Browsing by Keyword "Myocardial infarction"
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Publication A Neutrophil Timer Coordinates Immune Defense and Vascular Protection(2019-02) Adrover, Jose M; del Fresno, Carlos; Crainiciuc, Georgiana; Cuartero, Maria Isabel; Casanova-Acebes, Maria; Weiss, Linnea A; Huerga-Encabo, Hector; Silvestre-Roig, Carlos; Rossaint, Jan; Cossio, Itziar; Lechuga-Vieco, Ana V.; Garcia-Prieto, Jaime; Gomez-Parrizas, Monica; Quintana, Juan A.; Ballesteros, Ivan; Martin-Salamanca, Sandra; Aroca-Crevillen, Alejandra; Chong, Shu Zhen; Evrard, Maximilien; Balabanian, Karl; López, Jorge; Bidzhekov, Kiril; Bachelerie, Françoise; Abad-Santos, Francisco; Muñoz-Calleja, Cecilia; Zarbock, Alexander; Soehnlein, Oliver; Weber, Christian; Ng, Lai Guan; Lopez-Rodriguez, Cristina; Sancho, David; Moro, Maria Angeles; Ibáñez, Borja; Hidalgo, Andres; Ministerio de Economía, Industria y Competitividad (España); Unión Europea. Comisión Europea; Unión Europea. Comisión Europea. European Research Council (ERC); Deutsche Forschungsgemeinschaft (Alemania); German Centre for Cardiovascular Research; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Fundación ProCNIC; Instituto de Salud Carlos III; Centro de Investigación Biomedica en Red - CIBERNeutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by CXCR4 (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection.Publication Atrial Infarction and Ischemic Mitral Regurgitation Contribute to Post-MI Remodeling of the Left Atrium(Elsevier, 2017-12-12) Aguero, Jaume; Galan-Arriola, Carlos; Fernandez-Jimenez, Rodrigo; Sanchez-Gonzalez, Javier; Ajmone, Nina; Delgado, Victoria; Solis, Jorge; Lopez-Martin, Gonzalo J.; Molina-Iracheta, Antonio; Hajjar, Roger J; Bax, Jeroen J; Fuster, Valentin; Ibáñez, Borja; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Economía, Industria y Competitividad (España); Fundación ProCNIC; Unión Europea. Comisión Europea; Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz; Philiphs Healthcare; Fundación Jesús Serra; Fundación Interhospitalaria de Investigación CardiovascularBACKGROUND: Left atrial (LA) remodeling after an acute myocardial infarction (MI) is poorly characterized regarding its determinants or its effect on ischemic mitral regurgitation (MR) development. OBJECTIVES: The purpose of this study was: 1) to compare LA structural remodeling in experimental MI swine models recapitulating the effects of left ventricular (LV) dysfunction, ischemic MR, and left atrial infarction (LAI); and 2) to analyze how LA remodeling influences ischemic MR development. METHODS: Three models of MI were generated: 1) proximal left circumflex (LCx) coronary artery occlusion involving the LA branch (LAI group); 2) proximal LCx occlusion not involving the LA branch (LCx group); and 3) left anterior descending (LAD) occlusion (LAD group). Serial cardiac magnetic resonance scans were performed to define LA and LV remodeling and ischemic MR, and were correlated with histology. RESULTS: Occlusion of the LA branch (LAI group) induced a greater degree of LA dilation at 1 and 8 weeks post-MI than the LCx and LAD groups, along with early and severe impairment of LA function. In the LCx and LAD groups, LA dysfunction was less pronounced and not consistent. Development of ischemic MR was more pronounced in the LAI group than in the LCx group. Histology confirmed atrial infarction with extensive fibrosis in the LAI group and interstitial fibrosis in the LCx group. In the LAD group, LA remodeling was not observed by cardiac magnetic resonance or histology. CONCLUSIONS: We provide the first experimental evidence of the deleterious effect of acute LAI on atrial structural remodeling, characterized by early LA dilation, dysfunction, and fibrosis, and early occurrence of ischemic MR.Publication Bmi1(+) cardiac progenitor cells contribute to myocardial repair following acute injury(BioMed Central (BMC), 2016) Valiente-Alandi, I; Albo-Castellanos, Carmen; Herrero, Diego; Sanchez, Iria; Bernad, Antonio; Ministerio de Ciencia e Innovación (España); Comunidad de Madrid (España); Instituto de Salud Carlos III; Unión Europea. Comisión EuropeaBackground: The inability of the adult mammalian heart to replace cells lost after severe cardiac injury compromises organ function. Although the heart is one of the least regenerative organs in the body, evidence accumulated in recent decades indicates a certain degree of renewal after injury. We have evaluated the role of cardiac Bmi1(+) progenitor cells (Bmi1-CPC) following acute myocardial infarction (AMI). Methods: Bmi1(Cre/+); Rosa26(YFP/+) (Bmi1-YFP) mice were used for lineage tracing strategy. After tamoxifen (TM) induction, yellow fluorescent protein (YFP) is expressed under the control of Rosa26 regulatory sequences in Bmi1(+) cells. YFP+ cells were tracked following myocardial infarction. Additionally, whole transcriptome analysis of isolated YFP+ cells was performed in unchallenged hearts and after myocardial infarction. Results: Deep-sequencing analysis of Bmi1-CPC from unchallenged hearts suggests that this population expresses high levels of pluripotency markers. Conversely, transcriptome evaluation of Bmi1-CPC following AMI shows a rich representation of genes related to cell proliferation, movement, and cell cycle. Lineage-tracing studies after cardiac infarction show that the progeny of Bmi1-expressing cells contribute to de novo cardiomyocytes (CM) (13.8 +/- 5 \% new YFP+ CM compared to 4.7 +/- 0.9 \% in age-paired