Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis.

OBJECTIVE: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN: Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. RESULTS: Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. CONCLUSIONS: This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. TRIAL REGISTRATION NUMBER: NCT03202498.

Genetic characteristics involved in COVID-19 severity. The CARGENCORS case-control study and meta-analysis.

Pre-existing coronary artery disease (CAD), and thrombotic, inflammatory, or virus infectivity response phenomena have been associated with COVID-19 disease severity. However, the association of candidate single nucleotide variants (SNVs) related to mechanisms of COVID-19 complications has been seldom analysed. Our aim was to test and validate the effect of candidate SNVs on COVID-19 severity. CARGENCORS (CARdiovascular GENetic risk score for Risk Stratification of patients positive for SARS-CoV-2 [COVID-19] virus) is an age- and sex-matched case-control study with 818 COVID-19 cases hospitalized with hypoxemia, and 1636 controls with COVID-19 treated at home. The association between severity and SNVs related to CAD (n = 32), inflammation (n = 19), thrombosis (n = 14), virus infectivity (n = 11), and two published to be related to COVID-19 severity was tested with adjusted logistic regression models. Two external independent cohorts were used for meta-analysis (SCOURGE and UK Biobank). After adjustment for potential confounders, 14 new SNVs were associated with COVID-19 severity in the CARGENCORS Study. These SNVs were related to CAD (n = 10), thrombosis (n = 2), and inflammation (n = 2). We also confirmed eight SNVs previously related to severe COVID-19 and virus infectivity. The meta-analysis showed five SNVs associated with severe COVID-19 in adjusted analyses (rs11385942, rs1561198, rs6632704, rs6629110, and rs12329760). We identified 14 novel SNVs and confirmed eight previously related to COVID-19 severity in the CARGENCORS data. In the meta-analysis, five SNVs were significantly associated to COVID-19 severity, one of them previously related to CAD.

Association between different diet quality scores and depression risk: the REGICOR population-based cohort study.

BACKGROUND: Our aim was to determine the association between diet quality and depression incidence in the population-based REGICOR cohort study, Catalonia, Spain. METHODS: Prospective observational study using participants' baseline (2003-2006), follow-up (2007-2013) and clinical records data. Five diet quality scores were derived from a food frequency questionnaire (FFQ) at baseline: the relative Mediterranean Diet Score (rMED), the Modified Mediterranean Diet Score (ModMDS), a Dietary Approaches to Stop Hypertension (DASH) score, a Healthful Plant-based Diet Index (HPDI) and the World Health Organization Healthy Diet Indicator (WHO-HDI). Participants using pharmacological antidepressant treatment were excluded as a proxy for presence of depression at baseline. At follow-up, the Patient Health Questionnaire (PHQ-9) was applied to assess depressive symptoms (≥ 10 defining depressive disorder). A secondary outcome was depression diagnosis assessed through clinical records. Logistic regression and Cox proportional hazards models were used. RESULTS: Main analysis included 3046 adults (50.3% women) with a mean age of 54.7 (SD = 11.6) years. After 6-years follow-up, 184 (6.04%) cases of depressive disorder were identified. There was 16% lower odds of depressive disorder per 1SD increase of rMED (OR = 0.84; 95%CI = 0.71-0.98). Secondary outcome analysis (n = 4789) identified 261 (5.45%) incident cases of clinical depression diagnosis over 12 years follow-up, and 19% lower risk of clinical depression was observed with the WHO-HDI (HR = 0.81; 95%CI = 0.70-0.93). Adjusting for BMI did not attenuate the findings. CONCLUSIONS: A significant inverse association between diet quality and depression incidence was found in this population-based cohort study, independent of sociodemographic, health and lifestyle. Adherence to a healthy diet could be a complementary intervention for the prevention of depression.

Correction: A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

[This corrects the article DOI: 10.1371/journal.pgen.1008629.].

A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.

The "Bayés Spirit" as a guide for new generations: How to combine one's personal life and friendships with science and profession.

Recent studies suggest that up to a quarter of physicians in training suffer from burnout and psychological disorders. Scientist-physicians, cardiologists, cardiology residents, and first-year medical residents seem to be more prone to developing varying degrees of emotional distress. Concerned about the new generations of clinicians and researchers, the authors aim to provide guidelines for reconciling professional success with a fulfilling and satisfying personal life. The figure of Antonio Bayés de Luna (cardiology and electrocardiology guru) is used as the ideal example to learn how to combine one's personal life, family, and friendships with science and their professional career. This can be done in a healthy and balanced way, prioritizing the former while continuing to have an intense dedication to the latter.

