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Background The association between common carotid artery intima‐media thickness (CCA‐IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA‐IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta‐analysis of 20 prospective studies from the Proof‐ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA‐IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA‐IMT was 0.71 mm (SD, 0.17 mm). Over a median follow‐up of 5.9 years (5th–95th percentile, 1.9–19.0 years), 8278 individuals developed first‐ever carotid plaque. We combined study‐specific odds ratios (ORs) for incident carotid plaque using random‐effects meta‐analysis. Baseline CCA‐IMT was approximately log‐linearly associated with the odds of developing carotid plaque. The age‐, sex‐, and trial arm–adjusted OR for carotid plaque per SD higher baseline CCA‐IMT was 1.40 (95% CI, 1.31–1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low‐ and high‐density lipoprotein cholesterol, and lipid‐lowering and antihypertensive medication was 1.34 (95% CI, 1.24–1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29–1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large‐scale individual participant data meta‐analysis demonstrated that CCA‐IMT is associated with the long‐term risk of developing first‐ever carotid plaque, independent of traditional cardiovascular risk factors.

Abstract Introduction Several anthropometric measurements are variably recommended to assess adiposity in routine practice, with less agreement on their comparative performance. We assessed and compared the relationship of seven anthropometric measures of adiposity—waist circumference (WC), waist‐to‐height ratio (WHtR), Body Mass Index (BMI), Ponderal Index (PI), Conicity Index (C index), A Body Shape Index (ABSI), and Body Roundness Index (BRI)—with blood pressure (BP) levels and prevalent hypertension in adult Cameroonians. Methods Data were collected as Cameroon's contribution to the global May Measurement Month 2017(MMM17) survey. Participants were nonpregnant adults, who had no BP measurement in the past year and with no prior hypertension diagnosis. Hypertension was defined as systolic BP ≥140 mm Hg and/or diastolic ≥90 mm Hg. Odds ratios (ORs) for the presence of hypertension per 1 SD increase in each adiposity metrics were estimated in separate logistic regression models. Assessment and comparison of discrimination used the area under the receiver operating characteristics curve (AUC) and nonparametric methods. Results We included 14 424 participants (8210 [58.25%] female; 39.84 ± 14.33 years). There was a graded association between measures of adiposity and prevalent screen‐detected (newly diagnosed) hypertension, with effect sizes being mostly within the same range across measures of adiposity. AUC for hypertension prediction ranged from 0.709 with PI to 0.721 with BRI for single measures, and from 0.736 to 0.739 with combinations of measures of adiposity. Conclusion WC, WHtR, and BRI were strongly associated with BP and better predicted prevalent hypertension, with effects enhanced with the inclusion of BMI.

IntroductionOver the past few decades, the prevalence of hypertension has dramatically increased in Sub-Saharan Africa. Poor adherence has been identified as a major cause of failure to control hypertension. Scarce data are available in Africa.AimsWe assessed adherence to medication and identified socioeconomics, clinical and treatment factors associated with low adherence among hypertensive patients in 12 sub-Saharan African countries.MethodWe conducted a cross-sectional survey in urban clinics of both low and middle income countries. Data were collected by physicians on demographics, treatment and clinical data among hypertensive patients attending the clinics. Adherence was assessed by questionnaires completed by the patients. Factors associated with low adherence were investigated using logistic regression with a random effect on countries.ResultsThere were 2198 individuals from 12 countries enrolled in the study. Overall, 678 (30.8%), 738 (33.6%), 782 (35.6%) participants had respectively low, medium and high adherence to antihypertensive medication. Multivariate analysis showed that the use of traditional medicine (OR: 2.28, 95%CI [1.79-2.90]) and individual wealth index (low vs. high wealth: OR: 1.86, 95%CI [1.35-2.56] and middle vs. high wealth: OR: 1.42, 95%CI [1.11-1.81]) were significantly and independently associated with poor adherence to medication. In stratified analysis, these differences in adherence to medication according to individual wealth index were observed in low-income countries (pConclusionThis study revealed the high frequency of poor adherence in African patients and the associated factors. These findings should be useful for tailoring future programs to tackle hypertension in low income countries that are better adapted to patients, with a potential associated enhancement of their effectiveness.

