Publications by authors named "Jerzy Leppert"

73 Publications

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

Respir Med 2021 Jan 5;176:106282. Epub 2020 Dec 5.

Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institute, Huddinge, Sweden; Region Dalarna, Falun, Sweden; School of Health and Social Sciences, Dalarna University, Falun, Sweden. Electronic address:

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 (FEV%) 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 FEV% in both the discovery and replication sample, regardless of stratification by smoking status. The combined proteomic data cumulatively explained 5% of the variation in FEV%. 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 FEV% 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 FEV%.

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.
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http://dx.doi.org/10.1016/j.rmed.2020.106282DOI Listing
January 2021

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

Atherosclerosis 2020 10 6;311:143-149. Epub 2020 Jul 6.

Centre for Clinical Research, Uppsala University, Västmanland County Hospital, Västerås, Sweden; Department of Clinical Physiology, Västmanland County Hospital, Västerås, Sweden.

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 L-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 < 0.001) and yielded an AUC of 0.76 (95%CI 0.71-0.80). A higher discriminatory performance was observed in the validation cohort (AUC 0.84; 95% CI 0.76-0.92).

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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.06.015DOI Listing
October 2020

The association between plasma proteomics and incident cardiovascular disease identifies MMP-12 as a promising cardiovascular risk marker in patients with chronic kidney disease.

Atherosclerosis 2020 08 9;307:11-15. Epub 2020 Jul 9.

Education, Health and Social Studies, Dalarna University, Falun, Sweden; Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Alfred Nobels Allé 23, SE 14183, Huddinge, Sweden.

Background And Aims: Previous proteomics efforts in patients with chronic kidney disease (CKD) have predominantly evaluated urinary protein levels. Therefore, our aim was to investigate the association between plasma levels of 80 cardiovascular disease-related proteins and the risk of major adverse cardiovascular events (MACE) in patients with CKD.

Methods: Individuals with CKD stages 3-5 (eGFR below 60 ml min-1 [1.73 m]-2) from three community-based cohorts (PIVUS, ULSAM, SAVA), one diabetes cohort (CARDIPP) and one cohort with peripheral artery disease patients (PADVA) with information on 80 plasma protein biomarkers, assessed with a proximity extension assay, and follow-up data on incident MACE, were used as discovery sample. To validate findings and to asses generalizability to patients with CKD in clinical practice, an outpatient CKD-cohort (Malnutrition, Inflammation and Vascular Calcification (MIVC)) was used as replication sample.

Results: In the discovery sample (total n = 1316), 249 individuals experienced MACE during 7.0 ± 2.9 years (range 0.005-12.9) of follow-up, and in the replication sample, 71 MACE events in 283 individuals over a mean ± SD change of 2.9 ± 1.2 years (range 0.1-4.0) were documented. Applying Bonferroni correction, 18 proteins were significantly associated with risk of MACE in the discovery cohort, adjusting for age and sex in order of significance, GDF-15, FGF-23, REN, FABP4, IL6, TNF-R1, AGRP, MMP-12, AM, KIM-1, TRAILR2, TNFR2, CTSL1, CSF1, PlGF, CA-125, CCL20 and PAR-1 (p < 0.000625 for all). Only matrix metalloproteinase 12 (MMP-12) was significantly associated with an increased risk of MACE in the replication sample (hazard ratio (HR) per SD increase, 1.36, 95% CI (1.07-1.75), p = 0.013).

Conclusions: Our proteomics analyses identified plasma MMP-12 as a promising cardiovascular risk marker in patients with CKD.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.06.013DOI Listing
August 2020

Do self-reported pregnancy complications add to risk evaluation in older women with established cardiovascular disease?

BMC Womens Health 2019 12 16;19(1):160. Epub 2019 Dec 16.

Department of Medical Sciences, Cardiology, Uppsala University, S-751 85, Uppsala, Sweden.

Background: In postmenopausal women with established cardiovascular disease (CVD), it is unknown whether a history of pregnancy complications are related to multisite artery disease (MSAD), defined as atherosclerotic lesions in at least two major vascular beds. Pregnancy complications are an established risk factor for CVD. This study aimed to investigate the frequency of pregnancy complications and their association to specific atherosclerotic manifestations and prediction of MSAD in older women with and without CVD.

Methods: In total, 556 women were invited to participate in the study. Of these women 307 reported former pregnancy from a cohort of women with (n = 233) and without CVD (n = 74). The self-reported frequency of pregnancy complications were surveyed retrospectively by a questionnaire that included miscarriage, subfertility, gestational hypertension (GHT) and/or preeclampsia (PE), low birth weight, preterm birth, bleeding in late pregnancy, gestational diabetes mellitus and high birth weight. Three vascular beds were examined, the peripheral, carotid and coronary arteries.

Results: The mean age was 67.5 (SD 9.5) years. GHT and/or PE tended to be more common, but not significant, in women with CVD than in women without (20.3% vs 10.8%, p = 0.066). Among women with GHT and/or PE, hypertension later in life were more frequent than in women without (66.7% vs 47.4%, p = 0.010). GHT and/or PE were not associated with specific atherosclerotic manifestations or prediction of MSAD.

Conclusions: In older women with established CVD, pregnancy complications was not associated to specific atherosclerotic manifestations and may not provide additional value to the risk evaluation for MSAD.
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http://dx.doi.org/10.1186/s12905-019-0851-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916002PMC
December 2019

Cathepsin D improves the prediction of undetected diabetes in patients with myocardial infarction.

