Temporal dynamics and pathophysiology of the edematous response after acute myocardial infarction: a translational journey

Post-myocardial infarction tissue composition is highly dynamic and can be characterized by cardiac magnetic resonance, which has been used to assess surrogate outcomes and efficacy endpoints in many experimental and clinical studies. However, there is a paucity of studies tracking the temporal dynamics of these processes and analyzing their pathophysiology in a comprehensive manner. The experimental and clinical work contained in this dissertation shows that the degree and extent of post-myocardial infarction tissue composition changes (mainly edema; but also necrosis, hemorrhage and microvascular obstruction) as assessed by cardiac magnetic resonance are variable according to the time from infarction, duration of ischemia, cardioprotective strategies, and the interplay between them. These dynamic changes should be taken into consideration when performing image acquisition. Comparative studies should be performed at similar timings to avoid the bias of these dynamic changes. Thus, and in contrast to the accepted view, it is shown for the first time that myocardial edema in the week after ischemia/reperfusion is a bimodal phenomenon, both in pigs and humans. The initial wave of edema, appearing abruptly upon reperfusion and which is significantly attenuated at 24 hours, is due to the reperfusion process itself. The deferred wave of edema, appearing progressively days after ischemia/reperfusion and reaching a plateau between days 4 to 7, is mainly caused by the tissue healing processes. These findings highlight the need for standardizing experimental and clinical protocols for post-myocardial infarction tissue characterization aiming to quantify edema, myocardial area at risk, infarct size, myocardial salvage, intramyocardial hemorrhage and microvascular obstruction. The timeframe between day 4 and 7 post-infarction seems a good compromise solution according to translational data here presented. However, further studies and expert consensus are needed to stablish more precise recommendations

Prevención primordial para evitar la aparición de factores de riesgo: la infancia como ventana de oportunidad

XII Curso de Fisiopatología Cardiovacular. Madrid, 30 de noviembre - 1 de diciembre, 2018Centro Nacional de Investigaciones Cardiovasculares; Sociedad Española de Cardiologí

Predicting Subclinical Atherosclerosis in Low-Risk Individuals Ideal Cardiovascular Health Score and Fuster-BEWAT Score

BACKGROUND The ideal cardiovascular health score (ICHS) is recommended for use in primary prevention. Simpler tools not requiring laboratory tests, such as the Fuster-BEWAT (blood pressure [B], exercise [E], weight [W], alimentation [A], and tobacco [T]) score (FBS), are also available. OBJECTIVES The purpose of this study was to compare the effectiveness of ICHS and FBS in predicting the presence and extent of subclinical atherosclerosis. METHODS A total of 3,983 participants 40 to 54 years of age were enrolled in the PESA (Progression of Early Subclinical Atherosclerosis) cohort. Subclinical atherosclerosis was measured in right and left carotids, abdominal aorta, right and left iliofemoral arteries, and coronary arteries. Subjects were classified as having poor, intermediate, or ideal cardiovascular health based on the number of favorable ICHS or FBS. RESULTS With poor ICHS and FBS as references, individuals with ideal ICHS and FBS showed lower adjusted odds of having atherosclerotic plaques (ICHS odds ratio [OR]: 0.41; 95\% confidence interval [CI]: 0.31 to 0.55 vs. FBS OR: 0.49; 95\% CI: 0.36 to 0.66), coronary artery calcium (CACS) >= 1 (CACS OR: 0.41; 95\% CI: 0.28 to 0.60 vs. CACS OR: 0.53; 95\% CI: 0.38 to 0.74), higher number of affected territories (OR: 0.32; 95\% CI: 0.26 to 0.41 vs. OR: 0.39; 95\% CI: 0.31 to 0.50), and higher CACS level (OR: 0.40; 95\% CI: 0.28 to 0.58 vs. OR: 0.52; 95\% CI: 0.38 to 0.72). Similar levels of significantly discriminating accuracy were found for ICHS and FBS with respect to the presence of plaques (C-statistic: 0.694; 95\% CI: 0.678 to 0.711 vs. 0.692; 95\% CI: 0.676 to 0.709, respectively) and for CACS >= 1 (C-statistic: 0.782; 95\% CI: 0.765 to 0.800 vs. 0.780; 95\% CI: 0.762 to 0.798, respectively). CONCLUSIONS Both scores predict the presence and extent of subclinical atherosclerosis with similar accuracy, highlighting the value of the FBS as a simpler and more affordable score for evaluating the risk of subclinical disease. (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.The PESA study was co-funded by Fundacion Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and Banco Santander. Funding was also provided by Institute of Health Carlos III (PI15/02019) and European Regional Development Fund. CNIC is supported by the Ministry of Economy, Industry and Competitiveness and Pro CNIC Foundation; and is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work is part of a project that received funding from the European Union Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant 707642 and American Heart Association grant 14SFRN20490315. Dr. Bueno has received research funding from Instituto de Salud Carlos III (PIE16/00021), AstraZeneca, Bristol-Myers Squibb, Janssen, and Novartis; is a consultant for Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer, and Novartis; and has received speakers fees and travel and attendance support from AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer, Ferrer, Novartis, Servier, and Medscape. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Matthew Budoff, MD, served as Guest Editor for this paper.S

