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Objective Type D personality, a joint tendency toward negative affectivity and social inhibition, has been linked to adverse events in patients with heart disease, although with inconsistent findings. Here, we apply an individual patient-data meta-analysis to data from 19 prospective cohort studies (N = 11,151) to investigate the prediction of adverse outcomes by type D personality in patients with acquired cardiovascular disease. Method For each outcome (all-cause mortality, cardiac mortality, myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, major adverse cardiac event, any adverse event), we estimated type D's prognostic influence and the moderation by age, sex, and disease type. Results In patients with cardiovascular disease, evidence for a type D effect in terms of the Bayes factor (BF) was strong for major adverse cardiac event (BF = 42.5; odds ratio [OR] = 1.14) and any adverse event (BF = 129.4; OR = 1.15). Evidence for the null hypothesis was found for all-cause mortality (BF = 45.9; OR = 1.03), cardiac mortality (BF = 23.7; OR = 0.99), and myocardial infarction (BF = 16.9; OR = 1.12), suggesting that type D had no effect on these outcomes. This evidence was similar in the subset of patients with coronary artery disease (CAD), but inconclusive for patients with heart failure (HF). Positive effects were found for negative affectivity on cardiac and all-cause mortality, with the latter being more pronounced in male than female patients. Conclusion Across 19 prospective cohort studies, type D predicts adverse events in patients with CAD, whereas evidence in patients with HF was inconclusive. In both patients with CAD and HF, we found evidence for a null effect of type D on cardiac and all-cause mortality.

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)

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.

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 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.

Background: 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. Materials and methods: 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. Results: 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). Conclusions: 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. Trial registration:ClinicalTrials.gov identifier: NCT01452178.

A few studies have examined biomarkers in patients with myocardial infarction (MI) and peripheral artery disease (PAD), i.e. multisite artery disease (MSAD). The aim of the study was firstly, to associate biomarkers with the occurrence of PAD/MSAD and secondly, if those can, in addition to clinical characteristics, identify MI patients with MSAD.In two prospectively observational studies including unselected patients with recent MI, PAD was defined as an abnormal ankle–brachial index (ABI) score (1.4). The proximity extension assay (PEA) technique was used, simultaneously analyzing 92 biomarkers with association to cardiovascular disease. Biomarkers were tested for univariate associations with PAD. Random forest was used to identify biomarkers with a higher association to PAD. The additional discriminatory accuracy of adding biomarkers to clinical characteristics was analyzed by the c-statistics. Nine biomarkers were identified as significantly associated with MSAD/PAD in the primary patient cohort, analyzed early after the MI. In the prediction analysis, six biomarkers were identified associated with PAD. Three of these; Tumor necrosis factor receptor (TNFR-1), Tumor necrosis factor receptor 2 (TNFR-2) and Growth Differentiation Factor 15 (GDF-15) improved c-statistics when added to clinical characteristics from 0.683 (95% CI 0.610–0.756) to 0.715 (95% CI 0.645–0.784) in the primary patient cohort with a similar result, 0.729 (95% CI 0.687–0.770) to 0.752 (95% CI 0.771–0.792) in the secondary patient cohort. Biomarkers associated with inflammatory pathways are associated with MSAD in MI patients. Three biomarkers of 92; TNFR-1, TNFR-2 and GDF-15, in this exploratory added information in the prediction of MSAD and emphasis the importance of further studies.

Background: Patients with peripheral arterial disease (PAD) are generally less intensively managed than patients with coronary heart disease (CHD), despite that their risk of complications is believed to be equivalent. Identification of PAD patients at risk of poorly controlled blood pressure (BP) could lead to improved treatment, thus lowering the risk of cardiovascular (CV) complications. We aimed to describe the prevalence of poorly controlled cardiovascular (CV) risk factors, focusing on BP, in outpatients with PAD diagnosed in a vascular ultrasound laboratory. Methods: Consecutive outpatients with carotid and/or lower extremity PAD were included (n = 402) and examined with blood sampling, clinical BP, and 24-h ambulatory BP measurements. A poorly controlled clinical BP was defined as ≥140/90 mmHg, ambulatory BP ≥130/80 mmHg, low-density lipoprotein (LDL)-cholesterol level ≥2.5 mmol/L, and glycated hemoglobin (HbA1c) level >53 mmol/mol in those with diabetes. Results: Most of the patients had poorly controlled clinical (76.6%) and ambulatory BP (51.7%) profiles. Antihypertensive medications were prescribed in 84% of the patients. However, >40% of them used only 0–1 medication, and 53 mmol/mol was present in 55% of diabetic patients. Conclusion: Poorly controlled clinical and ambulatory systolic BP profiles were common. In addition, suboptimal control of other important CV risk factors was detected. The findings of this study highlight the need for better preventive efforts against CV risk factors in outpatients with PAD.

