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A longitudinal alteration in health-related quality of life (HRQoL) over a two-year period and its association with early-stage chronic kidney disease (CKD) progression was investigated among 1748 older adults (>75 years). HRQoL was measured by the Euro-Quality of Life Visual Analog Scale (EQ-VAS) at baseline and at one and two years after recruitment. A full comprehensive geriatric assessment was performed, including sociodemographic and clinical characteristics, the Geriatric Depression Scale-Short Form (GDS-SF), Short Physical Performance Battery (SPPB), and estimated glomerular filtration rate (eGFR). The association between EQ-VAS decline and covariates was investigated by multivariable analyses. A total of 41% of the participants showed EQ-VAS decline, and 16.3% showed kidney function decline over the two-year follow-up period. Participants with EQ-VAS decline showed an increase in GDS-SF scores and a greater decline in SPPB scores. The logistic regression analyses showed no contribution of a decrease in kidney function on EQ-VAS decline in the early stages of CKD. However, older adults with a greater GDS-SF score were more likely to present EQ-VAS decline over time, whereas an increase in the SPPB scores was associated with less EQ-VAS decline. This finding should be considered in clinical practice and when HRQoL is used to evaluate health interventions among older adults.

Peer reviewed: True, Funder: University of New South Wales; FundRef: http://dx.doi.org/10.13039/501100001773, OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN: Pooled analysis. DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate

AimsA high intake of salt raises blood pressure and the risk of cardiovascular disease. Previous studies have reported on the association between salt intake and carotid stenosis, but the association with coronary atherosclerosis has not been reported. Therefore, this project aimed at studying the association between salt intake and both carotid and coronary atherosclerosis in a contemporary community-based cohort.Methods and resultsEstimated 24-h sodium excretion (est24hNa) was calculated by the Kawasaki formula for participants of two sites (Uppsala and Malmö) of the Swedish Cardiopulmonary bioImage Study, who underwent a coronary computed tomography (n = 9623) and measurement of coronary artery calcium score (CACS, n = 10 289). Carotid ultrasound was used to detect carotid plaques (n = 10 700). Ordered logistic regression was used to calculate odds ratios (OR) per 1000 mg increase in est24hNa. We also investigated potential J-formed associations using quintiles of est24hNa. Increased est24hNa was associated with increased occurrence of carotid plaques [OR: 1.09, P < 0.001, confidence interval (CI): 1.06–1.12], higher CACS (OR: 1.16, P < 0.001, CI: 1.12–1.19), and coronary artery stenosis (OR: 1.17, P < 0.001, CI: 1.13–1.20) in minimal adjusted models. Associations were abolished when adjusting for blood pressure. When adjusting for established cardiovascular risk factors (not including blood pressure), associations remained for carotid plaques but not for coronary atherosclerosis. There was no evidence of J-formed associations.ConclusionHigher est24hNa was associated with both coronary and carotid atherosclerosis in minimal adjusted models. The association seemed mainly mediated by blood pressure but to some degree also influenced by other established cardiovascular risk factors.

Background: Patients with peripheral vascular disease (PVD) are often underdiagnosed and undertreated. Nocturnal nondipping blood pressure (BP) pattern, as diagnosed by ambulatory BP monitoring (ABPM), is associated with increased cardiovascular risk, but has not been studied in patients with PVD. We aimed to investigate if a nondipping BP pattern predicts cardiovascular events or all-cause death in outpatients with PVD. Methods: Consecutive outpatients with carotid or lower-extremity PVD were examined with 24-hour ABPM ( n = 396). Nondipping was defined as a < 10% fall in systolic BP level during night-time. We used Cox regression models adjusting for potential confounders. We also evaluated the incremental prognostic value of dipping status in the COPART risk score. Our primary composite outcome was cardiovascular events or all-cause death. Results: In the cohort (mean age 70; 40% women), 137 events occurred during a 5.1-year median follow-up; incident rate of 7.35 events per 100 person-years. Nondipping was significantly associated with outcome (hazard ratio 1.55, 95% CI 1.07–2.26, p = 0.021) in a fully adjusted model. When adding nondipping to the risk markers in the COPART risk score, the model fit significantly improved (χ2 7.91, p < 0.005) and the C-statistic increased from 0.65 to 0.67. Conclusion: In a cohort of outpatients with PVD, nondipping was an independent risk factor for future cardiovascular events or mortality and seemed to be a strong predictor in patients with carotid artery disease but not in lower-extremity PVD. Additional studies are needed to evaluate the clinical utility of ABPM for improved prevention in these high-risk patients. (ClinicalTrials.gov Identifier: NCT01452165)

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

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

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.

