| 1. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 2. |
- Molvin, John, et al.
(författare)
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Proteomic exploration of common pathophysiological pathways in diabetes and cardiovascular disease
- 2020
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Ingår i: ESC Heart Failure. - : Wiley. - 2055-5822. ; 7:6, s. 4151-4158
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Tidskriftsartikel (refereegranskat)abstract
- Aims The epidemiological association between diabetes and cardiovascular disease is well established, but the pathophysiological link is complex and multifactorial. We investigated seven proteins, previously linked to incident diabetes mellitus, and their association with cardiovascular disease and mortality. Methods and results Plasma samples from 1713 individuals from the Swedish population-based Malmo Preventive Project (mean age 67.4 +/- 6.0 years; 29.1% women) were analysed with a proximity extension assay panel. Seven proteins [scavenger receptor cysteine rich type 1 protein M130 (CD163), fatty acid-binding protein 4 (FABP4), plasminogen activator inhibitor 1 (PAI), insulin-like growth factor-binding protein 2 (IGFB2), cathepsin D (CTSD), galectin-4 (GAL4), and paraoxonase-3 (PON3)] previously shown to be associated with incident diabetes were analysed for associations with all-cause mortality (ACM), cardiovascular mortality (CVM), incident coronary events (CEs), and incident heart failure (HF). After exclusion of prevalent cases of respective outcome, proteins that met Bonferroni-corrected significance were analysed in multivariable Cox regression models. Significant associations were identified between five proteins [GAL4 (hazard ratio; 95% confidence interval: 1.17-1.41), CTSD (1.15-1.37), CD163 (1.09-1.30), IGFBP2 (1.05-1.30), and FABP4 (1.04-1.29)] and ACM and four proteins [GAL4 (1.38-1.56), CTSD (1.14-1.43), CD163 (1.09-1.36), and IGFBP2 (1.03-1.35)] with CVM. Three proteins [GAL4 (1.14-1.57), CTSD (1.12-1.50), and FABP4 (1.05-1.55)] were significantly associated with incident CE and two [GAL4 (1.03-1.54) and CTSD (1.01-1.46)] were associated with incident HF after adjusting for traditional risk factors including N-terminal pro-brain natriuretic peptide. Conclusions In a general Swedish population, four proteins previously shown to be associated with diabetes were associated with ACM and CVM. Three proteins were associated with incident CE. Finally, GAL4 and CTSD displayed novel associations with incident HF and were the only proteins associated with all outcomes.
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| 3. |
- Hoffmann, Mikael, et al.
(författare)
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Do patients or their physicians more accurately assess long-term risk associated with hypertension? A population-based study
- 2020
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Ingår i: Scandinavian Journal of Primary Health Care. - : Informa UK Limited. - 0281-3432 .- 1502-7724. ; 38:2, s. 166-175
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To compare the assessments of 10-year probability by patients and their physicians of cardiovascular complications of hypertension with actual outcomes. Design: Patients with uncomplicated hypertension treated with at least one antihypertensive drug at inclusion were followed for 10 years through mandatory national health registers. Setting: 55 primary health care centres, 11 hospital outpatient clinics in Sweden Patients: 848 patient, 212 physicians. Main outcome measures: Patients and physicians estimated the probability of hypertension-related complications with treatment (death, heart failure, acute myocardial infarction/AMI, and stroke) for each patient in 848 pairs. Estimates were compared with the clinical outcomes 10 years later using data from the Mortality Register and the National Patient Register. Results: Patients were significantly better (p < 0.001) than their physicians in estimating the average probability of heart failure compared with actual outcome data (14% vs. 24%, outcome 15%), AMI (16% vs. 26%, outcome 8%), and stroke (15% vs. 25%, outcome 11%). Patients were significantly worse (p < 0.001) at estimating the average probability of death (10% vs. 18%, actual outcome 20%). Neither the patients nor the physicians were able to distinguish reliably between low-risk and high-risk patients after adjustment for age and sex. Conclusions: Patients were better than their physicians in estimating the average probability of morbidity due to hypertension. Both the patients and their attending physicians had difficulty in estimating the individual patient’s risk of complications. The results support the use of evidence-based tools in consultations for assessing the risk of cardiovascular complications associated with hypertension.Key points •Shared decision making relies on a common understanding of risks and benefits. Tools for risk assessment of hypertension have been introduced in the last two decades. •Without tools for risk assessment, both patients and physicians had difficulties in estimating the individual patient’s risk of cardiovascular morbidity. •Patients were better than physicians in estimating actual average cardiovascular morbidity due to hypertension during a follow-up of 10 years. •The results support the use of evidence-based tools in consultations for assessing the risk of cardiovascular complications associated with hypertension. © 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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| 4. |
- Midlöv, Patrik, et al.
