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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.

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 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: 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

Summary Background Adverse loading conditions and cardiac injury lead to remodelling of the heart into different patterns of left ventricular (LV) geometry. Geometry can be classified into LV hypertrophy (LVH), concentric remodelling (CR) or normal geometry (NG). The prognostic implications of the different geometric patterns have been extensively studied in middle-aged subjects, but data are scarcer for elderly populations. Methods From a community-based random sample of 75-year-old men and women, subjects with normal LVEF were selected (n = 303). All-cause and cardiovascular mortality was analysed by LV geometry with Cox regression (unadjusted and adjusted for sex, prevalent hypertension, smoking, diabetes and prevalent ischaemic heart disease). Median follow-up time was 9·9 years. Results Prevalence of CR and LVH was 19% and 17%, respectively. Hazard ratios (HRs) for CR were 0·93 (95% CI 0·54–1·58) for all-cause and 1·13 (0·48–2·65) for cardiovascular mortality. HRs for LVH were 2·01 (1·30–3·10) for all-cause and 3·55 (1·89–6·67) for cardiovascular mortality. As non-proportionality was present in the form of an increasing hazard for LVH, we partitioned the follow-up time at the median event time (approximately 7 years) and performed Cox regression separately within each time period. HRs for LVH during the first period were 1·23 (0·63–2·42) for all-cause and 1·79 (0·69–4·65) for cardiovascular mortality, while HRs for the second period were 3·06 (1·73–5·41) for all-cause and 6·60 (2·82–15·39) for cardiovascular mortality. Conclusion In this community-based sample of 75-year-old men and women with normal LVEF, LVH was associated with an adverse prognosis during long-term follow-up, whereas CR was not.

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.

We studied Psychological General Well-Being (PGWB) and its relation to 10-year survival in 75-year-olds from the general population. The PGWB global score (sum of six subscale scores) and the subscale scores were transformed to 0-100 scales. Ten-year survival in relation to PGWB global and subscale scores was studied in a cohort of 204 men and 213 women. Global PGWB score (median) was 83 in men and 79 in women (for difference p = 0.001). Significantly higher male scores were found for most PGWB subscales. Global PGWB score was significantly related to better 10-year survival in men (relative risk per ten points of score was 0.80; p = 0.001 and 0.85; p = 0.022 adjusting for chronic diseases and living alone) but not in women (relative risk 0.94; p = 0.478 unadjusted). Among 75-year-olds, PGWB score was significantly higher for men. A high PGWB score was significantly related to better survival in men but not in women.

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.

Mitral annulus motion (MAM) is a predictor of mortality in selected patient groups, but its prognostic value in less selected populations is not known. In a community-based random sample of 75-year-old men and women (n = 408), left ventricular function was measured as: (1) maximum amplitude of MAM; and (2) wall-motion index. During a median follow-up of 7.2 years, 83 persons died (26 from cardiac causes). Left ventricular function as measured by MAM predicted the risk of all-cause and cardiac mortality independently of other potential risk factors in this community-based sample. Regarding cardiac mortality, the predictive ability of MAM was also independent of left ventricular systolic function measured as wall-motion index. MAM may prove to be a valuable complement to other echocardiographic methods in the assessment of prognosis in less selected populations.

Background Plasma concentration of B-type natriuretic peptide (BNP) has been suggested as a powerful screening tool for left ventricular systolic dysfunction. However, there are reports indicating that the 12-lead electrocardiogram (ECG) could be just as powerful. We aimed to evaluate the 12-lead ECG and BNP as screening tools for left ventricular systolic dysfunction in an elderly, unselected population. Methods In a randomly selected population-based sample of 75-year-old men and women (n 407), diagnostic characteristics were evaluated for the ECG and plasma concentration of BNP to detect left ventricular systolic dysfunction. Results Sensitivity, specificity, and negative and positive predictive values for the ECG to detect left ventricular systolic dysfunction were 96%, 79%, 100%, and 26%, respectively. The corresponding values for the BNP (cut-off value 28 pg/mL) were 93%, 55%, 99%, and 13%. In participants without major abnormalities in the ECG, left ventricular systolic dysfunction was found in 1% (1/302), irrespective of BNP concentrations. In participants with abnormal ECGs, systolic dysfunction was more prevalent in persons with abnormal BNP concentrations than in those with normal concentrations (35% vs 3%, difference 32%, 95%CI for the difference 16%‐44%) Conclusions In 75-year-old subjects both the ECG and the plasma concentration of BNP are highly efficient in excluding left ventricular systolic dysfunction. However, compared with the BNP, the ECG yields a lower number of false positive cases. In screening for left ventricular systolic dysfunction, the BNP has a diagnostic value in addition to the ECG, but only in individuals with abnormal ECGs. (Am Heart J 2004;148:524‐9.)