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.

Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder. In animal models, OSA has been shown to alter the gut microbiota; however, little is known about such effects in humans. Here, we used respiratory polygraphy data from 3,570 individuals aged 50–64 from the Swedish CardioPulmonary bioImage Study (SCAPIS) and deep shotgun metagenomics to identify OSA-associated gut microbiota features. We found that OSA-related hypoxia parameters were associated with 128 bacterial species, including positive associations with Blautia obeum and Collinsela aerofacines. The latter was also associated with increased systolic blood pressure. Further, the cumulative time in hypoxia was associated with nine gut microbiota metabolic pathways, including propionate production from lactate, a biomarker of hypoxia. In conclusion, in this first large-scale study on gut microbiota alterations in OSA, we found that OSA-related hypoxia is associated with specific microbiota features. Our findings can direct future research on microbiota-mediated health effects of OSA.

BACKGROUNDGut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis, and to explore relevant clinical correlates.METHODSWe conducted a cross-sectional study of 8973 participants aged 50 to 65 without overt atherosclerotic disease from the population-based Swedish Cardiopulmonary BioImage Study (SCAPIS). Coronary atherosclerosis was measured using coronary artery calcium score (CACS) and coronary computed tomography angiography (CCTA). Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of stool samples, and their association with coronary atherosclerosis was evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva.RESULTSThe mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3% of participants, and 5.4% had at least one stenosis with more than 50% occlusion. Sixty-four species were associated with CACS independent of cardiovascular risk factors, with the strongest associations observed forStreptococcus anginosusandS. oralissubsp. oralis(P-5). Associations were largely similar across CCTA-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations and 16 with neutrophil counts. Oral species in the gut were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid beta-oxidation and amino acid degradation was associated with CACS.CONCLUSIONSThis study provides evidence of an association of a gut microbiota composition characterized by increased abundance ofStreptococcusspp. and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation. Further longitudinal and experimental studies are warranted to explore the potential implication of a bacterial component in atherogenesis.CLINICAL PERSPECTIVEWHAT IS NEW?Shotgun metagenomics identified associations between gut species and subclinical atherosclerosis assessed with computed tomography-derived coronary artery calcium score (CACS) in 8973 participants, with an overrepresentation of theStreptococcusandOscillobactergenera.The relative abundance of CACS-associated oral species detected in fecal samples was negatively associated with indole propionate, while positively associated with secondary bile acids and imidazole propionate.GutStreptococcusspp. were positively associated with circulating biomarkers of systemic inflammation and infection response, and with the same species located in the mouth, which were in turn associated with oral pathologies.WHAT ARE THE CLINICAL IMPLICATIONS?We describe the link between gut microbiota composition, especially species commonly found in the mouth, with subclinical coronary atherosclerosis and biomarkers of inflammation in the largest cardiovascular and metagenomics study to date.The effects of gut and oralStreptococcusspp. on risk for coronary artery disease merit further longitudinal and experimental studies.

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.

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.