(författare)
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PERson-centredness in hypertension management using information technology (PERHIT): a protocol for a randomised controlled trial in primary health care
- 2020
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Ingår i: Blood Pressure. - : TAYLOR & FRANCIS LTD. - 0803-7051 .- 1651-1999. ; 29:3, s. 149-156
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: For primary health care (PHC), hypertension is the number one diagnosis for planned health care visits. The treatment of high blood pressure (BP) and its consequences constitutes a substantial economic burden. In spite of efficient antihypertensive medications, a low percentage of patients reach a well-controlled BP. The PERson-centredness in Hypertension management using Information Technology (PERHIT) Study is a multicentre randomised controlled trial. PERHIT is designed to evaluate the effect of supporting self-management on systolic blood pressure by the use of information technology in Swedish primary health care. Materials and Methods: After inclusion, 900 patients from 36 PHC centres are randomised to two groups. In the intervention group, patients are provided with a self-management support system including a home-BP monitor and further requested to perform self-reports and measure BP every evening for eight consecutive weeks. In the control group, patients receive treatment as usual. Results: The primary outcome will be the change in systolic blood pressure in patients with hypertension. In addition, person-centredness, daily life activities, awareness of risk and health care costs will also be evaluated. Conclusion: The results of this randomised controlled trial with assessment of blood pressure and same-day self-reports will provide patients a tool to understand the interplay between blood pressure and lifestyle applicable to primary health care. The self-management support system may be of importance for improved adherence to treatment and persistence to treatment recommendations.
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| 5. |
- Molvin, John, et al.
(författare)
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A diabetes-associated genetic variant is associated with diastolic dysfunction and cardiovascular disease.
- 2020
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Ingår i: ESC heart failure. - : Wiley. - 2055-5822. ; 7:1, s. 345-353
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Tidskriftsartikel (refereegranskat)abstract
- Although the epidemiological association between Type 2 diabetes and congestive heart failure (CHF) as well as cardiovascular disease (CVD) is well established, associations between diabetes-related single-nucleotide polymorphisms (SNPs), CHF, and CVD have been surprisingly inconclusive. Our aim is to examine if 43 diabetes-related SNPs were associated with prevalent diastolic dysfunction assessed by echocardiography and incident CVD and/or CHF.We genotyped 43 SNPs that previously reported genome-wide significant associations with Type 2 diabetes, in 1444 subjects from the population-based Malmö Preventive Project-Re-examination Study (MPP-RES) (mean age 68 years; 29% women, 36% prevalent diabetes) (discovery cohort) and in 996 subjects from the VARA cohort (mean age 51 years, 52% women, 7% prevalent diabetes) (replication cohort). Multivariable logistic regression was assessed. Genetic variants that reached significant association with diastolic dysfunction in both cohorts were then analysed for association with incident CVD/CHF in a larger sample of the MPP-RES cohort (3,407 cases and 11,776 controls, median follow up >30 years) using Cox regression analysis. A common variant at the HNF1B [major allele (T) coded, also the risk allele for diabetes] was the only SNP associated with increased risk of prevalent diastolic dysfunction in both the discovery [MPP-RES; odds ratio (OR) 1.21, P = 0.024), and the replication cohort (VARA; OR 1.38, P = 0.042]. Cox regression analysis showed that carriers of the T-allele of rs757210 had an increased risk of future CVD (HR 1.05, P = 0.042). No significant association was seen for incident CHF.The diabetes susceptibility locus HNF1B is associated with prevalent diastolic dysfunction in two independent Swedish cohorts as well as incident cardiovascular disease.
