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BACKGROUND: Atrial fibrillation (AF) ablation strategy is associated with a non-negligible risk of complications and often requires repeat procedures (AF ablation track), implying repetitive exposure to procedural risk. OBJECTIVE: The purpose of this study was to develop and validate a model to estimate individualized cumulative risk of complications in patients undergoing the AF ablation track (Atrial Fibrillation TRAck Complication risK [AF-TRACK] calculator). METHODS: The model was derived from a multicenter cohort including 3762 AF ablation procedures in 2943 patients. A first regression model was fitted to predict the propensity for repeat ablation. The AF-TRACK calculator computed the risk of AF ablation track complications, considering the propensity for repeat ablation. Internal (cross-validation) and external (independent cohort) validation were assessed for discrimination capacity (area under the curve [AUC]) and goodness of fit (Hosmer-Lemeshow [HL] test). RESULTS: Complications (N = 111) occurred in 3.7% of patients (2.9% of procedures). Predictors included female sex, heart failure, sleep apnea syndrome, and repeat procedures. The model showed fair discrimination capacity to predict complications (AUC 0.61 [0.55-0.67]) and likelihood of repeat procedure (AUC 0.62 [0.60-0.64]), with good calibration (HL χ2 12.5; P = .13). The model maintained adequate discrimination capacity (AUC 0.67 [0.57-0.77]) and calibration (HL χ2 5.6; P = .23) in the external validation cohort. The validated model was used to create the Web-based AF-TRACK calculator. CONCLUSION: The proposed risk model provides individualized estimates of the cumulative risk of complications of undergoing the AF ablation track. The AF-TRACK calculator is a validated, easy-to-use, Web-based clinical tool to calibrate the risk-to-benefit ratio of this treatment strategy.

Data de publicació electrònica: 02-05-2023 Objectives: To identify prognostic models which estimate the risk of critical COVID-19 in hospitalized patients and to assess their validation properties. Study design and setting: We conducted a systematic review in Medline (up to January 2021) of studies developing or updating a model that estimated the risk of critical COVID-19, defined as death, admission to intensive care unit, and/or use of mechanical ventilation during admission. Models were validated in two datasets with different backgrounds (HM [private Spanish hospital network], n = 1,753, and ICS [public Catalan health system], n = 1,104), by assessing discrimination (area under the curve [AUC]) and calibration (plots). Results: We validated 18 prognostic models. Discrimination was good in nine of them (AUCs ≥ 80%) and higher in those predicting mortality (AUCs 65%-87%) than those predicting intensive care unit admission or a composite outcome (AUCs 53%-78%). Calibration was poor in all models providing outcome's probabilities and good in four models providing a point-based score. These four models used mortality as outcome and included age, oxygen saturation, and C-reactive protein among their predictors. Conclusion: The validity of models predicting critical COVID-19 by using only routinely collected predictors is variable. Four models showed good discrimination and calibration when externally validated and are recommended for their use.

Background Consumption of a Mediterranean diet, adequate levels of physical activity, and energy-restricted lifestyle interventions have been individually associated with improvements in HDL functions. Evidence of intensive interventions with calorie restriction and physical activity is, however, scarce. Objectives To determine whether an intensive lifestyle intervention with an energy-restricted Mediterranean diet plus physical activity enhanced HDL function compared to a non-hypocaloric Mediterranean eating pattern without physical activity. Methods In 391 older adults with metabolic syndrome (mean age, 65 years; mean BMI, 33.3 kg/m2) from 1 of the Prevencion con Dieta Mediterranea-Plus trial centers, we evaluated the impact of a 6-month intervention with an energy-restricted Mediterranean diet plus physical activity (intensive lifestyle; n = 190) relative to a nonrestrictive Mediterranean diet without physical activity (control; n = 201) on a set of HDL functional traits. These included cholesterol efflux capacity, HDL oxidative/inflammatory index, HDL oxidation, and levels of complement component 3, serum amyloid A, sphingosine-1-phosphate, triglycerides, and apolipoproteins A-I, A-IV, C-III, and E in apoB-depleted plasma. Results The intensive-lifestyle intervention participants displayed greater 6-month weight reductions (-3.83 kg; 95% CI: -4.57 to -3.09 kg) but no changes in HDL cholesterol compared with control-diet participants. Regarding HDL functional traits, the intensive lifestyle decreased triglyceride levels (-0.15 mg/g protein; 95% CI: -0.29 to -0.014 mg/g protein) and apoC-III (-0.11 mg/g protein; 95% CI: -0.18 to -0.026 mg/g protein) compared to the control diet, with weight loss being the essential mediator (proportions of mediation were 77.4% and 72.1% for triglycerides and apoC-III levels in HDL, respectively). Conclusions In older adults with metabolic syndrome, an energy-restricted Mediterranean diet plus physical activity improved the HDL triglyceride metabolism compared with a nonrestrictive Mediterranean diet without physical activity. This trial is registered at isrctn.com as ISRCTN89898870.