Ups J Med Sci 2019 Aug 20;124(3):187-192. Epub 2019 Aug 20.

Centre for Clinical Research, Uppsala University, Västmanland County Hospital , Västerås , Sweden.

Newer therapeutic agents for type 2 diabetes mellitus can improve cardiovascular outcomes, but diabetes remains underdiagnosed in patients with myocardial infarction (MI). We sought to identify proteomic markers of undetected dysglycaemia (impaired fasting glucose, impaired glucose tolerance, or diabetes mellitus) to improve the identification of patients at highest risk for diabetes. In this prospective cohort, 626 patients without known diabetes underwent oral glucose tolerance testing (OGTT) during admission for MI. Proximity extension assay was used to measure 81 biomarkers. Multivariable logistic regression, adjusting for risk factors, was used to evaluate the association of biomarkers with dysglycaemia. Subsequently, lasso regression was performed in a 2/3 training set to identify proteomic biomarkers with prognostic value for dysglycaemia, when added to risk factors, fasting plasma glucose, and glycated haemoglobin A1c. Determination of discriminatory ability was performed in a 1/3 test set. In total, 401/626 patients (64.1%) met the criteria for dysglycaemia. Using multivariable logistic regression, cathepsin D had the strongest association with dysglycaemia. Lasso regression selected seven markers, including cathepsin D, that improved prediction of dysglycaemia (area under the receiver operator curve [AUC] 0.848 increased to 0.863). In patients with normal fasting plasma glucose, only cathepsin D was selected (AUC 0.699 increased to 0.704). Newly detected dysglycaemia, including manifest diabetes, is common in patients with acute MI. Cathepsin D improved the prediction of dysglycaemia, which may be helpful in the a priori risk determination of diabetes as a motivation for confirmatory OGTT.
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http://dx.doi.org/10.1080/03009734.2019.1650141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182365PMC
August 2019

Risk factors for subarachnoid haemorrhage: a nationwide cohort of 950 000 adults.

Int J Epidemiol 2019 12;48(6):2018-2025

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Background: Subarachnoid haemorrhage (SAH) is a devastating disease, with high mortality rate and substantial disability among survivors. Its causes are poorly understood. We aimed to investigate risk factors for SAH using a novel nationwide cohort consortium.

Methods: We obtained individual participant data of 949 683 persons (330 334 women) between 25 and 90 years old, with no history of SAH at baseline, from 21 population-based cohorts. Outcomes were obtained from the Swedish Patient and Causes of Death Registries.

Results: During 13 704 959 person-years of follow-up, 2659 cases of first-ever fatal or non-fatal SAH occurred, with an age-standardized incidence rate of 9.0 [95% confidence interval (CI) (7.4-10.6)/100 000 person-years] in men and 13.8 [(11.4-16.2)/100 000 person-years] in women. The incidence rate increased exponentially with higher age. In multivariable-adjusted Poisson models, marked sex interactions for current smoking and body mass index (BMI) were observed. Current smoking conferred a rate ratio (RR) of 2.24 (95% CI 1.95-2.57) in women and 1.62 (1.47-1.79) in men. One standard deviation higher BMI was associated with an RR of 0.86 (0.81-0.92) in women and 1.02 (0.96-1.08) in men. Higher blood pressure and lower education level were also associated with higher risk of SAH.

Conclusions: The risk of SAH is 45% higher in women than in men, with substantial sex differences in risk factor strengths. In particular, a markedly stronger adverse effect of smoking in women may motivate targeted public health initiatives.
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http://dx.doi.org/10.1093/ije/dyz163DOI Listing
December 2019

Corrigendum to "Basic Anthropometric Measures in Acute Myocardial Infarction Patients and Individually Sex- and Age-Matched Controls from the General Population".

J Obes 2018 18;2018:3126805. Epub 2018 Dec 18.

Center for Clinical Research, Region Vastmanland-Uppsala University, Hospital of Vastmanland, Västerås, Sweden.

[This corrects the article DOI: 10.1155/2018/3839482.].
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http://dx.doi.org/10.1155/2018/3126805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312588PMC
December 2018

Rationale for a Swedish cohort consortium.

Ups J Med Sci 2019 Jan 8;124(1):21-28. Epub 2019 Jan 8.

b Uppsala Clinical Research Center (UCR) , Uppsala , Sweden.

We herein outline the rationale for a Swedish cohort consortium, aiming to facilitate greater use of Swedish cohorts for world-class research. Coordination of all Swedish prospective population-based cohorts in a common infrastructure would enable more precise research findings and facilitate research on rare exposures and outcomes, leading to better utilization of study participants' data, better return of funders' investments, and higher benefit to patients and populations. We motivate the proposed infrastructure partly by lessons learned from a pilot study encompassing data from 21 cohorts. We envisage a standing Swedish cohort consortium that would drive development of epidemiological research methods and strengthen the Swedish as well as international epidemiological competence, community, and competitiveness.
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http://dx.doi.org/10.1080/03009734.2018.1556754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450580PMC
January 2019

Basic Anthropometric Measures in Acute Myocardial Infarction Patients and Individually Sex- and Age-Matched Controls from the General Population.

J Obes 2018 2;2018:3839482. Epub 2018 Oct 2.

Center for Clinical Research, Region Vastmanland-Uppsala University, Hospital of Vastmanland, Västerås, Sweden.