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| 6. |
- Jujić, Amra, et al.
(författare)
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Glucose-dependent insulinotropic peptide and risk of cardiovascular events and mortality : a prospective study
- 2020
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 63:5, s. 1043-1054
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk.Methods: GIP concentrations were successfully measured during OGTTs in two independent populations (Malmo Diet Cancer-Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD.Results: In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 x 10(-5)) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD.Conclusions/interpretation: In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5-9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.
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| 7. |
- Rydberg, Mattias, et al.
(författare)
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Diabetes mellitus as a risk factor for compression neuropathy: a longitudinal cohort study from southern Sweden
- 2020
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Ingår i: BMJ open diabetes research & care. - : BMJ. - 2052-4897. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Compression neuropathies (CN) in the upper extremity, the most common being carpal tunnel syndrome (CTS) and ulnar nerve entrapment (UNE), are frequent among patients with diabetes mellitus (DM). Earlier studies have shown contradicting results regarding DM as a risk factor for CN. Thus, the aim of the present population-based, longitudinal study was to explore potential associations between DM, CTS, and UNE during long-term follow-up. Research design and methods A total of 30 466 participants aged 46–73 years, included in the population-based Malmö Diet and Cancer Study during 1991–1996, were followed up in Swedish national registries regarding incident CTS and UNE until 2016. Associations between prevalent DM at baseline and incident CTS or UNE were calculated using Cox proportional hazard models, adjusted for baseline confounders, such as sex, age at study entry, smoking, hypertension, use of antihypertensive treatment, alcohol consumption, and body mass index (BMI). HbA1c and fasting plasma glucose levels had been measured at baseline in a subgroup of 5508 participants and were related to incident CTS and UNE in age and sex-adjusted binary logistic regression models. Results A total of 1081 participants developed CTS and 223 participants developed UNE during a median follow-up of 21 years. Participants with incident CTS or UNE had higher prevalence of DM and higher BMI at baseline. Using multivariate Cox regression models, prevalent DM at baseline was independently associated with both incident CTS (HR 2.10; 95% CI 1.65 to 2.70, p<0.0001) and incident UNE (HR 2.20; 95% CI 1.30 to 3.74, p=0.003). Higher levels of HbA1c and plasma glucose were associated with an increased risk for CTS, but not for UNE. Conclusion This study establishes DM as a major risk factor in the development of both CTS and UNE. Furthermore, a higher BMI is associated with both CTS and UNE. Finally, hyperglycemia seems to affect the median and ulnar nerves differently.
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| 8. |
- Swärd, Per, et al.
(författare)
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Patterns of urinary albumin and IgM associate with markers of vascular ageing in young to middle-aged individuals in the Malmö offspring study
- 2020
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Increased urinary excretion of IgM and low-grade albuminuria are associated with increased risk of cardiovascular morbidity and mortality. The objective of this study was to investigate the association between urinary IgM, albuminuria, and vascular parameters reflecting arterial structure and function. METHODS: Subjects of the present study were from the Malmö Offspring study (MOS) cohort, and included 1531 offspring (children and grand-children) to first-generation subjects that participated in the Malmö Diet Cancer-Cardiovascular Arm study cohort. At baseline, technical measurements of arterial stiffness (carotid-femoral pulse wave velocity; c-f PWV), carotid arterial morphology, 24-h ambulatory blood pressure recordings, ankle-brachial-index (ABI), and evaluation of endothelial function (reactive hyperemia index, RHI) were performed. Urinary (U) IgM, U-albumin, and U-creatinine were measured. Multivariate adjusted logistic regression was used to test whether U-IgM excretion and increasing urinary albumin excretion were related to vascular parameters. RESULTS: Detectable U-IgM was independently associated with higher systolic blood pressure, odds ratio (OR) 1.021, 95% confidence interval (CI, 1.003-1.039), p = 0.025 and lower ABI; ABI dx: OR 0.026, 95% CI (0.002-0.381), p = 0.008, ABI sin: OR 0.040, 95% CI (0.003-0.496), p = 0.012. Low-grade albuminuria was independently associated with systolic and diastolic blood pressure, aortic blood pressure, the c-f PWV and the number of carotid intima plaques (p < 0.05). CONCLUSIONS: In young to middle-aged, mostly healthy individuals, increased U-IgM excretion and low-grade albuminuria are associated with adverse vascular parameters. Increased U-IgM excretion may reflect subclinical peripheral atherosclerosis, whereas increased U-albumin excretion is associated with a wide range of cardiovascular abnormalities. This may reflect different pathophysiological mechanisms.