The biplane disc summation method is the recommended echocardiographic procedure to determine left ventricular (LV) ejection fraction (EF). Assessment of mitral annulus motion (MAM) or wall motion scoring index (WMI) has been reported to be less dependent on image quality compared with the recommended method, and proposed as a surrogate to the disc summation method in calculation of LVEF. We aimed to compare MAM and WMI in the echocardiographic assessment of LVEF. In a randomly selected population-based sample of 75-year-old men and women in sinus rhythm (n = 409) MAM, as measured by M-mode, was compared with WMI, calculated as the mean value of wall motion scoring in 9 LV segments. LVEF, as measured by the biplane disc summation method was used as reference. The limits of agreement (mean difference +/- 1.96 SD) between LVEF and corresponding MAM values were -18 to +13 LVEF%, and between LVEF and corresponding WMI values were -12 to +13 LVEF%. The areas under the receiver operating characteristic curves for MAM and WMI to predict a LVEF < 50% were 0.892 and 0.998, respectively (95% confidence interval of the difference 0.062-0.149). The corresponding areas for MAM and WMI to predict a LVEF < 40% were 0.955 and 0.998, respectively (95% confidence interval of the difference 0.017-0.069). In conclusion, the ability of WMI to estimate LVEF was more favorable than MAM in this population-based sample of 75-year-old participants. The findings suggest that the WMI is preferable to MAM in estimating LVEF.

The aim of the present study was to obtain reference values of maximum and minimum left atrial volumes (maxLAV and minLAV, respectively) in a population-based subset without apparent cardiovascular disease or other factors potentially associated with left atrial enlargement. Because left ventricular diastolic dysfunction is commonly found in elderly subjects, we also tried to identify the presence of possible preclinical diastolic dysfunction in the study population. A population-based sample of 168 subjects (127 men and 41 women) underwent two-dimensional echocardiography using the single-plane disc method to determine maxLAV and minLAV. maxLAV and minLAV were indexed to body surface area (maxLAVi and minLAVi, respectively). maxLAVi was independent of age and sex, and produced reference limits (mean +/- A 1.96 SD) of 15-37 mL/m(2). minLAVi was correlated with age, and produced estimated reference limits of 3-15 and 7-23 mL/m(2) in 40- and 80-year-old subjects, respectively. Based on the age-dependent reference values from the European Association of Cardiovascular Imaging, < 5 % of the study population had possible preclinical left ventricular diastolic dysfunction. The present study established normal ranges for maxLAVi and minLAVi in a well-characterized population-based subset without apparent cardiovascular disease or other factors potentially associated with left atrial volume enlargement.

Reduced performance of the left ventricle to eject blood – left ventricular systolic dysfunction (LVSD) – is a common predecessor of the heart failure syndrome. With or without symptoms, LVSD is associated with a poor prognosis. However, with adequate treatment, the development or progression of symptoms, the need for hospitalisation and mortality can all be reduced. In the present work, the occurrence of LVSD was evaluated by echocardiography in a community-based sample of 75-year-old men and women (n = 433). LVSD was a common condition, with a prevalence rate of 6.8%. In nearly half the participants with LVSD, there was no clinical evidence of heart failure.Community-based screening for asymptomatic LVSD has been proposed as a strategy to reduce the incidence of heart failure. Because of the high costs and low availability, echocardiography is not a suitable screening tool. The plasma concentration of B-type natriuretic peptide (BNP) has been the most advocated screening tool. Another alternative is the standard 12-lead electrocardiogram (ECG). Both the ECG and BNP were effective in excluding LVSD in our 75-year-old community-based sample. However, compared with BNP, the ECG had considerably better specificity. In screening for LVSD, BNP had a diagnostic value in addition to the ECG, but only in individuals with abnormal ECGs.The left ventricular ejection fraction (LVEF) measured by echocardiography is a well-established index for describing left ventricular systolic function. The wall motion index (WMI) and the amplitude of mitral annulus motion (MAM) are suggested as alternative echocardiographic methods. Compared with MAM, the WMI had a more favourable agreement with the LVEF in our 75-year-old participants. Nonetheless, MAM was a strong predictor of mortality. MAM predicted the risk of all-cause and cardiac mortality independently of other risk factors. In addition, when it came to cardiac mortality, the predictive ability of MAM was independent of the LV function measured as the WMI.