non-infarcted hearts). However, apical resection of TM-induced day 1 Bmi1-YFP pups indicated a very minor contribution of Bmi1-derived cells to de novo CM. Conclusions: Cardiac Bmi1 progenitor cells respond to cardiac injury, contributing to the generation of de novo CM in the adult mouse heart.Publication Cardiac MRI Endpoints in Myocardial Infarction Experimental and Clinical Trials: JACC Scientific Expert Panel(Elsevier, 2019-07) Ibáñez, Borja; Aletras, Anthony H; Arai, Andrew E; Arheden, Hakan; Bax, Jeroen J; Berry, Colin; Bucciarelli-Ducci, Chiara; Croisille, Pierre; Dall'Armellina, Erica; Dharmakumar, Rohan; Eitel, Ingo; Fernandez-Jimenez, Rodrigo; Friedrich, Matthias G; Garcia-Dorado, David; Hausenloy, Derek J; Kim, Raymond J; Kozerke, Sebastian; Kramer, Christopher M; Salerno, Michael; Sanchez-Gonzalez, Javier; Sanz, Javier; Fuster, Valentin; Instituto de Salud Carlos III; Fundación ProCNIC; Ministerio de Ciencia, Innovación y Universidades (España); National Institutes of Health (Estados Unidos); NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Red Madrileña de Nanomedicina e Imagen Molecular; Unión Europea. Comisión Europea; Fundación BBVA; National Health Service (Reino Unido); British Heart Foundation; Centro de Investigación Biomedica en Red - CIBER; National Medical Research Council (Singapur); Unión Europea. European Cooperation in Science and Technology (COST); Swedish Heart-Lung FoundationAfter a reperfused myocardial infarction (MI), dynamic tissue changes occur (edema, inflammation, microvascular obstruction, hemorrhage, cardiomyocyte necrosis, and ultimately replacement by fibrosis). The extension and magnitude of these changes contribute to long-term prognosis after MI. Cardiac magnetic resonance (CMR) is the gold-standard technique for noninvasive myocardial tissue characterization. CMR is also the preferred methodology for the identification of potential benefits associated with new cardioprotective strategies both in experimental and clinical trials. However, there is a wide heterogeneity in CMR methodologies used in experimental and clinical trials, including time of post-MI scan, acquisition protocols, and, more importantly, selection of endpoints. There is a need for standardization of these methodologies to improve the translation into a real clinical benefit. The main objective of this scientific expert panel consensus document is to provide recommendations for CMR endpoint selection in experimental and clinical trials based on pathophysiology and its association with hard outcomes.Publication Cardiovascular imaging: what have we learned from animal models?(Frontiers Media, 2015) Santos, Arnoldo; Fernandez-Friera, Leticia; Villalba-Orero, Maria; Lopez-Melgar, Beatriz; Espana, Samuel; Mateo, Jesus; Mota, Ruben A.; Jimenez-Borreguero, Luis J.; Ruiz-Cabello, Jesus; Comunidad de Madrid; European CommissionCardiovascular imaging has become an indispensable tool for patient diagnosis and follow up. Probably the wide clinical applications of imaging are due to the possibility of a detailed and high quality description and quantification of cardiovascular system structure and function. Also phenomena that involve complex physiological mechanisms and biochemical pathways, such as inflammation and ischemia, can be visualized in a non-destructive way. The widespread use and evolution of imaging would not have been possible without animal studies. Animal models have allowed for instance, (i) the technical development of different imaging tools, (ii) to test hypothesis generated from human studies and finally, (vi) to evaluate the translational relevance assessment of in vitro and ex-vivo results. In this review, we will critically describe the contribution of animal models to the use of biomedical imaging in cardiovascular medicine. We will discuss the characteristics of the most frequent models used in/for imaging studies. We will cover the major findings of animal studies focused in the cardiovascular use of the repeatedly used imaging techniques in clinical practice and experimental studies. We will also describe the physiological findings and/or learning processes for imaging applications coming from models of the most common cardiovascular diseases. In these diseases, imaging research using animals has allowed the study of aspects such as: ventricular size, shape, global function, and wall thickening, local myocardial function, myocardial perfusion, metabolism and energetic assessment, infarct quantification, vascular lesion characterization, myocardial fiber structure, and myocardial calcium uptake. Finally we will discuss the limitations and future of imaging research with animal models.Publication Contaminant Metals as Cardiovascular Risk Factors: A Scientific Statement From the American Heart Association(American Heart Association (AHA), 2023-07-04) Lamas, Gervasio A; Bhatnagar, Aruni; Jones, Miranda R; Mann, Koren K; Nasir, Khurram; Tellez-Plaza, Maria; Ujueta, Francisco; Navas-Acien, Ana; American Heart Association Council on Epidemiology and Prevention; Council on Cardiovascular and Stroke Nursing; Council on Lifestyle and Cardiometabolic Health; Council on Peripheral Vascular Disease; Council on the Kidney in Cardiovascular DiseaseExposure to environmental pollutants is linked to increased risk of cardiovascular disease. Beyond the extensive evidence for particulate air pollution, accumulating evidence supports that exposure to nonessential metals such as lead, cadmium, and arsenic is a significant