[This corrects the article DOI: 10.1371/journal.pone.0191172.].

AIMS:Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. METHODS AND RESULTS:From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. CONCLUSIONS:We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.

Background The mechanisms underlying the association between obstructive sleep apnea (OSA) and cardiovascular disease may include accelerated vascular aging. The aim was to compare the magnitude of vascular aging in patients with high versus low risk of OSA. Methods and Results In 2 community‐based studies, the PPS3 (Paris Prospective Study 3) and the Maastricht Study, high risk of OSA was determined with the Berlin questionnaire (a screening questionnaire for OSA). We assessed carotid artery properties (carotid intima‐media thickness, Young’s elastic modulus, carotid‐femoral pulse wave velocity, carotid pulse wave velocity, carotid diameter using high precision ultrasound echography), and carotid‐femoral pulse wave velocity (in the Maastricht Study only). Regression coefficients were estimated on pooled data using multivariate linear regression. A total of 8615 participants without prior cardiovascular disease were included (6840 from PPS3, 62% men, mean age 59.5±6.2 years, and 1775 from the Maastricht Study, 51% men, 58.9±8.1 years). Overall, high risk of OSA prevalence was 16.8% (n=1150) in PPS3 and 23.8% (n=423) in the Maastricht Study. A high risk of OSA was associated with greater carotid intima‐media thickness (β=0.21; 0.17–0.26), Young’s elastic modulus (β=0.21; 0.17–0.25), carotid‐femoral pulse wave velocity (β=0.24; 0.14–0.34), carotid pulse wave velocity (β=0.31; 0.26–0.35), and carotid diameter (β=0.43; 0.38–0.48), after adjustment for age, sex, total cholesterol, smoking, education level, diabetes mellitus, heart rate, and study site. Consistent associations were observed after additional adjustments for mean blood pressure, body mass index, or antihypertensive medications. Conclusions These data lend support for accelerated vascular aging in individuals with high risk of OSA. This may, at least in part, underlie the association between OSA and cardiovascular disease.

Background: Large artery stiffness is an index of vascular ageing associated with cardiovascular mortality. While traditional risk factors for arterial stiffness are known, the contribution of socioeconomic factors are less reported. We sought to determine the relationship between arterial stiffness and socioeconomic deprivation (at the individual and neighborhood levels) in healthy males and females. Methods: In 7803 adults, carotid stiffness was determined by high-precision carotid echotracking. Individual deprivation data included education, living alone, occupation and Evaluation of the Deprivation and Inequalities of Health in Healthcare Centers (EPICES) score. Neighborhood deprivation was determined from commune level data (smallest administrative sub-division) available from French National Institute of statistics and Economic Studies (2011) using principal component analysis. The separate and combined associations between individual and neighborhood deprivation (main exposures) and carotid stiffness (outcome) were quantified using linear and multilevel model adjusted for traditional risk factors including age, mean blood pressure, body mass index, fasting glucose, high density lipoprotein, triglycerides, heart rate, history of cardiovascular disease, smoking, alcohol, and physical activity. Analyses were conducted separately in males and females. Results: Individual deprivation (lower education and occupation in males, and living alone and higher EPICES in both populations) was adversely related to carotid stiffness, independently of potential confounders (p < 0.05). Neighborhood deprivation was adversely related to carotid stiffness in males (p < 0.05) but not in females. Conclusion: Socioeconomic deprivation, both at the individual and, to a lesser extent, neighborhood level are associated with carotid stiffness in males. Only individual deprivation is associated with carotid stiffness in females.