We compared weight, height, waist and hip circumferences (hip), body mass index (BMI), and waist-to-hip ratio in acute myocardial infarction (MI) patients and individually sex- and age-matched control subjects from the general population in the catchment area of the patients and predicted the risk of MI status by these basic anthropometric measures. The study cohort comprised 748 patients ≤80 years of age with acute MI from a major Swedish cardiac center and their individually sex- and age-matched controls. The analyses were stratified for sex and age (≤65/≥66 years). Risk of MI was assessed by conditional logistic regression. A narrow hip in men ≥66 years was the single strongest risk factor of MI among the anthropometric measures. The combination of was particularly efficient in discriminating men ≥66 years with MI from their controls (area under the receiver operating characteristic (AUROC) curve = 0.82). In men ≤65 years, the best combination was hip, BMI, and height (AUROC = 0.79). In women ≥66 years, the best discriminatory model contained only waist-to-hip ratio (AUROC = 0.67), whereas in women ≤65 years, the best combination was hip and BMI (AUROC = 0.68). A narrow hip reasonably reflects small gluteal muscles. This finding might suggest an association between MI and sarcopenia, possibly related to deficiencies in physical activity and nutrition.
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http://dx.doi.org/10.1155/2018/3839482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247440PMC
September 2019

Adipose tissue fatty acid composition and cognitive impairment.

Nutrition 2018 10 20;54:153-157. Epub 2018 Apr 20.

Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden. Electronic address:

Objective: The aim of this study was to examine the association among adipose tissue eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and the ratios of EPA to AA and DHA to AA with impaired cognitive function.

Methods: This cross-sectional analysis comprised 481 men participating in the Cohort of Swedish Men-Clinical and for whom adipose tissue fatty acid composition and results from a telephone-based cognitive test were available. Impaired cognitive function was defined using a predefined cutoff on the cognitive test. Binomial log-linear regression models were used to estimate prevalence ratios. In secondary analyses, Cox proportional hazards models were used to estimate relative risk for incident dementia ascertained by linkage with population-based registers.

Results: We observed a graded reduction in the prevalence of impaired cognitive function across tertiles of adipose tissue EPA/AA- ratio (P = 0.01); compared with the lowest tertile, the multivariable-adjusted prevalence ratios were, respectively, 0.89 (95% confidence interval [CI], 0.67-1.17) and 0.64 (95% CI, 0.45-0.91) for the second and third tertiles. EPA, DHA, and the DHA/AA ratio showed similar patterns of association; however, the CIs included the null. AA alone was not associated with impaired cognitive function. Although with lower precision, estimates obtained from the prospective analysis were broadly consistent with the main analysis.

Conclusions: Findings from this study suggest that a high ratio of EPA to AA in adipose tissue may be associated with better cognitive function. A similar association was observed with EPA, DHA, and the ratio of DHA to AA, but the results did not exclude a null association.
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http://dx.doi.org/10.1016/j.nut.2018.04.006DOI Listing
October 2018

Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes.

Diabetologia 2018 08 24;61(8):1748-1757. Epub 2018 May 24.

Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Alfred Nobels Allé 23, SE 14183, Huddinge, Sweden.

Aims/hypothesis: Multiplex proteomics could improve understanding and risk prediction of major adverse cardiovascular events (MACE) in type 2 diabetes. This study assessed 80 cardiovascular and inflammatory proteins for biomarker discovery and prediction of MACE in type 2 diabetes.

Methods: We combined data from six prospective epidemiological studies of 30-77-year-old individuals with type 2 diabetes in whom 80 circulating proteins were measured by proximity extension assay. Multivariable-adjusted Cox regression was used in a discovery/replication design to identify biomarkers for incident MACE. We used gradient-boosted machine learning and lasso regularised Cox regression in a random 75% training subsample to assess whether adding proteins to risk factors included in the Swedish National Diabetes Register risk model would improve the prediction of MACE in the separate 25% test subsample.

Results: Of 1211 adults with type 2 diabetes (32% women), 211 experienced a MACE over a mean (±SD) of 6.4 ± 2.3 years. We replicated associations (<5% false discovery rate) between risk of MACE and eight proteins: matrix metalloproteinase (MMP)-12, IL-27 subunit α (IL-27a), kidney injury molecule (KIM)-1, fibroblast growth factor (FGF)-23, protein S100-A12, TNF receptor (TNFR)-1, TNFR-2 and TNF-related apoptosis-inducing ligand receptor (TRAIL-R)2. Addition of the 80-protein assay to established risk factors improved discrimination in the separate test sample from 0.686 (95% CI 0.682, 0.689) to 0.748 (95% CI 0.746, 0.751). A sparse model of 20 added proteins achieved a C statistic of 0.747 (95% CI 0.653, 0.842) in the test sample.

Conclusions/interpretation: We identified eight protein biomarkers, four of which are novel, for risk of MACE in community residents with type 2 diabetes, and found improved risk prediction by combining multiplex proteomics with an established risk model. Multiprotein arrays could be useful in identifying individuals with type 2 diabetes who are at highest risk of a cardiovascular event.
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http://dx.doi.org/10.1007/s00125-018-4641-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061158PMC
August 2018

Growth differentiation factor 15 in a community-based sample: age-dependent reference limits and prognostic impact.

Ups J Med Sci 2018 Jun 1;123(2):86-93. Epub 2018 May 1.

a Center for Clinical Research , Uppsala University, Västmanland County Hospital , Västerås , Sweden.