contributor to cardiovascular disease worldwide. Humans are exposed to metals through air, water, soil, and food and extensive industrial and public use. Contaminant metals interfere with critical intracellular reactions and functions leading to oxidative stress and chronic inflammation that result in endothelial dysfunction, hypertension, epigenetic dysregulation, dyslipidemia, and changes in myocardial excitation and contractile function. Lead, cadmium, and arsenic have been linked to subclinical atherosclerosis, coronary artery stenosis, and calcification as well as to increased risk of ischemic heart disease and stroke, left ventricular hypertrophy and heart failure, and peripheral artery disease. Epidemiological studies show that exposure to lead, cadmium, or arsenic is associated with cardiovascular death mostly attributable to ischemic heart disease. Public health measures reducing metal exposure are associated with reductions in cardiovascular disease death. Populations of color and low socioeconomic means are more commonly exposed to metals and therefore at greater risk of metal-induced cardiovascular disease. Together with strengthening public health measures to prevent metal exposures, development of more sensitive and selective measurement modalities, clinical monitoring of metal exposures, and the development of metal chelation therapies could further diminish the burden of cardiovascular disease attributable to metal exposure.Publication Data on administration of cyclosporine, nicorandil, metoprolol on reperfusion related outcomes in ST-segment Elevation Myocardial Infarction treated with percutaneous coronary intervention(2017-10) Campo, Gianluca; Pavasini, Rita; Morciano, Giampaolo; Lincoff, Michael A; C Gibson, Michael; Kitakaze, Masafumi; Lonborg, Jacob; Ahluwalia, Amrita; Ishii, Hideki; Frenneaux, Michael; Ovize, Michel; Galvani, Marcello; Atar, Dan; Ibáñez, Borja; Cerisano, Giampaolo; Biscaglia, Simone; Neil, Brandon J; Asakura, Masanori; Engstrom, Thomas; Jones, Daniel A; Dawson, Dana; Ferrari, Roberto; Pinton, Paolo; Ottani, FilippoMortality and morbidity in patients with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) are still high [1]. A huge amount of the myocardial damage is related to the mitochondrial events happening during reperfusion [2]. Several drugs directly and indirectly targeting mitochondria have been administered at the time of the PCI and their effect on fatal (all-cause mortality, cardiovascular (CV) death) and non fatal (hospital readmission for heart failure (HF)) outcomes have been tested showing conflicting results [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Data from 15 trials have been pooled with the aim to analyze the effect of drug administration versus placebo on outcome [17]. Subgroup analysis are here analyzed: considering only randomized clinical trial (RCT) on cyclosporine or nicorandil [3], [4], [5], [9], [10], [11], excluding a trial on metoprolol [12] and comparing trial with follow-up length <12 months versus those with longer follow-up [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. This article describes data related article titled "Clinical Benefit of Drugs Targeting Mitochondrial Function as an Adjunct to Reperfusion in ST-segment Elevation Myocardial Infarction: a Meta-Analysis of Randomized Clinical Trials" [17].Publication Dynamic Changes in Microvascular Flow Conductivity and Perfusion After Myocardial Infarction Shown by Image-Based Modeling(American Heart Association (AHA), 2019-04-02) Gkontra, Polyxeni; El-Bouri, Wahbi K; Norton, Kerri-Ann; Santos, Andres; Popel, Aleksander S; Payne, Stephen J; Arroyo, Alicia G; Ministerio de Ciencia, Innovación y Universidades (España); Fundación ProCNIC; NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos); National Institutes of Health (Estados Unidos); Unión Europea. Comisión EuropeaBackground Microcirculation is a decisive factor in tissue reperfusion inadequacy following myocardial infarction ( MI ). Nonetheless, experimental assessment of blood flow in microcirculation remains a bottleneck. We sought to model blood flow properties in coronary microcirculation at different time points after MI and to compare them with healthy conditions to obtain insights into alterations in cardiac tissue perfusion. Methods and Results We developed an image-based modeling framework that permitted feeding a continuum flow model with anatomical data previously obtained from the pig coronary microvasculature to calculate physiologically meaningful permeability tensors. The tensors encompassed the microvascular conductivity and were also used to estimate the arteriole-venule drop in pressure and myocardial blood flow. Our results indicate that the tensors increased in a bimodal pattern at infarcted areas on days 1 and 7 after MI while a nonphysiological decrease in arteriole-venule drop in pressure was observed; contrary, the tensors and the arteriole-venule drop in pressure on day 3 after MI , and in remote areas, were closer to values for healthy tissue. Myocardial blood flow calculated using the condition-dependent arteriole-venule drop in pressure decreased in infarcted areas. Last, we simulated specific modes of vascular remodeling, such as vasodilation, vasoconstriction, or pruning, and quantified their distinct impact on microvascular conductivity. Conclusions Our study unravels time- and region-dependent alterations of tissue perfusion related to the structural changes occurring in the coronary microvasculature