Prognostic Value of Cardiovascular Biomarkers in the Population.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

Nondipping blood pressure pattern predicts cardiovascular events and mortality in patients with atherosclerotic peripheral vascular disease.

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).

Type D Personality as a Risk Factor for Adverse Outcome in Patients With Cardiovascular Disease: An Individual Patient-Data Meta-analysis.

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.

Are the results from a multiplex proteomic assay and a conventional immunoassay for NT-proBNP and GDF-15 comparable?

BACKGROUND: We aimed to compare absolute plasma concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and growth differentiation factor 15 (GDF-15) obtained by a conventional immunoassay with the corresponding relative concentrations from a proximity extension assay (PEA) and compare the prognostic impact of the protein levels obtained from these assays. METHODS: We evaluated 437 patients with peripheral arterial disease (PAD) and a population-based cohort of 643 individuals without PAD. Correlations were calculated using Spearman's rank correlation coefficients (rho). The discriminatory accuracy of the protein levels to predict future cardiovascular events was analyzed with Cox regression and presented as time-dependent areas under the receiver-operator-characteristic curves (tdAUCs). RESULTS: For NT-proBNP, the two assays correlated with rho 0.93 and 0.93 in the respective cohort. The PEA values leveled off at higher values in both cohorts. The corresponding correlations for GDF-15 were 0.91 and 0.89. At 5 years follow-up, the tdAUCs in the patient cohort were similar for NT-proBNP and GDF-15 regardless of assay used (0.65-0.66). The corresponding tdAUCs in the population-based cohort were between 0.72 and 0.77. CONCLUSION: Except for the highest levels of NT-proBNP, we suggest that PEA data for NT-proBNP and GDF-15 reliably reflects absolute plasma levels and contains similar prognostic information.

Screening of biomarkers for prediction of multisite artery disease in patients with recent myocardial infarction.

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 (<0.9 or >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.

Poorly controlled ambulatory blood pressure in outpatients with peripheral arterial disease.

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 <25% of them used three or more agents. Clinical BP, a low number of medications, body mass index, and the presence of diabetes independently predicted a poorly controlled ambulatory BP. Nearly one-third of the patients were smokers, and most of the cohort had an LDL-cholesterol level of ≥2.5 mmol/L. An HbA1c level of >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.

Staphylococcus aureus bacteremia and cardiac implantable electronic devices in a county hospital setting: a population-based retrospective cohort study.

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.

Plasma Protein Profile of Carotid Artery Atherosclerosis and Atherosclerotic Outcomes: Meta-Analyses and Mendelian Randomization Analyses.

[Figure: see text].

Effects of oral appliance treatment on inflammatory biomarkers in obstructive sleep apnea: A randomised controlled trial.

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-α 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.

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

BACKGROUND: Underlying mechanism leading to impaired lung function are incompletely understood. OBJECTIVES: To investigate whether protein profiling can provide novel insights into mechanisms leading to impaired lung function. METHODS: We used four community-based studies (n = 2552) to investigate associations between 79 cardiovascular/inflammatory proteins and forced expiratory volume in 1 s percent predicted (FEV1%) assessed by spirometry. We divided the cohorts into discovery and replication samples and used risk factor-adjusted linear regression corrected for multiple comparison (false discovery rate of 5%). We performed Mendelian randomization analyses using genetic and spirometry data from the UK Biobank (n = 421,986) to assess causality. MEASUREMENTS AND MAIN RESULTS: In cross-sectional analysis, 22 proteins were associated with lower FEV1% in both the discovery and replication sample, regardless of stratification by smoking status. The combined proteomic data cumulatively explained 5% of the variation in FEV1%. In longitudinal analyses (n = 681), higher plasma levels of growth differentiation factor 15 (GDF-15) and interleukin 6 (IL-6) predicted a more rapid 5-year decline in lung function (change in FEV1% per standard deviation of protein level -1.4, (95% CI, -2.5 to -0.3) for GDF-15, and -0.8, (95% CI, -1.5 to -0.2) for IL-6. Mendelian randomization analysis in UK-biobank provided support for a causal effect of increased GDF-15 levels and reduced FEV1%. CONCLUSIONS: Our combined approach identified GDF-15 as a potential causal factor in the development of impaired lung function in the general population. These findings encourage additional studies evaluating the role of GDF-15 as a causal factor for impaired lung function.

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

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.

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

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 < 0.001) and yielded an AUC of 0.76 (95%CI 0.71-0.80). A higher discriminatory performance was observed in the validation cohort (AUC 0.84; 95% CI 0.76-0.92). CONCLUSIONS: In a large-sample targeted proteomics assay, we identified two proteins that improved risk prediction beyond the COPART risk score. The use of high-throughput proteomics assays may identify potential biomarkers for improved risk prediction in patients with PAD.

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

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.

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

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.

Associations of left atrial volumes and Doppler filling indices with left atrial function in acute myocardial infarction.

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 100× (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 ~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.

