Impact of a partial smoke-free legislation on myocardial infarction incidence, mortality and case-fatality in a population-based registry: the REGICOR Study

Abstract Background and Objective Coronary heart disease (CHD) is the leading cause of death, and smoking its strongest modifiable risk factor. Our aim was to determine the impact of the Spanish 2006 partial smoke-free legislation on acute myocardial infarction (AMI) incidence, hospitalization and mortality rates, and 28-day case-fatality in Girona, Spain. Methods Using a population-based registry (the REGICOR Study), we compared population incidence, hospitalization, and mortality rates, and 28-day case-fatality in the pre- and post-ban periods (2002-2005 and 2006-2008, respectively) by binomial regression analysis adjusted for confounding factors. We also analyzed the ban's impact on the outcomes of interest using the AMI definitions of the American Heart Association (AHA)/European Society of Cardiology (ESC) and the World Health Organization (WHO)-Monitoring trends and determinants in cardiovascular diseases (MONICA). Results In the post-ban period, AMI incidence and mortality rates significantly decreased (relative risk [RR] = 0.89; 95% confidence interval [CI] = 0.81-0.97 and RR = 0.82; 95% CI = 0.71-0.94, respectively). Incidence and mortality rates decreased in both sexes, especially in women, and in people aged 65-74 years. Former and non-smokers (passive smokers) showed diminished incidence rates. Implementation of the ban was not associated with AMI case-fatality. Models tended to be more significant with the WHO-MONICA than with the AHA/ESC definition. Conclusions The 2006 Spanish partial smoke-free legislation was associated with a decrease in population AMI incidence and mortality, particularly in women, in people aged 65-74 years, and in passive smokers. These results clarify the association between AMI mortality and the enactment of a partial smoke-free legislation and reinforce the effectiveness of smoking regulations in preventing CH

Deciphering the genetic crosstalk between microglia and oligodendrocyte precursor cells during demyelination and remyelination using transcriptomic data

Demyelinating disorders show impaired remyelination due to failure in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature myelin-forming oligodendrocytes, a process driven by microglia-OPC crosstalk. Through conducting a transcriptomic analysis of microarray studies on the demyelination-remyelination cuprizone model and using human samples of multiple sclerosis (MS), we identified molecules involved in this crosstalk. Differentially expressed genes (DEGs) of specific regions/cell types were detected in GEO transcriptomic raw data after cuprizone treatment and in MS samples, followed by functional analysis with GO terms and WikiPathways. Additionally, microglia-OPC crosstalk between microglia ligands, OPC receptors and target genes was examined with the NicheNet model. We identified 108 and 166 DEGs in the demyelinated corpus callosum (CC) at 2 and 4 weeks of cuprizone treatment; 427 and 355 DEGs in the remyelinated (4 weeks of cuprizone treatment + 14 days of normal diet) compared to 2- and 4-week demyelinated CC; 252 DEGs in MS samples and 2730 and 12 DEGs in OPC and microglia of 4-week demyelinated CC. At this time point, we found 95 common DEGs in the CC and OPCs, and one common DEG in microglia and OPCs, mostly associated with myelin and lipid metabolism. Crosstalk analysis identified 47 microglia ligands, 43 OPC receptors and 115 OPC target genes, all differentially expressed in cuprizone-treated samples and associated with myelination. Our differential expression pipeline identified demyelination/remyelination transcriptomic biomarkers in studies using diverse platforms and cell types/tissues. Cellular crosstalk analysis yielded novel markers of microglia ligands, OPC receptors and target genes.This research was funded by Spanish Government MCIN/AEI/10.13039/501100011033 (Project BFU2017-87843-R- and Project PID2020-120222GB-I00 to A.P.-M.) and by the Carlos III Health Institute and the European Regional Development Fund (CIBERCV CB16/11/00229 and FIS PI21/00163 to I.R.D.), and by the Marató TV3 Foundation (202119-33 to I.R.D.)

A TRPV2 interactome-based signature for prognosis in glioblastoma patients

Proteomics aids to the discovery and expansion of protein-protein interaction networks, which are key to understand molecular mechanisms in physiology and physiopathology, but also to infer protein function in a guilt-by-association fashion. In this study we use a systematic protein-protein interaction membrane yeast two-hybrid method to expand the interactome of TRPV2, a cation channel related to nervous system development. After validation of the interactome in silico, we define a TRPV2-interactome signature combining proteomics with the available physio-pathological data in Disgenet to find interactome-disease associations, highlighting nervous system disorders and neoplasms. The TRPV2-interactome signature against available experimental data is capable of discriminating overall risk in glioblastoma multiforme prognosis, progression, recurrence, and chemotherapy resistance. Beyond the impact on glioblastoma physiopathology, this study shows that combining systematic proteomics with in silico methods and available experimental data is key to open new perspectives to define novel biomarkers for diagnosis, prognosis and therapeutics in disease

Prevalence and prognosis of high-risk myocardial infarction patient candidates to extended antiplatelet therapy.

