DJ-1 administration exerts cardioprotection in a mouse model of acute myocardial infarction.

Cardiovascular diseases, and particularly acute myocardial infarction (MI), are the most common causes of death worldwide. Infarct size is the major predictor of clinical outcomes in MI. The Parkinson's disease associated protein, DJ-1 (also known as PARK7), is a multifunctional protein with chaperone, redox sensing and mitochondrial homeostasis activities. Previously, we provided the evidence for a central role of endogenous DJ-1 in the cardioprotection of post-conditioning. In the present study, we tested the hypothesis that systemic administration of recombinant DJ-1 exerts cardioprotective effects in a mouse model of MI and also explored the associated transcriptional response. We report a significant treatment-induced reduction in infarct size, leukocyte infiltration, apoptosis and oxidative stress. Effects potentially mediated by G-protein-coupled receptor signaling and modulation of the immune response. Collectively, our results indicate a protective role for the exogenously administrated DJ-1 upon MI, and provide the first line of evidence for an extracellular activity of DJ-1 regulating cardiac injury in vivo.This work was supported by grants from: the Spanish Ministry of Science and Innovation and Agencia Estatal de Investigación SAF-2016-76819-R (to LB), MCIN/AEI/ 10.13039/501100011033, Plan Nacional Proyectos Investigación Desarrollo (PID 2019-107160RB-I00 to LB), and PGC 2018-094025-B-I00 (to GV); the Instituto de Salud Carlos III: CIBER-CV and ERA-CVD JTC 2020-023/AC 209-00054 (to LB) and FIS PI19/01687 (to TP). AG is a pre-doctoral fellow from BES-2017-081378. This article is part of AG PhD project at Universitat Autònoma de Barcelona (UAB).S

High-density lipoprotein remodelled in hypercholesterolaemic blood induce epigenetically driven down-regulation of endothelial HIF-1α expression in a preclinical animal model

Altres ajuts: This work was supported by the Plan Nacional de Salud (PNS) from the Spanish Ministry of Science and Innovation and funds FEDER 'Una Manera de Hacer Europa'; a grant from the Spanish Society of Cardiology (Beca FEC Investigacio'n Ba'sica/2016 to G.V); the Instituto de Salud Carlos III (ISCIII); and CIBERCV (to L.B). We thank the support of the Generalitat of Catalunya (Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat,) and the Fundación Investigación Cardiovascular-Fundación Jesus Serra for their continuous support.High-density lipoproteins (HDLs) are circulating micelles that transport proteins, lipids, and miRNAs. HDL-transported miRNAs (HDL-miRNAs) have lately received attention but their effects on vascular cells are not fully understood. Additionally, whether cardiovascular risk factors affect HDL-miRNAs levels and miRNA transfer to recipient cells remains equally poorly known. Here, we have investigated the changes induced by hypercholesterolaemia on HDL-miRNA levels and its effect on recipient endothelial cells (ECs). Pigs were kept on a high-fat diet (HC; n = 10) or a normocholesterolaemic chow (NC; n = 10) for 10 days reaching cholesterol levels of 321.0 (229.7-378.5) mg/dL and 74.0 (62.5-80.2) mg/dL, respectively. HDL particles were isolated, purified, and quantified. HDL-miRNA profiling (n = 149 miRNAs) of HC- and NC-HDLs was performed by multipanel qPCR. Cell cultures of porcine aortic ECs were used to determine whether HDL-miRNAs were delivered to ECs. Potential target genes modulated by miRNAs were identified by bioinformatics and candidate miRNAs were validated by molecular analysis. In vivo effects in the coronary arteries of normocholesterolaemic swine administered HC- or NC-HDLs were analysed. Among the HDL-miRNAs, four were found in different amounts in HC- and NC-HDL (P < 0.05). miR-126-5p and -3p and miR-30b-5p (2.7×, 1.7×, and 1.3×, respectively) were found in higher levels and miR-103a-3p and miR-let-7g-5p (−1.6×, −1.4×, respectively) in lower levels in HC-HDL. miR-126-5p and -3p were transferred from HC-HDL to EC (2.5×; P < 0.05), but not from NC-HDL, by a SRB1-mediated mechanism. Bioinformatics revealed that HIF1α was the miR-126 target gene with the highest predictive value, which was accordingly found to be markedly reduced in HC-HDL-treated ECs and in miR126 mimic transfected ECs. In vivo validation confirmed that HIF1α was diminished in the coronary endothelial layer of NC pigs administered HC-HDL vs. those administered NC-HDL (P < 0.05). Hypercholesterolaemia induces changes in the miRNA content of HDL enhancing miR126 and its delivery to ECs with the consequent down-regulation of its target gene HIF1α