Determinants and Trends of the Use of Intravenous Thrombolysis for Minor Stroke: A Population-Based Study, 2016 to 2020.

BACKGROUND: We analyzed the main factors associated with intravenous thrombolysis (IVT) in patients with minor ischemic stroke. METHODS: Data were obtained from a prospective, government-mandated, population-based registry of stroke code patients in Catalonia (6 Comprehensive Stroke Centers, 8 Primary Stroke Centers, and 14 TeleStroke Centers). We selected patients diagnosed with ischemic stroke and National Institutes of Health Stroke Scale (NIHSS) ≤5 at hospital admission from January 2016 to December 2020. We excluded patients with a baseline modified Rankin Scale score of ≥3, absolute contraindication for IVT, unknown stroke onset, or admitted to hospital beyond 4.5 after stroke onset. The main outcome was treatment with IVT. We performed univariable and binary logistic regression analyses to identify the most important factors associated with IVT. RESULTS: We included 2975 code strokes; 1433 (48.2%) received IVT of which 30 (2.1%) had a symptomatic hemorrhagic transformation. Patients treated with IVT as compared to patients who did not receive IVT were more frequently women, had higher NIHSS, arrived earlier to hospital, were admitted to a Comprehensive Stroke Centers, and had large vessel occlusion. After binary logistic regression, NIHSS score 4 to 5 (odds ratio, 40.62 [95% CI, 31.73-57.22]; P<0.001) and large vessel occlusion (odds ratio, 16.39 [95% CI, 7.25-37.04]; P<0.001) were the strongest predictors of IVT. Younger age, female sex, baseline modified Rankin Scale score of 0, earlier arrival to hospital (<120 minutes after stroke onset), and the type of stroke center were also independently associated with IVT. The weight of large vessel occlusion on IVT was higher in patients with lower NIHSS. CONCLUSIONS: Minor stroke female patients, with higher NIHSS, arriving earlier to the hospital, presenting with large vessel occlusion and admitted to a Comprehensive Stroke Centers were more likely to receive intravenous thrombolysis.

Dysfunctional High-Density Lipoproteins Are Associated With a Greater Incidence of Acute Coronary Syndrome in a Population at High Cardiovascular Risk: A Nested Case-Control Study.

BACKGROUND: Studies have failed to establish a clear link between high-density lipoprotein (HDL) cholesterol and cardiovascular disease, leading to the hypothesis that the atheroprotective role of HDL lies in its biological activity rather than in its cholesterol content. However, to date, the association between HDL functional characteristics and acute coronary syndrome has not been investigated comprehensively. METHODS: We conducted a case-control study nested within the PREDIMED (Prevención con Dieta Mediterránea) cohort, originally a randomized trial in which participants followed a Mediterranean or low-fat diet. Incident acute coronary syndrome cases (N=167) were individually matched (1:2) to control patients by sex, age, intervention group, body mass index, and follow-up time. We investigated 2 individual manifestations (myocardial infarction, unstable angina) as secondary outcomes. We measured the following functional characteristics: HDL cholesterol concentration (in plasma); cholesterol efflux capacity; antioxidant ability, measured by the HDL oxidative-inflammatory index; phospholipase A2 activity; and sphingosine-1-phosphate, apolipoproteins A-I and A-IV, serum amyloid A, and complement 3 protein (in apolipoprotein B-depleted plasma). We used conditional logistic regression models adjusted for HDL cholesterol levels and cardiovascular risk factors to estimate odds ratios (ORs) between 1-SD increments in HDL functional characteristics and clinical outcomes. RESULTS: Low values of cholesterol efflux capacity (OR1SD, 0.58; 95% CI, 0.40-0.83) and low levels of sphingosine-1-phosphate (OR1SD, 0.70; 95% CI, 0.52-0.92) and apolipoprotein A-I (OR1SD, 0.58; 95% CI, 0.42-0.79) were associated with higher odds of acute coronary syndrome. Higher HDL oxidative inflammatory index values were marginally linked to acute coronary syndrome risk (OR1SD, 1.27; 95% CI, 0.99-1.63). Low values of cholesterol efflux capacity (OR1SD, 0.33; 95% CI, 0.18-0.61), sphingosine-1-phosphate (OR1SD: 0.60; 95% CI: 0.40-0.89), and apolipoprotein A-I (OR1SD, 0.59; 95% CI, 0.37-0.93) were particularly linked to myocardial infarction, whereas high HDL oxidative-inflammatory index values (OR1SD, 1.53; 95% CI, 1.01-2.33) and low apolipoprotein A-I levels (OR1SD, 0.52; 95% CI, 0.31-0.88) were associated with unstable angina. CONCLUSIONS: Low cholesterol efflux capacity values, pro-oxidant/proinflammatory HDL particles, and low HDL levels of sphingosine-1-phosphate and apolipoprotein A-I were associated with increased odds of acute coronary syndrome and its manifestations in individuals at high cardiovascular risk. CLINICAL TRIAL REGISTRATION: URL: https://www.controlled-trials.com/ISRCTN35739639. Unique identifier: ISRCTN35739639.

