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Valvular heart disease is a leading cause of cardiovascular morbidity and mortality and a major contributor of symptoms and functional disability. Knowledge of valvular heart disease epidemiology and a deep comprehension of the geographical and temporal trends are crucial for clinical advances and the formulation of effective health policy for primary and secondary prevention. This review mainly focuses on the epidemiology of primary (organic, related to the valve itself) valvular disease and its management, especially emphasizing the importance of heart valve centers in ensuring the best care of patients through a multidisciplinary team.

Fermentation of orange juice (OJ) by Pichia kluyveri enhances the content of melatonin, a molecule with potent antioxidant effect. This study explores the levels of urine 6- sulfatoxymelatonin (6-SMT) in healthy subjects after fermented orange juice (FOJ) intake, and their association with antioxidant activity status. Nine participants ingested 500 mL of FOJ and their urine was collected at baseline and after 2, 5, 10, 15 and 24 h. After a two-week washout period, the intervention was repeated with OJ. 6-SMT levels were quantified by ELISA and antioxidant activity by TAC, FRAP and ORAC assays. A significant increase in both 6-SMT levels and antioxidant activity in urine was observed after FOJ ingestion compared to OJ. A positive correlation between TAC and 6-SMT levels was observed only after FOJ intake. This study shows for the first time that fermentation process increases melatonin bioavailability of OJ associated with an enhancement in antioxidant status., This research was funded by the Andalusian Government [project P09-AGR4814M] and the PAIDI Program from the Andalusian Government [CTS160, BIO311]. I.C.-C. was supported by a postdoctoral fellowship from the Andalusian Government Ministry of Economy, Knowledge, Business, and University [DOC_00587/2020]. G.S.-S. was supported by a FPU grant from the Spanish Ministerio de Educación, Cultura y Deporte [FPU16/02339]. N.A.-S. was supported by a fellowship from the National Net RETICEF for Aging Studies [RD12/0043/0012 from the Instituto de Salud Carlos III, Spanish Ministerio de Ciencia e Innovación].

BackgroundIt has been suggested that the baseline triglyceride-glucose (TyG) index, a simple surrogate measure for insulin resistance, is significantly associated with the occurrence of stroke. Nevertheless, the impact of longitudinal patterns of TyG on the stroke risk in hypertensive patients is still unknown. Hence, this study aimed to investigate the association between TyG index trajectory and stroke risk among hypertensive patients.MethodsThis prospective study included 19,924 hypertensive patients from the Kailuan Study who underwent three waves survey and were free of myocardial infarction, cancer and stroke before or during 2010. The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2], and latent mixed modelling was used to identify the trajectory of TyG during the exposure period (2006–2010). Furthermore, the Cox proportional hazard models were applied to estimate the hazard ratio (HR) and 95% confidence interval (CI) for incident stroke of different trajectory groups.ResultsFive distinct TyG trajectory were identified during 2006–2010: low-stable (n = 2483; range, 8.03–8.06), moderate low-stable (n = 9666; range, 8.58–8.57), moderate high-stable (n = 5759; range, 9.16–9.09), elevated-stable (n = 1741; range, 9.79–9.75), and elevated-increasing (n = 275; range, 10.38–10.81). During the median follow-up of 9.97 years, 1,519 cases of incident stroke were identified, including 1,351 with ischemic stroke and 215 with hemorrhage stroke. After adjusting for confounding variables, the HR and 95% CI of stroke were 2.21 (1.49,3.28) for the elevated-increasing group, 1.43 (1.13,1.83) for the elevated-stable group, 1.35 (1.10,1.64) for the moderate high-stable group, 1.26 (1.06,1.52) for the moderate low-stable group, respectively, when compare with the low-stable group. Similar results were observed in ischemic stroke, but a significant association was not found between TyG trajectory and risk of hemorrhage stroke.ConclusionA long-term elevated TyG index in hypertensive patients is associated with an increased risk of stroke, especially ischemic stroke. This finding implies that regular monitoring of TyG index may assist in identifying individuals at a higher risk of stroke among patients with hypertension.

Valvular heart disease is a leading cause of cardiovascular morbidity and mortality and a major contributor of symptoms and functional disability. Knowledge of valvular heart disease epidemiology and a deep comprehension of the geographical and temporal trends are crucial for clinical advances and the formulation of effective health policy for primary and secondary prevention. This review mainly focuses on the epidemiology of primary (organic, related to the valve itself) valvular disease and its management, especially emphasizing the importance of heart valve centers in ensuring the best care of patients through a multidisciplinary team.

Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall and underlies the development of cardiovascular diseases, such as myocardial infarction and ischemic stroke. As such, atherosclerosis stands as the leading cause of death and disability worldwide and intensive scientific efforts are made to investigate its complex pathophysiology, which involves the deregulation of crucial intracellular pathways and intricate interactions between diverse cell types. A growing body of evidence, including in vitro and in vivo studies involving cell-specific deletion of autophagy-related genes (ATGs), has unveiled the mechanistic relevance of cell-specific (endothelial, smooth-muscle, and myeloid cells) defective autophagy in the processes of atherogenesis. In this review, we underscore the recent insights on autophagy's cell-type-dependent role in atherosclerosis development and progression, featuring the relevance of canonical catabolic functions and emerging noncanonical mechanisms, and highlighting the potential therapeutic implications for prevention and treatment of atherosclerosis and its complications.

Self-care is essential in the long-term management of chronic heart failure. Heart failure guidelines stress the importance of patient education on treatment adherence, lifestyle changes, symptom monitoring and adequate response to possible deterioration. Self-care is related to medical and person-centred outcomes in patients with heart failure such as better quality of life as well as lower mortality and readmission rates. Although guidelines give general direction for self-care advice, health care professionals working with patients with heart failure need more specific recommendations. The aim of the management recommendations in this paper is to provide practical advice for health professionals delivering care to patients with heart failure. Recommendations for nutrition, physical activity, medication adherence, psychological status, sleep, leisure and travel, smoking, immunization and preventing infections, symptom monitoring, and symptom management are consistent with information from guidelines, expert consensus documents, recent evidence and expert opinion. Jaarsma, T (corresponding author), Univ Linkoping, Fac Hlth Sci, Kungsgatan 40, S-60174 Norrkoping, Sweden. tiny.jaarsma@liu.se