Background: Despite the growing body of evidence on growth differentiation factor 15 (GDF-15) reference values for patients with existing cardiovascular disease, limited investigation has been dedicated to characterizing the distribution and prognostic impact of GDF-15 in predominantly healthy populations. Furthermore, current cutoff values for GDF-15 fail to account for the well-documented age-dependence of circulating GDF-15.

Methods: From 810 community-dwelling older adults, we selected a group of apparently healthy participants (n = 268). From this sample, circulating GDF-15 was modeled using the generalized additive models for location scale and shape (GAMLSS) to develop age-dependent centile values. Unadjusted and adjusted Cox proportional hazards models were used to assess the association between the derived GDF-15 reference values (expressed as centiles) and all-cause mortality.

Results: Smoothed centile curves showed increasing GDF-15 with age in the apparently healthy participants. An approximately three-fold difference was observed between the 95th and 5th GDF-15 centiles across ages. In a median 8.0 years of follow-up, 97 all-cause deaths were observed in 806 participants with eligible values. In unadjusted Cox regression analyses, the hazard ratio (95% CI) for all-cause mortality per 25-unit increase in GDF-15 centile was 1.80 (1.48-2.20) and dichotomized at the 95th centile, ≥95th versus <95th, was 3.04 (1.99-4.65). Age-dependent GDF-15 centiles remained a significant predictor of all-cause mortality in all subsequent adjusted models.

Conclusions: Age-dependent GDF-15 centile values developed from a population of apparently healthy older adults are independently predictive of all-cause mortality. Therefore, GDF-15 reference values could be a useful tool for risk-stratification in a clinical setting. ClinicalTrials.gov Identifier: NCT01452178.
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http://dx.doi.org/10.1080/03009734.2018.1460427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055745PMC
June 2018

Incremental prognostic value of coronary and systemic atherosclerosis after myocardial infarction.

Int J Cardiol 2018 06;261:6-11

Örebro University, Faculty of Health, Department of Cardiology, Sweden.

Background: The role of systemic atherosclerosis in myocardial infarction (MI) patients is not fully understood. We investigated the incremental prognostic value of coronary and systemic atherosclerosis after acute MI by estimating extra-cardiac artery disease (ECAD) and extent of coronary atherosclerosis.

Methods And Results: The study included 544 prospective MI patients undergoing coronary angiography. For all patients, the longitudinal coronary atherosclerotic extent, expressed as Sullivan extent score (SES) was calculated. In addition, the patients underwent non-invasive screening for ECAD in the carotid, aortic, renal and lower limb. SES was found to be associated with ECAD independent of baseline clinical parameters [adjusted odds ratio (OR) 1.04 95% confidence interval (CI) 1.02-1.06, P < 0.001]. Extensive systemic atherosclerosis, defined as the combination of extensive coronary disease (SES ≥ 17) and ECAD, was associated with higher risk for all-cause mortality compared to limited systemic atherosclerosis (SES < 17 and no ECAD) (hazard ratio [HR] 2.9 95% CI 1.9-4.5, P < 0.001, adjusted for Global Registry of Acute Coronary Events risk score parameters 1.8, 95% CI 1.1-3.0, P = 0.019). The risk for the composite endpoint of cardiovascular death or hospitalization was significantly higher in patients with extensive systemic atherosclerosis compared to patients with limited systemic atherosclerosis (HR 3.1, 95% CI 2.1-4.7, P < 0.001, adjusted HR 1.9, 95% CI 1.2-3.1, P < 0.004).

Conclusions: Visual estimation of the longitudinal coronary atherosclerotic extent at the time of MI predicts ECAD. Coexistence of extensive coronary disease and ECAD defines a group with particularly poor prognosis after MI.
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http://dx.doi.org/10.1016/j.ijcard.2018.02.035DOI Listing
June 2018

Prevalence and prognostic impact of electrocardiographic abnormalities in outpatients with extracardiac artery disease.

Clin Physiol Funct Imaging 2018 Sep 24;38(5):823-829. Epub 2017 Nov 24.

Department of Clinical Physiology, Västmanland County Hospital, Västerås, Sweden.

Identifying cardiac disease in patients with extracardiac artery disease (ECAD) is essential for clinical decision-making. Electrocardiography (ECG) is an easily accessible tool to unmask subclinical cardiac disease and to risk stratify patient with or without manifest cardiovascular disease (CV). We aimed to examine the prevalence and prognostic impact of ECG changes in outpatients with ECAD. Outpatients with carotid or lower extremity artery disease (n = 435) and community-based controls (n = 397) underwent resting ECG. The patients were followed during a median of 4·8 years for CV events (hospitalization or death caused by ischaemic heart disease, cardiac arrest, heart failure, or stroke). ECG abnormalities were classified according to the Minnesota Code. Major (33% versus 15%, P<0·001) but not minor ECG abnormalities (23% versus 26%, P = 0·42) were significantly more common in patients versus controls. During the follow-up, 141 patients experienced CV events. Both major ECG abnormalities [hazard ratio (HR) 1·58, 95% confidence interval (CI) 1·11-2·25, P = 0·012] and any ECG abnormalities (HR 1·57, 95% CI 1·06-2·33, P = 0·024) were significantly associated with CV events after adjustment for potential risk factors. In conclusion, ECG abnormalities were common in these outpatients with ECAD. Major and any ECG abnormalities were independent predictors of CV events. Addition of easily accessible ECG information might be useful in risk stratification for such patients.
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http://dx.doi.org/10.1111/cpf.12488DOI Listing
September 2018

Socioeconomic characteristics and comorbidities of diverticular disease in Sweden 1997-2012.