Advanced interatrial block and P-wave duration are associated with atrial fibrillation and stroke in older adults with heart disease: the BAYES registry.

AIMS: Advanced interatrial block (IAB), is an unrecognized surrogate of atrial dysfunction and a trigger of atrial dysrhythmias, mainly atrial fibrillation (AF). Our aim was to prospectively assess whether advanced IAB in sinus rhythm is associated with AF and stroke in elderly outpatients with structural heart disease, a group not previously studied. METHODS AND RESULTS: Prospective observational registry that included outpatients aged ≥70 years with structural heart disease and no previous diagnosis of AF. Patients were divided into three groups: normal P-wave duration (<120 ms), partial IAB (P-wave duration ≥120 ms, positive in the inferior leads), and advanced IAB [P-wave duration ≥120 ms, biphasic (plus/minus) morphology in the inferior leads]. Among 556 individuals, 223 had normal P-wave (40.1%), 196 partial IAB (35.3%), and 137 advanced IAB (24.6%). After a median follow-up of 694 days, 93 patients (16.7%) developed AF, 30 stroke (5.4%), and 34 died (6.1%). Advanced IAB was independently associated with AF -[hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.7-5.1; P < 0.001], stroke [HR 3.8, 95% CI 1.4-10.7; P = 0.010), and AF/stroke (HR 2.6, 95% CI 1.5-4.4; P = 0.001). P-wave duration (ms) was independently associated with AF (HR 1.05, 95% CI 1.03-1.07; P < 0.001), AF/stroke (HR 1.04, 95% CI 1.02-1.06; P < 0.001), and mortality (HR 1.04, 95% CI 1.00-1.08; P = 0.021). CONCLUSIONS: The presence of advanced IAB in sinus rhythm is independently associated with AF and stroke in an elderly population with structural heart disease and no previous diagnosis of AF. P-wave duration was also associated with all-cause mortality.

Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling.

BACKGROUND: Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of the nitric oxide pathway as a therapeutic strategy. METHODS: We analyzed the association of common and rare genetic variants in 2 genes that mediate nitric oxide signaling (Nitric Oxide Synthase 3 [NOS3] and Guanylate Cyclase 1, Soluble, Alpha 3 [GUCY1A3]) with a range of human phenotypes. We selected 2 common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335 464 participants in the UK Biobank and summary association results from 7 large-scale genome-wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27 815). RESULTS: A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease (odds ratio, 0.37; 95% confidence interval [CI], 0.31-0.45; P=5.5*10-26], peripheral arterial disease (odds ratio 0.42; 95% CI, 0.26-0.68; P=0.0005), and stroke (odds ratio, 0.53; 95% CI, 0.37-0.76; P=0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (95% CI, 12-34; P=5.6*10-5) and a 3-fold higher risk of coronary heart disease (odds ratio, 3.03; 95% CI, 1.29-7.12; P=0.01). CONCLUSIONS: A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke. Pharmacological stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.

Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease.

RATIONALE: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. OBJECTIVE: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. METHODS AND RESULTS: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). CONCLUSIONS: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.

Anthracycline-induced cardiotoxicity in diffuse large B-cell lymphoma: NT-proBNP and cardiovascular score for risk stratification.