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| 9. |
- Andell, Pontus, et al.
(författare)
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Neighborhood socioeconomic status and aortic stenosis : A Swedish study based on nationwide registries and an echocardiographic screening cohort
- 2020
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 318, s. 153-159
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aortic stenosis (AS) is the most common valvular heart disease in developed countries, confers high mortality in advanced cases, but can effectively be reversed using endovascular or open-heart surgery. We evaluated the association between AS and neighborhood socioeconomic status (NSES). Methods: We used Swedish population-based nationwide registers and an echocardiography screening cohort during the study period 1997–2014. NSES was determined by an established neighborhood deprivation index composed of education, income, unemployment, and receipt of social welfare. Multilevel adjusted logistic regression models determined the association between NSES and incident AS (according to ICD-10 diagnostic codes). Results: The study population of men and women (n=6,641,905) was divided into individuals living in high (n = 1,608,815 [24%]), moderate (n = 3,857,367 [58%]) and low (n = 1,175,723 [18%]) SES neighborhoods. There were 63,227 AS cases in total. Low NSES (versus high) was associated with a slightly increased risk of AS (OR 1.06 [95% CI 1.03–1.08]) in the nationwide study population. In the echocardiography screening cohort (n = 1586), the association between low NSES and AS was markedly stronger (OR: 2.73 [1.05–7.12]). There were more previously undiagnosed AS cases in low compared to high SES neighborhoods (3.1% versus 1.0%). Conclusions: In this nationwide Swedish register study, low NSES was associated with a slightly increased risk of incident AS. However, the association was markedly stronger in the echocardiography screening cohort, which revealed an almost three-fold increase of AS among individuals living in low SES neighborhoods, possibly indicating an underdiagnosis of AS among these individuals.
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| 10. |
- Bruno, Rosa Maria, et al.
(författare)
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Early and supernormal vascular aging : Clinical characteristics and association with incident cardiovascular events
- 2020
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Ingår i: Hypertension. - 0194-911X. ; , s. 1616-1624
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Tidskriftsartikel (refereegranskat)abstract
- Pulse wave velocity is an established marker of early vascular aging but may also help identifying individuals with supernormal vascular aging. We tested the hypothesis that individuals with the largest difference (Δ-age) between chronological and vascular age show the lowest rate of cardiovascular events and may thus be defined as supernormal vascular aging. Vascular age was defined as the predicted age in the best fitting multivariable regression model including classical risk factors and treatment and pulse wave velocity, in a subset of the Reference Values for Arterial Stiffness Collaboration Database (n=3347). Δ-age was then calculated as chronological age minus vascular age, and the 10th and 90th percentiles were used to define early (Δ-age<-5.7 years), normal (Δ-age -5.7 to 6.8 years) and supernormal vascular aging (Δ-age>6.8 years). The risk for fatal and nonfatal cardiovascular events associated with vascular aging categories was investigated in the Malmö Diet and Cancer Study cohort (n=2642). In the Malmö Diet and Cancer Study Cohort (6.6-year follow-up, 286 events), Δ-age was significantly (P<0.01) and inversely associated with cardiovascular events. Compared with normal vascular aging, supernormal vascular aging had lower risk (hazard ratio, 0.59 [95% CI, 0.41-0.85]), whereas early vascular aging had higher risk (hazard ratio, 2.70 [95% CI, 1.55-4.70]) of cardiovascular events, in particular coronary events. There was no significant association with all-cause mortality. This study represents the first validation of the clinical significance of the supernormal vascular aging concept, based on prospective data. Its further characterization may help discovering novel protective molecular pathways and providing preventive strategies for successful vascular aging.
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