Background and aims: Previous studies reported divergent results on whether metabolically healthy obesity is associated with increased coronary artery calcium and carotid plaques. We investigated this in a cross-sectional fashion in a large, well-defined, middle-aged population using coronary CT angiography (CCTA) and carotid ultrasound.Methods: In the SCAPIS study (50-65 years, 51% female), CCTA and carotid artery ultrasound were performed in 23,674 individuals without clinical atherosclerotic disease. These subjects were divided into six groups according to BMI (normal weight, overweight, obese) and the presence of metabolic syndrome (MetS) according to the NCEP consensus criteria.Results: The severity of coronary artery stenosis was increased in individuals with obesity without MetS compared to normal-weight individuals without MetS (OR 1.47, 95%CI 1.34-1.62; p < 0.0001), even after adjusting for non-HDL-cholesterol and several lifestyle factors. Such difference was not observed for the presence of carotid artery plaques (OR 0.94, 95%CI 0.87-1.02; p = 0.11). Obese or overweight individuals without any MetS criteria (except the waist criterion) showed significantly more pronounced stenosis in the coronary arteries as compared to the normal-weight individuals, while one criterion was needed to show increased plaque prevalence in the carotid arteries. High blood pressure was the most important single criterion for increased atherosclerosis in this respect.Conclusions: Individuals with obesity without MetS showed increased severity of coronary artery stenosis, but no increased occurrence of carotid artery plaques compared to normal-weight individuals without MetS, further emphasizing that obesity is not a benign condition even in the absence of MetS. Funding Agencies|SCAPIS is the Swedish Heart -Lung Foundation; Knut and Alice Wallenberg Foundation; Swedish Research Council; VINNOVA (Swedens Innovation agency) the University of Gothenburg and Sahlgrenska University Hospital; Karolinska Institutet and Stockholm county council; Linkoping University and University Hospital; Lund University and Skane University Hospital; Ume University and University Hospital; Uppsala University and University Hospital

Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous GFR-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterised by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules < 1kDa dominating the glomerular filtrate e.g., water, urea, creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterised by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines. This article is protected by copyright. All rights reserved.

Aims The interplay between pain of different chronicity and cardiovascular disease (CVD) is incompletely understood. We aimed to investigate the association between different levels of chronic or nonchronic pain and risk of CVD. Methods and results Participants in the UK Biobank who reported pain at baseline were divided into three groups according to pain duration and widespreadness. Participants reporting no pain were controls. Multivariable Cox regression was used to investigate the association between pain and incidence of myocardial infarction, heart failure, stroke, cardiovascular mortality, and composite CVD (defined as any of the before-mentioned cardiovascular events). Of 475 171 participants, 189 289 reported no pain, 87 830 reported short-term pain, 191 716 chronic localized pain, and 6336 chronic widespread pain (CWP). During a median of 7.0 years’ follow-up, participants with chronic localized pain and CWP had, after adjustment for age, sex, established cardiovascular risk factors, physical activity, anxiety, depression, cancer, chronic inflammatory/painful disease, pain/anti-inflammatory medication, socioeconomic status, a significantly increased risk for composite CVD [hazard ratio (HR) 1.14, confidence interval (CI) 1.08–1.21, P < 0.001; and HR 1.48, CI 1.28–1.73, P < 0.001, respectively] compared with controls, with similar results when using the different specific CVDs as outcomes. Population attributable risk proportion for chronic pain as a risk factor for composite CVD was comparable with that of diabetes (8.6 vs. 7.3%, respectively). Conclusion Chronic pain is associated with an increased risk for myocardial infarction, stroke, heart failure, and cardiovascular death independent of established cardiovascular risk factors, socioeconomic factors, comorbidities and medication. Our study, the largest to date, confirms and extends our understanding of chronic pain as an underestimated cardiovascular risk factor with important public health implications.

The detrimental effects of increased length of stay at the emergency department (ED-LOS) for patient outcome have been sparsely studied in the Swedish setting. Our aim was to further explore the association between ED-LOS and short-term mortality in patients admitted to the EDs of two large University hospitals in Sweden. All adult patients (> 18 years) visiting the ED at the Karolinska University Hospital, Sweden, from 1/1/2010 to 1/1/2015 (n = 639,385) were retrospectively included. Logistic regression analysis was used to determine association between ED-LOS and 7- and 30-day mortality rates. All patients were triaged according to the RETTS-A into different levels of medical urgency and subsequently separated into five quintiles of ED-LOS. Mortality rate was highest in highest triage priority level (7-day mortality 5.24%, and 30-day mortality 9.44%), and decreased by lower triage priority group. For patients with triage priority levels 2–4, prolonged ED-LOS was associated with increased mortality, especially for lowest priority level, OR for priority level 4 and highest quintile of ED-LOS 30-day mortality 1.49 (CI 95% 1.20–1.85). For patients with highest triage priority level the opposite was at hand, with decreasing mortality risk with increasing quintile of ED-LOS for 7-day mortality, and lower mortality for the two highest quintile of ED-LOS for 30-day mortality. In patients not admitted to in-hospital care higher ED-LOS was associated with higher mortality. Our data suggest that increased ED-LOS could be associated with slightly increased short-term mortality in patients with lower clinical urgency and dismissed from the ED.