Sex Differences in Heart Failure Following Acute Coronary Syndromes

Background: There have been conflicting reports regarding outcomes in women presenting with an acute coronary syndrome (ACS). Objectives: The objective of the study was to examine sex-specific differences in 30-day mortality in patients with ACS and acute heart failure (HF) at the time of presentation. Methods: This was a retrospective study of patients included in the International Survey of Acute Coronary Syndromes-ARCHIVES (ISACS-ARCHIVES; NCT04008173). Acute HF was defined as Killip classes ≥2. Participants were stratified according to ACS presentation: ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation ACS (NSTE-ACS). Differences in 30-day mortality and acute HF presentation at admission between sexes were examined using inverse propensity weighting based on the propensity score. Estimates were compared by test of interaction on the log scale. Results: A total of 87,812 patients were included, of whom 30,922 (35.2%) were women. Mortality was higher in women compared with men in those presenting with STEMI (risk ratio [RR]: 1.65; 95% CI: 1.56-1.73) and NSTE-ACS (RR: 1.18; 95% CI: 1.09-1.28; Pinteraction &lt;0.001). Acute HF was more common in women when compared to men with STEMI (RR: 1.24; 95% CI: 1.20-1.29) but not in those with NSTE-ACS (RR: 1.02; 95% CI: 0.97-1.08) (Pinteraction &lt;0.001). The presence of acute HF increased the risk of mortality for both sexes (odds ratio: 6.60; 95% CI: 6.25-6.98)

Statins for primary prevention among elderly men and women.

We undertook a propensity match-weighted cohort study to investigate whether statin treatment recommendations for statins translate into improved cardiovascular (CV) outcomes in the current routine clinical care of the elderly. We included in our analysis (ISACS Archives -NCT04008173) a total of 5619 Caucasian patients with no known prior history of CV disease who presented to hospital with a first manifestation of CV disease with age of 65 years or older. The risk of ST-segment elevation myocardial infarction (STEMI) was much lower in statin users than in non-users in both patients aged 65-75 years [14.7% absolute risk reduction; relative risk (RR): 0.55, 95% CI 0.45-0.66] and those aged 76 years and older (13.3% absolute risk reduction; RR: 0.58, 95% CI 0.46-0.72). Estimates were similar in patients with and without history of hypercholesterolaemia (interaction test; P-values = 0.24 and 0.35). Proportional reductions in STEMI diminished with female sex in the old (P for interaction = 0.002), but not in the very old age (P for interaction = 0.26). We also observed a remarkable reduction in the risk of 30 day mortality from STEMI with statin therapy in both age groups (10.2% absolute risk reduction; RR: 0.39; 95% CI 0.23-0.68 for patients aged 76 or over and 3.8% absolute risk reduction; RR 0.37; 95% CI 0.17-0.82 for patients aged 65-75 years old; interaction test, P-value = 0.46). Preventive statin therapy in the elderly reduces the risk of STEMI with benefits in mortality from STEMI, irrespective of the presence of a history of hypercholesterolaemia. This effect persists after the age of 76 years. Benefits are less pronounced in women. Randomized clinical trials may contribute to more definitively determine the role of statin therapy in the elderly.EMMACE was funded by the National Institute for Health Research and the British Heart Foundation.S

Determinants of Progression and Regression of Subclinical Atherosclerosis Over 6 Years.