Int J Colorectal Dis 2017 Nov 7;32(11):1591-1596. Epub 2017 Aug 7.

Department of Surgery, Västmanland's Hospital Västerås, SE-721 89, Västerås, Sweden.

Purpose: This study aimed to evaluate the association of socioeconomic status and comorbidities with uncomplicated and complicated diverticular disease (DD) in Sweden.

Methods: We identified all individuals aged ≥30 years in Sweden diagnosed with DD between 1997 and 2012 using the Swedish National Population and Housing Census and the Hospital Discharge Register. Data were analyzed by multivariable logistic regression, with individual-level characteristics as covariates.

Results: A total of 79,481 patients (median age 66 [range 30-86] years) were hospitalized for DD, 15,878 (20%) of whom for complicated DD. Admissions for both uncomplicated and complicated DD were more common in women (p < 0.001). A low education level was identified as a risk factor for uncomplicated (unadjusted hazard ratio [HR] 1.79, 95% confidence interval [CI] 1.75-1.82; adjusted HR 1.22, 95% CI 1.19-1.24) and complicated DD (unadjusted HR 1.84, 95% CI 1.77-1.92; adjusted HR 1.26, 95% CI 1.21-1.32). Patients with the lowest income had a lower risk of hospitalization for uncomplicated (adjusted HR 0.94, 95% CI 0.91-0.96) and complicated DD (adjusted HR 0.87, 95% CI 0.83-0.92) than those with the highest income. The correlation coefficient between income and education was 0.25. Diabetes and cardiovascular disease were identified as protective factors against uncomplicated DD (adjusted HR 0.68, 95% CI 0.66-0.69 and HR 0.79, 95% CI 0.74-0.84, respectively).

Conclusions: Patients with the lowest education level had an increased risk of hospitalization for DD. Further studies are needed to explore the association of diabetes and cardiovascular disease with uncomplicated DD.
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http://dx.doi.org/10.1007/s00384-017-2853-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635093PMC
November 2017

GDF-15 and TRAIL-R2 are powerful predictors of long-term mortality in patients with acute myocardial infarction.

Eur J Prev Cardiol 2017 10 1;24(15):1576-1583. Epub 2017 Aug 1.

2 Region Västmanland - Uppsala University, Centre for Clinical Research, Hospital of Västmanland Västerås, Sweden.

Background The Proximity Extension Assay proteomics chip provides a large-scale analysis of 92 biomarkers linked to cardiovascular disease or inflammation. We aimed to identify the biomarkers that best predicted long-term all-cause mortality in patients with acute myocardial infarction. Methods In this prospective cohort study, 92 biomarkers were analysed in 847 consecutive patients from the Västmanland Myocardial Infarction Study with a median follow-up of 6.9 years. Results The mean (± standard deviation) age of the patients was 70 (11.8) years and 32.7% were female. Two hundred and seven patients had died after follow-up. The biomarkers most strongly linked to all-cause mortality were growth differentiation factor 15 (GDF-15) and tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2). Cox regression analysis showed that GDF-15 (hazard ratio 1.25 per unit change, 95% confidence interval, 1.02-1.53, p = 0.031) and TRAIL-R2 (hazard ratio 1.37 per unit change, 95% confidence interval 1.12-1.67, p = 0.002) were independent predictors of long-term all-cause mortality after adjusting for age, gender, diabetes, previous myocardial infarction, stroke, heart failure, hypertension, smoking, hypercholesterolaemia, body mass index, ST-elevation myocardial infarction, left ventricular ejection fraction, troponin I, estimated glomerular filtration rate, N-terminal pro-brain natriuretic peptide and C-reactive protein. The combination of GDF-15 and TRAIL-R2 with established risk factors and biomarkers showed a discriminating accuracy of separating survivors from non-survivors with a cross-validated area under the receiving operating characteristics curve of 0.88 within five years. Conclusion GDF-15 and TRAIL-R2 were the most powerful Proximity Extension Assay chip biomarkers in predicting long-term all-cause mortality in patients with acute myocardial infarction.
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http://dx.doi.org/10.1177/2047487317725017DOI Listing
October 2017

Prognostic impact of subclinical or manifest extracoronary artery diseases after acute myocardial infarction.

Atherosclerosis 2017 Aug 26;263:53-59. Epub 2017 May 26.

Centre for Clinical Research, Uppsala University, Västmanland County Hospital, Västerås, Sweden; Department of Clinical Physiology, Västmanland County Hospital, Västerås, Sweden.

Background And Aims: In patients with coronary artery disease (CAD), clinically overt extracoronary artery diseases (ECADs), including claudication or previous strokes, are associated with poor outcomes. Subclinical ECADs detected by screening are common among such patients. We aimed to evaluate the prognostic impact of subclinical versus symptomatic ECADs in patients with acute myocardial infarction (AMI).

Methods: In a prospective observational study, 654 consecutive patients diagnosed with AMI underwent ankle brachial index (ABI) measurements and ultrasonographic screening of the carotid arteries and abdominal aorta. Clinical ECADs were defined as prior strokes, claudication, or extracoronary artery intervention. Subclinical ECADs were defined as the absence of a clinical ECAD in combination with an ABI ≤0.9 or >1.4, carotid artery stenosis, or an abdominal aortic aneurysm.