Background: Physical activity (PA) is beneficial for baroreflex sensitivity (BRS), but it is unclear whether the type of PA has similar effects on the neural (nBRS) or vascular (carotid stiffness) components of BRS. We sought to determine this in healthy adults from a community- based study via assessment of occupational (OPA), sport (SPA), leisure (LPA) and total PA (TPA). Methods: In 8649 adults aged 50 to 75 years, resting nBRS (estimated by low frequency gain, from carotid distension rate and heart rate) and carotid stiffness were measured by high-precision carotid echotracking. PA was self-reported using the Baecke questionnaire, which distinguishes OPA, SPA, LPA and TPA. The associations between PA and nBRS and carotid stiffness were quantified using multivariate linear regression analysis. Analyses were conducted separately in the working and non- working population. Results: In working adults (n = 5039), OPA was associated with lower nBRS function (p = 0.026) and borderline higher carotid stiffness (p = 0.08). When stratified by education, this association remained only in those with less than tertiary education. SPA was associated with higher nBRS (p = 0.0005) and borderline lower carotid stiffness (p = 0.052). Neither LPA nor TPA was associated with nBRS or carotid stiffness. In non-working adults (n = 3610), SPA and TPA were both associated with lower carotid stiffness (p = 0.012 and p = 0.020), but not nBRS. LPA was not associated with either parameter. Conclusion: Occupation-related PA is associated with lower nBRS function and higher carotid stiffness, especially in those with lower education. Higher amounts of sport-related PA are associated with higher nBRS and lower carotid stiffness.

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P

Background: Although sudden cardiac death (SCD) is recognized as a high-priority public health topic, reliable estimates of the incidence of SCD or, more broadly, out-of-hospital cardiac arrest (OHCA), in the population are scarce, especially in the European Union.Objectives: The study objective was to determine the incidence of SCD and OHCA in the European Union.Methods: The study examined 4 large (ie, >2 million inhabitants) European population-based prospective registries collecting emergency medical services (EMS)-attended (ie, with attempted resuscitation) OHCA and SCD (OHCA without obvious extracardiac causes) for >5 consecutive years from January 2012 to December 2017 in the Paris region (France), the North Holland region (the Netherlands), the Stockholm region (Sweden), and in all of Denmark.Results: The average annual incidence of SCD in the 4 registries ranged from 36.8 per 100,000 (95% CI: 23.5-50.1 per 100,000) to 39.7 per 100,000 (95% CI: 32.6-46.8 per 100,000). When extrapolating to each European country and accounting for age and sex, this yields to 249,538 SCD cases per year (95% CI: 155,377-343,719 SCD cases per year). The average annual incidence of OHCA in the 4 registries ranged from 47.8 per 100,000 (95% CI: 21.2-74.4 per 100,000) to 57.9 per 100,000 (95% CI: 19.6-96.3 per 100,000), corresponding to 343,496 OHCA cases per year (95% CI: 216,472-464,922 OHCA cases per year) in the European Union. Incidence rates of SCD and OHCA increased with age and were systematically higher in men compared with women.Conclusions: By combining data from 4 large, population-based registries with at least 5 years of data collection, this study provided an estimate of the incidence of SCD and OHCA in the European Union. [ABSTRACT FROM AUTHOR]

Abstract Heart rate, a measure of the frequency of the cardiac cycle, reflects the health of the cardiovascular system, metabolic rate, and activity of the autonomic nervous system. Whether changes in resting heart rate are related to lifespan has not yet been explored to our best knowledge. In this study, we examined the association between resting heart rate and lifespan using linear regression in the Paris Prospective Study I, the Whitehall I Study, and the Framingham Heart Study. We used Cox proportional hazards regression to relate changes in heart rate over years to mortality risk. We observed a statistically significant association between increases in resting heart rate over a 5-year period and risk of mortality in the Paris Prospective Study I (HR mortality per 10 bpm increase over time: 1.20; 95% CI: 1.13 to 1.27) and over an 8-year period in the Framingham Heart Study (HR: 1.13; 95% CI: 1.07 to 1.19 for men and HR: 1.09; 95% CI: 1.04 to 1.15 for women), after adjusting for classical risk factors and resting heart rate. Our study shows that men and women who increase their resting heart rate over time increase their risk of mortality.