INTRODUCTION AND OBJECTIVES: Secondary prevention in myocardial infarction patients is paramount to prevent recurrences. Dual antiplatelet therapy has been shown to reduce the risk of subsequent events up to 1 year and beyond in the PEGASUS-TIMI 54 trial. This study aimed to estimate the annual number of myocardial infarction patients with PEGASUS characteristics in Spain and to analyze short- and long-term outcomes in these patients. METHODS: The number of myocardial infarction patients was estimated assuming a Poisson distribution. Myocardial infarction incidence and mortality rates obtained from population registries (IBERICA and REGICOR) were properly adjusted. The proportion of myocardial infarction patients with PEGASUS characteristics was estimated with a REGICOR cohort of consecutive patients from 2003-2009 (n=1391). This cohort follow-up was used to compare the occurrence of reinfarction and death at 1 year and at the end of the follow-up (4.7 years) in patients with and without PEGASUS characteristics by Cox regression. RESULTS: The estimated annual number of stable myocardial infarction patients aged ≥ 50 years and without bleeding events was 41 311. Of these, 22 493 had at least 1 PEGASUS characteristic (diabetes, previous myocardial infarction, or chronic kidney disease). At 4.7 years of follow-up, having any PEGASUS characteristic or age ≥ 65 years was associated with a higher risk of cardiovascular and all-cause death in adjusted analyses (hazard ratio=3.44 and 2.21, 95% confidence interval, 1.22-9.74 and 1.11-4.42, respectively). CONCLUSIONS: In Spain, more than 50% of the stable myocardial infarction patients aged ≥ 50 years are estimated to have at least 1 PEGASUS characteristic, which substantially increases the long-term risk of cardiovascular and all-cause death.The REGICOR AMI Registry was supported by the Instituto de Salud Carlos III-FEDER (grant numbers RD06/0009, RD12/0042, FIS-90/0672, FIS-93/0568, FIS 94/0539, FIS96/0026-01, FIS99/0655, FIS99/0013-01, FIS 99/9342, PI081327, PI11/01801, CP12/03287 [MG], and IFI14/00007 [SSB]), the Catalan Agency for Management of University and Research Grants (grant numbers 2005SGR00577, 2009SGR1195, 2014SGR240), Fundació La Marató TV3 (grant number ID #081630) and Agència d’Informació, Avaluació i Qualitat en Salut (grant number AATRM 034/33/02). I.R. Dégano was funded by the RECERCAIXA Program, Obra Social ‘‘La Caixa’’ (grant number RE087465)

Trend and Joinpoint Analysis of Cancer Incidence and 1-Year Mortality in North-East Spain 2005–2020

Cancer is the second leading cause of death. It is thus essential to examine cancer trends in all regions. In addition, trend data after 2019 and on cancer 1-year mortality are scarce. Our aim was to analyze incidence and 1-year mortality cancer trends in northeastern Spain during 2005–2020. We used the Osona Tumor Registry, which registers cancer incidence and mortality in Osona. The mortality information came from the Spanish Death Index. We analyzed age-standardized incidence rates and 1-year mortality by sex in the population aged > 17 years during 2005–2020. Trends were examined with negative binomial and joinpoint regression. Incidence rates of colorectal, lung and bronchus, and urinary bladder cancer increased annually in females by 2.86%, 4.20%, and 4.56%, respectively. In males, the incidence of stomach and prostate cancer decreased annually by 3.66% and 2.05%, respectively. One-year mortality trends decreased annually for endometrium cancer (−9.0%) and for colorectal cancer in males (−3.1%). From 2019 to 2020, the incidence of cancer decreased, while 1-year mortality increased in both sexes. In a North-Eastern Spanish county, 1-year mortality decreased for endometrium cancer in females and for colorectal cancer in males. Our results suggest a trend of decreasing cancer incidence and increasing cancer mortality as a result of the COVID-19 pandemic

A TRPV2 interactome-based signature for prognosis in glioblastoma patients

Proteomics aids to the discovery and expansion of protein-protein interaction networks, which are key to understand molecular mechanisms in physiology and physiopathology, but also to infer protein function in a guilt-by-association fashion. In this study we use a systematic protein-protein interaction membrane yeast two-hybrid method to expand the interactome of TRPV2, a cation channel related to nervous system development. After validation of the interactome in silico, we define a TRPV2-interactome signature combining proteomics with the available physio-pathological data in Disgenet to find interactome-disease associations, highlighting nervous system disorders and neoplasms. The TRPV2-interactome signature against available experimental data is capable of discriminating overall risk in glioblastoma multiforme prognosis, progression, recurrence, and chemotherapy resistance. Beyond the impact on glioblastoma physiopathology, this study shows that combining systematic proteomics with in silico methods and available experimental data is key to open new perspectives to define novel biomarkers for diagnosis, prognosis and therapeutics in disease.This project has been carried out with funding from Spanish Government (MICINN-SAF2010-21385 and BFU2017-87843-R to A.P.-M), a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (PIOF-GA-2009-237120 to A.P.-M.), the Generalitat de Catalunya research program (AGAUR, 2014-SGR-1628 to A.P.-M.). P.D.-M. was the recipient of a FI fellowship from Generalitat de Catalunya (FI-2013FIB00251); A.P.-M. was the recipient of the Universitat Autònoma de Barcelona-Programa Banco de Santander Fellowshi

