Central Europe and Finland; lower incidence in men from Iceland, Latin America, Southern Europe, Norway and Western Europe; and among women from Iceland, Southern Europe, Norway, Denmark and Western Europe.CONCLUSION:It is important to be aware of the increased incidence of CHF in some immigrant groups, especially from countries and areas where the immigrants have been refugees, in order to enable for a timely diagnosis, treatment of and prevention of CHF and its debilitating complications.
Published: 2018

41. Targeted proteomic analysis of habitual coffee consumption

Author: Lars Lind, Sölve Elmståhl, Stefan Söderberg, Johan Ärnlöv, Stefan Gustafsson, Marilyn C. Cornelis, Karl Michaëlsson, Erik Ingelsson, and Johan Sundström
Subjects: Leptin, Male, Proteomics, 0301 basic medicine, Fas Ligand Protein, Population, 030209 endocrinology & metabolism, Coffee consumption, TNF-Related Apoptosis-Inducing Ligand, Coffee, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Surveys and Questionnaires, Environmental health, Internal Medicine, Humans, Medicine, Chitinase-3-Like Protein 1, Longitudinal Studies, Prospective Studies, education, Aged, education.field_of_study, 030109 nutrition & dietetics, business.industry, Middle Aged, 3. Good health, Biotechnology, Cardiovascular Diseases, Female, business, Biomarkers
Abstract: Coffee drinking has been implicated in mortality and a variety of diseases but potential mechanisms underlying these associations are unclear. Large-scale systems epidemiological approaches may offer novel insights to mechanisms underlying associations of coffee with health.We performed an analysis of known and novel protein markers linked to cardiovascular disease and their association with habitual coffee intake in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS, n = 816) and followed up top proteins in the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 635) and EpiHealth (n = 2418).In PIVUS and ULSAM, coffee intake was measured by 7-day dietary records whilst a computer-based food frequency questionnaire was used in EpiHealth. Levels of up to 80 proteins were assessed in plasma by a proximity extension assay.Four protein-coffee associations adjusted for age, sex, smoking and BMI, met statistical significance in PIVUS (FDR5%, P2.31 × 10The current study supports an inverse association between coffee intake and plasma LEP and CHI3L1 levels. The coffee-CHI3L1 association is novel and warrants further investigation given links between CHI3L1 and health conditions that are also potentially influenced by coffee.
Published: 2017

42. Incidence and determinants of hyperkalemia and hypokalemia in a large healthcare system

Author: Karin M. Henriksson, Alessandro Gasparini, Morgan E. Grams, Josef Coresh, Erik Nilsson, Juan Jesus Carrero, Hairong Xu, and Johan Ärnlöv
Subjects: Adult, Male, medicine.medical_specialty, Hyperkalemia, Renal function, Hypokalemia, 030204 cardiovascular system & hematology, urologic and male genital diseases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, Cumulative incidence, 030212 general & internal medicine, Myocardial infarction, Intensive care medicine, Thiazide, Aged, Retrospective Studies, Sweden, Creatinine, business.industry, Incidence, Incidence (epidemiology), nutritional and metabolic diseases, Middle Aged, medicine.disease, chemistry, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Delivery of Health Care, medicine.drug
Abstract: Background Hypo- and hyperkalemia in clinical settings are insufficiently characterized and large-scale data from Europe lacking. We studied incidence and determinants of these abnormalities in a large Swedish healthcare system. Methods Observational study from the Stockholm CREAtinine Measurements project, including adult individuals from Stockholm accessing healthcare in 2009 (n=364,955). Over 3-years, we estimated the incidence of hypokalemia, defined as potassium 5mmol/L, and moderate/severe hyperkalemia, defined as potassium>5.5mmol/L. Kidney function was assessed by estimated glomerular filtration rate (eGFR). Results Of 364,955 participants, 69.4% had 1–2 potassium tests, 16.7% had 3–4 tests and the remaining 13.9% had >4potassiumtests/year. Hypokalemia occurred in 49,662 (13.6%) individuals, with 33% recurrence. Hyperkalemia occurred in 25,461 (7%) individuals, with 35.7% recurrence. Moderate/severe hyperkalemia occurred in 9059 (2.5%) with 28% recurrence. The frequency of potassium testing was an important determinant of dyskalemia risk. The incidence proportion of hyperkalemia was higher in the presence of diabetes, lower eGFR, myocardial infarction, heart failure (HF), or use of renin angiotensin-aldosterone system inhibitors (RAASi). In adjusted analyses, women and use of loop/thiazide diuretics were associated with lower hyperkalemia risk. Older age, lower eGFR, diabetes, HF and use of RAASi were associated with higher hyperkalemia risk. On the other hand, women, younger age, higher eGFR and baseline use of diuretics were associated with higher hypokalemia risk. Conclusion Hypo- and hyperkalemia are common in healthcare. Optimal RAASi and diuretics use and careful potassium monitoring in the presence of certain comorbidities, especially lower eGFR, is advocated.
Published: 2017