Abstract Person-centered cardiovascular health (CVH) may facilitate cardiovascular disease primordial prevention in low resources settings. The study aims to assess the validity of person-centered CVH compared to gold standard measured CVH by examining the concordance between person-centered vs. measured CVH together with their respective association with incident cardiovascular disease events (CVD). Life’s Simple 7 (LS7) CVH metrics, including non-smoking, Body Mass Index, diet, physical activity, blood glycemia, blood pressure, and blood cholesterol were collected from 19,473 adults participating in the e-cohort NutriNet-Santé study from 2011 to 2014 and were followed until September 2020. Clinical examinations and blood analyses defined the measured biological metrics, while diagnoses, medication, or treatment for type 2 diabetes, hypertension, and hypercholesterolemia defined person-centered biological metrics. Declared behavioral metrics were common for both measured and person-centered CVH. The study included 18,714 CVD-free participants (mean age 51 years, 73% women), among whom 16.52% and 38.75% had 5–7 ideal LS7 metrics according to measured and person-centered CVH, respectively. Weighted concordance of person-centered and measured CVH was 0.87 [0.86; 0.88]. Over median follow-up of 8.05 years, 749 CVD events occurred. There was a 7% (HR 0.93 [0.88; 0.99]) and 13% (HR 0.87 [0.83; 0.92]) risk reduction of CVD risk by additional measured and person-centered ideal metrics, respectively. In conclusion, person-centered CVH may represent a reliable alternative to measured CVH.

Detection of primary aldosteronism, the most common form of secondary arterial hypertension, is essential for targeted management and prevention of cardiovascular complications. Here, the authors identify genetic loci associated with primary aldosteronism, suggesting new mechanisms of disease.

Background A higher burden of cardiovascular disease risk factors has been reported in sexual minority populations. Primordial prevention may therefore be a relevant preventative strategy. The study's objectives are to estimate the associations of Life's Essential 8 (LE8) and Life's Simple 7 (LS7) cardiovascular health scores with sexual minority status. Methods and Results The CONSTANCES is a nationwide French epidemiological cohort study that recruited randomly selected participants older than 18 years in 21 cities. Sexual minority status was based on self‐reported lifetime sexual behavior and categorized as lesbian, gay, bisexual, or heterosexual. The LE8 score includes nicotine exposure, diet, physical activity, body mass index, sleep health, blood glucose, blood pressure, and blood lipids. The previous LS7 score included 7 metrics without sleep health. The study included 169 434 cardiovascular disease–free adults (53.64% women; mean age, 45.99 years). Among 90 879 women, 555 were lesbian, 3149 were bisexual, and 84 363 were heterosexual. Among 78 555 men, 2421 were gay, 2748 were bisexual, and 70 994 were heterosexual. Overall, 2812 women and 2392 men declined to answer. In multivariable mixed effects linear regression models, lesbian (β=−0.95 [95% CI, −1.89 to −0.02]) and bisexual (β=−0.78 [95% CI, −1.18 to −0.38]) women had a lower LE8 cardiovascular health score compared with heterosexual women. Conversely, gay (β=2.72 [95% CI, 2.25–3.19]) and bisexual (β=0.83 [95% CI, 0.39–1.27]) men had a higher LE8 cardiovascular health score compared with heterosexual men. The findings were consistent, although of smaller magnitudes for the LS7 score. Conclusions Cardiovascular health disparities exist in sexual minority adults, particularly lesbian and bisexual women, who may represent a priority population for primordial cardiovascular disease prevention.

Abstract Background Since the start of the COVID-19 outbreak, a large number of COVID-19-related papers have been published. However, concerns about the risk of expedited science have been raised. We aimed at reviewing and categorizing COVID-19-related medical research and to critically appraise peer-reviewed original articles. Methods The data sources were Pubmed, Cochrane COVID-19 register study, arXiv, medRxiv and bioRxiv, from 01/11/2019 to 01/05/2020. Peer-reviewed and preprints publications related to COVID-19 were included, written in English or Chinese. No limitations were placed on study design. Reviewers screened and categorized studies according to i) publication type, ii) country of publication, and iii) topics covered. Original articles were critically appraised using validated quality assessment tools. Results Among the 11,452 publications identified, 10,516 met the inclusion criteria, among which 7468 (71.0%) were peer-reviewed articles. Among these, 4190 publications (56.1%) did not include any data or analytics (comprising expert opinion pieces). Overall, the most represented topics were infectious disease (n = 2326, 22.1%), epidemiology (n = 1802, 17.1%), and global health (n = 1602, 15.2%). The top five publishing countries were China (25.8%), United States (22.3%), United Kingdom (8.8%), Italy (8.1%) and India (3.4%). The dynamic of publication showed that the exponential growth of COVID-19 peer-reviewed articles was mainly driven by publications without original data (mean 261.5 articles ± 51.1 per week) as compared with original articles (mean of 69.3 ± 22.3 articles per week). Original articles including patient data accounted for 713 (9.5%) of peer-reviewed studies. A total of 576 original articles (80.8%) showed intermediate to high risk of bias. Last, except for simulation studies that mainly used large-scale open data, the median number of patients enrolled was of 102 (IQR = 37–337). Conclusions Since the beginning of the COVID-19 pandemic, the majority of research is composed by publications without original data. Peer-reviewed original articles with data showed a high risk of bias and included a limited number of patients. Together, these findings underscore the urgent need to strike a balance between the velocity and quality of research, and to cautiously consider medical information and clinical applicability in a pressing, pandemic context. Systematic review registration https://osf.io/5zjyx/