Aims Exergaming is a new tool to increase physical activity. This study aimed to determine the effects of access to a home-based exergame (Nintendo Wii) in patients with heart failure (HF) on exercise capacity, self-reported physical activity and patient-reported outcome measures. Methods and results We enrolled 605 HF patients in New York Heart Association functional class I-IV, independent of ejection fraction, in an international multicentre randomized controlled trial. Patients were randomized to exergame (intervention) or motivational support (control). The primary endpoint was change in submaximal aerobic exercise capacity as measured by the distance walked in 6 min (6MWT) between baseline and 3 months. Secondary endpoints included long-term submaximal aerobic exercise capacity, muscle function, self-reported physical activity, exercise motivation, exercise self-efficacy at 3, 6 and 12months. At baseline, patients on average walked 403142m on the 6MWT. Patients in the exergame group walked further compared to controls at 3 months (454123 vs. 420 +/- 127m, P = 0.005), at 6 months (452 +/- 123 vs. 426 +/- 133m, P = 0.015) and 12months (456 +/- 122 vs. 420 +/- 135m, P = 0.004). However, correcting for baseline 6MWT values by means of a linear mixed-effects model revealed no main effect for the intervention on 6MWT. Small significant effects on muscle function were found. Statistically significant treatment effects were found for muscle function but after correction for baseline and confounders, only the treatment effect for the heel-rise left at 6 months was significant (PFunding Agencies|Swedish National Science Council [K2013-69X-22302-01-3, 2016-01390]; Swedish National Science Council/Swedish Research Council for Health, Working Life and Welfare, VR-FORTE [2014-4100]; Swedish Heart and Lung AssociationSwedish Heart-Lung Foundation [E085/12]; Swedish Heart and Lung FoundationSwedish Heart-Lung Foundation [20130340, 20160439]; Vardal Foundation [2014-0018]; Medical Research Council of Southeast Sweden [FORSS 474681]

Advanced science 9(10), 2105783 (2022). doi:10.1002/advs.202105783 special issue: "Health, Medical, and Life Sciences Virtual Issue for Advanced Science", Published by Wiley-VCH, Weinheim

Objective Associations of eveningness with health hazards benefit from analyzing to what extent the polygenic score for morningness correlates with the assessments of the behavioral trait of morningness-eveningness and chronotype. Methods With a population-based sample of 17,243 Finnish adults, aged 25–74 years, this study examines the associations of four feasible assessment methods of chronotype, a) biological the genetic liability based on the polygenic score for morningness (PGSmorn), b) the widely-used single item for self-assessed morningness/eveningness (MEQi19) of the original Morningness-Eveningness Questionnaire (MEQ), c) the behavioral trait of morningness-eveningness as assessed with the score on the shortened version (sMEQ) of the original MEQ, and d) the phase of entrainment as assessed with the habitual midpoint of sleep based on the self-reported sleep-wake schedule during weekend (Sleepmid-wknd) as well as the sleep debt corrected midpoint of sleep (Sleepmid-corr). Results All self-report measures correlated with each other, but very weakly with the PGSmorn, which explained 1–2% of the variation in diurnal preference or habitual sleep-wake schedule. The influence of age was greater on Sleepmid-wknd and Sleepmid-corr than on the sMEQ or MEQi19, indicating that the diurnal preference might be a more stable indicator for morningness-eveningness than the sleep-wake schedule. Analyses of the discrepancies between sMEQ and MEQi19 indicated that eveningness can be over-estimated when relying on only the single-item self-assessment. Conclusions The current polygenic score for morningness explains only a small proportion of the variation in diurnal preference or habitual sleep-wake schedule. The molecular genetic basis for morningness-eveningness needs further elucidation.

Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk outcome pairs, and new data on risk exposure levels and risk outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings In 2017,34.1 million (95% uncertainty interval [UI] 33.3-35.0) deaths and 121 billion (144-1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6-62.4) of deaths and 48.3% (46.3-50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39-11.5) deaths and 218 million (198-237) DALYs, followed by smoking (7.10 million [6.83-7.37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6.53 million [5.23-8.23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4.72 million [2.99-6.70] deaths and 148 million [98.6-202] DALYs), and short gestation for birthweight (1.43 million [1.36-1.51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3-6.5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd.

Heart development is a complex process, tightly regulated by numerous molecular mechanisms. Key components of the regulatory network underlying heart development are transcription factors (TFs) and microRNAs (miRNAs), yet limited investigation of the role of miRNAs in heart development has taken place. Here, we report the first parallel genome-wide profiling of polyadenylated RNAs and miRNAs in a developing murine heart. These data enable us to identify dynamic activation or repression of numerous biological processes and signaling pathways. More than 200 miRNAs and 25 long non-coding RNAs were differentially expressed during embryonic heart development compared to the mature heart; most of these had not been previously associated with cardiogenesis. Integrative analysis of expression data and potential regulatory interactions suggested 28 miRNAs as novel regulators of embryonic heart development, representing a considerable expansion of the current repertoire of known cardiac miRNAs. To facilitate follow-up investigations, we constructed HeartMiR (http://heartmir.sysbiolab.eu), an open access database and interactive visualization tool for the study of gene regulation by miRNAs during heart development., Graphical Abstract

Modulation of vessel growth holds great promise for treatment of cardiovascular disease. Strategies to promote vascularization can potentially restore function in ischaemic tissues. On the other hand, plaque neovascularization has been shown to associate with vulnerable plaque phenotypes and adverse events. The current lack of clinical success in regulating vascularization illustrates the complexity of the vascularization process, which involves a delicate balance between pro-and anti-angiogenic regulators and effectors. This is compounded by limitations in the models used to study vascularization that do not reflect the eventual clinical target population. Nevertheless, there is a large body of evidence that validate the importance of angiogenesis as a therapeutic concept. The overall aim of this Position Paper of the ESC Working Group of Atherosclerosis and Vascular biology is to provide guidance for the next steps to be taken from pre-clinical studies on vascularization towards clinical application. To this end, the current state of knowledge in terms of therapeutic strategies for targeting vascularization in post-ischaemic disease is reviewed and discussed. A consensus statement is provided on how to optimize vascularization studies for the identification of suitable targets, the use of animal models of disease, and the analysis of novel delivery methods.

Goal: We introduce a novel approach to estimate cardiac output (CO) and central systolic blood pressure (cSBP) from noninvasive measurements of peripheral cuff-pressure and carotid-to-femoral pulse wave velocity (cf-PWV). Methods: The adjustment of a previously validated one-dimensional arterial tree model is achieved via an optimization process. In the optimization loop, compliance and resistance of the generic arterial tree model as well as aortic flow are adjusted so that simulated brachial systolic and diastolic pressures and cf-PWV converge towards the measured brachial systolic and diastolic pressures and cf-PWV. The process is repeated until full convergence in terms of both brachial pressures and cf-PWV is reached. To assess the accuracy of the proposed framework, we implemented the algorithm on in vivo anonymized data from 20 subjects and compared the method-derived estimates of CO and cSBP to patient-specific measurements obtained with Mobil-O-Graph apparatus (central pressure) and two-dimensional transthoracic echocardiography (aortic blood flow). Results: Both CO and cSBP estimates were found to be in good agreement with the reference values achieving an RMSE of 0.36 L/min and 2.46 mmHg, respectively. Low biases were reported, namely −0.04 ± 0.36 L/min for CO predictions and −0.27 ± 2.51 mmHg for cSBP predictions . Significance: Our one-dimensional model can be successfully “tuned” to partially patient-specific standards by using noninvasive, easily obtained peripheral measurement data. The in vivo evaluation demonstrated that this method can potentially be used to obtain central aortic hemodynamic parameters in a noninvasive and accurate way.