BACKGROUND Atherosclerosis is a systemic disease that frequently begins early in life. However, knowledge about the temporal disease dynamics (ie, progression or regression) of human subclinical atherosclerosis and their determinants is scarce. OBJECTIVES This study sought to investigate early subclinical atherosclerosis disease dynamics within a cohort of middle-aged, asymptomatic individuals by using multiterritorial 3-dimensional vascular ultrasound (3DVUS) imaging. METHODS A total of 3,471 participants from the PESA (Progression of Early Subclinical Atherosclerosis) cohort study (baseline age 40-55 years; 36% female) underwent 3 serial 3DVUS imaging assessments of peripheral arteries at 3-year intervals. Subclinical atherosclerosis was quantified as global plaque volume (mm3) (bilateral carotid and femoral plaque burden). Multivariable logistic regression models for progression and regression were developed using stepwise forward variable selection. RESULTS Baseline to 6-year subclinical atherosclerosis progression occurred in 32.7% of the cohort (17.5% presenting with incident disease and 15.2% progressing from prevalent disease at enrollment). Regression was observed in 8.0% of those patients with baseline disease. The effects of higher low-density lipoprotein cholesterol (LDL-C) and elevated systolic blood pressure (SBP) on 6-year subclinical atherosclerosis progression risk were more pronounced among participants in the youngest age stratum (Pinteraction = 0.04 and 0.02, respectively). CONCLUSIONS Over 6 years, subclinical atherosclerosis progressed in one-third of middle-age asymptomatic subjects. Atherosclerosis regression is possible in early stages of the disease. The impact of LDL-C and SBP on subclinical atherosclerosis progression was more pronounced in younger participants, a finding suggesting that the prevention of atherosclerosis and its progression could be enhanced by tighter risk factor control at younger ages, with a likely long-term impact on reducing the risk of clinical events. (Progression of Early Subclinical Atherosclerosis [PESA; also PESA-CNIC-Santander]; NCT01410318).S

Post-Genomic Methodologies and Preclinical Animal Models: Chances for the Translation of Cardioprotection to the Clinic

Although many cardioprotective strategies have demonstrated benefits in animal models of myocardial infarction, they have failed to demonstrate cardioprotection in the clinical setting highlighting that new therapeutic target and treatment strategies aimed at reducing infarct size are urgently needed. Completion of the Human Genome Project in 2001 fostered the post-genomic research era with the consequent development of high-throughput &#8220;omics&#8222; platforms including transcriptomics, proteomics, and metabolomics. Implementation of these holistic approaches within the field of cardioprotection has enlarged our understanding of ischemia/reperfusion injury with each approach capturing a different angle of the global picture of the disease. It has also contributed to identify potential prognostic/diagnostic biomarkers and discover novel molecular therapeutic targets. In this latter regard, &#8220;omic&#8222; data analysis in the setting of ischemic conditioning has allowed depicting potential therapeutic candidates, including non-coding RNAs and molecular chaperones, amenable to pharmacological development. Such discoveries must be tested and validated in a relevant and reliable myocardial infarction animal model before moving towards the clinical setting. Moreover, efforts should also focus on integrating all &#8220;omic&#8222; datasets rather than working exclusively on a single &#8220;omic&#8222; approach. In the following manuscript, we will discuss the power of implementing &#8220;omic&#8222; approaches in preclinical animal models to identify novel molecular targets for cardioprotection of interest for drug development

Post-Genomic Methodologies and Preclinical Animal Models : Chances for the Translation of Cardioprotection to the Clinic

Although many cardioprotective strategies have demonstrated benefits in animal models of myocardial infarction, they have failed to demonstrate cardioprotection in the clinical setting highlighting that new therapeutic target and treatment strategies aimed at reducing infarct size are urgently needed. Completion of the Human Genome Project in 2001 fostered the post-genomic research era with the consequent development of high-throughput "omics" platforms including transcriptomics, proteomics, and metabolomics. Implementation of these holistic approaches within the field of cardioprotection has enlarged our understanding of ischemia/reperfusion injury with each approach capturing a different angle of the global picture of the disease. It has also contributed to identify potential prognostic/diagnostic biomarkers and discover novel molecular therapeutic targets. In this latter regard, "omic" data analysis in the setting of ischemic conditioning has allowed depicting potential therapeutic candidates, including non-coding RNAs and molecular chaperones, amenable to pharmacological development. Such discoveries must be tested and validated in a relevant and reliable myocardial infarction animal model before moving towards the clinical setting. Moreover, efforts should also focus on integrating all "omic" datasets rather than working exclusively on a single "omic" approach. In the following manuscript, we will discuss the power of implementing "omic" approaches in preclinical animal models to identify novel molecular targets for cardioprotection of interest for drug development

Type 2 Diabetes in Obesity: A Systems Biology Study on Serum and Adipose Tissue Proteomic Profiles