BackgroundEarly childhood may represent an opportune time to commence primordial prevention of cardiovascular disease (CVD, i.e., prevention of risk factors onset), but epidemiological evidence is scarce. We aimed to examine the distribution and parental and early life determinants of ideal cardiovascular health (CVH) in children up to 5 years and to compare the level of cognitive development between children with and without ideal CVH at age 5 years.MethodsUsing data from the Etude sur les déterminants pré et post natals précoces du Développement psychomoteur et de la santé de l'Enfant (EDEN) study, a French population-based mother–child cohort study, CVH was examined in children at 5 years of age based on the American Heart Association CVH metrics (ideal body mass index, physical activity, diet, blood pressure, cholesterol and glucose levels, and passive smoking, considered in sensitivity analysis only). Children were categorized as having ideal (five to six ideal metrics) or non-ideal CVH (

Summary: Background: Kidney allograft failure is a common cause of end-stage renal disease. We aimed to develop a dynamic artificial intelligence approach to enhance risk stratification for kidney transplant recipients by generating continuously refined predictions of survival using updates of clinical data. Methods: In this observational study, we used data from adult recipients of kidney transplants from 18 academic transplant centres in Europe, the USA, and South America, and a cohort of patients from six randomised controlled trials. The development cohort comprised patients from four centres in France, with all other patients included in external validation cohorts. To build deeply phenotyped cohorts of transplant recipients, the following data were collected in the development cohort: clinical, histological, immunological variables, and repeated measurements of estimated glomerular filtration rate (eGFR) and proteinuria (measured using the proteinuria to creatininuria ratio). To develop a dynamic prediction system based on these clinical assessments and repeated measurements, we used a Bayesian joint models—an artificial intelligence approach. The prediction performances of the model were assessed via discrimination, through calculation of the area under the receiver operator curve (AUC), and calibration. This study is registered with ClinicalTrials.gov, NCT04258891. Findings: 13 608 patients were included (3774 in the development cohort and 9834 in the external validation cohorts) and contributed 89 328 patient-years of data, and 416 510 eGFR and proteinuria measurements. Bayesian joint models showed that recipient immunological profile, allograft interstitial fibrosis and tubular atrophy, allograft inflammation, and repeated measurements of eGFR and proteinuria were independent risk factors for allograft survival. The final model showed accurate calibration and very high discrimination in the development cohort (overall dynamic AUC 0·857 [95% CI 0·847–0·866]) with a persistent improvement in AUCs for each new repeated measurement (from 0·780 [0·768–0·794] to 0·926 [0·917–0·932]; p