due to MI . It also paves the way for conducting simulations in new therapeutic interventions in MI and for image-based microvascular modeling by applying continuum flow models in other biomedical scenarios.Publication Dynamic Edematous Response of the Human Heart to Myocardial Infarction Implications for Assessing Myocardial Area at Risk and Salvage(Lippincott Williams & Wilkins (LWW), 2017) Fernandez-Jimenez, Rodrigo; Barreiro-Perez, Manuel; Martin-Garcia, Ana; Sanchez-Gonzalez, Javier; Aguero, Jaume; Galan-Arriola, Carlos; Garcia-Prieto, Jaime; Diaz-Pelaez, Elena; Vara, Pedro; Martinez, Irene; Zamarro, Ivan; Garde, Beatriz; Sanz, Javier; Fuster, Valentin; Sánchez, Pedro L; Ibáñez, Borja; Sociedad Española de Cardiología; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Economía, Industria y Competitividad (España); Fundación Jesús Serra; Fundación Interhospitalaria de Investigación Cardiovascular; Centro Nacional de Investigaciones Cardiovasculares Carlos III (España); Fundación ProCNICBACKGROUND: Clinical protocols aimed to characterize the post-myocardial infarction (MI) heart by cardiac magnetic resonance (CMR) need to be standardized to take account of dynamic biological phenomena evolving early after the index ischemic event. Here, we evaluated the time course of edema reaction in patients with ST-segment-elevation MI by CMR and assessed its implications for myocardium-at-risk (MaR) quantification both in patients and in a large-animal model. METHODS: A total of 16 patients with anterior ST-segment-elevation MI successfully treated by primary angioplasty and 16 matched controls were prospectively recruited. In total, 94 clinical CMR examinations were performed: patients with ST-segment-elevation MI were serially scanned (within the first 3 hours after reperfusion and at 1, 4, 7, and 40 days), and controls were scanned only once. T2 relaxation time in the myocardium (T2 mapping) and the extent of edema on T2-weighted short-tau triple inversion-recovery (ie, CMR-MaR) were evaluated at all time points. In the experimental study, 20 pigs underwent 40-minute ischemia/reperfusion followed by serial CMR examinations at 120 minutes and 1, 4, and 7 days after reperfusion. Reference MaR was assessed by contrast-multidetector computed tomography during the index coronary occlusion. Generalized linear mixed models were used to take account of repeated measurements. RESULTS: In humans, T2 relaxation time in the ischemic myocardium declines significantly from early after reperfusion to 24 hours, and then increases up to day 4, reaching a plateau from which it decreases from day 7. Consequently, edema extent measured by T2-weighted short-tau triple inversion-recovery (CMR-MaR) varied with the timing of the CMR examination. These findings were confirmed in the experimental model by showing that only CMR-MaR values for day 4 and day 7 postreperfusion, coinciding with the deferred edema wave, were similar to values measured by reference contrast-multidetector computed tomography. CONCLUSIONS: Post-MI edema in patients follows a bimodal pattern that affects CMR estimates of MaR. Dynamic changes in post-ST-segment-elevation MI edema highlight the need for standardization of CMR timing to retrospectively delineate MaR and quantify myocardial salvage. According to the present clinical and experimental data, a time window between days 4 and 7 post-MI seems a good compromise solution for standardization. Further studies are needed to study the effect of other factors on these variables.Publication Eplerenone in patients with myocardial infarction and "mid-range" ejection fraction: An analysis from the EPHESUS trial(Wiley, 2019-11) Ferreira, João Pedro; Rossello, Xavier; Pitt, Bertram; Rossignol, Patrick; Zannad, Faiez; Centro Nacional de Investigaciones Cardiovasculares Carlos III (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); French Development AgencyBACKGROUND: Trials using mineralocorticoid receptor antagonists (MRAs) in myocardial infraction (MI) without heart failure (HF) or systolic impairment have been underpowered to assess morbidity-mortality benefit. In EPHESUS 6632 patients were included, of whom 11% had an ejection fraction (EF) of 40% and HF or diabetes. We aim to assess the potential benefit of MRAs in MI with EF of 40%. METHODS: Cox models with interaction term for EF. The primary outcome was a composite of cardiovascular death or hospitalization for cardiovascular reasons. HYPOTHESIS: Patients with an EF of 40% benefit similarly from MRA therapy to those with an EF <40%. RESULTS: In EPHESUS, 753 patients had an EF = 40% and 5864 an EF < 40%. Patients with an EF = 40% were younger (63 vs 64 years), had lower heart rate (73 vs 75 bpm), less atrial fibrillation (10% vs 14%), previous MI (21% vs 28%), HF hospitalization (5% vs 8%), and had more often reperfusion therapy and/or revascularization (55% vs 44%). The mean EF was 40.0 ± 0.3% in those with EF = 40% vs 32.2 ± 5.9% in those with EF < 40%. The primary outcome occurred in 13.3% (10 events per 100 py) of the patients with EF = 40% vs 22.9% (19 events per 100 py) in those with EF < 40%; adjusted HR for EF = 40% vs <40% = 0.65 (0.53-0.81). Eplerenone reduced the event-rate homogenously regardless of EF (interaction p EF = 40% vs EF < 40% = 0.21). Similar findings were observed for cardiovascular and all-cause death. CONCLUSION: Eplerenone reduces hospitalizations and mortality in patients with MI and EF = 40% similarly to patients with EF < 40%. These findings suggest