Introduction and objectives COVID-19 is currently causing high mortality and morbidity worldwide. Information on cardiac injury is scarce. We aimed to evaluate cardiovascular damage in patients with COVID-19 and determine the correlation of high-sensitivity cardiac-specific troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) with the severity of COVID-19. Methods We included 872 consecutive patients with confirmed COVID-19 from February to April 2020. We tested 651 patients for high-sensitivity troponin T (hs-TnT) and 506 for NT-proBNP on admission. Cardiac injury was defined as hs-TnT > 14ng/L, the upper 99th percentile. Levels of NT-proBNP > 300 pg/mL were considered related to some extent of cardiac injury. The primary composite endpoint was 30-day mortality or mechanical ventilation (MV). Results Cardiac injury by hs-TnT was observed in 34.6% of our COVID-19 patients. Mortality or MV were higher in cardiac injury than noncardiac injury patients (39.1% vs 9.1%). Hs-TnT and NT-proBNP levels were independent predictors of death or MV (HR, 2.18; 95%CI, 1.23-3.83 and 1.87 (95%CI, 1.05-3.36), respectively) and of mortality alone (HR, 2.91; 95%CI, 1.211-7.04 and 5.47; 95%CI, 2.10-14.26, respectively). NT-ProBNP significantly improved the troponin model discrimination of mortality or MV (C-index 0.83 to 0.84), and of mortality alone (C-index 0.85 to 0.87). Conclusions Myocardial injury measured at admission was a common finding in patients with COVID-19. It reliably predicted the occurrence of mortality and need of MV, the most severe complications of the disease. NT-proBNP improved the prognostic accuracy of hs-TnT.

Background Genetic, observational, and clinical intervention studies indicate that circulating levels of triglycerides and cholesterol transported in triglyceride-rich lipoproteins (remnant cholesterol) can predict cardiovascular events. Objectives This study evaluated the association of triglycerides and remnant cholesterol (remnant-C) with major cardiovascular events in a cohort of older individuals at high cardiovascular risk. Methods This study determined the baseline lipid profile and searched for major adverse cardiovascular events (MACEs) in the high-risk primary prevention PREDIMED (Prevencion con Dieta Mediterranea) trial population (mean age: 67 years; body mass index: 30 kg/m2; 43% men; 48% with diabetes) after a median follow-up of 4.8 years. Unadjusted and adjusted Cox proportional hazard models were used to assess the association between lipid concentrations (either as continuous or categorical variables) and incident MACEs (N = 6,901; n cases = 263). Results In multivariable-adjusted analyses, triglycerides (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 1.02 to 1.06, per 10 mg/dl [0.11 mmol/l]; p 150 mg/dl [1.69 mmol/l] and HDL-C Conclusions In overweight or obese subjects at high cardiovascular risk, levels of triglycerides and remnant-C, but not LDL-C, were associated with cardiovascular outcomes independent of other risk factors.

Background: The aim of the study was to determine the association between previous stroke and mortality after coronavirus disease 2019 (COVID-19) according to sex, age groups, and stroke subtypes. Methods: Prospective population-based cohort study including all COVID-19 positive cases between February 1 and July 31, 2020. Comorbidities and mortality were extracted using linked health administration databases. Previous stroke included transient ischemic attack, ischemic stroke, hemorrhagic stroke, spontaneous subarachnoid hemorrhage, and combined stroke for cases with more than one category. Other comorbidities were obesity, diabetes, hypertension, ischemic heart disease, atrial fibrillation, heart failure, chronic obstructive pulmonary disease, chronic kidney disease, cirrhosis, dementia, individual socioeconomic index, and deprivation index. Cases were followed up until December 31, 2020. Primary outcome was mortality of any cause after COVID-19 positivity. Cox proportional regression analysis adjusted for comorbidities was used. Stratified analyses were performed for sex and age ( Results: There were 91 629 COVID-19 cases. Previous strokes were 5752 (6.27%), of which 3887 (67.57%) were ischemic, 1237 (21.50%) transient ischemic attack, 255 (4.43%) combined, 203 (3.53%) hemorrhagic, and 170 (2.96%) subarachnoid hemorrhage. There were 9512 deaths (10.38%). Mortality was associated with previous stroke (hazard ratio [HR]=1.12 [95% CI, 1.06–1.18]; P P =0.001; women=1.09 [1.01–1.18]; P =0.023), in people P P P =0.437). Ischemic (HR=1.11 [1.05–1.18]; P =0.001), hemorrhagic (HR=1.53 [1.20–1.96]; P =0.001) and combined (HR=1.31 [1.05–1.63]; P =0.016) strokes were associated but not transient ischemic attack. Subarachnoid hemorrhage was associated only in people P =0.003). Conclusions: Previous stroke was associated with a higher mortality in people younger than 80 years. The association occurred for both ischemic and hemorrhagic stroke but not for transient ischemic attack. These data might help healthcare authorities to establish prioritization strategies for COVID-19 vaccination.