We aimed to determine the prevalence of left ventricular systolic dysfunction (LVSD) in outpatients with peripheral atherosclerotic vascular disease (PAVD). Further, the associations of stenotic internal carotid artery disease (SICAD) and lower extremity artery disease (LEAD) with LVSD were evaluated.In the Peripheral Artery Disease in Västmanland study, consecutive outpatients with ultrasonographically identified mild to severe stenosis in the internal carotid artery or symptoms of claudication combined with either ankle brachial index of ≤0.90 or ultrasonographic occlusive findings were included (n = 437). Population-based control subjects were matched to the patients (n = 395). LVSD was defined as echocardiographically determined left ventricular ejection fraction (LVEF)55%, and moderate or greater LVSD was defined as LVEF45%. The prevalence of LVSD was significantly greater in patients than in controls (13.7% vs. 6.1%, P 0.001). The prevalence of moderate or greater LVSD in participants not on treatment with a combination of angiotensin-converting enzyme inhibitor and beta-blocker was 2.3% in patients and 1.3% in controls (P = 0.31). When LEAD and SICAD were analysed together, adjusted for potential confounders, SICAD [odds ratio (OR) 2.54, 95% confidence interval (CI) 1.03-6.32], but not LEAD (OR 1.59, 95% CI 0.80-3.18), was independently associated with LVSD.In outpatients with PAVD, we found a 13.7% prevalence of LVSD. However, the prevalence of at least moderate LVSD in patients not on treatment with angiotensin-converting enzyme inhibitor and a beta-blocker was only 2.3% and not significantly different from controls. Stenotic artery disease in the internal carotid artery, but not in the lower extremities, was independently associated with LVSD.

High blood concentrations of inflammatory markers, including white blood cell (WBC) count, are closely related to the metabolic syndrome. Both conditions predict dismal survival. We determined prospective associations between mortality and factors derived by a factor analysis of WBC count and the basic components of the metabolic syndrome.We performed a factor analysis of WBC count and the continuous components of the metabolic syndrome in 196 men and 200 women, comprising 64% of the originally invited 75 year olds from the Swedish city Västerås. The analysis revealed three factors in men and two in women. The first factor included fasting glucose, high-density lipoprotein cholesterol, triglycerides, and waist circumference in men and in addition WBC count in women. The second factor included diastolic blood pressure and systolic blood pressure in both sexes. In men, the third factor included fasting glucose and WBC count. These factors explained 66% (first factor, 28%; second factor, 23%; third factor, 15%) of the variation in men and 57% (first factor, 34%; second factor, 23%) in women. Prospective associations of the derived factors and all-cause mortality during 10-year follow-up were assessed by Cox regression [hazard ratio (HR)]. The first factor was significantly related to increased mortality in men: HR=1.22 [95% confidence interval (CI) 1.05-1.41; p=0.008] and women: HR=1.25 (95% CI 1.06-1.48; p=0.010). Pooling men and women adjusting for established cardiovascular risk factors gave HR=1.16 (95% CI 1.04-1.29; p=0.010). In men the third factor was significantly related to mortality; HR=1.29 (95% CI 1.07-1.57; p=0.009).A metabolic inflammatory factor and a blood pressure factor were identified. In men, the former was split into a metabolic and an inflammatory factor. Factors including metabolic and inflammatory components were significantly related to 10-year mortality and the relation remained after adjusting for established cardiovascular risk factors.

Continuous positive airway pressure treatment has been shown to lower blood pressure (BP) in patients with obstructive sleep apnea (OSA). The aims of the present pilot study were to evaluate the potential effects of oral appliance (OA) therapy on BP, to assess various outcome BP measures, and to inform sample size calculation.Seventy-two patients with OSA and hypertension were randomly assigned to intervention with either an OA with mandibular advancement (active group) or an OA without advancement (control group). Before and after 3 months of treatment, the patients underwent nocturnal somnographic registration and 24-h ambulatory BP monitoring.Among the various BP measures, the largest trend toward effect of OA treatment was seen in 24-h mean systolic BP with a 1.8 mmHg stronger BP reduction in the active group compared with controls. A stronger trend toward effect was seen in a subgroup with baseline ambulatory daytime mean systolic BP135/85 mmHg where the mean systolic BP fell, on average, 2.6 mmHg. Additional exclusion of patients with baseline apnea hypopnea index (AHI) ≤15 gave a significant reduction in mean systolic BP of 4.4 mmHg (P = 0.044) in the active group compared with controls.In patients with OSA and hypertension, OA treatment had a modest trend toward effect on reducing BP. A stronger trend toward treatment effect was seen after excluding patients with normal baseline ambulatory BP. Additional exclusion of patients with baseline AHI ≤15 showed a significant treatment effect. Data to inform sample size for an adequately powered randomized study are provided.