43. Alterations in Multiple Lifestyle Factors in Subjects with the Metabolic Syndrome Independently of Obesity

Author: Lars Lind, Erik Ingelsson, Johan Ärnlöv, Sölve Elmståhl, Johan Sundström, and Vendela Roos
Subjects: Male, medicine.medical_specialty, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, Overweight, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Risk Factors, Surveys and Questionnaires, Internal medicine, Internal Medicine, medicine, Humans, Obesity, 030212 general & internal medicine, education, Exercise, Life Style, National Cholesterol Education Program, Aged, Metabolic Syndrome, education.field_of_study, business.industry, Smoking, Feeding Behavior, Middle Aged, medicine.disease, Cross-Sectional Studies, Quality of Life, Physical therapy, Female, Metabolic syndrome, medicine.symptom, business, Body mass index
Abstract: Many lifestyle factors have been associated with the metabolic syndrome (MetS). However, most of these studies have not considered the potential impact of obesity and have often only investigated one lifestyle factor at the time. We aimed to investigate the interplay between body mass index (BMI) and MetS with respect to multiple lifestyle factors.BMI and MetS [National Cholesterol Education Program (NCEP)/Adult Treatment Panel III criteria] were assessed in a sample of 18,880 subjects aged 45-75 years from the population-based EpiHealth study. Participants were categorized into six groups according to BMI category (normal weight/BMI25 kg/mPrevalent MetS (23% in the sample) was associated with less physical activity (P 0.0001), more TV watching (P 0.0001), more years of smoking (P 0.0001), lower education level (P = 0.007), and experiencing a poor general quality of life (P 0.0001). These lifestyle factors were all associated with MetS, independently of each other and independently of BMI. Similar results were generated when number of MetS components and presence/absence of individual MetS components were used as outcomes.This cross-sectional study identified alterations in a number of lifestyle factors associated with MetS independently of each other and independently of BMI. Future longitudinal studies are needed to assess causal and temporal relationships between lifestyle factors and MetS development.
Published: 2017