Fast T2 gradient-spin-echo (T2-GraSE) mapping for myocardial edema quantification: first in vivo validation in a porcine model of ischemia/reperfusion

Background: Several T2-mapping sequences have been recently proposed to quantify myocardial edema by providing T2 relaxation time values. However, no T2-mapping sequence has ever been validated against actual myocardial water content for edema detection. In addition, these T2-mapping sequences are either time-consuming or require specialized software for data acquisition and/or post-processing, factors impeding their routine clinical use. Our objective was to obtain in vivo validation of a sequence for fast and accurate myocardial T2-mapping (T2 gradient-spin-echo [GraSE]) that can be easily integrated in routine protocols. Methods: The study population comprised 25 pigs. Closed-chest 40 min ischemia/reperfusion was performed in 20 pigs. Pigs were sacrificed at 120 min (n = 5), 24 h (n = 5), 4 days (n = 5) and 7 days (n = 5) after reperfusion, and heart tissue extracted for quantification of myocardial water content. For the evaluation of T2 relaxation time, cardiovascular magnetic resonance (CMR) scans, including T2 turbo-spin-echo (T2-TSE, reference standard) mapping and T2-GraSE mapping, were performed at baseline and at every follow-up until sacrifice. Five additional pigs were sacrificed after baseline CMR study and served as controls. Results: Acquisition of T2-GraSE mapping was significantly (3-fold) faster than conventional T2-TSE mapping. Myocardial T2 relaxation measurements performed by T2-TSE and T2-GraSE mapping demonstrated an almost perfect correlation (R-2 = 0.99) and agreement with no systematic error between techniques. The two T2-mapping sequences showed similarly good correlations with myocardial water content: R-2 = 0.75 and R-2 = 0.73 for T2-TSE and T2-GraSE mapping, respectively. Conclusions: We present the first in vivo validation of T2-mapping to assess myocardial edema. Given its shorter acquisition time and no requirement for specific software for data acquisition or post-processing, fast T2-GraSE mapping of the myocardium offers an attractive alternative to current CMR sequences for T2 quantification.This work was supported by a competitive grant from the Ministry of Economy and Competitiveness (MINECO) through the Carlos III Institute of Health -Fondo de Investigacion Sanitaria (PI13/01979)-, the Fondo Europeo de Desarrollo Regional (FEDER, RD: SAF2013-49663-EXP), and in part by the FP7-PEOPLE-2013-ITN Next generation training in cardiovascular research and innovation-Cardionext. Rodrigo Fernandez-Jimenez is recipient of a Rio Hortega fellowship from the Ministry of Economy and Competitiveness through the Instituto de Salud Carlos III, and a FICNIC fellowship from the Fundacio Jesus Serra, the Fundacion Interhospitalaria de Investigacion Cardiovascular (FIC) and the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC). Javier Sanchez-Gonzalez is an employee of Philips Healthcare. Jaume Aguero is a FP7-PEOPLE-2013-ITN-Cardionext fellow. Carlos Galan-Arriola is recipient of a ``Contrato Predoctoral de Formacion en Investigacion en Salud (PFIS), FI14/00356´´. This study forms part of a Master Research Agreement (MRA) between CNIC and Philips Healthcare. Borja Ibanez is supported by the Red de Investigacion Cardiovascular (RIC) of the Spanish Ministry of Health (RD 12/0042/0054). The CNIC is supported by the Spanish Ministry of Economy and Competitiveness and the Pro-CNIC Foundation.S

Human Pleural Fluid Elicits Pyruvate and Phenylalanine Metabolism in Acinetobacter baumannii to Enhance Cytotoxicity and Immune Evasion