Obesity is associated with metabolic disorders such as insulin resistance and type 2 diabetes mellitus (T2DM), further increasing an already heightened cardiovascular risk. Here, amongst obese class III bariatric surgery patients, we have investigated the effect of T2DM in serum and in two, same patient, adipose tissue (AT) depots through proteomic profile expression analyses. Serum and AT samples from subcutaneous (SAT) and visceral (VAT) fat were collected during bariatric surgery. Bead-based targeted multiplex assay systems were used to simultaneously detect and quantify multiple targets in serum samples (targeted proteomics) and analyze changes in adipokine serum composition. AT samples were assessed through an untargeted proteomics approach. Through a systems biology analysis of the proteomic data, information on the affected biological pathways was acquired. In obese class III individuals, the presence of T2DM induced a significantly higher systemic release of ghrelin, GLP-1, glucagon, MMP3, BAFF, chitinase 3-like 1, TNF-R1 and TNF-R2, and a lower systemic release of IL-8. SAT and VAT proteomes belonging to the same patient showed significant differences in local protein content. While the proteins upregulated in VAT were indicative of metabolic dysregulation, SAT protein upregulation suggested adequate endocrine regulation. The presence of T2DM significantly affected VAT protein composition through the upregulation of dysregulating metabolic pathways, but SAT protein composition was not significantly modified. Our results show that T2DM induces metabolic dysregulation in obese individuals with changes in systemic marker levels and impairment of proteostasis in VAT but not in SAT

Relation of Advanced Interatrial Block to Risk of Atrial Fibrillation and Stroke

Advanced interatrial block (A-IAB) has been associated to atrial fibrillation (AF) and ischemic stroke, raising the question as to whether such patients, even when still in sinus rhythm without documented AF, could benefit from oral anticoagulation. AF and A-IAB are both markers of stroke. The anatomical substrate in both is fibrotic atrial cardiomyopathy, resulting in atrial electromechanical dyssynchrony, dysfunction, and left atrial remodelling, that favour blood stasis and hypercoagulation. Under these conditions thrombogenic cascade may be triggered, resulting in systemic embolization. Before proposing oral anticoagulation in the management of selected patients with A-IAB, as is currently recommended in patients with AF and high CHA2DS2-Vasc score, a randomized clinical trial will have to demonstrate efficacy and safety of anticoagulation in this setting. In the meantime, an individualized approach may be considered based on the recognition of those patients at a higher risk of stroke. These may be elderly patients with A-IAB and several risk factors and, thus, with a high CHA2DS2-Vasc score and the presence of environmental arrhythmias.Sin financiación2.778 JCR (2020) Q3, 81/142 Cardiac & Cardiovascular Systems1.394 SJR (2020) Q1, 64/349 Cardiology and Cardiovascular MedicineNo data IDR 2020UE

Early insulin resistance in normoglycemic low-risk individuals is associated with subclinical atherosclerosis.

BACKGROUND Elevated glycated hemoglobin (HbA1c) is associated with a higher burden of subclinical atherosclerosis (SA). However, the association with SA of earlier insulin resistance markers is poorly understood. The study assessed the association between the homeostatic model assessment of insulin resistance index (HOMA-IR) and SA in addition to the effect of cardiovascular risk factors (CVRFs) in individuals with normal HbA1c. METHODS A cohort of 3,741 middle-aged individuals from the Progression of Early Subclinical Atherosclerosis (PESA) study with basal HbA1c < 6.0% (< 42 mmol/mol) and no known CV disease underwent extensive imaging (multiterritorial vascular ultrasound and coronary artery calcium score, CACS) to assess the presence, burden, and extent of SA. RESULTS Individuals with higher HOMA-IR values had higher rates of CVRFs. HOMA-IR showed a direct association with the multiterritorial extent of SA and CACS (p  0 (odds ratio 1.74; 95%CI: 1.20 to 2.54, p = 0.004), as compared with the HOMA-IR < 2 (the reference HOMA-IR category). In a stratified analysis, this association remained significant in individuals with a low-to-moderate SCORE2 risk estimate (75.6% of the cohort) but not in high-risk individuals. CONCLUSIONS The use of HOMA-IR identified low-risk individuals with a higher burden of SA, after adjusting for the effects of key traditional CVRFs and HbA1c. HOMA-IR is a simple measure that could facilitate earlier implementation of primary CV prevention strategies in clinical practice.The PESA study is co-funded by the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain, and Banco Santander, Madrid, Spain. The study also receives funding from the Instituto de Salud Carlos III (ISCIII) (PI15/02019) and the European Regional Development Fund (ERDF) “Una manera de hacer Europa”. RF-J is the recipient of grants PI19/01704 and PI22/01560 funded by the ISCIII-Fondo de Investigación Sanitaria and co-funded by the European Union. The CNIC is supported by the ISCIII, the Ministerio de Ciencia, Innovación y Universidades, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020- 001041-S funded by MICIN/AEI/https://doi.org/10.13039/501100011033).S