that MI patients with EF in the "mid-range zone" may also benefit from MRA therapy which might help clinicians in their treatment decisions.Publication Extracellular Vesicle-Based Therapeutics for Heart Repair(Multidisciplinary Digital Publishing Institute (MDPI), 2021-02-25) Saludas, Laura; Oliveira, Cláudia C.; Roncal, Carmen; Ruiz-Villalba, Adrián; Prósper, Felipe; Garbayo, Elisa; Blanco-Prieto, María J.; [Saludas,L; Garbayo,E; Blanco-Prieto,MJ] Department of Pharmaceutical Technology and Chemistry, Faculty of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain. [Saludas,L; Roncal,C; Prósper,F; Garbayo,E; Blanco-Prieto,MJ] Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. [Oliveira,CC; Ruiz-Villalba,A] Department of Animal Biology, Institute of Biomedicine of Málaga (IBIMA), Faculty of Science, University of Málaga, Málaga, Spain. [Oliveira,CC; Ruiz-Villalba,A] Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain. [Roncal,C] Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA, University of Navarra, Pamplona, Spain. [Roncal,C] Centro de Investigación Biomédica en Red (CIBERCV), Carlos III Institute of Health, Madrid, Spain. [Prósper,F] Program of Regenerative Medicine, CIMA, University of Navarra, Pamplona, Spain. [Prósper,F] Cell Therapy Area and Haematology Department, Clínica Universidad de Navarra, Pamplona, Spain. [Prósper,F] Centro de Investigación Biomédica en Red (CIBERONC), Carlos III Institute of Health, Madrid, Spain.Extracellular vesicles (EVs) are constituted by a group of heterogeneous membrane vesicles secreted by most cell types that play a crucial role in cell-cell communication. In recent years, EVs have been postulated as a relevant novel therapeutic option for cardiovascular diseases, including myocardial infarction (MI), partially outperforming cell therapy. EVs may present several desirable features, such as no tumorigenicity, low immunogenic potential, high stability, and fine cardiac reparative efficacy. Furthermore, the natural origin of EVs makes them exceptional vehicles for drug delivery. EVs may overcome many of the limitations associated with current drug delivery systems (DDS), as they can travel long distances in body fluids, cross biological barriers, and deliver their cargo to recipient cells, among others. Here, we provide an overview of the most recent discoveries regarding the therapeutic potential of EVs for addressing cardiac damage after MI. In addition, we review the use of bioengineered EVs for targeted cardiac delivery and present some recent advances for exploiting EVs as DDS. Finally, we also discuss some of the most crucial aspects that should be addressed before a widespread translation to the clinical arena.Publication Extracellular Vesicle-Mediated Immune Regulation of Tissue Remodeling and Angiogenesis After Myocardial Infarction(2018) Sánchez-Alonso, Santiago; Alcaraz-Serna, Ana; Sanchez-Madrid, Francisco; Alfranca, Arantzazu; Instituto de Salud Carlos III; Centro de Investigación Biomedica en Red - CIBER; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Comunidad de Madrid (España); Ministerio de Economía y Competitividad (España); Fundación ProCNIC; Unión Europea. Comisión Europea; Unión Europea. Comisión Europea. European Research Council (ERC)Myocardial ischemia-related disorders constitute a major health problem, being a leading cause of death in the world. Upon ischemia, tissue remodeling processes come into play, comprising a series of inter-dependent stages, including inflammation, cell proliferation and repair. Neovessel formation during late phases of remodeling provides oxygen supply, together with cellular and soluble components necessary for an efficient myocardial reconstruction. Immune system plays a central role in processes aimed at repairing ischemic myocardium, mainly in inflammatory and angiogenesis phases. In addition to cellular components and soluble mediators as chemokines and cytokines, the immune system acts in a paracrine fashion through small extracellular vesicles (EVs) release. These vesicular structures participate in multiple biological processes, and transmit information through bioactive cargoes from one cell to another. Cell therapy has been employed in an attempt to improve the outcome of these patients, through the promotion of tissue regeneration and angiogenesis. However, clinical trials have shown variable results, which put into question the actual applicability of cell-based therapies. Paracrine factors secreted by engrafted cells partially mediate tissue repair, and this knowledge has led to the hypothesis that small EVs may become a useful tool for cell-free myocardial infarction therapy. Current small EVs engineering strategies allow delivery of specific content to selected cell types, thus revealing the singular properties of these vesicles for myocardial ischemia treatment.Publication Fast T2 gradient-spin-echo (T2-GraSE) mapping for myocardial edema quantification: first in vivo validation in a porcine model of ischemia/reperfusion(BioMed Central (BMC), 2015) Fernandez-Jimenez, Rodrigo; Sanchez-Gonzalez, Javier; Aguero, Jaume; del Trigo, Maria; Galan-Arriola, Carlos; Fuster, Valentin; Ibáñez, Borja; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Economía y Competitividad (España); Fundación Jesús Serra; Fundación Interhospitalaria de Investigación Cardiovascular; Centro de Investigación Biomédica en Red - CIBERCV (Enfermedades Cardiovasculares); Fundación ProCNICBackground: 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.Publication