OBJECTIVE: To evaluate the role of N-terminal pro-brain-type natriuretic peptide (NT-proBNP) and a cardiovascular (CV) risk score named FRESCO for predicting anthracycline-induced cardiotoxicity (AIC) in diffuse large B-cell lymphoma (DLBCL). METHODS: A total of 130 consecutive DLBCL patients treated in first-line with anthracycline-containing immunochemotherapy. Competitive risk between NT-proBNP, FRESCO, and time to AIC was considered. RESULTS: Cumulative incidence of AIC was 12.2% and 17.5% at 1 and 5 years, respectively. Median time to development cardiotoxicity was 6.4 months, with half of the cases showing heart failure and the other half silent AIC. Both NT-proBNP levels and FRESCO score were independently associated with higher risk of AIC (P = 0.001 and P = 0.03, respectively). Patients with NT-proBNP ≥600 pg/mL or those with FRESCO ≥4.5% had 3.97 or 2.54 times higher risk of AIC than those with lower values (P = 0.001 and P = 0.048, respectively). According to the previous cutoffs, three groups of patients with a significantly different risk of AIC could be identified (P < 0.0001). CONCLUSIONS: Doxorubicin-containing chemotherapy is associated with increased risk of silent and overt AIC. Baseline NT-proBNP levels and FRESCO CV risk score are accurate predictors of AIC and can identify groups of patients at different risk, in which personalized cardiologic evaluation should be offered.

DNA Methylation and Age-Independent Cardiovascular Risk, an Epigenome-Wide Approach: The REGICOR Study (REgistre GIroní del COR).

OBJECTIVE: The objectives of this study were to decipher whether age-independent cardiovascular risk is associated with DNA methylation at 5'-cytosine-phosphate-guanine-3' (CpG) level and to determine whether these differential methylation signatures are associated with the incidence of cardiovascular events. APPROACH AND RESULTS: We designed a 2-stage, cross-sectional, epigenome-wide association study. Age-independent cardiovascular risk calculation was based on vascular age and on the residuals of the relationship between age and cardiovascular risk. Blood DNA methylomes from 2 independent populations were profiled using the Infinium HumanMethylation450 BeadChip. The discovery stage of these studies was performed in the REGICOR cohort (REgistre GIroní del COR; n=645). Next, we validated the initial findings in the Framingham Offspring Study (n=2542). Eight CpGs located in 4 genes (AHRR, CPT1A, PPIF, and SBNO2) and 3 intergenic regions showed differential methylation in association with age-independent cardiovascular risk (P≤1.17×10-7). These CpGs explained 12.01% to 15.16% of the variability of age-independent cardiovascular risk in REGICOR and 7.51% to 8.53% in Framingham Offspring Study. Four of them were only related to smoking, 3 were related to smoking and body mass index, and 1 to diabetes mellitus, triglycerides levels, and body mass index (P≤7.81×10-4). In addition, we developed methylation risk scores based on these CpGs and observed an association between these scores and cardiovascular disease incidence (hazard ratio=1.32; 95% confidence interval: 1.16-1.51). CONCLUSIONS: Age-independent cardiovascular risk was related to different DNA methylation profiles, with 8 CpGs showing differential methylation patterns. Most of these CpGs were associated with smoking, and 3 of them were also related to body mass index. Risk scores based on these differential methylation patterns were associated with cardiovascular events and could be useful predictive indices.

Early smoking-onset age and risk of cardiovascular disease and mortality.

Early smoking onset age (SOA) is a public health concern with scant empirical evidence of its role in health outcomes. The study had two aims: i) to assess whether an early SOA was associated with the risk of fatal and non-fatal CVD and all-cause and CVD mortality and ii) to explore the linear and non-linear association between SOA and the outcomes of interest. Data from 4499 current or former smokers, recruited from 1995 to 2005, aged 25 to 79 years, and with a median 7.02 years of follow-up, were obtained from the REGICOR population-based cohort. In the present analysis, performed in 2018, the independent variable was SOA and the dependent variables were CVD events, CVD mortality, and all-cause mortality. Penalized smoothing spline methods were used to assess the linear and non-linear association. During follow-up, 361 deaths and 210 CVD events were recorded. A significant non-linear component was identified in the association between SOA and CVD outcomes with a cut-off point at 12 years: In the group aged ≤12 years, each year of delay in SOA was inversely associated with CVD risk (HR = 0.71; 95%CI = 0.53-0.96) and CVD mortality (HR = 0.58; 95%CI = 0.37-0.90). No association was observed in the older SOA group. A linear association was observed between SOA and all-cause mortality, and each year of delay was associated with 4% lower risk of mortality (HR = 0.96; 95%CI = 0.93-0.98). The associations were adjusted for lifelong exposure to tobacco and cardiovascular risk factors. These results reinforce the value of preventing tobacco use among teenagers and adolescents.

Association between long-term air pollution exposure and DNA methylation: The REGICOR study.