Background: The PROFRUVE study is a controlled intervention based on the Theory of Planned Behavior (TPB), which follows those behavioral theories that have proved to be the most effective at changing infant fruit and vegetable (F\/) intake pattern. The main purpose of the study is to evaluate the effectiveness of an intervention program in increasing FV consumption in schoolchildren aged 8 to 10 and based on TPB. Methods: Eligible classrooms within schools from Vitoria-Gasteiz (Basque Country, Spain) will be randomly assigned to the intervention (classrooms n = 4; children n = 86) or control (classrooms n = 4; children n = 86) group. The intervention group will receive 14 sessions of 60 min during an academic year (October to June). These sessions, designed by a multidisciplinary team, are based on TPB and are directed at modifying determinants of behavior (attitudes, subjective norms, perceived behavioral control and intention of consumption), and intake of FV itself. Both the process and the evolution of consumption and determinants of behavior will be evaluated (before, during, shortly after and a year after) using validated surveys, 7 day food records, 24 h reminders and questionnaires. Discussion: This study will provide a valid and useful tool to achieve changes in the consumption of FV at school level. A negative result will be helpful in redefining new strategies in the framework of changing habits in the consumption of FV. This study is supported by the Government of the Basque Country (IT572/13), CIBERobn (Centro de Investigacion Biomedica en Red, ISCIII), City Council of Vitoria-Gasteiz and University of the Basque Country (Programa de Fomento del Consumo de Fruta y Verdura en la Poblacion Infantil de Vitoria-Gasteiz FASE II US14/15). In order to be founded by the University of the Basque Country, the project "Programa de Fomento del Consumo de Fruta y Verdura en la Poblacion Infantil de Vitoria-Gasteiz FASE II US14/15" was evaluated and peer reviewed by ANEP (National Agency for Evaluation and Forecastig). Arrizabalaga-Lopez M is a PhD fellowship holder from the University of the Basque Country UPV/EHU. This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results.

OBJECTIVE: Few studies have been able to contrast associations of anxiety and depression with heart disease. These disorders can be grouped in fear and distress disorders. Aim of this study was to study the association between fear and distress disorders with subsequent heart disease, taking into account the temporal order of disorders. METHODS: Twenty household surveys were conducted in 18 countries (n=53791; person years=2,212,430). The Composite International Diagnostic Interview assessed lifetime prevalence and age at onset of disorders, and respondents were categorized into categories based on the presence and timing of fear and distress disorders. Heart disease was indicated by self-report of physician-diagnosed heart disease or self-report of heart attack, together with year of onset. Survival analyses estimated associations between disorder categories and heart disease. RESULTS: Most respondents with fear or distress disorders had either pure distress or pure fear (8.5% and 7.7% of total sample), while fear preceded distress in the large majority of respondents with comorbid fear and distress (3.8% of total sample). Compared to the "no fear or distress disorder" category, respondents with pure fear disorder had the highest odds of subsequent heart disease (OR:1.8; 95%CI:1.5-2.2; p

AIMS: To evaluate the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on aortic pulse wave velocity (PWV) as a surrogate marker of arterial stiffness and early atherosclerosis in people with early type 2 diabetes.METHODS: A total of 45 people with type 2 diabetes (median [interquartile range] age 63 [54-66] years, 61% men, mean ± standard deviation glycated haemoglobin [HbA1c] 6.3% ± 0.4% [45 ± 4.6 mmol/mol]), without cardiovascular disease and naïve to antidiabetic treatment, were randomized (1:1) to treatment with linagliptin 5 mg once daily or placebo for 26 weeks in a double-blind fashion. PWV was assessed at baseline, 4 and 26 weeks of treatment, and again at 30, 4 weeks after treatment. The primary endpoint was between-group difference in PWV (corrected for systolic blood pressure [SBP]) at week 26. Secondary endpoints included differences in central SBP and augmentation index (AIx).RESULTS: Compared with placebo, 26 weeks of linagliptin decreased PWV by an average of 0.91 m/s (95% confidence interval -1.76 to -0.06; P = .035). PWV returned to baseline after 4 weeks washout. Differences in central SBP and AIx were not different between linagliptin and placebo. Linagliptin decreased HbA1c (-0.4%; P CONCLUSIONS: Linagliptin decreased aortic PWV in people with early-stage type 2 diabetes as compared with placebo after 26 weeks of treatment. These results suggest that linagliptin has a favourable effect on arterial stiffness.

Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk outcome pairs, and new data on risk exposure levels and risk outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings In 2017,34.1 million (95% uncertainty interval [UI] 33.3-35.0) deaths and 121 billion (144-1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6-62.4) of deaths and 48.3% (46.3-50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39-11.5) deaths and 218 million (198-237) DALYs, followed by smoking (7.10 million [6.83-7.37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6.53 million [5.23-8.23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4.72 million [2.99-6.70] deaths and 148 million [98.6-202] DALYs), and short gestation for birthweight (1.43 million [1.36-1.51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3-6.5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd.

Extracellular vesicles (EV) mediated intercellular communication between monocytes and endothelial cells (EC) might play a major role in vascular inflammation and atherosclerotic plaque formation during cardiovascular diseases (CVD). While critical involvement of small (exosomes) and large EV (microvesicles) in CVD has recently been appreciated, the pro- and/or anti-inflammatory impact of a bulk EV (exosomes + microvesicles) on vascular cell function as well as their inflammatory capacity are poorly defined. This study aims to unravel the immunomodulatory content of EV bulk derived from control (uEV) and TNF-alpha induced inflamed endothelial cells (tEV) and to define their capacity to affect the inflammatory status of recipients monocytes (THP-1) and endothelial cells (HUVEC) in vitro. Here, we show that EV derived from inflamed vascular EC were readily taken up by THP-1 and HUVEC. Human inflammation antibody array together with ELISA revealed that tEV contain a pro-inflammatory profile with chemotactic mediators, including intercellular adhesion molecule (ICAM)-1, CCL-2, IL-6, IL-8, CXCL-10, CCL-5, and TNF-alpha as compared to uEV. In addition, EV may mediate a selective transfer of functional inflammatory mediators to their target cells and modulate them toward either pro-inflammatory (HUVEC) or anti/pro-inflammatory (THP-1) mode. Accordingly, the expression of pro-inflammatory markers (IL-6, IL-8, and ICAM-1) in tEV-treated HUVEC was increased. In the case of THP-1, EC-EV do induce a mixed of pro- and anti-inflammatory response as indicated by the elevated expression of ICAM-1, CCL-4, CCL-5, and CXCL-10 proteins. At the functional level, EC-EV mediated inflammation and promoted the adhesion and migration of THP-1. Taken together, our findings proved that the EV released from inflamed EC were enriched with a cocktail of inflammatory markers, chemokines, and cytokines which are able to establish a targeted cross-talk between EC and monocytes and reprogramming them toward a pro- or anti-inflammatory phenotypes. This work was co-financed by the EU through the Interreg IV Flanders-the Netherlands project Interreg V Flanders-the Netherlands project Trans Tech Diagnostics (TTD).