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

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

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

BACKGROUND: Despite the growing body of evidence on growth differentiation factor 15 (GDF-15) reference values for patients with existing cardiovascular disease, limited investigation has been dedicated to characterizing the distribution and prognostic impact of GDF-15 in predominantly healthy populations. Furthermore, current cutoff values for GDF-15 fail to account for the well-documented age-dependence of circulating GDF-15. METHODS: From 810 community-dwelling older adults, we selected a group of apparently healthy participants (n = 268). From this sample, circulating GDF-15 was modeled using the generalized additive models for location scale and shape (GAMLSS) to develop age-dependent centile values. Unadjusted and adjusted Cox proportional hazards models were used to assess the association between the derived GDF-15 reference values (expressed as centiles) and all-cause mortality. RESULTS: Smoothed centile curves showed increasing GDF-15 with age in the apparently healthy participants. An approximately three-fold difference was observed between the 95th and 5th GDF-15 centiles across ages. In a median 8.0 years of follow-up, 97 all-cause deaths were observed in 806 participants with eligible values. In unadjusted Cox regression analyses, the hazard ratio (95% CI) for all-cause mortality per 25-unit increase in GDF-15 centile was 1.80 (1.48-2.20) and dichotomized at the 95th centile, ≥95th versus <95th, was 3.04 (1.99-4.65). Age-dependent GDF-15 centiles remained a significant predictor of all-cause mortality in all subsequent adjusted models. CONCLUSIONS: Age-dependent GDF-15 centile values developed from a population of apparently healthy older adults are independently predictive of all-cause mortality. Therefore, GDF-15 reference values could be a useful tool for risk-stratification in a clinical setting. ClinicalTrials.gov Identifier: NCT01452178.

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

AIMS/HYPOTHESIS: Multiplex proteomics could improve understanding and risk prediction of major adverse cardiovascular events (MACE) in type 2 diabetes. This study assessed 80 cardiovascular and inflammatory proteins for biomarker discovery and prediction of MACE in type 2 diabetes. METHODS: We combined data from six prospective epidemiological studies of 30-77-year-old individuals with type 2 diabetes in whom 80 circulating proteins were measured by proximity extension assay. Multivariable-adjusted Cox regression was used in a discovery/replication design to identify biomarkers for incident MACE. We used gradient-boosted machine learning and lasso regularised Cox regression in a random 75% training subsample to assess whether adding proteins to risk factors included in the Swedish National Diabetes Register risk model would improve the prediction of MACE in the separate 25% test subsample. RESULTS: Of 1211 adults with type 2 diabetes (32% women), 211 experienced a MACE over a mean (±SD) of 6.4 ± 2.3 years. We replicated associations (<5% false discovery rate) between risk of MACE and eight proteins: matrix metalloproteinase (MMP)-12, IL-27 subunit α (IL-27a), kidney injury molecule (KIM)-1, fibroblast growth factor (FGF)-23, protein S100-A12, TNF receptor (TNFR)-1, TNFR-2 and TNF-related apoptosis-inducing ligand receptor (TRAIL-R)2. Addition of the 80-protein assay to established risk factors improved discrimination in the separate test sample from 0.686 (95% CI 0.682, 0.689) to 0.748 (95% CI 0.746, 0.751). A sparse model of 20 added proteins achieved a C statistic of 0.747 (95% CI 0.653, 0.842) in the test sample. CONCLUSIONS/INTERPRETATION: We identified eight protein biomarkers, four of which are novel, for risk of MACE in community residents with type 2 diabetes, and found improved risk prediction by combining multiplex proteomics with an established risk model. Multiprotein arrays could be useful in identifying individuals with type 2 diabetes who are at highest risk of a cardiovascular event.

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

BACKGROUND: The role of systemic atherosclerosis in myocardial infarction (MI) patients is not fully understood. We investigated the incremental prognostic value of coronary and systemic atherosclerosis after acute MI by estimating extra-cardiac artery disease (ECAD) and extent of coronary atherosclerosis. METHODS AND RESULTS: The study included 544 prospective MI patients undergoing coronary angiography. For all patients, the longitudinal coronary atherosclerotic extent, expressed as Sullivan extent score (SES) was calculated. In addition, the patients underwent non-invasive screening for ECAD in the carotid, aortic, renal and lower limb. SES was found to be associated with ECAD independent of baseline clinical parameters [adjusted odds ratio (OR) 1.04 95% confidence interval (CI) 1.02-1.06, P < 0.001]. Extensive systemic atherosclerosis, defined as the combination of extensive coronary disease (SES ≥ 17) and ECAD, was associated with higher risk for all-cause mortality compared to limited systemic atherosclerosis (SES < 17 and no ECAD) (hazard ratio [HR] 2.9 95% CI 1.9-4.5, P < 0.001, adjusted for Global Registry of Acute Coronary Events risk score parameters 1.8, 95% CI 1.1-3.0, P = 0.019). The risk for the composite endpoint of cardiovascular death or hospitalization was significantly higher in patients with extensive systemic atherosclerosis compared to patients with limited systemic atherosclerosis (HR 3.1, 95% CI 2.1-4.7, P < 0.001, adjusted HR 1.9, 95% CI 1.2-3.1, P < 0.004). CONCLUSIONS: Visual estimation of the longitudinal coronary atherosclerotic extent at the time of MI predicts ECAD. Coexistence of extensive coronary disease and ECAD defines a group with particularly poor prognosis after MI.