INTRODUCTION: Limited evidence suggests that epigenetic mechanisms may partially mediate the adverse effects of air pollution on health. Our aims were to identify new genomic loci showing differential DNA methylation associated with long-term exposure to air pollution and to replicate loci previously identified in other studies. METHODS: A two-stage epigenome-wide association study was designed: 630 individuals from the REGICOR study were included in the discovery and 454 participants of the EPIC-Italy study in the validation stage. DNA methylation was assessed using the Infinium HumanMethylation450 BeadChip. NOX, NO2, PM10, PM2.5, PMcoarse, traffic intensity and traffic load exposure were measured according to the ESCAPE protocol. A systematic review was undertaken to identify those cytosine-phosphate-guanine (CpGs) associated with air pollution in previous studies and we screened for them in the discovery study. RESULTS: In the discovery stage of the epigenome-wide association study, 81 unique CpGs were associated with air pollution (p-value <10-5) but none of them were validated in the replication sample. Furthermore, we identified 15 CpGs in the systematic review showing differential methylation with a p-value fulfilling the Bonferroni criteria and 1673 CpGs fulfilling the false discovery rate criteria, all of which were related to PM2.5 or NO2. None of them was replicated in the discovery study, in which the top hits were located in an intergenic region on chromosome 1 (cg10893043, p-value = 6.79·10-5) and in the LRRC45 and PXK genes (cg05088605, p-value = 2.15·10-04; cg16560256, p-value = 2.23·10-04). CONCLUSIONS: Neither new genomic loci associated with long-term air pollution were identified, nor previously identified loci were replicated. Continued efforts to test this potential association are warranted.

Advanced interatrial block is a surrogate for left atrial strain reduction which predicts atrial fibrillation and stroke.

BACKGROUND: The association between advanced interatrial block (aIAB) and atrial fibrillation (AF) is known as "Bayes' Syndrome." There is little information on the prognostic role that new speckle tracking echocardiographic (STE) imaging techniques could play in it. We have examined the relationship between left atrial (LA) STE and the prediction of new-onset AF and/or stroke in IAB patients. METHODS: This is an observational prospective and unicentric cohort study with 98 outpatients: 55 (56.2%) controls with normal ECG without IAB, 21 (21.4%) with partial IAB (pIAB) and 22 (22.4%) with aIAB. The end point was new-onset AF, ischemic stroke and the composite of both. RESULTS: During a mean follow-up of 1.9 (1.7-2.3) years, 20 patients presented the end point (18 new-onset AF and two strokes): 8 (14.5%) in the control group, 3 (14.3%) in pIAB and 9 (40.9%) in aIAB, p = 0.03. In multivariable comprehensive Cox regression analyses, a decrease in absolute value of strain rate during the booster pump function phase (SRa) was the only variable independently related to the appearance in the evolution of the end point, in the first model (age, P-wave duration and SRa): HR 19.9 (95% CI, 3.12-127.5), p = 0.002 and in the second (age, presence of aIAB and SRa): HR 24.2 (95% CI, 3.15-185.4), p = 0.002. CONCLUSIONS: In patients with IAB, a decrease in absolute value of LA SRa with STE predicts new-onset AF and ischemic stroke. Future studies should confirm our results and assess the prognostic usefulness of LA STE in patients with IAB.

New electrocardiographic score for the prediction of atrial fibrillation: The MVP ECG risk score (morphology-voltage-P-wave duration).

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia and has significant morbidity. A score composed of easily measured electrocardiographic variables to identify patients at risk of AF would be of great value in order to stratify patients for increased monitoring and surveillance. The purpose of this study was to develop an electrocardiographic risk score for new-onset AF. METHODS: A total of 676 patients without previous AF undergoing coronary angiography were retrospectively studied. Points were allocated based on P-wave morphology in inferior leads, voltage in lead 1, and P-wave duration (MVP). Patients were divided into three risk groups and followed until development of AF or last available clinical appointment. RESULTS: Mean age was 65 years, and 68% were male. The high- and intermediate-risk groups were more likely to develop AF than the low-risk group (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.3-4.4; p = 0.006 and OR 2.1, 95% CI 1.4-3.27; p = 0.009, respectively). The high-risk group had a significantly shorter mean time to development of AF (258 weeks; 95% CI 205-310 weeks) compared to the intermediate- (278 weeks; 95% CI 252-303 weeks) and low-risk groups (322 weeks 95% CI 307-338 weeks), p = 0.005. CONCLUSIONS: A simple risk score composed of easy-to-measure electrocardiographic variables can help to predict new-onset AF. Further validation studies will be needed to assess the ability of this risk score to predict AF in other populations.