Objectives To investigate the incidence and determinants of heart failure (HF) following a myocardial infarction (MI) in a contemporary cohort of patients with MI using routinely collected primary and hospital care electronic health records (EHRs).Methods Data were used from the CALIBER programme, linking EHRs in England from primary care, hospital admissions, an MI registry and mortality data. Subjects were eligible if they were 18 years or older, did not have a history of HF and survived a first Ml. Factors associated with time to HF were examined using Cox proportional hazard models.Results Of the 24 479 patients with Ml, 5775 (23.6%) developed HF during a median follow-up of 3.7 years (incidence rate per 1000 person-years: 63.8, 95% Cl 62.2 to 65.5). Baseline characteristics significantly associated with developing HF were: atrial fibrillation (HR 1.62, 95% Cl 1.51 to 1.75), age (per 10 years increase: 1.45, 1.41 to 1.49), diabetes (1.45, 1.35 to 1.56), peripheral arterial disease (1.38, 1.26 to 1.51), chronic obstructive pulmonary disease (1.28, 1.17 to 1.40), greater socioeconomic deprivation (5th vs 1st quintile: 1.27, 1.13 to 1.41), ST segment elevation MI at presentation (1.19, 1.11 to 1.27) and hypertension (1.16, 1.09 to 1.23). Results were robust to various sensitivity analyses such as competing risk analysis and multiple imputation.Conclusion In England, one in four survivors of a first MI develop HF within 4years. This contemporary study demonstrates that patients with MI are at considerable risk of HF. Baseline patient characteristics associated with time until HF were identified, which may be used to target preventive strategies.

Standard therapies for heart failure with preserved ejection fraction (HFpEF) have been unsuccessful, demonstrating that the contribution of the underlying diastolic dysfunction pathophysiology differs from that of systolic dysfunction in heart failure and currently is far from being understood. Complicating the investigation of HFpEF is the contribution of several comorbidities. Here, we selected three established rat models of diastolic dysfunction defined by three major risk factors associated with HFpEF and researched their commonalities and differences. The top differentially expressed genes in the left ventricle of Dahl salt sensitive (Dahl/SS), spontaneous hypertensive heart failure (SHHF), and diabetes 1 induced HFpEF models were derived from published data in Gene Expression Omnibus and used for a comprehensive interpretation of the underlying pathophysiological context of each model. The diversity of the underlying transcriptomic of the heart of each model is clearly observed by the different panel of top regulated genes: the diabetic model has 20 genes in common with the Dahl/SS and 15 with the SHHF models. Advanced analytics performed in Ingenuity Pathway Analysis (IPA (R)) revealed that Dahl/SS heart tissue transcripts triggered by upstream regulators lead to dilated cardiomyopathy, hypertrophy of heart, arrhythmia, and failure of heart. In the heart of SHHF, a total of 26 genes were closely linked to cardiovascular disease including cardiotoxicity, pericarditis, ST-elevated myocardial infarction, and dilated cardiomyopathy. IPA Upstream Regulator analyses revealed that protection of cardiomyocytes is hampered by inhibition of the ERBB2 plasma membrane-bound receptor tyrosine kinases. Cardioprotective markers such as natriuretic peptide A (NPPA), heat shock 27 kDa protein 1 (HSPB1), and angiogenin (ANG) were upregulated in the diabetes 1 induced model; however, the model showed a different underlying mechanism with a majority of the regulated genes involved in metabolic disorders. In conclusion, our findings suggest that multiple mechanisms may contribute to diastolic dysfunction and HFpEF, and thus drug therapies may need to be guided more by phenotypic characteristics of the cardiac remodeling events than by the underlying molecular processes.

Objectives: To investigate the incidence and determinants of heart failure (HF) following a myocardial infarction (MI) in a contemporary cohort of patients with MI using routinely collected primary and hospital care electronic health records (EHRs).\ud \ud \ud \ud Methods: Data were used from the CALIBER programme, linking EHRs in England from primary care, hospital admissions, an MI registry and mortality data. Subjects were eligible if they were 18 years or older, did not have a history of HF and survived a first MI. Factors associated with time to HF were examined using Cox proportional hazard models.\ud \ud \ud \ud Results: Of the 24 479 patients with MI, 5775 (23.6%) developed HF during a median follow-up of 3.7 years (incidence rate per 1000 person-years: 63.8, 95% CI 62.2 to 65.5). Baseline characteristics significantly associated with developing HF were: atrial fibrillation (HR 1.62, 95% CI 1.51 to 1.75), age (per 10 years increase: 1.45, 1.41 to 1.49), diabetes (1.45, 1.35 to 1.56), peripheral arterial disease (1.38, 1.26 to 1.51), chronic obstructive pulmonary disease (1.28, 1.17 to 1.40), greater socioeconomic deprivation (5th vs 1st quintile: 1.27, 1.13 to 1.41), ST-segment elevation MI at presentation (1.19, 1.11 to 1.27) and hypertension (1.16, 1.09 to 1.23). Results were robust to various sensitivity analyses such as competing risk analysis and multiple imputation.\ud \ud \ud \ud Conclusion: In England, one in four survivors of a first MI develop HF within 4 years. This contemporary study demonstrates that patients with MI are at considerable risk of HF. Baseline patient characteristics associated with time until HF were identified, which may be used to target preventive strategies.

BACKGROUND AND AIMS: Earlier studies in our group suggested that traditionally prepared buttermilk influences cholesterol metabolism. We therefore designed a study to evaluate whether traditionally prepared buttermilk lowers serum low-density lipoprotein cholesterol (LDL-C) and/or prevents the LDL-C raising effect of egg yolks. METHODS AND RESULTS: Mildly hypercholesterolemic subjects were randomly allocated to one of four diet groups consuming daily at lunch 80 ml skimmed milk with (n = 23) or without (n = 25) lutein-enriched egg yolk (28 g from 1.5 eggs providing 323 mg cholesterol) or traditionally prepared buttermilk with (n = 23) or without (n = 21) lutein-enriched egg yolk during a 12 week period. Fasting blood samples were taken to measure concentrations of serum lipids, (apo)lipoproteins, liver and kidney function markers, and plasma lutein, zeaxanthin and high-sensitive C-reactive protein (hsCRP). Egg yolk consumption significantly increased serum total cholesterol (total-C) (p = 0.035) and LDL-C concentrations (p = 0.022). Buttermilk did not change the effects of egg yolk on serum lipids and (apo)lipoproteins. There was a trend towards significant lower total-C (p = 0.077), but not LDL-C (p = 0.204) concentrations in the buttermilk groups. Plasma lutein and zeaxanthin concentrations increased significantly (p < 0.001) in the egg yolk groups. CONCLUSION: In mildly hypercholesterolemic subjects, daily consumption of traditionally prepared buttermilk for 12 weeks did not lower serum total-C or LDL-C concentrations, nor did it prevent the serum total-C and LDL-C raising effect of daily egg yolk consumption. REGISTRATION NUMBER: This study is registered at www.clinicaltrials.gov as NCT01566305.