The CCAAT box-harboring proteins represent a family of heterotrimeric transcription factors which is highly conserved in eukaryotes. In fungi, one of the particularly important homologs of this family is the Hap complex that separates the DNA-binding domain from the activation domain and imposes essential impacts on regulation of a wide range of cellular functions. So far, a comprehensive summary of this complex has been described in filamentous fungi but not in the yeast. In this review, we summarize a number of studies related to the structure and assembly mode of the Hap complex in a list of representative yeasts. Furthermore, we emphasize recent advances in understanding the regulatory functions of this complex, with a special focus on its role in regulating respiration, production of reactive oxygen species (ROS) and iron homeostasis.Fil: Nyah, Rodman. California State University; Estados UnidosFil: Martinez, Jasmine. California State University; Estados UnidosFil: Fung, Sammie. California State University; Estados UnidosFil: Nakanouchi, Jun. California State University; Estados UnidosFil: Myers, Amber L.. California State University; Estados UnidosFil: Harris, Caitlin M.. California State University; Estados UnidosFil: Dang, Emily. California State University; Estados UnidosFil: Fernandez, Jennifer. California State University; Estados UnidosFil: Liu, Christine. California State University; Estados UnidosFil: Mendoza, Anthony M.. California State University; Estados UnidosFil: Jimenez, Verónica. California State University; Estados UnidosFil: Nikolaidis, Nikolas. California State University; Estados UnidosFil: Brennan, Catherine A.. California State University; Estados UnidosFil: Bonomo, Robert A.. Louis Stokes Cleveland Department of Veterans Affairs Medical Cente; Estados Unidos. Center for Antimicrobial Resistance and Epidemiology; Estados Unidos. Case Western Reserve University School of Medicine; Estados UnidosFil: Sieira, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ramirez, Maria Soledad. California State University; Estados Unido

Trends in primary total hip arthroplasty in Spain from 2001 to 2008: Evaluating changes in demographics, comorbidity, incidence rates, length of stay, costs and mortality

<p>Abstract</p> <p>Background</p> <p>Hip arthroplasties is one of the most frequent surgical procedures in Spain and are conducted mainly in elderly subjects. We aim to analyze changes in incidence, co-morbidity profile, length of hospital stay (LOHS), costs and in-hospital mortality (IHM) of patients undergoing primary total hip arthroplasty (THA) over an 8-year study period in Spain.</p> <p>Methods</p> <p>We selected all surgical admissions in individuals aged ≥40 years who had received a primary THA (ICD-9-CM procedure code 81.51) between 2001 and 2008 from the National Hospital Discharge Database. Age- and sex-specific incidence rates, LOHS, costs and IHM were estimated for each year. Co-morbidity was assessed using the Charlson comorbidity index.</p> <p>Multivariate analysis of time trends was conducted using Poisson regression. Logistic regression models were conducted to analyze IHM.</p> <p>Results</p> <p>We identified a total of 161,791 discharges of patients having undergone THA from 2001 to 2008. Overall crude incidence had increased from 99 to 105 THA per 100.000 inhabitants from 2001 to 2008 (p < 0.001). In 2001, 81% of patients had a Charlson Index of 0, 18.4% of 1-2, and 0.6% > 2 and in 2008, the prevalence of 1-2 or >2 had increased to 20.4% and 1.1% respectively (p < 0.001). The mean LOHS was 13 days in 2001 and decreased to 10.45 days in 2008 (p < 0.001). During the period studied, the mean cost per patient increased from 6,634 to 9,474 Euros. Multivariate analysis shows that from 2001 to 2008 the incidence of THA hospitalizations has significantly increased for both sexes and only men showed a significant reduction in IHM after THA.</p> <p>Conclusions</p> <p>The current study provides clear and valid data indicating increased incidence of primary THA in Spain from 2001 to 2008 with concomitant reductions in LOHS, slight reduction IHM, but a significant increase in cost per patient. The health profile of the patient undergoing a THA seems to be worsening in Spain.</p

The challenge of sustainability: Long-term results from the Fifty-Fifty peer group-based intervention in cardiovascular risk factors.