Resumen: Objetivo: Determinar el valor pronóstico de tener un índice tobillo-brazo (ITB) bajo para padecer distintas enfermedades cardiovasculares y si mejora la capacidad predictiva de las principales funciones de riesgo cardiovascular. Diseño: Estudio de cohorte poblacional. Emplazamiento: Área sanitaria Don Benito-Villanueva de la Serena (Badajoz). España. Participantes: Se seleccionaron 2.833 sujetos representativos de los residentes, entre 25 y 79 años. Mediciones: Se midió el ITB en la inclusión y se registró el primer episodio de cardiopatía isquémica o ictus, la mortalidad cardiovascular y total en siete años de seguimiento. Se calcularon los hazard ratio (HR), ajustados por factores de riesgo cardiovascular, para el ITB bajo (< 0,9). Se determinaron los índices de reclasificación neta por categorías, clínica y continua para las funciones REGICOR, FRESCO cardiopatía isquémica, FRESCO enfermedad cardiovascular y SCORE. Resultados: Se analizaron 2.665 sujetos tras excluir las personas con antecedentes cardiovasculares y las pérdidas. El ITB bajo se asoció con un mayor riesgo, alcanzando una HR (IC 95%) de 6,45 (3,00 – 13,86), 2,60 (1,15 – 5,91), 3,43 (1,39 – 8,44), 2,21 (1,27 – 3,86) para ictus, cardiopatía isquémica, mortalidad cardiovascular y total, respectivamente. La inclusión del ITB mejoró el índice de reclasificación (IC 95%) en el riesgo intermedio según FRESCO cardiovascular en un 24,1% (10,1 – 38,2). Conclusiones: El ITB bajo está asociado con un incremento importante del riesgo de ictus, cardiopatía isquémica, mortalidad cardiovascular y total en nuestro medio. La inclusión del ITB mejoró la reclasificación de las personas con riesgo intermedio, según FRESCO cardiovascular, por lo que estaría justificada su utilización en esa categoría de riesgo. Abstract: Objective: The objectives have been to determine the prognostic value of having a low ankle-brachial index (ABI) for different cardiovascular diseases and whether it improves the predictive capacity of the main cardiovascular risk scores proposed for Spain. Design: Population-based cohort study Location: A health area of the province of Badajoz (Spain) Participants: 2,833 subjects, representative of residents, between 25 and 79 years old, Measurements: The ABI was measured at baseline and the first episode of ischemic heart disease or stroke, cardiovascular and total mortality, was recorded during 7 years of follow-up. The hazard ratio (HR) adjusted for cardiovascular risk factors and net reclassification index (NRI) by category, clinical and continuous for the risk functions REGICOR, FRESCO coronary heart disease, FRESCO cardiovascular disease and SCORE, were calculated. Results: 2,665 subjects were analysed after excluding people with cardiovascular history and loss of follow-up. Low ABI was associated with adjusted HR (95% CI): 6.45 (3.00 - 13.86), 2.60 (1.15 - 5.91), 3.43 (1.39 - 8.44), 2.21 (1.27 - 3.86) for stroke, ischemic heart disease, cardiovascular mortality and total mortality respectively. The ABI improved the NRI (95% CI) in the intermediate risk category according to FRESCO cardiovascular equation by 24.1% (10.1 - 38.2). Conclusions: Low ABI is associated with a significant increase in the risk of stroke, ischemic heart disease, cardiovascular mortality and total mortality in our population. The inclusion of ABI improved the reclassification of people at intermediate risk, according to FRESCO cardiovascular, so its use in that risk category would be justified.