Objective.To estimate costs of illness in a cross-sectional cohort of patients with gout attending an outpatient rheumatology clinic, and to evaluate which factors contribute to higher costs.Methods.Altogether, 126 patients with gout were clinically assessed. They completed a series of questionnaires. Health resource use was collected using a self-report questionnaire that was cross-checked with the electronic patient file. Productivity loss was assessed by the Work Productivity and Activity Impairment Questionnaire, addressing absenteeism and presenteeism. Resource use and productivity loss were valued by real costs, and annual costs per patient were calculated. Factors contributing to incurring costs above the median were explored using logistic univariable and multivariable regression analysis.Results.Mean (median) annual direct costs of gout were €5647 (€1148) per patient. Total costs increased to €6914 (€1279) or €10,894 (€1840) per patient per year when adding cost for absenteeism or both absenteeism and presenteeism, respectively. Factors independently associated with high direct and high indirect costs were a positive history of cardiovascular disease, functional limitations, and female sex. In addition, pain, gout concerns, and unmet gout treatment needs were associated with high direct costs.Conclusion.The direct and indirect costs-of-illness of gout are primarily associated with cardiovascular disease, functional limitations, and female sex.

Background: Ultrafine particles (< 100 nm) are ubiquitous present in the air and may contribute to adverse cardiovascular effects. Exposure to air pollutants can alter miRNA expression, which can affect downstream signaling pathways. miRNAs are present both in the intracellular and extracellular environment. In adults, miR-222 and miR-146a were identified as associated with particulate matter exposure. However, there is little evidence of molecular effects of ambient air pollution in children. This study examined whether exposure to fine and ultrafine particulate matter (PM) is associated with changes in the extracellular content of miR-222 and miR-146a of children. Methods: Saliva was collected from 80 children at two different time points, circa 11 weeks apart and stabilized for RNA preservation. The extracellular fraction of saliva was obtained by means of differential centrifugation and ultracentrifugation. Expression levels of miR-222 and miR-146a were profiled by qPCR. We regressed the extracellular miRNA expression against recent exposure to ultrafine and fine particles measured at the school site using mixed models, while accounting for sex, age, BMI, passive smoking, maternal education, hours of television use, time of the day and day of the week. Results: Exposure to ultrafine particles (UFP) at the school site was positively associated with miR-222 expression in the extracellular fraction in saliva. For each IQR increase in particles in the class room (+8504 particles/cm(3)) or playground (+ 28776 particles/cm(3)), miR-222 was, respectively 23.5 % (95 % CI: 3.5 %-41.1 %; p = 0.021) or 29.9 % (95 % CI: 10.6 %-49.1 %; p = 0.0027) higher. No associations were found between miR-146a and recent exposure to fine and ultrafine particles. Conclusions: Our results suggest a possible epigenetic mechanism via which cells respond rapidly to small particles, as exemplified by miR-222 changes in the extracellular fraction of saliva. The COGNAC study is supported by grants from the European Research Council (ERC-2012-StG310898) and the Flemish Scientific Fund (FWO, G073315N). AV has a PhD fellowship from Bijzonder Onderzoeksfonds (BOF) Hasselt University. MK has a PhD fellowship of the Research Foundation Flanders (FWO). EP holds a shared VITO/FWO PhD scholarship. KV has a postdoctoral fellowship of the FWO.

Objectives To evaluate the research agenda of registered randomized trials comparing generic and brand-name drugs in terms of who sponsors them, whether they are published promptly, and whether they find favorable results. Methods We included randomized trials comparing the safety or efficacy of brand-name vs generic medications that were registered in ClinicalTrials.gov or other registries from January 1, 2000, through July 31, 2015. To identify published articles or results generated from such trials, we searched PubMed, Scopus, Google, and registry databases. Data were compared across sponsorship categories ("inbred" if the compared drugs were owned by the same company or its partners/subsidiaries, "competitive" if the compared drugs were owned by competing companies, and "apparently nonprofit"), and time to publication was evaluated with Cox analysis. Results We found 207 registered protocols reporting on 186 completed trials. Among those trials, 37 had published their results and another 56 had posted results in registries, for a total of 93 trials with available results. Four years after trial completion, results were available for 64 of 138 trials (46.4%), with substantial differences by sponsor: 70.8% (34 of 48), 28.1% (18 of 64), and 46.2% (12 of 26) of the inbred, competitive, and nonprofit trials, respectively. In multivariate modeling, inbred trials had a 1.73-fold risk of having results available compared with competitive trials ( P =.04). Almost all trials reported favorable results, with the exception of 4 (4.3% of the 93 trials with results). Conclusion Despite the importance of generic drugs, relatively few registered randomized trials have compared the health effects of generic vs brand-name medicines, and there is an associated unsatisfactory publication rate and almost ubiquitous favorable results. The overall literature on the topic is at high risk of bias, possibly in favor of generic drugs. Higher nonprofit funding and stronger pressure to register trials and publish results are needed.

Three types of vascular dysfunction have been described in multiple sclerosis (MS). First, findings from epidemiological studies suggest that patients with MS have a higher risk for ischaemic stroke than people who do not have MS. The underlying mechanism is unknown, but might involve endothelial dysfunction secondary to inflammatory disease activity and increased plasma homocysteine concentrations. Second, patients with MS have global cerebral hypoperfusion, which might predispose them to the development of ischaemic stroke. The widespread decrease in perfusion in normal-appearing white matter and grey matter in MS seems not to be secondary to axonal degeneration, but might be a result of reduced axonal activity, reduced astrocyte energy metabolism, and perhaps increased blood concentrations of endothelin-1. Data suggest that a subtype of focal MS lesions might have an ischaemic origin, and there seems to be a link between reduced white matter perfusion and cognitive dysfunction in MS. Third, the pathology of MS might be the consequence of a chronic state of impaired venous drainage from the CNS, for which the term chronic cerebrospinal venous insufficiency (CCSVI) has been coined. A number of recent vascular studies do not support the CCSVI theory, but some elements of CCSVI might be explained by slower cerebral venous blood flow secondary to the reduced cerebral perfusion in patients with MS compared with healthy individuals.