Results: At baseline, subclinical and clinical ECADs were prevalent in 21.6% and 14.4% of the patients, respectively. Patients with ECADs received evidence-based medication more often at admission but similar medications at discharge compared with patients without ECADs. During a median follow-up of 5.2 years, 166 patients experienced endpoints of hospitalization for AMI, heart failure, stroke, or cardiovascular death. With ECAD-free cases as reference and after adjustment for risk factors, a clinical ECAD (hazard ratio [HR] 2.10, 95% confidence interval [CI] 1.34-3.27, p=0.001), but not a subclinical ECAD (HR 1.35, 95% CI 0.89-2.05, p=0.164), was significantly associated with worse outcomes.

Conclusions: Despite receiving similar evidence-based medication at discharge, patients with clinical ECAD, but not patients with a subclinical ECAD, had worse long-term prognosis than patients without an ECAD after AMI.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.05.027DOI Listing
August 2017

Gambling frequency and symptoms of attention-deficit hyperactivity disorder in relation to problem gambling among Swedish adolescents: a population-based study.

Ups J Med Sci 2017 Jun 24;122(2):119-126. Epub 2017 Apr 24.

a Centre for Clinical Research, Uppsala University, Västmanland County Hospital , Västerås , Sweden.

Aim: To investigate the associations between gambling frequency, attention-deficit hyperactivity disorder (ADHD) symptoms, and problem gambling among adolescent boys and girls. One hypothesis was that adolescents with increased ADHD symptoms have a higher frequency of gambling compared to adolescents with fewer ADHD symptoms.

Method: A population-based sample of adolescents (aged 15-18 years) completed a questionnaire on demographics, gambling habits, ADHD symptoms, and problematic gambling; 1412 adolescents (from 4440 sampled) with gambling experience were included in the final sample.

Results: A zero-inflated negative binomial regression analysis revealed that increased ADHD symptoms, higher gambling frequency, and higher age were associated with lower odds for being non-susceptible to gambling problems. Moreover, gambling frequency interacted with ADHD symptoms in predicting probability of being non-susceptible to gambling problems. However, when analysing those already susceptible to problem gambling, ADHD symptoms did not modify the effect of gambling frequency on the expected magnitude of gambling problems. In susceptible individuals, problem gambling increased with both increased ADHD symptoms and increased gambling frequency, but the level of problems due to gambling frequency did not change depending on the ADHD symptom level. There was an interaction effect between sex and gambling frequency in relation to gambling problems.

Conclusions: Adolescents with ADHD symptoms seem to be more sensitive to gambling, in terms of being susceptible to developing gambling problems. However, once susceptible, adolescents with ADHD symptoms are affected by gambling frequency similarly to other susceptible participants.
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http://dx.doi.org/10.1080/03009734.2017.1294636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441372PMC
June 2017

Is type D personality an independent risk factor for recurrent myocardial infarction or all-cause mortality in post-acute myocardial infarction patients?

Eur J Prev Cardiol 2017 03 10;24(5):522-533. Epub 2017 Jan 10.

1 Centre for Clinical Research, Uppsala University, Sweden.

Background Type D personality refers to a combination of simultaneously high levels of negative affectivity and social inhibition. The present study aimed to examine whether type D personality was independently associated with recurrent myocardial infarction or all-cause mortality in post-acute myocardial infarction patients, using any of the previously proposed methods for measuring type D personality. Design This was a prospective cohort study. Methods Utilising data from the Västmanland Myocardial Infarction Study, 946 post-acute myocardial infarction patients having data on the DS14 instrument used to measure type D personality were followed-up for recurrent myocardial infarction and all-cause mortality until 9 December 2015. Data were analysed using Cox regression, adjusted for established risk factors. Results In total, 133 (14.1%) patients suffered from type D personality. During a mean follow-up time for recurrent myocardial infarction of 5.7 (3.2) years, 166 (17.5%) patients were affected by recurrent myocardial infarction, of which 26 (15.7%) had type D personality, while during a mean follow-up time for all-cause mortality of 6.3 (2.9) years, 321 (33.9%) patients died, of which 42 (13.1%) had type D personality. After adjusting for established risk factors, type D personality was not significantly associated with recurrent myocardial infarction or all-cause mortality using any of the previously proposed methods for measuring type D personality. A weak association was found between the social inhibition part of type D personality and a decreased risk of all-cause mortality, but this association was not significant after taking missing data into account in a multiple imputation analysis. Conclusions No support was found for type D personality being independently associated with recurrent myocardial infarction or all-cause mortality in post-acute myocardial infarction patients, using any of the previously proposed methods for measuring type D personality.
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http://dx.doi.org/10.1177/2047487316687427DOI Listing
March 2017

Long-term prognostic impact of left atrial volumes and emptying fraction in a community-based cohort.

Heart 2017 05 9;103(9):687-693. Epub 2016 Nov 9.

Department of Clinical Physiology, Västmanland County Hospital, Västerås, Sweden.

Objective: We hypothesised that left atrial emptying fraction (LAEF) would predict long-term cardiovascular outcome in the general population and better so than left atrial (LA) volumes.

Methods: A community-based sample (n=740) in sinus rhythm prospectively underwent clinical evaluation, echocardiography and blood analyses including N-terminal pro B-type natriuretic peptide (NTproBNP). The LA maximum (LAVmax) and minimum volumes (LAVmin) were indexed to body surface area (LAVImax and LAVImin, respectively). LAEF was calculated as LAVmax-LAVmin divided by LAVmax. The participants were followed for a median of 4.9 years regarding incident cardiovascular events (cardiovascular death or hospitalisation because of myocardial infarction, heart failure or stroke). Cox regression models were used to evaluate the associations of LA volumes and LAEF with the outcome.