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

Objective: Studies on the prognostic importance of the systolic blood pressure (SBP) response during exercise report ambiguous results. Most research focuses on younger and middle-aged selected patient groups and rarely includes women. We investigated the prognostic value of SBP response during exercise testing in 75-year-olds. Design: Prospective observational cohort study. Setting: A community-based random sample of 75-year-old men and women (n = 382). Main outcome measures: The prognostic value of SBP change from rest to peak exercise during a symptom-limited cycle test was evaluated for the endpoints all-cause mortality and cardiovascular mortality during long-term follow-up. Results: After a median follow-up of 10.6 years, 140 (37%) of the participants had died, 64 (17%) from cardiovascular causes. The all-cause mortalities for exercise SBP changes of ⩽30 mm Hg, 31–55 mm Hg and >55 mm Hg were 5.1, 4.2 and 2.6 per 100 person-years, respectively (logrank 9.6; p = 0.008). For every 10 mm Hg increase in SBP during exercise the relative hazard for all-cause mortality was reduced by 13% (p = 0.030) and for cardiovascular mortality by 26% (p = 0.004) after adjustment for sex, smoking, waist circumference, total/HDL cholesterol ratio, prevalent ischaemic heart disease, hypertension, diabetes, cardiovascular medication, pre-exercise SBP, exercise capacity, resting left ventricular ejection fraction and left ventricular mass index. Conclusions: Our findings suggest that an augmented SBP response during exercise is associated with an improved long-term survival among community-living 75-year-old individuals.

Factor analysis reduces a set of directly measured variables into a smaller set of underlying factors representing unique statistically independent domains termed "factors." In middle-aged people, previous factor analyses of the components of the metabolic syndrome have identified two to four factors. Many of these analyses report blood pressure as one of these factors.We performed a factor analysis of the individual continuous components of the metabolic syndrome among 198 men and 203 women comprising 65% of all 75 year olds from the city of Västerås in Sweden.The metabolic syndrome comprised two factors. Factor 1, the metabolic factor, consisted of waist circumference, high-density lipoprotein cholesterol, triglycerides, and fasting glucose, whereas factor 2, the blood pressure factor, consisted of systolic and diastolic blood pressure. These two factors explained 58% (factor 1, 31%, and factor 2, 27%) of the total variation in men. The corresponding figures for women were 63% (factor 1, 36%, and factor 2, 27%). Factor 1 was significantly related to a decreased 10 years of survival for men, with a hazard ratio (HR) of 1.30 (95% confidence interval [CI] 1.07-1.58, P = 0.008), and nearly significantly for women, with a HR of 1.27 (95% CI 0.98-1.64, P = 0.071). In a pooled analysis adjusting for sex, known cardiovascular disease, and hypertension, high blood pressure, and current smoking, the HR for factor 1 was 1.20 (95% CI 1.02-1.49, P = 0.026). Factor 2 was not significantly related to survival.Factor analysis of the basic variables of the metabolic syndrome among 75 year olds from a general population identified a metabolic factor and a blood pressure factor. The former factor was significantly related to 10-year survival and the relationship remained after adjusting for known cardiovascular disease and hypertension and current smoking.

Background Insulin resistance (IR) is a risk factor for diabetes and atherosclerotic diseases. The metabolic syndrome (MetS) reflects IR. Waist circumference (WC) is the most easily registered component of MetS. The objective was to compare WC alone with MetS as defined by the National Cholesterol Education Program (NCEP) and the International Diabetes Federation (IDF) for their abilities to predict IR in elderly without known diabetes. Methods The study included 223 women and 210 men comprising 70% of a random sample of 75-year-olds from a general population. IR was conventionally defined as the gender-specific upper quartile of the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) index in individuals without known diabetes. Results 1) The positive association between WC and IR is stronger in women than in men. 2) WC > 88 cm alone is nearly as good as MetS, using NCEP criteria, in predicting IR in women. 3) According to the ROC curve, the optimal cut-off point for WC predicting IR was between 96 and 97 cm (men) and between 88 and 89 cm (women). The relative risk of IR was 5.6 (95% CI: 3.1–11.9) for women with WC > 88 cm and 1.9 (1.5–2.8) for men with WC > 96 cm. 4) The NCEP criteria predicts IR significantly better than the IDF criteria. Conclusion WC > 88 cm in women indicates a high likelihood of IR and is almost as good as MetS defined using the NCEP criteria in predicting IR. MetS defined using the NCEP criteria predicts IR better than MetS defined using the IDF criteria.