Mediterranean Diet Improves High-Density Lipoprotein Function in High-Cardiovascular-Risk Individuals: A Randomized Controlled Trial.

BACKGROUND: The biological functions of high-density lipoproteins (HDLs) contribute to explaining the cardioprotective role of the lipoprotein beyond quantitative HDL cholesterol levels. A few small-scale interventions with a single antioxidant have improved some HDL functions. However, to date, no long-term, large-scale, randomized controlled trial has been conducted to assess the effects of an antioxidant-rich dietary pattern (such as a traditional Mediterranean diet [TMD]) on HDL function in humans. METHODS: This study was performed in a random subsample of volunteers from the PREDIMED Study (Prevención con Dieta Mediterránea; n=296) after a 1-year intervention. We compared the effects of 2 TMDs, one enriched with virgin olive oil (TMD-VOO; n=100) and the other enriched with nuts (TMD-Nuts; n=100), with respect to a low-fat control diet (n=96). We assessed the effects of both TMDs on the role of HDL particles on reverse cholesterol transport (cholesterol efflux capacity, HDL ability to esterify cholesterol, and cholesteryl ester transfer protein activity), HDL antioxidant properties (paraoxonase-1 arylesterase activity and total HDL antioxidant capacity on low-density lipoproteins), and HDL vasodilatory capacity (HDL ability to induce the release of nitric oxide in endothelial cells). We also studied the effects of a TMD on several HDL quality-related characteristics (HDL particle oxidation, resistance against oxidative modification, main lipid and protein composition, and size distribution). RESULTS: Both TMDs increased cholesterol efflux capacity relative to baseline (P=0.018 and P=0.013 for TMD-VOO and TMD-Nuts, respectively). The TMD-VOO intervention decreased cholesteryl ester transfer protein activity (relative to baseline, P=0.028) and increased HDL ability to esterify cholesterol, paraoxonase-1 arylesterase activity, and HDL vasodilatory capacity (relative to control, P=0.039, P=0.012, and P=0.026, respectively). Adherence to a TMD induced these beneficial changes by improving HDL oxidative status and composition. The 3 diets increased the percentage of large HDL particles (relative to baseline, P<0.001). CONCLUSIONS: The TMD, especially when enriched with virgin olive oil, improved HDL atheroprotective functions in humans. CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com. Unique identifier: ISRCTN35739639.

17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. METHODS: We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P<5×10-8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, respectively. RESULTS: The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: ß, 1.84; SE, 0.32; P=4.4×10-8) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: ß, 0.95; SE, 0.17; P=4.3×10-8) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 (P=0.04; meta-analysis P=2.5×10-9; heterogeneity, P=0.16) but not for 22q13 (P=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P=0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P=0.045). CONCLUSIONS: We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

Epigenome-wide association study identifies TXNIP gene associated with type 2 diabetes mellitus and sustained hyperglycemia.

Type 2 diabetes mellitus (DM) is an established risk factor for a wide range of vascular diseases, including ischemic stroke (IS). Glycated hemoglobin A1c (HbA1c), a marker for average blood glucose levels over the previous 12 weeks, is used as a measure of glycemic control and also as a diagnostic criterion for diabetes (HbA1c levels ≥ 6.5%). Epigenetic mechanisms, such as DNA methylation, may be associated with aging processes and with modulation of the risk of various pathologies, such as DM. Specifically, DNA methylation could be one of the mechanisms mediating the relation between DM and environmental exposures. Our goal was to identify new CpG methylation sites associated with DM. We performed a genome-wide methylation study in whole-blood DNA from an IS patient cohorts. Illumina HumanMethylation450 BeadChip array was used to measure DNA methylation in CpG sites. All statistical analyses were adjusted for sex, age, hyperlipidemia, body mass index (BMI), smoking habit and cell count. Findings were replicated in two independent cohorts, an IS cohort and a population-based cohort, using the same array. In the discovery phase (N = 355), we identified a CpG site, cg19693031 (located in the TXNIP gene) that was associated with DM (P = 1.17 × 10(-12)); this CpG was replicated in two independent cohorts (N = 167 and N = 645). Methylation of TXNIP was inversely and intensely associated with HbA1c levels (P = 7.3 × 10(-16)), specifically related to diabetic patients with poor control of glucose levels. We identified an association between the TXNIP gene and DM through epigenetic mechanisms, related to sustained hyperglycemia levels (HbA1c ≥ 7%).