Results: In a multivariable beta regression model, including clinical and echocardiographic baseline characteristics, higher plasma levels of NTproBNP, higher E/e' and left ventricular systolic dysfunction remained as independent determinants of a lower LAEF. After adjustment for baseline characteristics, including NTproBNP levels, LAEF (HR for 1 SD decrease 1.33, 95% CI 1.04 to 1.70, p=0.022), but not LAVImax (HR for 1 SD increase 0.88, 95% CI 0.70 to 1.10, p=0.25) or LAVImin (HR for 1 SD increase 1.02, 95% CI 0.83 to 1.27, p=0.83) remained independently associated with outcome.

Conclusions: In this community-based cohort, LAEF was a powerful predictor of incident cardiovascular events and its predictive ability was stronger than for LA volumes. Our findings suggest that LA dysfunction may represent a more advanced state of LA remodelling than LA enlargement.
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http://dx.doi.org/10.1136/heartjnl-2016-310242DOI Listing
May 2017

Thrombus aspiration in patients with large anterior myocardial infarction: A Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia trial substudy.

Am Heart J 2016 Feb 22;172:129-34. Epub 2015 Nov 22.

Department of Cardiology, Faculty of Health, Örebro University, Örebro, Sweden.

Background: The TASTE trial did not demonstrate clinical benefit of thrombus aspiration (TA). High-risk patients might benefit from TA.

Methods: The TASTE trial was a multicenter, randomized, controlled, open-label trial obtaining end points from national registries. Patients (n = 7,244) with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) were randomly assigned 1:1 to TA and PCI or to PCI alone. We assessed the 1-year clinical effect of TA in a subgroup with potentially large anterior STEMI: mid or proximal left anterior descending coronary artery infarct lesion, thrombolysis in myocardial infarction 0 to 2 flow, and symptom onset to PCI time ≤5 hours. In this substudy, patient eligibility criteria corresponded to that of the INFUSE-AMI study.

Results: In total, 1,826 patients fulfilled inclusion criteria. All-cause mortality at 1 year of patients randomized to TA did not differ from those randomized to PCI only (hazard ratio [HR] 1.05, 95% CI 0.74-1.49, P = .77). Rates of rehospitalization for myocardial infarction, heart failure, and stent thrombosis did not differ between groups (HR 0.87, 95% CI 0.51-1.46, P = .59; HR 1.10 95% CI 0.77-1.58, P = .58; and HR 0.75, 95% CI 0.30-1.86, P = .53, respectively). This was also the case for the combined end point of all-cause mortality and rehospitalization for myocardial infarction, heart failure, or stent thrombosis (HR 1.00, 95% CI 0.79-1.26, P = .99).

Conclusion: In patients with STEMI and large area of myocardium at risk, TA did not affect outcome within 1 year.
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http://dx.doi.org/10.1016/j.ahj.2015.11.012DOI Listing
February 2016

Left atrial minimum volume is more strongly associated with N-terminal pro-B-type natriuretic peptide than the left atrial maximum volume in a community-based sample.

Int J Cardiovasc Imaging 2016 Mar 26;32(3):417-25. Epub 2015 Oct 26.

Department of Clinical Physiology, Västmanland County Hospital, 721 89, Västerås, Sweden.

Previous data have demonstrated that left atrial (LA) minimum volume indexed for body surface area (LAVImin) is more strongly associated with the Doppler echocardiographic E/e' ratio than LA maximum volume index (LAVImax). We sought to explore if LAVImin was more closely related to serum levels of NT-proBNP than LAVImax and E/e' in the community. A community-based sample of 730 subjects underwent echocardiographic examinations and NT-proBNP measurements. The mean age of the participants was 66.3 years (range 38-86) and 72% were men. Age (Spearman correlation [rho] 0.533), LAVImin (rho 0.460), LAVImax (rho 0.360), estimated glomerular filtration rate (rho -0.349), and E/e' (rho 0.301; all P < 0.001) were strongly correlated with log-NT-proBNP. In a multiple linear regression model with log-NT-proBNP as dependent variable and LAVImin, LAVImax, E/e' ratio, and potential confounders as predictors, an adjusted R(2) of 44.9% was obtained. When excluding either of LAVImin (R(2) 42.6%, P < 0.001) or E/e' (R(2) 44.6%, P = 0.019) the model fit was significantly reduced. In contrast, when LAVImax was excluded the model fit was preserved (R(2) 45.0%, P = 0.69). To detect an NT-proBNP level of >125 ng/L, LAVImin yielded a significantly larger area under the receiver operating characteristic curve (AUC) of 0.749 than LAVImax (AUC 0.701; P < 0.001) and E/e' (AUC 0.661; P < 0.001). In our community-based sample, LAVImin was more strongly associated with NT-proBNP than LAVImax. Moreover, the discriminatory power to detect an elevated NT-proBNP level was stronger in LAVImin than in LAVImax and E/e'. Our findings support previous data that LAVImin may be more closely related to LV filling function than LAVImax.
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http://dx.doi.org/10.1007/s10554-015-0800-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751167PMC
March 2016

Interstudy heterogeneity of definitions of diastolic dysfunction severely affects reported prevalence.

Eur Heart J Cardiovasc Imaging 2016 Aug 15;17(8):892-9. Epub 2015 Sep 15.

Department of Clinical Physiology, Västmanland County Hospital, SE-72189 Västerås, Sweden Centre for Clinical Research, Uppsala University, Västmanland County Hospital, Västerås, Sweden.