INTRODUCTION: DNA methylation may be one of the biological mechanisms underlying the health benefits of physical activity (PA). Our objective was to determine the association between PA and genome-wide DNA methylation at CpG level. METHODS: We designed a two-stage epigenome wide association study. In the discovery stage, we used 619 individuals from the REGICOR cohort. Next, we validated the CpGs suggestively associated with PA (p-value

Resumen Introduccion y objetivos Se considera que los individuos con disminucion leve-moderada de la tasa de filtrado glomerular estimada (TFGe, 30-59 ml/min/1,73 m 2 ) estan en alto riesgo de enfermedad cardiovascular (ECV). Ningun estudio ha comparado este riesgo con TFGe 30-59, diabetes mellitus (DM) y enfermedad coronaria (EC) en regiones con baja incidencia de EC. Metodos Se realizo un estudio de cohortes retrospectivo en 122.443 individuos de 60-84 anos de una region de baja incidencia de EC con creatinina determinada entre el 1 de enero de 2010 y 31 de diciembre de 2011. Se identificaron los ingresos por EC (infarto de miocardio, angina de pecho) o ECV (EC, accidente cerebrovascular o accidente isquemico transitorio) hasta el 31 de diciembre de 2013 segun registros electronicos. Se estimaron las tasas de incidencia y la subdistribution hazard ratio (sHR) ajustadas mediante regresion de Cox considerando los riesgos competitivos en individuos con TFGe 30-59, DM y EC o combinaciones, respecto a individuos sin estas afecciones. Resultados La mediana de seguimiento fue de 38,3 [intervalo intercuartilico, 33,8-42,7] meses. Las sHR de EC de los individuos con TFGe 30-59, DM, TFGe 30-59 mas DM, EC previa, EC mas DM y EC mas TFGe 30-59 mas DM fueron, respectivamente, 1,34 (IC95%, 1,04-1,74), 1,61 (IC95%, 1,36-1,90), 1,96 (IC95%, 1,42-2,70), 4,33 (IC95%, 3,58-5,25), 7,05 (IC95%, 5,80-8,58) y 7,72 (IC95%, 5,72-10,41), y las sHR de ECV, 1,25 (IC95%, 1,06-1,46), 1,56 (IC95%, 1,41-1,74), 1,83 (IC95%, 1,50-2,23), 2,86 (IC95%, 2,48-3,29), 4,54 (IC95%, 3,93-5,24) y 5,33 (IC95%, 4,31-6,60). Conclusiones Los individuos de 60-84 anos con TFGe 30-59, de modo similar que la DM, presentaron un riesgo de ingreso por EC y ECV un 50% inferior que aquellos con EC previa. Una TFGe 30-59 no aparece como equivalente de riesgo coronario. Debe priorizarse un tratamiento mas intensivo del riesgo cardiovascular de los individuos con EC y DM o TFGe 30-59 mas DM.

Altres ajuts: acords transformatius de la UAB Aims: Several heart failure (HF) web-based risk scores are currently used in clinical practice. Currently, we lack head-to-head comparison of the accuracy of risk scores. This study aimed to assess correlation and mortality prediction performance of Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC-HF) risk score, which includes clinical variables + medications; Seattle Heart Failure Model (SHFM), which includes clinical variables + treatments + analytes; PARADIGM Risk of Events and Death in the Contemporary Treatment of Heart Failure (PREDICT-HF) and Barcelona Bio-Heart Failure (BCN-Bio-HF) risk calculator, which also include biomarkers, like N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods and results: A total of 1166 consecutive patients with HF from different aetiologies that had NT-proBNP measurement at first visit were included. Discrimination for all-cause mortality was compared by Harrell's C-statistic from 1 to 5 years, when possible. Calibration was assessed by calibration plots and Hosmer-Lemeshow test and global performance by Nagelkerke's R. Correlation between scores was assessed by Spearman rank test. Correlation between the scores was relatively poor (rho value from 0.66 to 0.79). Discrimination analyses showed better results for 1-year mortality than for longer follow-up (SHFM 0.817, MAGGIC-HF 0.801, PREDICT-HF 0.799, BCN-Bio-HF 0.830). MAGGIC-HF showed the best calibration, BCN-Bio-HF overestimated risk while SHFM and PREDICT-HF underestimated it. BCN-Bio-HF provided the best discrimination and overall performance at every time-point. Conclusions: None of the contemporary risk scores examined showed a clear superiority over the rest. BCN-Bio-HF calculator provided the best discrimination and overall performance with overestimation of risk. MAGGIC-HF showed the best calibration, and SHFM and PREDICT-HF tended to underestimate risk. Regular updating and recalibration of online web calculators seems necessary to improve their accuracy as HF management evolves at unprecedented pace.