Background: Due to a high incidence of cardiac implantable electronic device-associated infective endocarditis (CIED-IE) in cases of Staphylococcus aureus bacteremia (SAB) and high mortality with conservative management, guidelines advocate device removal in all subjects with SAB. We aimed to investigate the clinical course of SAB in patients with a CIED (SAB+CIED) in a Swedish county hospital setting and relate it to guideline recommendations. Methods: All CIED carriers with SAB, excluding clinical pocket infections, in the County of Västmanland during 2010–2017 were reviewed retrospectively. Results: There were 61 cases of SAB+CIED during the study period, and CIED-IE was diagnosed in 13/61 (21%) cases. In-hospital death occurred in 19/61 (31%) cases, 34/61 (56%) cases were discharged with CIED device retained, and 8/61 (13%) cases were discharged after device removal. Subjects dying during hospitalization were elderly and diseased. No events was seen if the CIED was removed. Among four discharged cases with conservatively managed CIED-IE one relapse occured. Among 30 cases discharged with retained CIED and no evidence of IE, 22/30 (73%) cases had an uneventful follow-up, whereas adverse events secondary to overlooked CIED-IE were likely in 1/30 (3%) cases and could not be definitely excluded in additionally 4/30 (13%) cases. Conclusions: During the study period, management became more active and prognosis improved. The heterogeneity within the population of SAB+CIED suggests that a management strategy based on an individual risk/benefit analysis could be an alternative to mandatory device removal.

Obstructive sleep apnea (OSA) may lead to increased circulating concentrations of inflammatory biomarkers and treatment may change these. We aimed to assess the effect of oral appliance (OA) therapy on inflammatory biomarkers in a randomised controlled pilot trial. A total of 71 patients with OSA and systemic hypertension were randomly allocated to an active, mandible protruded (OAa) or a passive, mandible non-protruded device (OAp) treatment. Serum concentrations of the inflammatory biomarkers white blood cells, high-sensitivity C-reactive protein, interleukin 6, interleukin 10, and tumour necrosis factor-alpha were measured at baseline and after 3 months of OA treatment. The differences between treatment groups in biomarker concentration change during the treatment were presented as the Vargha and Delaney effect size and evaluated with the Wilcoxon-Mann-Whitney test. This effect size expresses the probability of a higher value in a random participant from one group compared with a random patient from the other group, and a value of 0.5 means stochastically equal groups. After 3 months of treatment, there was a significant reduction of the apnea-hypopnea index in the OAa group compared with the OAp group (effect size 0.258, 95% confidence interval 0.146-0.386, p < .001). There were no significant differences between the groups in any of the inflammatory markers' concentration changes during the treatment period (effect sizes between 0.488 and 0.524; all p values >=.737). Thus, OA treatment for 3 months did not affect circulating concentrations of some common inflammatory markers in patients with OSA and systemic hypertension.

Recent findings suggest that left atrial (LA) function is more strongly related to adverse prognosis than LA volumes. We aimed to evaluate the associations between LA volumes and Doppler filling indices with LA function. Echocardiographic LA volumes (LAVs), mitral valve early (MV-E) and late (MV-A) peak flow velocities, and mitral atrioventricular plane tissue-Doppler early (TD-e ') and late (TD-a ') peak velocities were obtained in 320 patients with acute myocardial infarction (AMI) free from atrial fibrillation and more than moderate valvular disease. LA function was estimated as the LA emptying fraction (LAEF), that is 100x (LAVmax-LAVmin)/LAVmax. LA reservoir volume was calculated as LAVmax-LAVmin and LA transit volume as LV stroke volume-reservoir volume. In restricted cubic spline regression analyses with multivariable adjustment, a reduced LAEF was strongly associated with smaller reservoir volume, larger transit volume, LAVmax, LAVpreA and especially LAVmin. MV-E linearly increased with a lower LAEF, whereas MV-A decreased but only below LAEF levels of approximately 45%. The resulting E/A ratio showed a sudden increase in LAEF levels below similar to 45%. Lower TD-a ' was linearly associated with a lower LAEF. In conclusion, a reduced atrial function was associated with smaller LA reservoir volume, larger LA transit volume, lower TD-a ', a non-linear decrease in MV-A and a non-linear increase in E/A. Our findings are likely a reflection of the adaptation to sustain LV filling volume and counteracting a rise in pulmonary venous pressure in face of an enhanced LV end-diastolic pressure.