Background/Objectives: The baroreflex is a crucial mechanism acutely modulating vascular tone and heart rate response to maintain blood pressure (BP) in an optimal range. A decrease in baroreflex sensitivity (BRS) is associated with ageing, and pathological conditions such as hypertension and diabetes. Antihypertensive agents are generally known to have beneficial effect on the BRS, however it is still uncertain if the effect is mediated through a more compliant arterial wall or a sympathoinhibitory action. Methods: In the Paris Prospective Study III [1], spontaneous baroreflex, carotid stiffness and pharmacological drugs intake were available in 7967 adults (aged 55–75 years). The neural component of the baroreflex sensitivity (nBRS) was obtained with a cross-spectral analysis of variations in carotid distention rate and R-R intervals. Pharmacological classes were analysed according to the Anatomical Therapeutic Chemical (ATC) classification. Individuals with a BP lowering medication (BP-treated) were paired to non-BP treated individuals with a similar cardiovascular risk (controls) using a propensity score matching procedure (n = 1182 pairs). Results: Amongst pharmacological classes of BP lowering agents, only agents acting on the renin-angiotensin system (ACEi-ARB) were associated with nBRS (β = –0.08, p = 0.045). Compared to their matched controls, ACEi-ARB users had lower nBRS (2.79 ± 0.66 vs. 2.90 ± 0.62, p = 0.03). In multivariate analysis, ACEi-ARB remained significant (stdβ = –0.09, p = 0.025) after adjustment for carotid stiffness (stdβ = 0.25, p < 0.001) and systolic pressure (stdβ = –0.20, p < 0.001). Conclusion: In this epidemiological study, ACEi-ARB were negatively associated with nBRS. This effect is independent of BP and stiffness, which may suggest an inhibition of sympathetic activity by ACEi-ARB.

Background: Individuals whose arteries appears abnormally healthy in comparison to their CV risk factor burden (supernormal vascular aging, SUPERNOVA) represent an ideal model to discover novel pathways of cardiovascular protection. Purpose: 1) to introduce a novel definition of vascular age, as predicted age based on CV risk factors and PWV; 2) to test the hypothesis that individuals with the largest difference between chronological and vascular age (C-Vage) show a lower rate of CV events, and may thus be defined as SUPERNOVA. Methods: The best fitting model for age prediction was investigated in the multicenter, European, cross-sectional Reference Values for Arterial stiffness Collaboration Database (n = 11406). A survival analysis on the longitudinal cohort of the Malmo Diet and Cancer Study (MDCS, n = 2663) was then performed. The main outcome was a composite endpoint of fatal and non-fatal major cardiac events and strokes. Results: In the Reference Values Cohort, the model explained 59.8% of age variance, with PWV being the most relevant predictor (r2: 0.105). The model (derived on population >61 years) was used to calculate vascular age in the MDCS Cohort. In the Cox survival analysis (follow-up 6.6 years, 286 events), C-Vage was significantly and inversely associated with CV events (Figure 1). Individuals in the highest C-Vage decile (>8.8 years) were defined as SUPERNOVA. In the competing risk analysis, SUPERNOVA had a reduced age-adjusted rate of CV events [HR 0.51 (0.34–0.76)]. Figure 1 Conclusion: This proof-of-concept study demonstrated that SUPERNOVA individuals have a disproportionally lower rate of CV events. Future studies are needed to explore genetic/molecular mechanisms for this phenotype.

[This corrects the article DOI: 10.1371/journal.pone.0172995.].

Background: Late-life depression is related to poor quality of life and increased risk of mortality and cardiovascular disease. Effective interventions for prevention and treatment of late-life depression need to be developed, which requires a better understanding of late-life depression risk factors. Arterial stiffness may contribute to late-life depression via cerebrovascular damage, but evidence is scarce. Aim: To investigate the association between carotid artery stiffness and incident depressive symptoms in a large community-based cohort study. Methods: This longitudinal study included 7,013 participants (60 (SD 6) years; 36% women) free of depressive symptoms at baseline. Carotid stiffness (high-resolution echotracking) was determined at baseline. Presence of depressive symptoms was determined at baseline and at 4 and 6 years of follow-up and was defined as a score ≥7 on a validated 13-item questionnaire (Q2DA) and/or new use of antidepressants. Logistic regression and generalized estimating equations (GEE) were used. Results: In total, 6.9% (n = 484) of the participants had incident depressive symptoms at 4 or 6 years of follow-up. Greater carotid stiffness was associated with a higher incidence of depressive symptoms (Figure). Results were qualitatively similar when GEE was used instead of logistic regression. Conclusions: Greater carotid artery stiffness is associated with a higher incidence of depressive symptoms. This study supports the hypothesis that carotid artery stiffness contributes to the development of late-life depression.