The present study aimed to determine the relationship between the prevalence of cardiovascular risk factors and the number and severity of coronary artery atherosclerotic lesions obtained by coronary angiography. We reviewed and analyzed 1642 records from consecutive patients at the Catheter Laboratory of Talca Regional Hospital in Chile between March 2018 and May 2019. Patients were stratified according to the presence and severity of atherosclerotic lesions: 632 (38.5%) had no lesions or &lt, 30% stenosis and 1010 (61.5%) had at least one coronary atherosclerotic lesion with ≥30% stenosis (CALS-30). CALS-30 was more frequent in males, smokers, and patients with diabetes and/or hypertension (all p-values &lt, 0.02). Serum potassium, glycaemia, creatinine and glomerular filtration rates were also associated with CALS-30 (all p-values &lt, 0.01) in males. The age and the proportion of males with CALS-30 increased with the number of risk factors (p-values for trends &lt, 0.001). Our results showed a stronger association between the accumulation of risk factors and CALS-30 in women than in men. Serum potassium levels were inversely associated with CALS-30 in men but not in women.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): CIBERCV of cardiovascular diseases; CIBERESP. OnBehalf REGICOR investigators Background Although myocardial infarction (MI) severity trends are systematically measured with mortality rates, MI incidence trends and the precision of its estimation by linkage of anonymized electronic databases are relatively untested. We validated a linked-data method (LDM) to estimate a population MI incidence and case-fatality, and to analyse the 1990-2016 trends in North-Eastern Spain. Methods LDM consisted of linking MI hospital discharges (n = 4,533,981) and mortality registry data (n = 40,676) for 2008-2016, selecting key MI diagnostic codes. The prospective REGICOR study, including all MI cases in Girona, 1990-2009, was used as the gold standard for validation purposes. Standardized MI cumulated incidence and 28-day case fatality for population aged 35-74 years was calculated, 1990-2016 trends were analysed by linear and joinpoint regression and annual percentage change (APC). Results LDM and REGICOR MI incidence and case-fatality estimates were similar for 2008-09 (Table). LDM MI incidence and case-fatality significantly decreased: APC 1990-2016 [95% CI]) was -1.8 [-2.6;-0.9] in women, and APC 2002-2016 -2.8 [-3.8;-1.8] in men; case-fatality APC 1990-2016 was -4.7% [-5.7;-3.8] in women and APC 1995-2005 -6.5%[-8.5;-4.5] in men. Conclusions LDM in population aged 35-74 reliably estimated MI incidence and case-fatality. MI incidence and case-fatality significantly decreased after 1990. Comparative analysis of REGICOR vs LDM REGICOR 2008-2009 LDM 2008-2009 Estimate 95% CI Estimate 95% CI P-Value Cumulated incidence Men 245.4 228.3; 262.5 239.7 222.5; 256.3 0.626 Women 61.1 52.6; 69.6 58.2 49.9; 66.4 0.626 Overall 28-day case-fatality Men 23.5% 19.7; 27.2 21.3% 17.8; 24.9 0.422 Women 19.3% 6.7; 31.9 17.7% 6.3; 29.1 0.855 In-hospital case-fatality Men 6.9% 4.8; 9.0 5.7% 3.8; 7.6 0.394 Women 5.0% 1.9; 8.2 3.7% 1.0; 6.5 0.540 Pre-hospital case-fatality Men 16.5% 11.8; 21.3 15.6% 11.2; 20.1 0.791 Women 14.2 % 6.6; 21.9 14.0% 6.3; 21.7 0.961 CI Confidence Interval

Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Spanish Society of Cardiology OnBehalf REGICOR Study Background Cardiovascular risk assessment is the cornerstone of cardiovascular primary prevention. However, most of the recommended or regionally validated risk assessment tools are not updated. Purpose To analyze the effect of including longitudinal information of risk factors as well as competing risks for cardiovascular risk prediction. Methods Data from 10,152 general population individuals from North-Eastern Spain was included. Individuals were recruited in 1995-2000-2005 in three different cohorts of the REGICOR Study. Risk factor data was obtained at baseline and in 2 follow-up visits. Risk factor data included age, sex, education, lipid profile, blood pressure, glucose, smoking, body mass index, and treatment for hypercholesterolemia, hypertension and diabetes. Event data was obtained by cross linkage with healthcare and mortality databases. Cardiovascular events included myocardial infarction, angina and stroke. Cancer mortality and other mortality were included as competing risks. Four cox proportional hazards models developed to model time to coronary/cerebrovascular events with longitudinal or competing risk data. Interactions between age and risk factors were included. Discrimination was assessed with the area under the ROC curve (AUC) and Sommer’s D statistic, and compared with discrimination of Framingham-REGICOR function. Results The variable with the largest effect on coronary/cerebrovascular event incidence was diabetes treatment in the longitudinal models [Hazard ratio -HR- (95% confidence interval -CI-): 3.02 (2.00, 4.58)/2.58 (1.33, 5.00)] as well as in the competing risk models [HR (95% CI): 3.08 (2.09, 4.55)/2.77 (1.48, 5.18)]. In addition to currently used variables, medication for hypertension and diabetes, and interaction between age and diabetes medication were included in all models. Compared to the Framingham-REGICOR function, discrimination improved with the inclusion of longitudinal or competing risk data as shown in the Table. Conclusion Including longitudinal information of cardiovascular risk factors or competing risks improved discrimination of a regionally validated cardiovascular risk function. The availability of these data in healthcare databases would allow its use in primary care cardiovascular risk assessment. Discrimination analysis Models AUC (95% CI) developed models AUC (95% CI) Framingham-REGICORfunction p-value Competing risks - coronary events 0.80 (0.77-0.82) 0.74 (0.71-0.77) < 0.001 Competing risks - cerebrovascular events 0.78 (0.74-0.82) 0.68 (0.63-0.72) < 0.001 Longitudinal data - coronary events 0.79 (0.78-0.81) 0.76 (0.74-0.78) < 0.001 Longitudinal data - cerebrovascular events 0.80 (0.78-0.83) 0.71 (0.69-0.74) < 0.001