Heart wall rupture after a false negative computed tomography coronary angiography(Elsevier, 2019-01) Ventosa-Fernandez, Guillermo; Padrol, Daniel; Vidal Bonet, Laura; Fletcher-Sanfeliu, Delfina; Enriquez, Fernando; Tarrio-Fernandez, Ruben; Barril, Ramon; Saez de Ibarra, Jose IgnacioComputed tomography coronary angiography (CTCA) is considered to be the highest sensitivity, noninvasive test for the diagnosis of coronary artery disease, with a negative predictive value of 97 to 99%. The case is presented of a ventricular free wall rupture after myocardial infarction, with a delayed diagnosis due to a false negative CTCA result. We believe that this case highlights possible limitations of widening CTCA indications and the importance of experience in the correct interpretation of the test.Publication Impact of Left Ventricular Hypertrophy on Troponin Release During Acute Myocardial Infarction: New Insights From a Comprehensive Translational Study(Wiley, 2015) Fernandez-Jimenez, Rodrigo; Silva, Jacobo; Martinez-Martinez, Sara; Lopez-Maderuelo, Dolores; Nuno-Ayala, Mario; Garcia-Ruiz, Jose M; Garcia-Alvarez, Ana; Fernandez-Friera, Leticia; Pizarro, Gonzalo; Garcia-Prieto, Jaime; Sanz-Rosa, David; Lopez-Martin, Gonzalo J.; Fernandez-Ortiz, Antonio; Macaya, Carlos; Fuster, Valentin; Redondo, Juan Miguel; Ibáñez, Borja; Instituto de Salud Carlos III; Ministerio de Sanidad, Servicios Sociales e Igualdad (España); Ministerio de Economía y Competitividad (España); Fundación ProCNICBackground-Biomarkers are frequently used to estimate infarct size (IS) as an endpoint in experimental and clinical studies. Here, we prospectively studied the impact of left ventricular (LV) hypertrophy (LVH) on biomarker release in clinical and experimental myocardial infarction (MI). Methods and Results-ST-segment elevation myocardial infarction (STEMI) patients (n=140) were monitored for total creatine kinase (CK) and cardiac troponin I (cTnI) over 72 hours postinfarction and were examined by cardiac magnetic resonance (CMR) at 1 week and 6 months postinfarction. MI was generated in pigs with induced LVH (n=10) and in sham-operated pigs (n=8), and serial total CK and cTnI measurements were performed and CMR scans conducted at 7 days postinfarction. Regression analysis was used to study the influence of LVH on total CK and cTnI release and IS estimated by CMR (gold standard). Receiver operating characteristic (ROC) curve analysis was performed to study the discriminatory capacity of the area under the curve (AUC) of cTnI and total CK in predicting LV dysfunction. Cardiomyocyte cTnI expression was quantified in myocardial sections from LVH and sham-operated pigs. In both the clinical and experimental studies, LVH was associated with significantly higher peak and AUC of cTnI, but not with differences in total CK. ROC curves showed that the discriminatory capacity of AUC of cTnI to predict LV dysfunction was significantly worse for patients with LVH. LVH did not affect the capacity of total CK to estimate IS or LV dysfunction. Immunofluorescence analysis revealed significantly higher cTnI content in hypertrophic cardiomyocytes. Conclusions-Peak and AUC of cTnI both significantly overestimate IS in the presence of LVH, owing to the higher troponin content per cardiomyocyte. In the setting of LVH, cTnI release during STEMI poorly predicts postinfarction LV dysfunction. LV mass should be taken into consideration when IS or LV function are estimated by troponin release.Publication Induction of the calcineurin variant CnAβ1 after myocardial infarction reduces post-infarction ventricular remodelling by promoting infarct vascularization(European Society of Cardiology (ESC), 2014-06) Lopez-Olaneta, Marina; Villalba-Orero, Maria; Gomez-Salinero, Jesus M.; Jimenez-Borreguero, Luis J.; Breckenridge, Ross; Ortiz-Sanchez, Paula; García-Pavía, Pablo; Ibáñez, Borja; Lara-Pezzi, Enrique; Unión Europea. Comisión Europea; Ministerio de Ciencia e Innovación (España); Comunidad de Madrid (España); Instituto de Salud Carlos III; Fundación ProCNIC; Ministerio de Economía y Competitividad (España)AIMS: Ventricular remodelling following myocardial infarction progressively leads to loss of contractile capacity and heart failure. Although calcineurin promotes maladaptive cardiac hypertrophy, we recently showed that the calcineurin splicing variant, CnAβ1, has beneficial effects on the infarcted heart. However, whether this variant limits necrosis or improves remodelling is still unknown, precluding translation to the clinical arena. Here, we explored the effects and therapeutic potential of CnAβ1 overexpression post-infarction. METHODS AND RESULTS: Double transgenic mice with inducible cardiomyocyte-specific overexpression of CnAβ1 underwent left coronary artery ligation followed by reperfusion. Echocardiographic analysis showed depressed cardiac function in all infarcted mice 3 days post-infarction. Induction of CnAβ1 overexpression 1 week after infarction improved function and reduced ventricular dilatation. CnAβ1-overexpressing mice showed shorter, thicker scars, and reduced infarct expansion, accompanied by reduced myocardial remodelling. CnAβ1 induced vascular endothelial growth factor (VEGF) expression in cardiomyocytes, which resulted in increased infarct vascularization. This paracrine angiogenic effect of CnAβ1 was mediated by activation of the Akt/mammalian target of rapamycin pathway and VEGF. CONCLUSIONS: Our results indicate that CnAβ1 exerts beneficial