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.

Background Treatment of multimorbid patients can be improved. Development of patient-centred care of high-quality requires context-bound understanding of the multimorbid population’s patterns of demographics, co-morbidities and medication use. Objective The aim of this study was to identify patterns of multimorbidity in the total population of Region Stockholm, Sweden, by exploring demographics, claimed prescription drugs, risk of mortality and non-random association of conditions. Methods In this cross-sectional descriptive population-based cohort study, we extracted data from the Swedish VAL database (N = 2 323 667) including all consultations in primary and specialized outpatient care, all inpatient care and all prescriptions claimed during 2017. We report number of chronic conditions and claimed prescription drugs, physical and mental co-morbidity, and 1-year mortality. We stratified the analyses by sex. We examined non-random associations between diseases using cluster analysis. Results In total, 21.6% had multimorbidity (two or more chronic conditions) and 24.1% had polypharmacy (more than five claimed prescription drugs). Number of claimed drugs, co-occurrence of mental and physical conditions, and 1-year mortality increased as multimorbidity increased. We identified seven multimorbidity clusters with clinically distinct characteristics. The smallest cluster (7% of individuals) had prominent cardiovascular disease, the highest 1-year mortality rate, high levels of multimorbidity and polypharmacy, and was much older. The largest cluster (27% of individuals) was younger and heterogenous, with primarily mental health problems. Conclusions Individuals with chronic conditions often show clinical complexity with both concordant and discordant conditions and polypharmacy. This study indicates that clinical guidelines addressing clustering of conditions may be one strategy for managing complexity.

Background: Whether subjects with metabolically healthy obesity (MHO) have an increased risk of cardiovascular disease (CVD) is controversial. Some of this discrepancy could be due to differences i...

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

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.

Once considered a problem only for high-income countries, obesity rates are now rising worldwide. When evaluating test results from obese patients it is important to be aware of the effect of obesity on individual laboratory test results. The aim of the present study was to study the association between body mass index (BMI) and a group of frequently requested laboratory tests to evaluate which of these analytes that are affected by BMI. We analyzed the association between body mass index (BMI) and Alanine aminotransaminase (ALT), Albumin, Alkaline phosphatase, Pancreatic amylase, Apolipoprotein A1, Apolipoprotein B, Apolipoprotein B/Apolipoprotein A1 ratio, Aspartate aminotransferase (AST), AST/ALT ratio, Bilirubin, Calcium, Calprotectin, Cholesterol, HDL-cholesterol, Creatinine kinase (CK), Creatinine, C-reactive protein, Cystatin C, Gamma-glutamyl transferase (GGT), Iron, Iron saturation, Lactate dehydrogenase (LDH), Magnesium, Phosphate, Transferrin, Triglycerides, Urate, Urea, Zink, Hemoglobin, Platelet count and White blood cell count in an 80-year old population (n=531, 266 females and 265 males). There were significant Spearman rank associations between BMI and laboratory test results for several of the studied markers in both females and males. The strongest associations with BMI were noted for ALT, Apolipoprotein A1, HDL-cholesterol, Hemoglobin, CRP, Cystatin C, Triglycerides and Urate. In conclusion, several of the most frequently used laboratory markers are significantly associated with BMI. To be able to correctly interpret a test result it is important to be aware of the effects of BMI on the test results.

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)

Objective This study investigated how changes in 84 proteins over a 10-year period of aging were related to changes in measures of body fat and distribution over the same period. Methods Cardiovascular candidate proteins were measured using the proximal extension assay technique, along with BMI and waist-hip ratio (WHR), at ages 70, 75, and 80 in 1,016 participants of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Associations of changes in plasma protein levels, BMI, and WHR over time were analyzed using linear mixed models. Results Changes in 19 and 16 proteins were significantly associated with changes in BMI and WHR, respectively (P 0.05): endothelial cell-specific molecule 1, pentraxin-related protein PTX3, ST2 protein (also known as interleukin-1 receptor-like 1), and spondin-1. Five proteins tracked with change in WHR (P 0.05): caspase-8, cathepsin L1, oxidized low-density lipoprotein receptor 1, interleukin-6 receptor subunit alpha, and C-C motif chemokine 20. Conclusions This is the first large longitudinal study of how changes in plasma protein signatures are associated with changes in measures of body fat and distribution over 10 years of aging.