Background DNA methylation is associated with atherosclerosis and cardiovascular risk factors. However, little evidence regarding its association with cardiovascular diseases in large studies is currently available. We aimed to assess the association between DNA methylation and cardiovascular events, and to determine both the predictive capacity of the identified loci and the causality of those associations. Methods We defined two strategies: epigenome-wide (EWAS) and candidate-gene association studies. In both strategies, we designed one approach with prevalent cases of coronary heart disease (CHD) and another with incident cases of CHD and cardiovascular disease. We used data from three independent cohorts: the REgistre GIroní del COR (REGICOR) study, the Framingham Offspring Study and the Women’s Health Initiative. We also assessed the association between the identified CpGs and cardiovascular risk factors in the three populations. Then, we developed methylation risk scores to evaluate whether their inclusion in the Framingham risk function improved its predictive capacity. Finally, we performed a Mendelian randomization study to determine the causality of the identified associations. Results We found 17 CpGs related to prevalent CHD and/or incident cardiovascular events, two of them observed using both approaches ( p

Background The integration of different layers of omics information is an opportunity to tackle the complexity of cardiovascular diseases (CVD) and to identify new predictive biomarkers and potential therapeutic targets. Our aim was to integrate DNA methylation and gene expression data in an effort to identify biomarkers related to cardiovascular disease risk in a community-based population. We accessed data from the Framingham Offspring Study, a cohort study with data on DNA methylation (Infinium HumanMethylation450 BeadChip; Illumina) and gene expression (Human Exon 1.0 ST Array; Affymetrix). Using the MOFA2 R package, we integrated these data to identify biomarkers related to the risk of presenting a cardiovascular event. Results Four independent latent factors (9, 19, 21—only in women—and 27), driven by DNA methylation, were associated with cardiovascular disease independently of classical risk factors and cell-type counts. In a sensitivity analysis, we also identified factor 21 as associated with CVD in women. Factors 9, 21 and 27 were also associated with coronary heart disease risk. Moreover, in a replication effort in an independent study three of the genes included in factor 27 were also present in a factor identified to be associated with myocardial infarction (CDC42BPB, MAN2A2 and RPTOR). Factor 9 was related to age and cell-type proportions; factor 19 was related to age and B cells count; factor 21 pointed to human immunodeficiency virus infection-related pathways and inflammation; and factor 27 was related to lifestyle factors such as alcohol consumption, smoking and body mass index. Inclusion of factor 21 (only in women) improved the discriminative and reclassification capacity of the Framingham classical risk function and factor 27 improved its discrimination. Conclusions Unsupervised multi-omics data integration methods have the potential to provide insights into the pathogenesis of cardiovascular diseases. We identified four independent factors (one only in women) pointing to inflammation, endothelium homeostasis, visceral fat, cardiac remodeling and lifestyles as key players in the determination of cardiovascular risk. Moreover, two of these factors improved the predictive capacity of a classical risk function.

Treatment with calcitriol, the hormonal form of vitamin D, has shown beneficial effects in ex-perimental models of acute lung injury. In this study we aimed to analyze the associations be-tween calcitriol supplementation and the risk of SARS-CoV2 infection or COVID-19 mortality. Individuals ≥18 years old living in Catalonia and supplemented with calcitriol from April 2019 to February 2020 were compared with propensity score matched controls. Outcome variables were SARS-CoV2 infection, severe COVID-19 and COVID-19 mortality. Associations between calcitriol supplementation and outcome variables were analyzed using multivariable Cox proportional regression. A total of 8076 patients were identified as being on calcitriol treatment. Advanced chronic kidney disease and hypoparathyroidism were the most frequent reasons for calcitriol supplementation in our population. Calcitriol use was associated with reduced risk of SARS-CoV2 infection (HR 0.78 [CI 95% 0.64-0.94], p=0.010), reduced risk of severe COVID-19 and reduced COVID-19 mortality (HR 0.57 (CI 95% 0.41-0.80), p=0.001) in patients with advanced chronic kidney disease. In addition, an inverse association between mean daily calcitriol dose and COVID-19 severity or mortality was observed in treated patients, independently of renal function. Our findings point out that patients with advanced chronic kidney disease could benefit from calcitriol supplementation during the COVID-19 pandemic.