effects on the infarcted heart by promoting infarct vascularization and preventing infarct expansion. These findings emphasize the translational potential of CnAβ1 for gene-based therapies.Publication Intracoronary injection of haematopoietic precursor cells regenerates the borders, but not the core, of old myocardial scars(Wiley, 2020-10) Merino, Alvaro; Gayà, Antoni; Calvo Benito, Javier; Rotger, Ramon; Nuñez, JoanaAims: Cell therapy regenerative potential is hindered by cell access to the infarct zone. We studied function recovery at the scar zone and its impact in global left ventricular function after intracoronary injection of haematopoietic precursor cells. Methods and results: Haematopoietic precursor cells were obtained by blood apheresis in patients with an old myocardial infarction, and the presence of CD34+ and CD133+ cells was quantified. Left ventricular function, volumes, and infarct zone segmental motion were measured by magnetic resonance imaging (MRI) and echo left ventricular segmental strain (LVSS). The aphaeresis product was administered to 20 patients in the coronary artery responsible for the myocardial infarction. High cell yield in blood aphaeresis product allowed us to inject a high number of cells in most patients. Three patients were excluded because of insufficient CD133+ cell number, and one more patient was excluded because of artefacts in MRI images. The remaining 16 patients were compared with 16 controls. After 1 year, infarct zone reduction was related to the number of CD133+ (R = 0.53;P %3C 0.05) and CD34+ (R = 0.63;P %3C 0.01) cells injected. The number of CD133+ cells injected was also related to an improvement in LVSS (R = 0.62;P %3C 0.01). In turn, scar zone reduction was related to an improvement in LVSS (R = 0.64;P %3C 0.01). End-diastolic volume showed a reduction at follow-up in the treated group when compared with control patients. MRI infarct area segments systolic thickness increase improved after treatment in treated patients [expressed as median (interquartile range)] [0.42 (-0.38 to 1.14) vs. 1.06 (-0.10 to 2.12) mm; P %3C 0.01], but not in controls [2.02 (0.75 to 3.4) vs. 1.91 (0.77-3.17) mm; P = not significant (n.s.)]. In cell therapy patients, the borders of the infarct zone, but not the core, showed a significant recovery [proximal rim: 0.48 (-0.18 to 1.33) vs. 1.07 (0.22-2.40) mm; P %3C 0.05, distal rim: 0.75 (0.26-1.40) vs. 1.76 (0.65-2.86) mm; P %3C 0.05, and core: 0.36 (-0.33 to 1.20) vs. 0.60 (-0.18 to 1.62) mm; P = n.s.]. That improvement was not observed in the control group [proximal rim: 1.20 (0.33-2.53) vs. 0.82 (-0.13 to 1.65) mm; P = n.s., distal rim: 1.24 (0.80-1.72) vs. 0.96 (0.19-1.81) mm; P = n.s., and core: 0.30 (-0.42 to 1.64) vs. 0.07 (-0.60 to 1.20) mm; P = n.s.]. Only small size infarcts showed a complete recovery in the cell therapy patients [systolic thickness increase post-treatment increment in infarcts <= 6 segments vs. >6 segments affected: 0.28 (-0.19 to 0.71) vs. -1.21 (-2.60 to -0.53) mm; P %3C 0.01]. Conclusions: Intracoronary injection of peripheral blood-derived haematopoietic precursor cells produces a complete recovery of the borders and partial regeneration of the infarct core, which is directly related to the number of CD133+ and CD34+ cells injected. Cell therapy infarct zone regeneration prevents ventricular remodelling by preserving segmental contractility and halting left ventricular dilatation.Publication Labeling galectin-3 for the assessment of myocardial infarction in rats(Springer, 2014) Arias, Teresa; Petrov, Artiom; Chen, Jiqiu; de Haas, Hans; Perez-Medina, Carlos; Strijkers, Gustav J.; Hajjar, Roger J.; Fayad, Zahi A; Fuster, Valentin; Narula, Jagat; Centro Nacional de Investigaciones Cardiovasculares Carlos III (España)Background: Galectin-3 is a beta-galactoside-binding lectin expressed in most of tissues in normal conditions and overexpressed in myocardium from early stages of heart failure (HF). It is an established biomarker associated with extracellular matrix (ECM) turnover during myocardial remodeling. The aim of this study is to test the ability of I-123-galectin-3 (IG3) to assess cardiac remodeling in a model of myocardial infarction (MI) using imaging techniques. Methods: Recombinant galectin-3 was labeled with iodine-123 and in vitro binding assays were conducted to test I-123-galectin-3 ability to bind to ECM targets. For in vivo studies, a rat model of induced-MI was used. Animals were subjected to magnetic resonance and micro-SPETC/micro-CT imaging two (2 W-MI) or four (4 W-MI) weeks after MI. Sham rats were used as controls. Pharmacokinetic, biodistribution, and histological studies were also performed after intravenous administration of IG3. Results: In vitro studies revealed that IG3 shows higher binding affinity (measured as counts per minute, cpm) (p < 0.05) to laminin (2.45 +/- 1.67 cpm), fibronectin (4.72 +/- 1.95 cpm), and collagen type I (1.88 +/- 0.53 cpm) compared to bovine serum albumin (BSA) (0.88 +/- 0.31 cpm). Myocardial quantitative IG3 uptake (\%ID/g) was higher (p < 0.01) in the infarct of 2 W-MI rats (0.15 +/- 0.04\%) compared to control (0.05 +/- 0.03\%). IG3 infarct uptake correlates with the extent of scar (r(s) = 1, p = 0.017). Total collagen deposition in the infarct (percentage area) was higher (p < 0.0001) at 2 W-MI (24.2 +/- 5.1\%) and 4 W-MI (30.4 +/- 7.5\%) compared to control (1.9 +/- 1.1\%). However, thick collagen content in the infarct (square micrometer stained) was higher at 4 