Association between DNA methylation and coronary heart disease or other atherosclerotic events: A systematic review

BACKGROUND AND AIMS: The aim of this study was to perform a systematic review of the association between DNA methylation and coronary heart disease (CHD) or related atherosclerotic traits. METHODS: A systematic review was designed. The condition of interest was DNA methylation, and the outcome was CHD or other atherosclerosis-related traits. Three DNA methylation approaches were considered: global methylation, candidate-gene, and epigenome-wide association studies (EWAS). A functional analysis was undertaken using the Ingenuity Pathway Analysis software. RESULTS: In total, 51 articles were included in the analysis: 12 global methylation, 34 candidate-gene and 11 EWAS, with six studies using more than one approach. The results of the global methylation studies were inconsistent. The candidate-gene results were consistent for some genes, suggesting that hypermethylation in ESRα, ABCG1 and FOXP3 and hypomethylation in IL-6 were associated with CHD. The EWAS identified 84 genes showing differential methylation associated with CHD in more than one study. The probability of these findings was <1.37·10-5. One third of these genes have been related to obesity in genome-wide association studies. The functional analysis identified several diseases and functions related to these set of genes: inflammatory, metabolic and cardiovascular disease. CONCLUSIONS: Global DNA methylation seems to be not associated with CHD. The evidence from candidate-gene studies was limited. The EWAS identified a set of 84 genes highlighting the relevance of obesity, inflammation, lipid and carbohydrate metabolism in CHD. This set of genes could be prioritized in future studies assessing the role of DNA methylation in CHD

Trafficking of stretch-regulated TRPV2 and TRPV4 channels inferred through interactomics

Transient receptor potential cation channels are emerging as important physiological and therapeutic targets. Within the vanilloid subfamily, transient receptor potential vanilloid 2 (TRPV2) and 4 (TRPV4) are osmo- and mechanosensors becoming critical determinants in cell structure and activity. However, knowledge is scarce regarding how TRPV2 and TRPV4 are trafficked to the plasma membrane or specific organelles to undergo quality controls through processes such as biosynthesis, anterograde/retrograde trafficking, and recycling. This review lists and reviews a subset of protein-protein interactions from the TRPV2 and TRPV4 interactomes, which is related to trafficking processes such as lipid metabolism, phosphoinositide signaling, vesicle-mediated transport, and synaptic-related exocytosis. Identifying the protein and lipid players involved in trafficking will improve the knowledge on how these stretch-related channels reach specific cellular compartments.This work was supported by Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (PIOF-GA-2009-237120 to A.P.-M.), a Universitat Autònoma de Barcelona-Programa Banco de Santander Fellowship, and the Spanish Government grant MINECO BFU2017-87843-R to A.P.-M. P.D.-M. was a recipient of an FI fellowship from Generalitat de Catalunya (FI-2013FIB00251). I.R.D. was supported by the Carlos III Health Institute, co-financed with European Union European Regional Development Funds (CIBERCV CB16/11/00229), and by the Strategic Plan for research and health innovation (PERIS) (SLT006/17/00029)

Cholesterol and hypertension treatment improve coronary risk prediction but not time-dependent covariates or competing risks

Background and aims: cardiovascular (CV) risk functions are the recommended tool to identify high-risk individuals. However, their discrimination ability is not optimal. While the effect of biomarkers in CV risk prediction has been extensively studied, there are no data on CV risk functions including time-dependent covariates together with other variables. Our aim was to examine the effect of including time-dependent covariates, competing risks, and treatments in coronary risk prediction. Methods: participants from the REGICOR population cohorts (North-Eastern Spain) aged 35-74 years without previous history of cardiovascular disease were included (n = 8470). Coronary and stroke events and mortality due to other CV causes or to cancer were recorded during follow-up (median = 12.6 years). A multi-state Markov model was constructed to include competing risks and time-dependent classical risk factors and treatments (2 measurements). This model was compared to Cox models with basal measurement of classical risk factors, treatments, or competing risks. Models were cross-validated and compared for discrimination (area under ROC curve), calibration (Hosmer-Lemeshow test), and reclassification (categorical net reclassification index). Results: cancer mortality was the highest cumulative-incidence event. Adding cholesterol and hypertension treatment to classical risk factors improved discrimination of coronary events by 2% and reclassification by 7-9%. The inclusion of competing risks and/or 2 measurements of risk factors provided similar coronary event prediction, compared to a single measurement of risk factors. Conclusion: coronary risk prediction improves when cholesterol and hypertension treatment are included in risk functions. Coronary risk prediction does not improve with 2 measurements of covariates or inclusion of competing risks