The online version contains supplementary material available at https://doi.org/10.1186/s12966-021-01169-w Additional file 1 Supplementary Table 1.Characteristics of the validation study participants and the remaining participants of the population-based PASOS cohort. Additional file 2 Supplementary Table 2.Correlation coefficients and between-method agreement of moderate to vigorous physical activity measurements derived by the Physical Activity Unit 7-item screener, non-calibrated and calibrated, and the reference method (accelerometer),stratified by age [Abstract] Background Validation of self-reported tools, such as physical activity (PA) questionnaires, is crucial. The aim of this study was to determine test-retest reliability, internal consistency, and the concurrent, construct, and predictive validity of the short semi-quantitative Physical Activity Unit 7 item Screener (PAU-7S), using accelerometry as the reference measurement. The effect of linear calibration on PAU-7S validity was tested. Methods A randomized sample of 321 healthy children aged 8–16 years (149 boys, 172 girls) from the nationwide representative PASOS study completed the PAU-7S before and after wearing an accelerometer for at least 7 consecutive days. Weight, height, and waist circumference were measured. Cronbach alpha was calculated for internal consistency. Test-retest reliability was determined by intra-class correlation (ICC). Concurrent validity was assessed by ICC and Spearman correlation coefficient between moderate to vigorous PA (MVPA) derived by the PAU-7S and by accelerometer. Concordance between both methods was analyzed by absolute agreement, weighted kappa, and Bland-Altman statistics. Multiple linear regression models were fitted for construct validity and predictive validity was determined by leave-one-out cross-validation. Results The PAU-7S overestimated MVPA by 18%, compared to accelerometers (106.5 ± 77.0 vs 95.2 ± 33.2 min/day, respectively). A Cronbach alpha of 0.76 showed an acceptable internal consistency of the PAU-7S. Test-retest reliability was good (ICC 0.71 p

We aimed to explore the differences in the whole transcriptome of peripheral blood mononuclear cells between elderly individuals with and without type 2 diabetes (T2D). We conducted a microarray-based transcriptome analysis of 19 individuals with T2D and 15 without. Differentially expressed genes according to linear models were submitted to the Ingenuity Pathway Analysis system to conduct a functional enrichment analysis. We established that diseases, biological functions, and canonical signaling pathways were significantly associated with T2D patients when their logarithms of Benjamini&ndash, Hochberg-adjusted p-value were &gt, 1.30 and their absolute z-scores were &gt, 2.0 (&ge, 2.0 meant &ldquo, upregulation&rdquo, and &le, &minus, 2.0 &ldquo, downregulation&rdquo, ). Cancer signaling pathways were the most upregulated ones in T2D (z-score = 2.63, &minus, log(p-value) = 32.3, 88.5% (n = 906) of the total differentially expressed genes located in these pathways). In particular, integrin (z-score = 2.52, &minus, log(p-value) = 2.03) and paxillin (z-score = 2.33, &minus, log(p-value) = 1.46) signaling pathways were predicted to be upregulated, whereas the Rho guanosine diphosphate (Rho-GDP) dissociation inhibitor signaling pathway was predicted to be downregulated in T2D individuals (z-score = &minus, 2.14, &minus, log(p-value) = 2.41). Our results suggest that, at transcriptional expression level, elderly individuals with T2D present an increased activation of signaling pathways related to neoplastic processes, T-cell activation and migration, and inflammation.