The Fifty-Fifty trial demonstrated that a peer-group-based intervention was able to improve healthy behaviors in individuals with cardiovascular (CV) risk factors immediately post-intervention. To determine the long-term sustainability of a one-year peer-group-based intervention focused on CV health and behavior. A total of 543 adults aged 25 to 50 years with at least 1 CV risk factor were screened and recruited, received initial training through workshops, and were then randomized 1:1 to a peer-group-based intervention group (IG) or a self-management control group (CG) for 12 months. At a median of 52 months from baseline, 321 participants were re-assessed (~60% retention). The primary outcome was the mean change in a composite health score related to blood pressure, exercise, weight, alimentation, and tobacco use (Fuster-BEWAT score [FBS], range 0-15). Intervention effects were assessed using linear-mixed effects models. The mean age of retained participants was 48.0 years (SD: 5.4), and 73% were female. Consistent with previous results, the change of overall FBS was significantly greater in the IG than in the CG at 12-month follow-up (between-group difference, 0.60 points; 95% CI, 0.08-1.12; P = .025). Assessment of long-term sustainability (52-month follow-up) showed that there were no between-group differences in the mean overall FBS (IG mean score, 8.52; 95% CI, 7.97-9.07 vs CG mean score, 8.51; 95% CI, 7.93-9.10; P = .972) or in the change of overall FBS from screening (IG mean change, 0.64; 95% CI, 0.00-1.28; CG mean change, 0.46; 95% CI, -0.20-1.12; P = .497). A one-year peer-group-based intervention showed favorable results at immediate post-intervention but did not demonstrate significant differences between the IG and CG at 52 months. Combination of an initial training period (workshops) with the maintenance of peer-support groups or other re-intervention strategies may be required to achieve sustained effects on healthy behaviors. ClinicalTrials.gov identifier NCT02367963. Registered (https://clinicaltrials.gov/show/NCT02367963).This study was co-funded by the SHE Foundation -“la Caixa” Foundation (LCF/PR/CE16/10700001 and LCF/PR/MS19/12220001) and the Ministry of Health, Social Services and Equality. R.F-J is recipient of funding from the Instituto de Salud Carlos III-Fondo de Investigacion Sanitaria (PI19/01704) co-funded by the European Regional Development Fund/European Social Fund (“A way to make Europe”/“Investing in your future”). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministry of Science and Innovation, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer

Biomarcadores del cáncer; Cáncer metástico colorrectal; Terapias experimentalesCancer biomarkers; Colorectal metastatic cancer; Experimental therapiesBiomarcadors del càncer; Càncer metastàtic colorrectal; Teràpies experimentalsProtein biomarkers are widely used in cancer diagnosis, prognosis, and prediction of treatment response. Here we introduce the use of targeted multiplex proteomics (TMP) as a tool to simultaneously measure a panel of 54 proteins involved in oncogenic, tumour suppression, drug metabolism and resistance, in patients with metastatic colorectal cancer (mCRC). TMP provided valuable diagnostic information by unmasking an occult neuroendocrine differentiation and identifying a misclassified case based on abnormal proteins phenotype. No significant differences in protein levels between unpaired primary and metastatic samples were observed. Four proteins were found differentially expressed in KRAS-mutant as compared to wild-type tumours (overexpressed in mutant: KRAS, EGFR; overexpressed in wild-type: TOPO1, TOP2A). Survival analyses revealed the association between mesothelin expression and poor overall survival, whereas lack of PTEN protein expression associated with lower progression-free survival with anti-EGFR-based therapy in the first-line setting for patients with RAS wild-type tumour. Finally, outlier analysis identified putative targetable proteins in 65% of patients lacking a targetable genomic alteration. Our data show that TMP constitutes a promising, novel molecular prescreening tool in mCRC to identify protein expression alterations that may impact on patient outcomes and more precisely guide patient eligibility to clinical trials with novel targeted experimental therapies

Brief Report: CYP27B1 rs10877012 T Allele Was Linked to Non-AIDS Progression in ART-Naïve HIV-Infected Patients: A Retrospective Study.