Higher levels of daily air pollution are associated with an increased risk of acute cardiovascular events, including myocardial infarction, ventricular arrhythmias, and decompensation in patients with congestive heart failure.1–3 These effects are likely mediated by a combination of changes in autonomic nervous system activity, systemic inflammation, changes in hematologic parameters, and vascular endothelial cell injury.1 Short-term elevations in particulate matter—an important component of ambient air pollution—may also increase the short-term risk of stroke.3–5 For example, Dominici et al.3 found that a 10-μg/m3 increase in ambient fine particulate matter (PM2.5) was associated with a 0.8% increased risk of hospital admission for cerebrovascular events among Medicare beneficiaries in 204 US counties (95% confidence interval [CI] = 0.3% to 1.3%), although many other studies have failed to find such a link.6–14 Some heterogeneity among prior studies may be attributable to the broad definition of cerebrovascular disease. Few studies have specifically examined the association between particulate matter and the risk of acute ischemic stroke. The results of these more focused studies have been inconsistent, with some studies finding positive associations 15–18 and others finding no evidence of an association.19–21 Ischemic stroke is etiologically diverse with distinct mechanistic subtypes, including atherosclerosis of the large extracranial and intracranial arteries that supply the brain (termed large-artery strokes), occlusion of the small penetrating arteries of the brain due to lipohyalinosis and fibrosis (termed small-vessel strokes or lacunar infarcts), and arterial occlusions due to emboli presumed to arise in the heart (termed cardioembolic strokes).22 Given that particulate matter may have different effects on the heart (e.g. ventricular arrhythmias2) and blood vessels (e.g. endothelial function, platelet activation and blood pressure23–25), the effects of particulate matter on the risk of ischemic stroke likely differ according to the pathophysiologic mechanism of ischemic stroke. However, only one prior study20 has evaluated whether the association between particulate matter and ischemic stroke varies according to ischemic stroke etiology. Based on the putative mechanisms of particulate matter health effects, we hypothesized that short-term increases in particulate matter would preferentially increase the risk of acute stroke due to intra-vascular thrombosis compared to cardioembolism. Findings that the effects of ambient particles differ by ischemic stroke subtype could provide important insights into the mechanisms of particulate-related acute vascular events. An important limitation common to prior studies is that pollution exposure is assessed on the date of hospitalization rather than the date and time of stroke symptom onset. We have previously shown that this approach can lead to substantial exposure misclassification and thus bias health effects estimates towards the null hypothesis of no association.26 Most prior studies are also limited because patients with ischemic stroke are identified using discharge diagnosis codes that can have a low specificity and potentially further bias health-effect estimates toward the null. Moreover, discharge diagnosis codes in administrative datasets do not distinguish between etiologically distinct subtypes of ischemic stroke. Finally, identifying subgroups of the population who may be at greatest risk of particulate-related events is an important research priority, but few prior studies have had access to quality clinical and patient information. Evaluating whether patients with diabetes mellitus may be more susceptible is of particular interest given prior findings suggesting that these patients are more susceptible to the effects of particulate matter on the risk of all-cause mortality, cerebrovascular death, and cardiovascular hospitalizations.27–29 Accordingly, our goal was to evaluate the association between short-term changes in ambient fine particulate matter (PM2.5) levels and acute ischemic stroke onset in a cohort of patients hospitalized with clinically-confirmed acute ischemic stroke, documented date and time of stroke symptom onset, and detailed information on clinical and patient characteristics. We accomplished this using data from the Registry of the Canadian Stroke Network, a prospective multi-center registry of consecutive patients presenting with acute stroke to 11 regional stroke centers in the province of Ontario, Canada.30

International audience; Few studies have specifically focused on characteristics associated with consumption of combined fatty-salted and fatty-sweetened foods, whereas their identification could be useful for defining effective public health measures. The aim of the present study was to investigate the association between demographic, socio-economic, lifestyle and health characteristics and consumption of these types of food in a general sample of French adults. Dietary intake was assessed using a minimum of six 24 h dietary records collected over a 2-year period in 6240 subjects aged 35-60 years who participated in the Supplementation en VItamines Mineraux et AntioXydants cohort study. Associations of individual characteristics with high and intermediate consumption of fatty-sweetened and fatty-salted foods were assessed using multivariate polytomic logistic regression models. Risk of moderate or high consumption of fatty-salted foods decreased with increasing age. Current smokers, drinkers, individuals with overweight and with hypertension were more likely to consume moderate or high amounts of such foods. Risk of moderate or high consumption of fatty-sweetened foods decreased with increasing age. Women, individuals living as a couple, moderate drinkers and persons with low or medium physical activity level were more likely to consume moderate or high amounts of such foods. Lower educated subjects, current smokers, heavy drinkers and individuals with severe hypertriacylglycerolaemia were less likely to have moderate or high consumption. Consumption of fatty-sweetened and fatty-salted foods varied according to demographic, lifestyle and health characteristics. Common unhealthy behaviours such as smoking, low physical activity and alcohol drinking, associated with high consumption of these food groups, may help to effectively target public health efforts.

Background Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. Methods We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. Findings Analyses included data for 698 782 people (52765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6-09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. Interpretation Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and nonlinearly associated with risk of vascular disease.

Aims To determine 3-year event rates in outpatients with vascular disease enrolled in the REduction of Atherothrombosis for Continued Health (REACH) Registry. Methods and results REACH enrolled 67 888 outpatients with atherothrombosis [established coronary artery disease (CAD), cerebrovascular disease, or peripheral arterial disease (PAD)], or with at least three atherothrombotic risk factors, from 44 countries. Among the 55 499 patients at baseline with symptomatic disease, 39 675 were eligible for 3-year follow-up, and 32 247 had data available (81% retention rate). Among the symptomatic patients at 3 years, 92% were taking an antithrombotic agent, 91% an antihypertensive, and 76% were on lipid-lowering therapy. For myocardial infarction (MI)/stroke/vascular death, 1- and 3-year event rates for all patients were 4.2 and 11.0%, respectively. Event rates (MI/stroke/vascular death) were significantly higher for patients with symptomatic disease vs. those with risk factors only at 1 year (4.7 vs. 2.3%, P < 0.001) and at 3 years (12.0 vs. 6.0%, P < 0.001). One and 3-year rates of MI/stroke/vascular death/rehospitalization were 14.4 and 28.4%, respectively, for patients with symptomatic disease. Rehospitalization for a vascular event other than MI/stroke/vascular death was common at 3 years (19.0% overall; 33.6% for PAD; 23.0% for CAD). For patients with symptomatic vascular disease in one vascular bed vs. multiple vascular beds, 3-year event rates for MI/stroke/vascular death/rehospitalization were 25.5 vs. 40.5% ( P < 0.001). Conclusion Despite contemporary therapy, outpatients with symptomatic atherothrombotic vascular disease experience high rates of recurrent vascular events and rehospitalizations.

Time trends in coronary heart disease (CHD) mortality during a 40-year follow-up were studied in the Seven Countries Study. Thirteen cohorts of men aged 40¿59 at entry were enrolled in seven countries (USA, Finland, the Netherlands, Italy, Serbia, Greece and Japan) for a total of 10,628 subjects. Cardiovascular risk factors were measured at entry and at the 10-year follow-up examination and coronary heart disease mortality data collected during 40 years. During the 40-year follow-up, the hazard rate of the Weibull parametric distribution (annual conditional risk of death) for CHD mortality tended to slightly decline in the US, Finnish, Dutch and Japanese cohorts, moderately increased in Italy and exponentially increased in cohorts of Serbia and Greece. A strong positive association was found between the shape of the hazard curve, describing the acceleration of the hazard, and a score of population mean risk factor changes (serum cholesterol, systolic blood pressure and smoking prevalence) observed during the first 10 years of follow-up, with a correlation coefficient of 0.91 between the two indicators. The countries with a relative decline in the annual hazard function were the same where, during the same historical period, large decreases in official death rate from CHD were recorded, and viceversa. The acceleration in mortality risk for CHD mortality in different countries, described by the shape of the Weibull distribution, is related to changes in mean levels of major coronary risk factors.

Purpose Hypohydration has been suggested as a predisposing factor for several pathologies including cardiovascular diseases (CVD). While CVD are the leading cause of death worldwide, no study has investigated whether acute hypohydration affects endothelial function and cardiovascular function.Methods Ten young, healthy males participated in this crossover study (age: 24.3 +/- 2.3 year; weight: 80.8 +/- 5.3 kg; BMI: 24.3 +/- 0.4 kg m(-2)). Each subject completed two measurements of endothelial function by flow-mediated dilation (FMD) in euhydrated and hypohydrated state separated by 24 h. Following baseline assessment of hydration status and FMD, the subjects completed 100 min of low-intensity intermittent walking exercise to achieve hypohydration of -2 % of individual body mass. For the rest of the day, a standardized, low water content diet was provided. The following morning, hydration markers and endothelial function were recorded.Results Hypohydration by -1.9 +/- 0.1 % of body mass resulted in decreased plasma volume by -3.5 +/- 1.8 % and increased plasma osmolality by 9 +/- 2 mmol kg(-1) (P Conclusion The data suggested that a small degree of hypohydration induced by moderate exercise and fluid restriction significantly impaired endothelial function.

Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Study, and GEFOS cohorts.Introduction Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms are known to influence receptor function in vitro and in vivo (rs1042713, rs1042714, and rs1800888). We examined the role of these polymorphisms in the B2AR gene on human bone metabolism.Methods We performed nested case-control studies to determine the association of these polymorphisms with fracture risk in the Utrecht Cardiovascular Pharmacogenetics (UCP) cohort and in three cohorts of the Rotterdam Study. We also determined the association of these polymorphisms with bone mineral density (BMD) in the GEFOS Consortium. UCP contains drug-dispensing histories from community pharmacies linked to national registrations of hospital discharges in the Netherlands. The Rotterdam Study is a prospective cohort study investigating demographics and risk factors of chronic diseases. GEFOS is a large international collaboration studying the genetics of osteoporosis. Fractures were defined by ICD-9 codes 800-829 in the UCP cohort (158 cases and 2617 unmatched controls) and by regular X-ray examinations, general practitioner, and hospital records in the Rotterdam Study (2209 cases and 8559 unmatched controls). BMD was measured at the femoral neck and lumbar spine using dual-energy X-ray absorptiometry in GEFOS (N = 32,961).Results Meta-analysis of the two nested case-control studies showed pooled odds ratios of 0.98 (0.91-1.05, p = 0.52), 1.04 (0.97-1.12, p = 0.28), and 1.16 (0.83-1.62, p = 0.38) for the associations between rs1042713, rs1042714, and rs1800888 per minor allele and fractures, respectively. There were no significant associations of the polymorphisms and BMD in GEFOS.Conclusion In conclusion, polymorphisms in the beta-2 adrenergic receptor gene are not associated with fracture risk or BMD.

Background: In order to influence every day clinical practice professional organisations issue management guidelines. Cross-sectional surveys are used to evaluate the implementation of such guidelines. The present survey investigated screening for glucose perturbations in people with coronary artery disease and compared patients with known and newly detected type 2 diabetes with those without diabetes in terms of their life-style and pharmacological risk factor management in relation to contemporary European guidelines. Methods: A total of 6187 patients (18-80 years) with coronary artery disease and known glycaemic status based on a self reported history of diabetes (previously known diabetes) or the results of an oral glucose tolerance test and HbA1c (no diabetes or newly diagnosed diabetes) were investigated in EUROASPIRE IV including patients in 24 European countries 2012-2013. The patients were interviewed and investigated in order to enable a comparison between their actual risk factor control with that recommended in current European management guidelines and the outcome in previously conducted surveys. Results: A total of 2846 (46 %) patients had no diabetes, 1158 (19 %) newly diagnosed diabetes and 2183 (35 %) previously known diabetes. The combined use of all four cardioprotective drugs in these groups was 53, 55 and 60 %, respectively. A blood pressure target of 9.0 % (>75 mmol/mol). Of the patients with diabetes 69 % reported on low physical activity. The proportion of patients participating in cardiac rehabilitation programmes was low (approximate to 40 %) and only 27 % of those with diabetes had attended diabetes schools. Compared with data from previous surveys the use of cardioprotective drugs had increased and more patients were achieving the risk factor treatment targets. Conclusions: Despite advances in patient management there is further potential to improve both the detection and management of patients with diabetes and coronary artery disease.

PURPOSE: To investigate the relationship between duration and intensity of physical activity and disability 10 years later, and to investigate the possible effect of selective mortality. METHOD: Longitudinal data of 560 men aged 70?-?89 years, without disability at baseline from the Finland, Italy and The Netherlands Elderly (FINE) Study was used. Physical activity in 1990 was based on activities like walking, bicycling and gardening. Disability severity (three categories) in 1990 and 2000 was based on instrumental activities, mobility and basic activities of daily living. RESULTS: Men in the highest tertile of total physical activity had a lower risk of disability than men in the lowest tertile (odds ratio (OR) 0.46; 95% confidence interval (CI): 0.26-0.84). This was due to duration of physical activity (OR highest tertile 0.42; 95% CI: 0.23-0.78 compared to the lowest tertile). Intensity of physical activity was not associated with disability. Addition of deceased men as fourth category leaded to weaker associations between physical activity and disability (OR highest tertile 0.67; 95% CI: 0.44-1.02). CONCLUSIONS: Even in old age among relatively healthy men, a physically active lifestyle was inversely related to disability. To prevent disability duration of physical activity seems to be more important than intensity.

BACKGROUND: Based on studies published so far, the protective effect of physical activity on stroke remains controversial. Specifically, there is a lack of insight into the sources of heterogeneity between studies. METHODS: Meta-analysis of observational studies was used to quantify the relationship between physical activity and stroke and to explore sources of heterogeneity. In total, 31 relevant publications were included. Risk estimates and study characteristics were extracted from original studies and converted to a standard format for use in a central database. RESULTS: Moderately intense physical activity compared with inactivity, showed a protective effect on total stroke for both occupational (RR = 0.64, 95% CI: 0.48-0.87) and leisure time physical activity (RR = 0.85, 95% CI: 0.78-0.93). High level occupational physical activity protected against ischaemic stroke compared with both moderate (RR = 0.77, 95% CI: 0.60-0.98) and inactive occupational levels (RR = 0.57, 95% CI: 0.43-0.77). High level compared with low level leisure time physical activity protected against total stroke (RR = 0.78, 95% CI: 0.71-0.85), haemorrhagic stroke (RR = 0.74, 95% CI: 0.57-0.96) as well as ischaemic stroke (RR = 0.79, 95% CI: 0.69-0.91). Studies conducted in Europe showed a stronger protective effect (RR = 0.47, 95% CI: 0.33-0.66) than studies conducted in the US (RR = 0.82, 95% CI: 0.75-0.90). CONCLUSIONS: Lack of physical activity is a modifiable risk factor for both total stroke and stroke subtypes. Moderately intense physical activity is sufficient to achieve risk reduction.

Inflammation and genetics have key roles in the pathogenesis of atherosclerosis, and the etiology of myocardial infarction (MI). Recent studies have indicated that lower serum levels of fetuin-A may accelerate the vascular mineralization process, which leads to pathophysiological conditions, such as coronary heart disease and chronic renal failure. The aim of the present study was to evaluate the association between specific fetuin-A polymorphisms (742 and 766) that are associated with circulating serum levels, and MI cases. The study consisted of 292 participants; 146 healthy control subjects and 146 patients with MI. The patient group was divided into two subgroups: 56 MI ≤ 40 years and 90 MI ≥ 40 years. The genotype distribution of fetuin 742 (C/T) and fetuin 766 (C/G) were determined by restriction enzyme digestion of polymerase chain reaction products. A significant difference was determined between the patients with MI and the control subjects with regards to fetuin-A 742 C/T gene polymorphism (P=0.028), regardless of age. Genotype distributions of fetuin-A 742 (C/G, P=0.004) and 766 (C/T, P=0.017) were statistically different in the older patients with MI (MI ≥ 40 years old), as compared with the healthy controls; however, there were no significant differences between the younger patients with MI and the controls, with regards to fetuin-A 742 C/T (P=0.519) and 766 C/G (P=0.653) gene polymorphisms. In addition, an association was observed between the presence of fetuin-A 742 T and 766 G alleles, and MI cases. The present study demonstrates that fetuin-A 742 (C/T) and 766 (C/G) genotypes may be risk factors for MI in patients older than 40 years of age.