[This corrects the article DOI: 10.1371/journal.pmed.1002572.].

BACKGROUND:Anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are recognized as a major barrier to patients' access to organ transplantation and the major cause of graft failure. The capacity of circulating anti-HLA DSAs to activate complement has been suggested as a potential biomarker for optimizing graft allocation and improving the rate of successful transplantations. METHODS AND FINDINGS:To address the clinical relevance of complement-activating anti-HLA DSAs across all solid organ transplant patients, we performed a meta-analysis of their association with transplant outcome through a systematic review, from inception to January 31, 2018. The primary outcome was allograft loss, and the secondary outcome was allograft rejection. A comprehensive search strategy was conducted through several databases (Medline, Embase, Cochrane, and Scopus). A total of 5,861 eligible citations were identified. A total of 37 studies were included in the meta-analysis. Studies reported on 7,936 patients, including kidney (n = 5,991), liver (n = 1,459), heart (n = 370), and lung recipients (n = 116). Solid organ transplant recipients with circulating complement-activating anti-HLA DSAs experienced an increased risk of allograft loss (pooled HR 3.09; 95% CI 2.55-3.74, P = 0.001; I2 = 29.3%), and allograft rejection (pooled HR 3.75; 95% CI: 2.05-6.87, P = 0.001; I2 = 69.8%) compared to patients without complement-activating anti-HLA DSAs. The association between circulating complement-activating anti-HLA DSAs and allograft failure was consistent across all subgroups and sensitivity analyses. Limitations of the study are the observational and retrospective design of almost all included studies, the higher proportion of kidney recipients compared to other solid organ transplant recipients, and the inclusion of fewer studies investigating allograft rejection. CONCLUSIONS:In this study, we found that circulating complement-activating anti-HLA DSAs had a significant deleterious impact on solid organ transplant survival and risk of rejection. The detection of complement-activating anti-HLA DSAs may add value at an individual patient level for noninvasive biomarker-guided risk stratification. TRIAL REGISTRATION:National Clinical Trial protocol ID: NCT03438058.

BackgroundThe aim of this study was to investigate whether the association between baseline cardiovascular health (CVH) and incident cardiovascular disease differs according to coronary heart disease (CHD) and stroke subtypes, and to assess the mediating effect of inflammatory and hemostatic blood biomarkers. Methods and ResultsThe association of ideal CVH with outcomes was derived in 9312 middle‐aged men from Northern Ireland and France (whole cohort) in multivariable Cox proportional hazards regression analysis. The mediating effect of baseline inflammatory and hemostatic blood biomarkers was evaluated in a case–control study nested within the cohort after 10 years of follow‐up. After a median follow‐up of 10 years, 614 first CHD events and 117 first stroke events were adjudicated. Compared with those with poor CVH, those with an ideal CVH profile at baseline had a 72% lower risk of CHD (hazard ratio=0.28; 95% confidence interval, 0.17; 0.46) and a 76% lower risk of stroke (hazard ratio =0.24; 95% confidence interval, 0.06; 0.98). The magnitude of the risk reductions was similar for incident angina and myocardial infarction, but was lower for ischemic stroke. In the controls, the mean concentrations of high‐sensitivity C‐reactive protein, IL‐6, and fibrinogen decreased with higher CVH status. Furthermore, the association of behavioral CVH with incident CHD was partly mediated by high‐sensitivity C‐reactive protein (16.69%), IL‐6 (8.52%), and fibrinogen (7.30%) ConclusionsOur study shows no clear heterogeneity in the association of baseline CVH with the main subtypes of cardiovascular disease. This supports a universal promotion of ideal CVH for all cardiovascular disease subtypes. Furthermore, our mediation analysis suggests that the lower risk of CHD associated with ideal CVH is partly mediated by lower inflammatory and hemostatic blood biomarkers.

AimsDilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM.Methods and results116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-valueConclusionWe identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.