Background Heart failure (HF) contemporary management has significantly improved over the past two decades leading to better survival. How application of the contemporary HF management guidelines affects the risk of death estimated by available web-based risk scores is not elucidated. Objective To assess changes in mortality risk prediction after a after a 12-month management period in a multidisciplinary HF Clinic. Methods Out of 1,689 consecutive patients with HF admitted at our ambulatory HF Clinic from May 2006 to November 2018, those who completed one year follow-up were considered for the study. Patients without NTproBNP measurement or with more than 3 missing variables for risk estimation were excluded. Three contemporary web-based HF risk scores were evaluated: MAGGIC-HF, Seattle HF Model (SHFM) and the Barcelona Bio-HF Calculator containing NTproBNP (BCN Bio-HF). Risk of all-cause death at one year and at 3 years were calculated at baseline and re-evaluated after 12-month management in a multidsisciplinary HF Clinic. Wilcoxon paired data test was used to compare changes in mortality risk estimation over time and test equality of matched pairs for comparing estimated change among tools. 442 patients used to derive the Barcelona Bio-HF Calculator were excluded for discrimination purposes. Results 1,157 patients were included (age 65.7±12.7 years, 70.4% men). A significant reduction in mortality risk estimation was observed with the three HF risk scores evaluated at 12-months (Table). The BCN Bio-HF model showed significantly different changes in risk estimation, fact that indeed was partnered with numerically better discrimination. AUC at 1 and 3 years, respectively, were: BCN Bio-HF (0.773 and 0.775), MAGGIC HF (0.686 and 0.748) and SHFM (0.773 and 0.739). Conclusions The three web-based risk scores evaluated showed a significant reduction in mortality risk estimation after 12 month management in a multidisciplinary HF Clinic. The BCN Bio-HF score showed higher reduction in estimated risk, together with better discrimination, likely because it incorporates contemporary treatment and use of biomarkers. Funding Acknowledgement Type of funding source: None

Background Three heart failure (HF) web-based risk scores are currently used in clinical practice. Two only include clinical variables; one adds biomarkers, known to refine pathophysiological pathways in HF and to improve mortality prediction. Objective To assess inter-score agreement and to compare mortality prediction discrimination between MAGGIC-HF risk score, Seattle HF Model (SHFM) and Barcelona Bio-HF Risk Calculator (BCN Bio-HF), which includes both clinical and biomarker variables (NTproBNP). Methods Out of 1745 consecutive patients with HF from different etiologies admitted at our Unit from May 2006 to November 2018, 1689 with NTproBNP measurement at first visit were included. Absolute and consistency intraclass correlation coefficient (ICC) at individual level among the three risk estimation tools was assessed. Bland Altman graphics were used to illustrate the differences between scores across the broad spectrum of mortality risk. Discrimination of the three prediction tools was compared by AUC of the ROC curves for 1-, 3- and 5-year all-cause mortality. Patients used previously to derivate the BCN Bio-HF were excluded. Results Patients age 66.3±13.3 years, 70.4% men, LVEF 36.4%±14.4, ischemic etiology 43.7%. Absolute ICC was poor for the three tools (from 0.18 [–0.006 to 0.35] to 0.53 [0.42 to 0.62], while consistency ICC was slightly better (from 0.28 [0.24 to 0.33] to 0.57 [0.53 to 0.60], being highest the ICC of MAGGIC-HF and BCN Bio-HF. Correlation was better among scores in low-mortality risk profile patients but clinical scores tended to infraestimate the risk in comparison with the BCN Bio-HF in high-risk patients (Figure). Discrimination was numerically better with the BCN Bio-HF at every time risk (Table), significantly better when compared with SHFM. Conclusions In comparison with other clinical scores, the BCN Bio-HF calculator predicted better higher mortality risk. Correlation was globally poor for the three tools at individual level, although improved in the low risk patients. Discrimination tended to be numerically better with the BCN Bio-HF calculator, reaching statistical significance when compared with the SHFM. Bland Altman agreement among tools Funding Acknowledgement Type of funding source: None

Background: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD). Methods: We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I levels, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al. study, n = 24,925) and analyzed their association with CAD risk in a different study (CARDIoGRAMplusC4D, n = 184,305). We validated these results by defining our genetic variables in another database (METSIM, n = 8372) and studied their relationship with CAD in the CARDIoGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits and minimize potential pleiotropy, we used the Multi-trait-based Conditional & Joint analysis. Results: Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (β = 0.27 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (β = 0.29 [95%CI = 0.17; 0.40]), and triglyceride content in very large HDLs (β = 0.14 [95%CI = 0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (β = -0.076 [95%CI = -0.10; -0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDIoGRAMplusC4D data. Conclusions: Some qualitative HDL characteristics (related to size, particle distribution, and cholesterol and triglyceride content) are related to CAD risk while HDL cholesterol levels are not. This work was supported by the Instituto de Salud Carlos III– European Regional Development Fund [grant numbers CD17/00122, IFI14/00007, PI18/00017], the Medical Research Council [grant numbers MR/K501256/1, MR/N013468/1], the Spanish Ministry of Economy and Competitiveness [grant numbers BES-2014-069718, SAF2015-71653- R], the European Union's Horizon 2020 Research and Innovation Program [grant number 796216], and the Government of Catalonia through the Agency for Management of University and Research Grants [2017 SGR 222]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CIBER Enfermedades Cardiovasculares (CIBERCV), Epidemiología y Salud Pública (CIBERESP), and Fisiopatología de la Obesidad y Nutrición (CIBEROBN) are initiatives of the Instituto de Salud Carlos III, Madrid, Spain, and financed by the European Regional Development Fund.