W-MI (20.5 +/- 11.2 mu m(2)) compared to control (4.7 +/- 2.0 mu m(2), p < 0.001) and 2 W-MI (10.6 +/- 5.1 mu m(2), p < 0.05). Conclusions: This study shows, although preliminary, enough data to consider IG3 as a potential contrast agent for imaging of myocardial interstitial changes in rats after MI. Labeling strategies need to be sought to improve in vivo IG3 imaging, and if proven, galectin-3 might be used as an imaging tool for the assessment and treatment of MI patients.Publication Loss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunction(American Heart Association (AHA), 2019-07-05) Ortiz-Sanchez, Paula; Villalba-Orero, Maria; Lopez-Olaneta, Marina; Larrasa-Alonso, Javier; Sanchez-Cabo, Fatima; Marti-Gomez, Carlos; Camafeita, Emilio; Gomez-Salinero, Jesus M.; Ramos-Hernandez, Laura; Nielsen, Peter J; Vazquez, Jesus; Müller-McNicoll, Michaela; García-Pavía, Pablo; Lara-Pezzi, Enrique; Unión Europea. Comisión Europea; Ministerio de Economía y Competitividad (España); Instituto de Salud Carlos III; Comunidad de Madrid (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Ciencia, Innovación y Universidades (España); Fundación ProCNICRATIONALE: RBPs (RNA binding proteins) play critical roles in the cell by regulating mRNA transport, splicing, editing, and stability. The RBP SRSF3 (serine/arginine-rich splicing factor 3) is essential for blastocyst formation and for proper liver development and function. However, its role in the heart has not been explored. OBJECTIVE: To investigate the role of SRSF3 in cardiac function. METHODS AND RESULTS: Cardiac SRSF3 expression was high at mid gestation and decreased during late embryonic development. Mice lacking SRSF3 in the embryonic heart showed impaired cardiomyocyte proliferation and died in utero. In the adult heart, SRSF3 expression was reduced after myocardial infarction, suggesting a possible role in cardiac homeostasis. To determine the role of this RBP in the adult heart, we used an inducible, cardiomyocyte-specific SRSF3 knockout mouse model. After SRSF3 depletion in cardiomyocytes, mice developed severe systolic dysfunction that resulted in death within 8 days. RNA-Seq analysis revealed downregulation of mRNAs encoding sarcomeric and calcium handling proteins. Cardiomyocyte-specific SRSF3 knockout mice also showed evidence of alternative splicing of mTOR (mammalian target of rapamycin) mRNA, generating a shorter protein isoform lacking catalytic activity. This was associated with decreased phosphorylation of 4E-BP1 (eIF4E-binding protein 1), a protein that binds to eIF4E (eukaryotic translation initiation factor 4E) and prevents mRNA decapping. Consequently, we found increased decapping of mRNAs encoding proteins involved in cardiac contraction. Decapping was partially reversed by mTOR activation. CONCLUSIONS: We show that cardiomyocyte-specific loss of SRSF3 expression results in decapping of critical mRNAs involved in cardiac contraction. The molecular mechanism underlying this effect likely involves the generation of a short mTOR isoform by alternative splicing, resulting in reduced 4E-BP1 phosphorylation. The identification of mRNA decapping as a mechanism of systolic heart failure may open the way to the development of urgently needed therapeutic tools.Publication Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction(European Society of Cardiology (ESC), 2016-01) González-Santamaría, José; Villalba, María; Busnadiego, Oscar; Lopez-Olaneta, Marina; Sandoval, Pilar; Snabel, Jessica; López-Cabrera, Manuel; Erler, Janine T; Hanemaaijer, Roeland; Lara-Pezzi, Enrique; Rodríguez-Pascual, Fernando; Ministerio de Economía y Competitividad (España); Comunidad de Madrid (España); Unión Europea. Comisión EuropeaAIMS: After myocardial infarction (MI), extensive remodelling of the extracellular matrix contributes to scar formation. While aiming to preserve tissue integrity, this fibrotic response is also associated with adverse events, including a markedly increased risk of heart failure, ventricular arrhythmias, and sudden cardiac death. Cardiac fibrosis is characterized by extensive deposition of collagen and also by increased stiffness as a consequence of enhanced collagen cross-linking. Members of the lysyl oxidase (LOX) family of enzymes are responsible for the formation of collagen cross-links. This study investigates the contribution of LOX family members to the heart response to MI. METHODS AND RESULTS: Experimental MI was induced in C57BL/6 mice by permanent ligation of the left anterior descending coronary artery. The expression of LOX isoforms (LOX and LOXL1-4) was strongly increased upon MI, and this response was accompanied by a significant accumulation of mature collagen fibres in the infarcted area. LOX expression was observed in areas of extensive remodelling, partially overlapping with α-smooth muscle actin-expressing myofibroblasts. Tumour growth factor-β as well as hypoxia-activated pathways contributed to the induction of LOX expression in cardiac fibroblasts. Finally, in vivo post-infarction treatment with the broadband LOX inhibitor β-aminopropionitrile or, selectively, with a neutralizing antibody against the canonical LOX isoform attenuated collagen accumulation and maturation and also resulted in reduced ventricular dilatation and improved cardiac function. CONCLUSION: LOX family members contribute significantly to the detrimental effects of cardiac remodelling, highlighting LOX inhibition as a potential therapeutic strategy for post-infarction recovery.