Background: Oxidative stress plays an underlying pathophysiologic role in the development of diabetes complications. The aim of this study was to investigate peroxiredoxin 4 (Prx4), a proposed novel biomarker of oxidative stress, and its association with and capability as a biomarker in predicting (cardiovascular) mortality in type 2 diabetes mellitus.Methods: Prx4 was assessed in baseline serum samples of 1161 type 2 diabetes patients. Cox proportional hazard models were used to evaluate the relationschip between Prx4 and (cardiovascular) mortality. Risk prediction capabilities of Prx4 for (cardiovascular) mortality were assessed with Harrell's C statistic, the integrated discrimination improvement and net reclassification improvement.Results: Mean age was 67 and the median diabetes duration was 4.0 years. After a median follow-up period of 5.8 years, 327 patients died; 137 cardiovascular deaths. Prx4 was associated with (cardiovascular) mortality. The Cox proportional hazard models added the variables: Prx4 (model 1); age and gender (model 2), and BMI, creatinine, smoking, diabetes duration, systolic blood pressure, cholesterol-HDL ratio, history of macrovascular complications, and albuminuria (model 3). Hazard ratios (HR) (95% CI) for cardiovascular mortality were 1.93 (1.57 - 2.38), 1.75 (1.39 - 2.20), and 1.63 (1.28 - 2.09) for models 1, 2 and 3, respectively. HR for all-cause mortality were 1.73 (1.50 - 1.99), 1.50 (1.29 - 1.75), and 1.44 (1.23 - 1.67) for models 1, 2 and 3, respectively. Addition of Prx4 to the traditional risk factors slightly improved risk prediction of (cardiovascular) mortality.Conclusions: Prx4 is independently associated with (cardiovascular) mortality in type 2 diabetes patients. After addition of Prx4 to the traditional risk factors, there was a slightly improvement in risk prediction of (cardiovascular) mortality in this patient group.

International audience; OBJECTIVES:We aimed to estimate, in a large French cohort of middle-aged adults derived from the Supplémentation en Vitamines et Minéraux Antioxydants trial, the association of compliance with the guidelines of the French Nutrition and Health Program (PNNS) assessed at inclusion and change in health-related quality of life (HRQoL) over 12 years. A secondary objective was to identify the relative contribution of diet and physical activity to long-term change in HRQoL.DESIGN/SUBJECTS:Subjects were Supplémentation en Vitamines et Minéraux Antioxydants trial participants aged 45 to 60 years at inclusion in the cohort.MAIN OUTCOME MEASURES:Compliance with nutrition guidelines (diet and physical activity) was assessed by the PNNS Guideline Score (maximum 15 points) at inclusion. HRQoL was measured by the Medical Outcomes Survey Short Form 36 (SF-36) at 1 year (initial measurement) and 13 years (final measurement) after inclusion. The primary end point was change in the SF-36 physical component summary (PCS) and mental component summary (MCS) scores over 12 years.RESULTS:In total, 3,005 subjects (mean age 51.4 ± 4.3 years) completed the SF-36 at the initial and final measurement. The mean PNNS Guideline Score was 7.8 ± 1.9 and the mean PCS and MCS was 52.2 ± 6.4 and 50.3 ± 7.0, respectively, at the initial measurement and 48.0 ± 9.6 and 51.2 ± 8.7 at the final measurement. Better compliance with nutritional guidelines was associated with better initial and final HRQoL but not associated with change in HRQoL. Compliance with dietary guidelines was associated with positive change in PCS score but not associated with initial PCS score. In contrast, compliance with dietary guidelines was related to positive initial MCS score but not related to change in MCS score. Compliance with physical activity guidelines was related to initial PCS and MCS scores but not related to change in PCS and MCS scores.CONCLUSIONS:Following physical activity guidelines may be associated with better concomitant HRQoL and following dietary guidelines with better future physical HRQoL.

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P(overall) = 8.1 × 10(-59)), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol) = 0.002 and P(LDL) = 0.0008).Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.

International audience; Background: Antioxidant properties of some vitamins and trace elements may help to prevent cognitive decline. Objective: The aim of the current study was to estimate the long-term effects of antioxidant nutrient supplementation on the cognitive performance of participants in the Supplementation in Vitamins and Mineral Antioxidants (SU.VI.MAX) study 6 y after the end of the trial. Design: This study included 4447 French participants aged 45-60 y who were enrolled in the SU.VI.MAX study (1994-2002), which was a double-blind, placebo-controlled, randomized trial. From 1994 to 2002, participants received daily vitamin C (120 mg), beta-carotene (6 mg), vitamin E (30 mg), selenium (100 mu g), and zinc (20 mg) in combination or as a placebo. In 2007-2009, the cognitive performance of participants was assessed with 4 neuropsychological tests (6 tasks). Principal components analysis (PCA) was performed to identify cognitive-function summary scores. Associations between antioxidant supplementation and cognitive functions, in the full sample and by subgroups, were estimated through ANOVA and expressed as mean differences and 95% CIs. Subgroup analyses were performed according to baseline characteristics. Results: Subjects receiving active antioxidant supplementation had better episodic memory scores (mean difference: 0.61; 95% CI: 0.02, 1.20). PCA indicated 2 factors that were interpreted as showing verbal memory and executive functioning. Verbal memory was improved by antioxidant supplementation only in subjects who were nonsmokers or who had low serum vitamin C concentrations at baseline. Conclusion: This study supports the role of an adequate antioxidant nutrient status in the preservation of verbal memory under certain conditions. This trial was registered at clinicaltrials.gov as NCT00272428. Am J Clin Nutr 2011;94:892-9.

People with diabetes mellitus are at increased risk of cognitive dysfunction. This review explores the relation between caffeine intake, diabetes, cognition and dementia, focusing on type 2 diabetes (T2DM). Epidemiological studies on caffeine/coffee intake and T2DM risk are reviewed. Next, the impact of T2DM on cognition is addressed. Finally, the potential for caffeine to modulate the risk of cognitive decline in the context of diabetes is explored. The conclusion is that, although epidemiological studies indicate that coffee/caffeine consumption is associated with a decreased risk of T2DM and possibly also with a decreased dementia risk, we can at present not be certain that these associations are causal. For now, recommendations for coffee consumption in individuals with T2DM or pre-diabetic stages are therefore difficult to establish, but it should be acknowledged that caffeine does appear to have several properties that warrant further investigations in this field.

Int J Epidemiol