Aims: The aim of this article is to examine how the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE) recommendations on the classification of diastolic dysfunction (DDF) are interpreted in the scientific community and to explore how variations in the DDF definition affect the reported prevalence.

Methods And Results: A systematic review of studies citing the EACVI/ASE consensus document 'Recommendations for the evaluation of left ventricular diastolic function by echocardiography' was performed. The definition of DDF used in each study was recorded. Subsequently, several possible interpretations of the EACVI/ASE classification scheme were used to obtain DDF prevalence in a community-based sample (n = 714). In the systematic review, 60 studies were included. In 13 studies, no specification of DDF definition was presented, a one-level classification tree was used in 13, a two-level classification tree in 18, and in the remaining 16 studies, a DDF definition was presented but no grading of DDF was performed. In 17 studies, the DDF definition relied solely on early diastolic tissue velocity and/or left atrial size. In eight of these studies, a single parameter was used, in two studies the logical operator AND was used to combine two or more parameters, and the remaining seven studies used the logical operator OR. The resulting prevalence of DDF in the community-based sample varied from 12 to 84%, depending on the DDF definition used.

Conclusion: A substantial heterogeneity of definitions of DDF was evident among the studies reviewed, and the different definitions had a substantial impact on the reported prevalence of DDF.
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http://dx.doi.org/10.1093/ehjci/jev211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955290PMC
August 2016

Effects of adolescent online gaming time and motives on depressive, musculoskeletal, and psychosomatic symptoms.

Ups J Med Sci 2015 14;120(4):263-75. Epub 2015 Jun 14.

a 1 Centre for Clinical Research, Uppsala University, Västmanland County Hospital , S-72189 Västerås, Sweden.

Aim: To investigate whether adolescent online gaming time and the additive effect of gaming motives were associated with depressive, musculoskeletal, and psychosomatic symptoms. The hypothesis was that adolescents who engage in online gaming with escape motives and increased online gaming time have higher probability for depressive, musculoskeletal, and psychosomatic symptoms compared to adolescents with other online gaming motives and/or less online gaming time.

Method: An anonymous and voluntary questionnaire was completed during class hours by 7,757 Swedish adolescents aged 13-18 years. The questionnaire included demographic background, gaming habits, and depressive, musculoskeletal, and psychosomatic symptoms.

Results: It was found that increased online gaming time during weekdays increased the probability of having depressive, musculoskeletal, and psychosomatic symptoms. However, these relations with time spent gaming were further explained by online gaming motives. Weekday online gaming for more than five hours a day, in combination with escape motives, was associated with an increased probability of depressive symptoms (odds ratio (OR) 4.614, 95% CI 3.230-6.590), musculoskeletal symptoms (OR 2.494, 95% CI 1.598-3.892), and psychosomatic symptoms (OR 4.437, 95% CI 2.966-6.637). The probability of ill health decreased when gaming was for fun or had social motives.

Conclusion: Excessive gaming time and escape motives were found to be associated with increased probability of ill health among adolescents. Gaming motives may identify gamers in need of support to reduce unhealthy gaming behaviour as well as identify individuals at risk for ill health.
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http://dx.doi.org/10.3109/03009734.2015.1049724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816887PMC
August 2016

A case-control study of self-reported health, quality-of-life and general functioning among recent immigrants and age- and sex-matched Swedish-born controls.

Scand J Public Health 2014 Dec 23;42(8):734-42. Epub 2014 Sep 23.

Centre for Clinical Research Västmanland - Uppsala University, Sweden.

Aim: To examine whether new immigrants had inferior quality-of-life, well-being and general functioning compared with Swedish age- and sex-matched controls.

Methods: A prospective case-control study was designed including immigrants from non-European countries, 18-65 years of age, with recent Permanent Permits to Stay (PPS) in Sweden, and age- and sex-matched Swedish-born (SB) persons from the general population in Västmanland County, Sweden. The General Health Questionnaire (GHQ-12), the brief version of the World Health Organization Quality-of-Life (WHOQOL-BREF) Scale and the General Activity Functioning Assessment Scale (GAF) from DSM-IV were posted (SB), or applied in personal interviews (PPS) with interpreters. Differences between the PPS and SB groups were measured using McNemar's test and Wilcoxon signed-rank test conducted separately for observations at baseline, 6- and 12-month follow-up.

Results: There were 93 pairs (mean age 36 years). Persons from Somalia (67%) and Iraq (27%) dominated the PPS group. The differences between the groups were statistically significant for all time points for the Psychological health and Social relationship domains of WHOQOL-BREF, and for the baseline and 6-month follow-up time points of GHQ-12 where the PPS-group had a higher degree of well-being, health and quality-of-life than the SB. This tendency applied for both sexes in the immigrant group.

Conclusions: These new immigrants did not have inferior physical or psychological health, quality-of-life, well-being or social functioning compared with their age- and sex-matched Swedish born pairs during a 1-year follow-up. Thus, there is reason to advocate immigrants' fast integration into society.
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http://dx.doi.org/10.1177/1403494814550175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257997PMC
December 2014

Leisure-time physical inactivity and risk of myocardial infarction and all-cause mortality: a case-control study.

Int J Cardiol 2014 Dec 28;177(2):599-600. Epub 2014 Aug 28.

Clinical Research Center, Uppsala University, Västerås, Sweden.

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http://dx.doi.org/10.1016/j.ijcard.2014.08.137DOI Listing
December 2014