44. Metabolic Syndrome Development During Aging with Special Reference to Obesity Without the Metabolic Syndrome

Author: Erik Ingelsson, Johan Ärnlöv, Lars Lind, Johan Sundström, Vendela Roos, and Sölve Elmståhl
Subjects: Male, Gerontology, Aging, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030204 cardiovascular system & hematology, Body Mass Index, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Metabolically healthy obesity, Prevalence, Internal Medicine, medicine, Humans, Longitudinal Studies, Obesity, 030212 general & internal medicine, Exercise, National Cholesterol Education Program, Aged, Aged, 80 and over, Metabolic Syndrome, Sweden, business.industry, Middle Aged, Metabolic stability, medicine.disease, Cross-Sectional Studies, Normal weight, Female, Metabolic syndrome, business, Body mass index
Abstract: Obesity and its associated metabolic complications continue to increase worldwide. We investigated the development of metabolic syndrome (MetS) during aging in relation to body mass index (BMI) and exercise habits. We assigned special emphasis to the metabolic stability in individuals with obesity, but without MetS, a condition often referred to as metabolically healthy obesity.Cross-sectional analysis was carried out in a sample of 19,129 men and women aged 45-75 years from the EpiHealth study. In addition, longitudinal analyses were carried out in the ULSAM study (2322 men at baseline followed from age 50 to age 77) and in the PIVUS study (1016 men and women at baseline followed from age 70 to age 80). Participants were categorized into six groups according to BMI category (normal weight/BMI25 kg/mMetS prevalence and number of MetS components increased with age in all three samples. The PIVUS study showed that high baseline BMI, low baseline physical activity, and increasing BMI during follow-up were related to increasing MetS prevalence and increasing numbers of MetS components during follow-up. One-third to half of individuals initially belonging to the obesity without MetS category acquired MetS during aging.MetS prevalence increased during aging, especially in individuals with high BMI, low level of physical activity, and weight gain. Obesity without MetS was not a stable condition over time as many of those individuals gained metabolic disturbances during aging.
Published: 2017

45. Effects of cigarette smoking on cardiovascular-related protein profiles in two community-based cohort studies

Author: Per Svensson, Biying Huang, Erik Ingelsson, Johan Ärnlöv, Lars Lind, and Johan Sundström
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Longitudinal study, Proteome, 030204 cardiovascular system & hematology, Polymerase Chain Reaction, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Internal medicine, Epidemiology, Ethnicity, medicine, Humans, Longitudinal Studies, Prospective Studies, Endothelial dysfunction, Prospective cohort study, Aged, Sweden, COPD, biology, business.industry, Gene Expression Profiling, Smoking, C-reactive protein, Blood Proteins, Atherosclerosis, medicine.disease, Former Smoker, 030104 developmental biology, Cardiovascular Diseases, Immunology, Linear Models, biology.protein, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers, Cohort study
Abstract: Cardiovascular diseases account for the largest fraction of smoking-induced deaths. Studies of smoking in relation to cardiovascular-related protein markers can provide novel insights into the biological effects of smoking. We investigated the associations between cigarette smoking and 80 protein markers known to be related to cardiovascular diseases in two community-based cohorts, the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS, n = 969, 50% women, all aged 70 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 717, all men aged 77 years).Smoking status was self-reported and defined as current smoker, former smoker or never-smoker. Levels of the 80 proteins were measured using the proximity extension assay, a novel PCR-based proteomics technique.We found 30 proteins to be significantly associated with current cigarette smoking in PIVUS (FDR5%); and ten were replicated in ULSAM (p 0.05). Matrix metalloproteinase-12 (MMP-12), growth/differentiation factor 15 (GDF-15), urokinase plasminogen activator surface receptor (uPAR), TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), lectin-like oxidized LDL receptor 1 (LOX-1), hepatocyte growth factor (HGF), matrix metalloproteinase-10 (MMP-10) and matrix metalloproteinase-1 (MMP-1) were positively associated, while endothelial cell-specific molecule 1 (ESM-1) and interleukin-27 subunit alpha (IL27-A) showed inverse associations. All of them remained significant in a subset of individuals without manifest cardiovascular disease.The findings of the present study suggest that cigarette smoking may interfere with several essential parts of the atherosclerosis process, as evidenced by associations with protein markers representing endothelial dysfunction, inflammation, neointimal formation, foam cell formation and plaque instability.
Published: 2016

46. Associations Between Apolipoprotein A1, High-Density Lipoprotein Cholesterol, and Urinary Cytokine Levels in Elderly Males and Females