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

Objectives This study aimed to derive age-specific multivariate reference regions (MVRs) able to classify subjects into those having normal or abnormal filling patterns and to evaluate the prognostic impact of this classification. Background The integration of several parameters is necessary to diagnose disorders of left ventricular (LV) filling because no single measurement accurately describes the complexity of diastolic function. However, no generally accepted validated multiparametric algorithm currently exists. Methods A cohort of 1,240 apparently healthy subjects from HUNT (Nord-Trondelag Health Study) with measured early (E) and late (A) mitral inflow velocity and early mitral annular diastolic tissue velocity (e′) were used to derive univariate 95% reference bands and age-specific MVRs. Subsequently, the prognostic impact of this MVR-based classification was evaluated by Cox regression in a community-based cohort (n = 726) and in a cohort of subjects with recent acute myocardial infarction (n = 551). Both evaluation cohorts were derived from VaMIS (the Vastmanland Myocardial Infarction Study). Results Univariate reference bands and MVRs are presented graphically and as regression equations. After adjustment for sex, age, hypertension, body mass index, diabetes, prior ischemic heart disease, LV mass, LV ejection fraction, and left atrial size, the hazard ratio associated with abnormal filling patterns in the community-based cohort was 3.5 (95% confidence interval: 1.7 to 7.0; p Conclusions This study derived age-specific MVRs for identification of abnormal LV filling patterns and showed, in a community-based cohort and in a cohort of patients with recent acute myocardial infarction, that these MVRs conveyed important prognostic information. An MVR-based classification of LV filling patterns could lead to more consistent diagnostic algorithms for identification of different filling disorders.

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.

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. Funding Agencies|Swedish Research CouncilSwedish Research Council; Swedish Heart-Lung foundationSwedish Heart-Lung Foundation

Background Peripheral artery disease (PAD) is associated with increased risk of cardiovascular events and mortality. PAD is underdiagnosed in patients admitted for myocardial infarction (MI). Purpose To evaluate whether biomarkers in addition to clinical characteristics could improve the identification of PAD in MI patients. Methods Two prospectively observational studies including unselected patients with recent ST-elevation or non-ST elevation MI were used for the analyses. PAD was defined as abnormal ankle brachial indexes (ABI) score (1.4) on at least one side. The Proximity Extension Assay (PEA) technique was used to simultaneously analyze 92 biomarkers with association to cardiovascular disease (CVD I and III, Olink Proteomics) in samples early after the acute MI. Random forest was used to identify the biomarkers with higher association to PAD. The discriminating accuracy of adding biomarkers to clinical characteristics including age, sex, diabetes mellitus, hypertension and smoking were analyzed by the c-statistic. Results In the REBUS cohort (n=420) the mean age was 67 years, 22.1% were women, 26.4% were smoking, 16.2% had diabetes and 53.3% hypertension. In the VAMIS cohort (n=998) the mean age was 71 years, 33.5% were women, 19.9% were smoking, 18.1% and 49.9% had diabetes and hypertension, respectively. PAD was found in 20.0% and 22.8% of the patients in the REBUS and VAMIS cohort, respectively. Six biomarkers associated with PAD (Tnfrsf 14, tnf r2, tnf r1, GDF-15, IL-6 ra, ctsd) were identified in the REBUS cohort and validated in the VAMIS cohort. Additional predictive value of the biomarkers compared to the performance of the model with clinical characteristics, as measured by the c-statistic Clinical characteristics (CC) CC + Tnfrsf14 CC + Tnf r2 CC + Tnf r1 CC + GDF-15 CC + IL-6 ra CC + ctsd REBUS (n=420) 0.683 (0.610,0.756) 0.702 (0.632, 0.772) 0.703 (0.633, 0.773) 0.709 (0.640, 0.779) 0.710 (0.640, 0.781) 0.682 (0.608, 0.775) 0.683 (0.610, 0.757) VaMIS (n=998) 0.729 (0.687, 0.770) 0.732 (0.691, 0.733) 0.745 (0.704, 0.785) 0.746 (0.706, 0.787) 0.752 (0.711, 0.792) 0.729 (0.688, 0.770) 0.736 (0.695, 0.777) Tnfrsf 14 = tumor necrosis factor receptor superfamily member 14; Tnf r2 = tumor necrosis factor receptor 2; Tnf r1 = tumor necrosis factor receptor 1; GDF-15 = growth differentiation factor 15; IL-6 ra = interleukin-6 receptor subunit alpha; ctsd = Cathepsin D. Conclusion Out of a large panel of biomarkers, tumor necrosis factor and its receptors and GDF-15 were identified associated with PAD in MI patients. In this underdiagnosed manifestation of atherosclerosis in MI patients, clinical characteristics are strong predictors of PAD, but the cytokines may have an additional value. Further studies focusing on more widespread atherosclerosis in acute coronary syndrome might identify a patient group with benefit of treatment targeting inflammation. Acknowledgement/Funding None