Background: Arterial stiffness is increased with chronic inflammatory disorders. The reduction of inflammation by immunomodulatory therapy is associated with a restoration of arterial function. Objectives: To determine whether carotid-femoral pulse wave velocity (cf-PWV) is increased in subjects with inflammatory bowel disease (IBD). Data sources. A systematic literature search for arterial stiffness in IBD was performed using PubMed and Google Scholar databases (last accessed on 11 June 2015). The search terms were “arterial stiffness,” “vascular stiffness” or “pulse wave velocity” in combination with “inflammatory bowel disease,” “inflammatory bowel diseases,” “Crohn’s disease” or “ulcerative colitis.” Study eligibility criteria. Inclusion criteria included peer-reviewed publications reporting original data; a minimum of 10 subjects tested; and cf-PWV measured via validated devices. Participants. Adults with IBD. Methods: Publications with titles or abstracts appearing to meet the inclusion criteria were selected for detailed review. These articles were reviewed by two authors according to PRISMA 2009 guidelines. Results: A total of 9 cross-sectional studies met the inclusion criteria (234 patients with Crohn’s disease (CD), 342 with ulcerative colitis (UC) and 435 control patients). One study only included patients with UC. Arterial stiffness was significantly increased in subjects with IBD in 8 studies and slightly but not significantly increased in subjects with IBD in one study. Conclusions: Current cross-sectional studies suggest that arterial stiffness is increased in IBD subjects. Longitudinal studies are required to confirm preliminary data showing a reversibility of arterial stiffening by anti-TNF-alpha therapy. Systematic review registration number: CRD42015017364.

OBJECTIVE: To examine 1) the associations between history of cardio-cerebrovascular diseases (CVD) and insomnia complaints and excessive daytime sleepiness (EDS), and 2) the relationships between sleep complaints and future CVD in persons over 65. METHODS: CVD was assessed at baseline and during two, four, and six-year follow-up in 5494 non-demented subjects. Self-reported insomnia complaints (poor sleep quality, difficulty in initiating sleep, difficulty in maintening sleep, and early morning awakening), EDS and sleep medication use were evaluated at baseline. Logistic regression models and Cox proportional hazard models, with delayed entry and age of participants as the time scale, were adjusted for socio-demographic, lifestyle and clinical variables. RESULTS: At baseline, 748 participants had a past-history of CVD. A past-history of CVD was associated with EDS (OR = 1.28 95%CI = [1.05-1.57]) and the number of insomnia complaints (OR = 1.26 95%CI = [1.03-1.55] for 1-2 insomnia complaints; OR = 1.32 95%CI = [1.03-1.71] for ≥3 complaints). In longitudinal analyses, neither the four components of insomnia nor the number of insomnia complaints were significantly associated with first or recurrent CVD events (n = 391 events). EDS was independently associated with future CVD events even after adjusting for prescribed sleep medication and past-history of CVD (HR = 1.35 95%CI = [1.06-1.71]). CONCLUSION: Our results suggest that the relationships between sleep complaints and CVD could be complex. Insomnia complaints are more likely a consequence of CVD, whereas EDS appears to be a determinant of CVD independently of past-history of CVD. EDS screening may thus constitute a means of detecting persons at high risk of CVD.

BackgroundData from several previous studies examining heart-rate and cardiovascular risk have hinted at a possible relationship between heart-rate and non-cardiac mortality. We thus systematically examined the predictive value of heart-rate variables on the subsequent risk of death from cancer.MethodsIn the Paris Prospective Study I, 6101 asymptomatic French working men aged 42 to 53 years, free of clinically detectable cardiovascular disease and cancer, underwent a standardized graded exercise test between 1967 and 1972. Resting heart-rate, heart-rate increase during exercise, and decrease during recovery were measured. Change in resting heart-rate over 5 years was also available in 5139 men. Mortality including 758 cancer deaths was assessed over the 25 years of follow-up.FindingsThere were strong, graded and significant relationships between all heart-rate parameters and subsequent cancer deaths. After adjustment for age and tobacco consumption and, compared with the lowest quartile, those with the highest quartile for resting heart-rate had a relative risk of 2.4 for cancer deaths (95% confidence interval: 1.9-2.9, pInterpretationResting and exercise heart rate had consistent, graded and highly significant associations with subsequent cancer mortality in men.