Author: Johan Ärnlöv, Johanna Helmersson-Karlqvist, Bengt Fellström, Ping-Hsun Wu, Lars Lind, Anders Larsson, Inga Soveri, and Måns Thulin
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, medicine.medical_treatment, Urinary system, Immunology, Urine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Virology, Internal medicine, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Aged, biology, Apolipoprotein A-I, Cholesterol, business.industry, Cholesterol, HDL, Cell Biology, medicine.disease, 030104 developmental biology, Cytokine, Endocrinology, chemistry, biology.protein, Cytokines, lipids (amino acids, peptides, and proteins), Apolipoprotein A1, Female, business, Lipoprotein, Kidney disease
Abstract: There exists a close relationship between cardiovascular diseases and chronic kidney disease. Apolipoprotein A1 and high-density lipoprotein (HDL) cholesterol are widely used as cardiovascular risk markers but they also have anti-inflammatory properties. The aim of this study was to investigate any associations between HDL levels and cytokine levels in urine. We randomly selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The samples were analyzed with 2 multiplex assays, Multiplex Inflammation I and Cardiovascular II kits (Olink Bioscience, Uppsala, Sweden). We analyzed the correlations between 158 cytokines in urine with apolipoprotein A1, HDL cholesterol, apolipoprotein B, and low-density lipoprotein cholesterol. There were strong correlations for apolipoprotein A1 and HDL cholesterol with individual cytokines. After adjustment for multiplicity testing, there were 33 significant correlations between apolipoprotein A1 and cytokine levels and 14 of these were also significantly correlated with HDL cholesterol. The strongest associations were observed for IL-1α, SPON2, RAGE, PAR-1, TRAIL-R2, IL-4RA, TNFRSF11A, and SCF. A total of 28 out of 33 correlations were negative, indicating a negative relationship between apolipoprotein A1 and urinary cytokines. The study shows a negative correlation between apolipoprotein A1 and HDL cholesterol and urinary cytokine levels. The finding is in agreement with the anti-inflammatory properties of HDL.
Published: 2019

47. Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study

Author: Christian Gluud, Toralph Ruge, Axel C. Carlsson, Johan Ärnlöv, Jens Kastrup, Hans Jørn Kolmos, Per Winkel, Anders Larsson, Ahmed Sajadieh, Gorm B. Jensen, Christoph Nowak, Janus Christian Jakobsen, Erik Kjøller, and Jørgen Hilden
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Epidemiology, Renal function, Coronary Disease, Disease, 030204 cardiovascular system & hematology, Cardiovascular, 03 medical and health sciences, 0302 clinical medicine, Endostatin, Risk Factors, Internal medicine, Clarithromycin, medicine, Humans, Single-Blind Method, Myocardial infarction, Risk factor, Mortality, Aged, Unstable angina, business.industry, Proportional hazards model, Hazard ratio, Extracellular matrix, Middle Aged, medicine.disease, Endostatins, 030104 developmental biology, Cardiovascular Diseases, Cardiology, Female, Cardiology and Cardiovascular Medicine, business
Abstract: Background and aims Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but association with incident cardiovascular events in patients with stable coronary heart disease is uncertain. Methods The CLARICOR-trial is a randomized, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or all-cause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as discovery sample (1204 events, n = 1998) and the clarithromycin-treated group as replication sample (1220 events, n = 1979). Results In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95% CI 1.03–1.19, p = 0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95% CI 1.00–1.14, p = 0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction ( Conclusions Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.
Published: 2019