Aims The study concerns the relationship of the corrected QT (QTc) interval to 6.4 years of survival and to measures of cardiac function, such as echocardiographic variables and plasma levels of brain natriuretic peptide (BNP), in 75-year-old people. Methods and results QTc was measured in a 12-lead electrocardiogram (ECG) in 210 men and 223 women, comprising a randomly selected sample from the general population (70% participation rate). The Sicard 440/740 computer-analysis program, with Hodges’ formula for heart rate-based QT correction, was used. The optimal cut-off point for predicting survival according to the receiver operating characteristic curve was found between 429 and 430 ms. Individuals with a QTc interval of � 430 ms (n ¼ 115) had decreased survival when compared with those with shorter QTc interval (n ¼ 318); the relative risk was 2.4 (95% confidence interval 1.5–3.7). The predictive ability of QTc reflects an association between QTc and the following variables: BNP, left ventricular mass, and left ventricular ejection fraction (but not diastolic filling patterns). Both Hodges’ and Bazett’s formulae for heart rate correction of the QT interval were useful for predicting survival. The median QTc was 415 ms using Hodges’ formula and 430 ms with Bazett’s formula. The QRS component of QTc predicted survival better than the rest of the QTc interval and was approximately as useful as the QTc interval itself. Conclusion The computer-derived QTc obtained from the ordinary 12-lead ECG identifies high-risk individuals among elderly people from the general population.

Background A considerable body of echocardiographic studies has described how athletic training induces morphological adaptation of the left ventricle in male endurance athletes, but only a few studies have described left ventricular adaptation in female endurance athletes. In contrast to changes in the left ventricle far less attention has been directed towards right ventricular changes due to extensive physical exercise. The purpose of this study was to obtain normal values and to determine if there are any differences in right and left ventricular cavity and wall dimensions between female orienteers and females with a mainly sedentary lifestyle. Methods Echocardiography was performed in 42 highly trained elite female orienteers and 32 healthy female students with a predominantly sedentary lifestyle. The 74 females had no history of cardiac disease, a normal electrocardiogram and showed no echocardiographic abnormalities. M-mode and two-dimensional measurements of the right and left ventricular cavity and wall were obtained in elite orienteers and sedentary females. For the right ventricle and wall, multiple cross-sections were used and measurements were obtained from the right ventricular inflow and outflow tract. Results The left ventricular end-diastolic cavity dimension and the left ventricular wall thickness were significantly greater in the athletes compared with the sedentary controls. The right ventricular inflow tract measurements were all significantly greater in the orienteers compared with the controls but the right ventricular outflow tract measurements were comparable in the study groups. The right ventricular wall thickness, calculated as the mean of three different wall measurements was an average of 13% greater in the athletes compared with the sedentary controls. Conclusion This study suggests symmetrical cardiac enlargement with a concomitant increase in both the right and left ventricular wall, probably reflecting the increased haemodynamic loading in the female athletes.

Background: Low heart rate recovery (HRR) at exercise test and the metabolic syndrome (MetS) are both predictors of cardiovascular morbidity and mortality. We studied in 75-year-old women and men, representative of the general population, the relationship between (1) HRR and the MetS, (2) HRR and the individual components of the MetS, and (3) HRR and insulin sensitivity. Methods: A cross-sectional study of randomly selected 75-year-olds from a general population was performed (191 women and 194 men). The MetS was defined according to the National Cholesterol Education Program criteria. Heart rate was measured as beats per minute immediately after exercise and at 4 minutes into recovery. Results: Heart rate recovery (median and interquartile range, beat/min) was 48 (37-58) for women and 49 (38-58) for men. Thirty-seven percent of the women and 25% of the men had the MetS. Heart rate recovery was 52 (42-61) for women with the MetS and 42 (31-49) for those without. The corresponding values for men was 50 (39-61) and 47 (35-54); the difference between individuals with and without the MetS was significant for women (P < .001) but not for men (P = .084). The following significant correlation coefficients between HRR and MetS components were found: for women, waist circumference (-0.43, P < .001), high-density lipoprotein cholesterol (0.37, P < .001), insulin sensitivity (-0.37, P < .001), fasting plasma glucose (-0.30, P < .001), and triglycerides (-0.24, P = .001); for men, triglycerides (-0.20, P = .005). The sex disparity in the strength of correlation reached statistical significance for insulin sensitivity (P < .001) and waist circumference (P = .042). Conclusion: Among 75-year-olds, the MetS and related components are more strongly correlated to HRR in women than in men.