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.

Summary paragraphThe human gut microbiota produces a variety of small compounds, some of which enter the bloodstream and impact host health. Conversely, various exogenous nutritional and pharmaceutical compounds affect the gut microbiome composition before entering circulation. Characterization of the gut microbiota–host plasma metabolite interactions is an important step towards understanding the effects of the gut microbiota on human health. However, studies involving large and deeply phenotyped cohorts that would reveal such meaningful interactions are scarce. Here, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for detailed characterization of the fecal microbiota and plasma metabolome, respectively, of 8,584 participants invited at age 50 to 64 of the Swedish CArdioPulmonary bioImage Study (SCAPIS). After adjusting for multiple comparisons, we identified 1,008 associations between species alpha diversity and plasma metabolites, and 318,944 associations between specific gut metagenomic species and plasma metabolites. The gut microbiota explained up to 50% of the variance of individual plasma metabolites (mean of 4.7%). We present all results as the searchable association atlas “GUTSY” as a rich resource for mining associations, and exemplify the potential of the atlas by presenting novel associations between oral medication and the gut microbiome, and microbiota species strongly associated with levels of the uremic toxin p-cresol sulfate. The association atlas can be used as the basis for targeted studies of perturbation of specific bacteria and for identification of candidate plasma biomarkers of gut flora composition.

Objectives To develop a crude screening method for detecting biomarkers which frequently exhibit a rise (or fall) in level prior to a serious event (e.g. a stroke) in patients with a chronic disease, signalling that the biomarker may have an alarm-raising or prognostic potential. The subsequent assessment of the marker’s clinical utility requires costly, difficult longitudinal studies. Therefore, initial screening of candidate-biomarkers is desirable. Methods The method exploits a cohort of patients with biomarkers measured at entry and with recording of first serious event during follow-up. Copying those individual records onto a common timeline where a specific event occurs on the same day (Day 0) for all patients, the baseline biomarker level, when plotted against the patient’s entry time on the revised timeline, will have a positive (negative) regression slope if biomarker levels generally rise (decline) the closer one gets to the event. As an example, we study 1,958 placebo-treated patients with stable coronary artery disease followed for nine years in the CLARICOR trial (NCT00121550), examining 11 newer biomarkers. Results Rising average serum levels of cardiac troponin T and of N-terminal pro-B-type natriuretic peptide were seen prior to a fatal cardiovascular outcome. C-reactive protein rose prior to non-cardiovascular death. Glomerular filtration rate, seven lipoproteins, and nine newer cardiological biomarkers did not show convincing changes. Conclusions For early detection of biomarkers with an alarm-raising potential in chronic diseases, we proposed the described easy procedure. Using only baseline biomarker values and clinical course of participants with coronary heart disease, we identified the same cardiovascular biomarkers as those previously found containing prognostic information using longitudinal or survival analysis.

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.

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.

Context There is a dispute whether obesity without major metabolic derangements may represent a benign condition or not. Objective We aimed to compare the plasma metabolome in obese subjects without metabolic syndrome (MetS) with normal-weight subjects without MetS and with obese subjects with MetS. Methods This was a cross-sectional study at 2 academic centers in Sweden. Individuals from 3 population-based samples (EpiHealth, n = 2342, SCAPIS-Uppsala, n = 4985, and SCAPIS-Malmö, n = 3978) were divided into groups according to their body mass index (BMI) and presence/absence of MetS (National Cholesterol Education Program [NCEP]/consensus criteria). In total, 791 annotated endogenous metabolites were measured by ultra-performance liquid chromatography–tandem mass spectrometry. Results We observed major differences in metabolite profiles (427 metabolites) between obese (BMI ≥ 30 kg/m2) and normal-weight (BMI Conclusion Our data suggest a graded derangement of the circulating metabolite profile from lean to obese to MetS, in particular for metabolites involved in amino acid synthesis/metabolism and sphingolipid metabolism. Insulin resistance is a plausible mediator of this gradual metabolic deterioration.

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.