48. Estimated Glomerular Filtration Rate and the Risk of Cancer

Author: Carl Gustaf Elinder, Johan Ärnlöv, Kunihiro Matsushita, Mats Lambe, Hong Xu, Juan Jesus Carrero, Bengt Lindholm, Marco Trevisan, Guobin Su, and Peter Bárány
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Epidemiology, Population, 030232 urology & nephrology, Renal function, Critical Care and Intensive Care Medicine, Risk Assessment, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Neoplasms, medicine, Humans, education, Aged, Aged, 80 and over, Sweden, Transplantation, education.field_of_study, Proportional hazards model, business.industry, Incidence (epidemiology), Incidence, Hazard ratio, Cancer, Original Articles, Middle Aged, medicine.disease, Confidence interval, Nephrology, 030220 oncology & carcinogenesis, Cohort, Female, business, Glomerular Filtration Rate
Abstract: BACKGROUND AND OBJECTIVES: Community-based reports regarding eGFR and the risk of cancer are conflicting. We here explore plausible links between kidney function and cancer incidence in a large Scandinavian population–based cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the Stockholm Creatinine Measurements project, we quantified the associations of baseline eGFR with the incidence of cancer among 719,033 Swedes ages ≥40 years old with no prior history of cancer. Study outcomes were any type and site-specific cancer incidence rates on the basis of International Classification of Diseases-10 codes over a median follow-up of 5 years. To explore the possibility of detection bias and reverse causation, we divided the follow-up time into different time periods (≤12 and >12 months) and estimated risks for each of these intervals. RESULTS: In total, 64,319 cases of cancer (affecting 9% of participants) were detected throughout 3,338,226 person-years. The relationship between eGFR and cancer incidence was U shaped. Compared with eGFR of 90–104 ml/min, lower eGFR strata associated with higher cancer risk (adjusted hazard ratio, 1.08; 95% confidence interval, 1.05 to 1.11 for eGFR=30–59 ml/min and adjusted hazard ratio, 1.24; 95% confidence interval, 1.15 to 1.35 for eGFR
Published: 2019

49. The metabolites urobilin and sphingomyelin (30:1) are associated with incident heart failure in the general population

Author: Markus Stenemo, Andrea Ganna, Samira Salihovic, Christoph Nowak, Johan Sundström, Vilmantas Giedraitis, Corey D. Broeckling, Jessica E. Prenni, Per Svensson, Patrik K.E. Magnusson, Lars Lind, Erik Ingelsson, Johan Ärnlöv, and Tove Fall
Subjects: Heart Failure, Male, lcsh:Diseases of the circulatory (Cardiovascular) system, Kardiologi, Epidemiology, Incidence, Klinisk medicin, Middle Aged, Risk Assessment, Risk prediction, Sphingomyelins, lcsh:RC666-701, Original Research Articles, Metabolomics, Humans, Female, Cardiac and Cardiovascular Systems, Original Research Article, Longitudinal Studies, Prospective Studies, Urobilin, Clinical Medicine, Biomarkers, Aged
Abstract: Aims We aimed to investigate whether metabolomic profiling of blood can lead to novel insights into heart failure pathogenesis or improved risk prediction. Methods and results Mass spectrometry‐based metabolomic profiling was performed in plasma or serum samples from three community‐based cohorts without heart failure at baseline (total n = 3924; 341 incident heart failure events; median follow‐up ranging from 4.6 to 13.9 years). Cox proportional hazard models were applied to assess the association of each of the 206 identified metabolites with incident heart failure in the discovery cohorts Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) (n = 920) and Uppsala Longitudinal Study of Adult Men (ULSAM) (n = 1121). Replication was undertaken in the independent cohort TwinGene (n = 1797). We also assessed whether metabolites could improve the prediction of heart failure beyond established risk factors (age, sex, body mass index, low‐density and high‐density lipoprotein cholesterol, triglycerides, lipid medication, diabetes, systolic and diastolic blood pressure, blood pressure medication, glomerular filtration rate, smoking status, and myocardial infarction prior to or during follow‐up). Higher circulating urobilin and lower sphingomyelin (30:1) were associated with incident heart failure in age‐adjusted and sex‐adjusted models in the discovery and replication sample. The hazard ratio for urobilin in the replication cohort was estimated to 1.29 per standard deviation unit, 95% confidence interval (CI 1.03–1.63), and for sphingomyelin (30:1) to 0.72 (95% CI 0.58–0.89). Results remained similar after further adjustment for established heart failure risk factors in meta‐analyses of all three cohorts. Urobilin concentrations were inversely associated with left ventricular ejection fraction at baseline in the PIVUS cohort (β = −0.70, 95% CI −1.03 to −0.38). No major improvement in risk prediction was observed when adding the top 2 metabolites (C‐index 0.787, 95% CI 0.752–0.823) or nine Lasso‐selected metabolites (0.790, 95% CI 0.754–0.826) to a modified Atherosclerosis Risk in Communities heart failure risk score model (0.780, 95% CI 0.745–0.816). Conclusions Our metabolomic profiling of three community‐based cohorts study identified associations of circulating levels of the haem breakdown product urobilin, and sphingomyelin (30:1), a cell membrane component involved in signal transduction and apoptosis, with incident heart failure.
Published: 2019