HIV/AIDS progression is linked to vitamin D, which is regulated by several key cytochromes P450 (CYP). Single nucleotide polymorphisms (SNPs) in CYP genes influence vitamin D metabolism and serum levels. The objective of this study was to evaluate the association between CYP SNPs and the clinical AIDS progression in antiretroviral treatment (ART)-naïve HIV-infected patients. We performed a retrospective study in 661 ART-naïve HIV-infected patients who were stratified by their AIDS progression pattern [181 long-term nonprogressors (LTNPs), 332 moderate progressors, and 148 rapid progressors (RPs)]. Four CYP SNPs (CYP2R1 rs10500804, CYP2R1 rs1993116, CYP27B1 rs10877012, and CYP24A1 rs6013897) were genotyped using Agena Bioscience's MassARRAY platform. Correction for multiple testing was performed using the false discovery rate (Benjamini-Hochberg procedure). The adjusted regression showed a significant association only for CYP27B1 rs10877012 SNP. When analyzing all HIV patients, the rs10877012 T allele was protective against AIDS progression (ordinal outcome) under the dominant [adjusted odds ratio (aOR) = 0.69; P = 0.021) and additive (aOR) = 0.75; P = 0.025] inheritance models. When analyzing LTNPs versus RPs, the rs10877012 T allele also showed a significant protective association under the dominant (aOR = 0.45; P = 0.004) and additive (aOR = 0.54; P = 0.008) inheritance models. P values remained significant after correcting by multiple comparisons only for the comparison of LTNPs versus RPs (extreme phenotypes). The CYP27B1 rs10877012 T allele was linked to non-AIDS progression in ART-naïve HIV-infected patients. The rs10877012 SNP seems to have an impact on the clinical AIDS progression, possibly modifying vitamin D levels, which could be relevant for the pathogenesis of HIV infection.This work has been (partially) funded by the RD16/0025/0019 and RD16CIII/0002/0002, projects as part of Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (2013-2016) and cofinanced by Instituto de Salud Carlos III (ISCIII-Subdirección General de Evaluación) and Fondo Europeo de Desarrollo Regional (FEDER), RETIC PT17/0015/0042, Fondo de Investigación Sanitaria (FIS) (grant number PI16/01863, PI17/01115, PI17CIII/00003), EPIICAL Project and Comunidad de Madrid (B2017/BMD-3703). CIBER-BBN is an initiative funded by the VINational R&D&i Plan 2008-2011, Iniciativa Ingenio 2010, the Consolider Program, and CIBER Actions and financed by ISCIII with assistance from the European Regional Development Fund. This work has been supported partially by a EUROPARTNER: Strengthening and spreading international partnership activities of the Faculty of Biology and Environmental Protection for interdisciplinary research and innovation of the University of Lodz Programme: NAWA International Academic Partnership Programme. This article/publication is based upon work from COST Action CA 17140 "Cancer Nanomedicine from the Bench to the Bedside" supported by COST (European Cooperation in Science and Technology). AFR and MAJS are supported by “Instituto de Salud Carlos III” [grant number CP14/0010and CP17CIII/00007, respectivelly].Programa de Investigación de la Consejería de Sanidad de la Comunidad de Madrid to JLJ.S

Subclinical Atherosclerosis in Young, Socioeconomically Vulnerable Hispanic and Non-Hispanic Black Adults.

BACKGROUND Non-Hispanic Black persons are at greater risk of cardiovascular (CV) events than other racial/ethnic groups; however, their differential vulnerability to early subclinical atherosclerosis is poorly understood. OBJECTIVES This work aims to study the impact of race/ethnicity on early subclinical atherosclerosis in young socioeconomically disadvantaged adults. METHODS Bilateral carotid and femoral 3-dimensional vascular ultrasound examinations were performed on 436 adults (parents/caregivers and staff) with a mean age of 38.0 ± 11.1 years, 82.3% female, 66% self-reported as Hispanic, 34% self-reported as non-Hispanic Black, and no history of CV disease recruited in the FAMILIA (Family-Based Approach in a Minority Community Integrating Systems-Biology for Promotion of Health) trial from 15 Head Start preschools in Harlem (neighborhood in New York, New York, USA). The 10-year Framingham CV risk score was calculated, and the relationship between race/ethnicity and the presence and extent of subclinical atherosclerosis was analyzed with multivariable logistic and linear regression models. RESULTS The mean 10-year Framingham CV risk was 4.0%, with no differences by racial/ethnic category. The overall prevalence of subclinical atherosclerosis was significantly higher in the non-Hispanic Black (12.9%) than in the Hispanic subpopulation (6.6%). After adjusting for 10-year Framingham CV risk score, body mass index, fruit and vegetable consumption, physical activity, and employment status, non-Hispanic Black individuals were more likely than Hispanic individuals to have subclinical atherosclerosis (OR: 3.45; 95% CI: 1.44-8.29; P = 0.006) and multiterritorial disease (P = 0.026). CONCLUSIONS After adjustment for classic CV risk, lifestyle, and socioeconomic factors, non-Hispanic Black younger adults seem more vulnerable to early subclinical atherosclerosis than their Hispanic peers, suggesting that the existence of emerging or undiscovered CV factors underlying the residual excess risk (Family-Based Approach in a Minority Community Integrating Systems-Biology for Promotion of Health [FAMILIA (Project 2)]; NCT02481401).This study was funded by the American Heart Association under grant No 14SFRN20490315 and the Stephen Gellman Children’s Outreach Program. Dr Fernandez-Jimenez is recipient of grant PI19/01704 funded by the Fondo de Investigación Sanitaria- Instituto de Salud Carlos III (ISCIII) and co-funded by the European Regional Development Fund/European Social Fund "A way to make Europe"/"Investing in your future." Dr Santos-Beneit is recipient of grant LCF/PR/MS19/ 12220001 funded by “la Caixa” Foundation (ID 100010434). The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/ 501100011033). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S