Reply to "Letter to editor, Assessing the effect of coronary and systemic atherosclerosis following myocardial infarction" by dr Su Yueqiu et al.

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 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.

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 (amp;lt; 5% false discovery rate) between risk of MACE and eight proteins: matrix metalloproteinase (MMP)-12, IL-27 subunit alpha (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. Funding Agencies|European Union Horizon 2020 project [634869]; Swedish Research Council [2012-2215, 2015-03477]; Landstinget Dalarna (Falun, Sweden); Dalarna University (Falun, Sweden); Sparbanksstiftelsen Nya [552, 693, 932, 2297]; Region Vastmanland (Vasteras, Sweden); Swedish Medical Association; Swedish Heart-Lung Foundation [20150429]

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 = 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 hip and weight 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 = 66 years, the best discriminatory model contained only waist-to-hip ratio (AUROC = 0.67), whereas in women Corrigendum in: Journal of Obesity, Volume 2018, Article ID 3126805, https://doi.org/10.1155/2018/3126805

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

This study aimed to derive age-specific multivariate reference regions (MVRs) able to classify subjects into those having normal or abnormal filling patterns and to evaluate the prognostic impact of this classification.The integration of several parameters is necessary to diagnose disorders of left ventricular (LV) filling because no single measurement accurately describes the complexity of diastolic function. However, no generally accepted validated multiparametric algorithm currently exists.A cohort of 1,240 apparently healthy subjects from HUNT (Nord-Trøndelag Health Study) with measured early (E) and late (A) mitral inflow velocity and early mitral annular diastolic tissue velocity (e') were used to derive univariate 95% reference bands and age-specific MVRs. Subsequently, the prognostic impact of this MVR-based classification was evaluated by Cox regression in a community-based cohort (n = 726) and in a cohort of subjects with recent acute myocardial infarction (n = 551). Both evaluation cohorts were derived from VaMIS (the Västmanland Myocardial Infarction Study).Univariate reference bands and MVRs are presented graphically and as regression equations. After adjustment for sex, age, hypertension, body mass index, diabetes, prior ischemic heart disease, LV mass, LV ejection fraction, and left atrial size, the hazard ratio associated with abnormal filling patterns in the community-based cohort was 3.5 (95% confidence interval: 1.7 to 7.0; p 0.001) and that in the acute myocardial infarction cohort was 1.8 (95% confidence interval: 1.1 to 2.8; p = 0.011).This study derived age-specific MVRs for identification of abnormal LV filling patterns and showed, in a community-based cohort and in a cohort of patients with recent acute myocardial infarction, that these MVRs conveyed important prognostic information. An MVR-based classification of LV filling patterns could lead to more consistent diagnostic algorithms for identification of different filling disorders.

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 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.

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.

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 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

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.