50. In search of causal pathways in diabetes : a study using proteomics and genotyping data from a cross-sectional study

Author: Johan Sundström, Christoph Nowak, Kristina Beijer, Lars Lind, Johan Ärnlöv, and Tove Fall
Subjects: Male, 0301 basic medicine, Proteomics, Genotyping, Genotype, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Galectin 4, 030209 endocrinology & metabolism, Type 2 diabetes, Endocrinology and Diabetes, Bioinformatics, Cathepsin D, Article, Pathogenesis, Iduronidase, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Registries, Mendelian randomisation, Causal pathways, Aged, Sweden, Aryldialkylphosphatase, business.industry, Diabetes, Retinal Dehydrogenase, Human physiology, Mendelian Randomization Analysis, Middle Aged, medicine.disease, Alcohol Oxidoreductases, Insulin-Like Growth Factor Binding Protein 2, Lipoprotein Lipase, Cross-Sectional Studies, 030104 developmental biology, Diabetes Mellitus, Type 2, Gene Expression Regulation, Endokrinologi och diabetes, Female, business, Biomarkers
Abstract: Aims/hypothesis The pathogenesis of type 2 diabetes is not fully understood. We investigated whether circulating levels of preselected proteins were associated with the outcome ‘diabetes’ and whether these associations were causal. Methods In 2467 individuals of the population-based, cross-sectional EpiHealth study (45–75 years, 50% women), 249 plasma proteins were analysed by the proximity extension assay technique. DNA was genotyped using the Illumina HumanCoreExome-12 v1.0 BeadChip. Diabetes was defined as taking glucose-lowering treatment or having a fasting plasma glucose of ≥7.0 mmol/l. The associations between proteins and diabetes were assessed using logistic regression. To investigate causal relationships between proteins and diabetes, a bidirectional two-sample Mendelian randomisation was performed based on large, genome-wide association studies belonging to the DIAGRAM and MAGIC consortia, and a genome-wide association study in the EpiHealth study. Results Twenty-six proteins were positively associated with diabetes, including cathepsin D, retinal dehydrogenase 1, α-l-iduronidase, hydroxyacid oxidase 1 and galectin-4 (top five findings). Three proteins, lipoprotein lipase, IGF-binding protein 2 and paraoxonase 3 (PON-3), were inversely associated with diabetes. Fourteen of the proteins are novel discoveries. The Mendelian randomisation study did not disclose any significant causal effects between the proteins and diabetes in either direction that were consistent with the relationships found between the protein levels and diabetes. Conclusions/interpretation The 29 proteins associated with diabetes are involved in several physiological pathways, but given the power of the study no causal link was identified for those proteins tested in Mendelian randomisation. Therefore, the identified proteins are likely to be biomarkers for type 2 diabetes, rather than representing causal pathways. Electronic supplementary material The online version of this article (10.1007/s00125-019-4960-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Published: 2019

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