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dc.contributor.authorGalan-Arriola, Carlos 
dc.contributor.authorVilchez-Tschischke, Jean Paul
dc.contributor.authorLobo, Manuel
dc.contributor.authorLopez, Gonzalo Javier 
dc.contributor.authorMolina-Iracheta, Antonio 
dc.contributor.authorPérez-Martínez, Claudia
dc.contributor.authorVillena-Gutierrez, Rocio 
dc.contributor.authorMacias, Alvaro 
dc.contributor.authorDíaz-Rengifo, Iván A
dc.contributor.authorOliver, Eduardo 
dc.contributor.authorFuster, Valentin 
dc.contributor.authorSanchez-Gonzalez, Javier 
dc.contributor.authorIbáñez, Borja
dc.identifier.citationCardiovasc Res. 2021es_ES
dc.description.abstractThe aim of this study was to study changes in coronary microcirculation status during and after several cycles of anthracycline treatment. Large-White male pigs (n = 40) were included in different experimental protocols (ExPr.) according to anthracycline cumulative exposure (0.45 mg/kg intracoronary (IC) doxorubicin per injection) and follow-up: Control (no doxorubicin); Single injection and sacrifice either at 48 hours (ExPr. 1) or 2 weeks (ExPr. 2); Three injections two weeks apart (low cumulative dose) and sacrifice either 2 weeks (ExPr. 3) or 12 weeks (ExPr. 4) after third injection; Five injections two weeks apart (high cumulative dose) and sacrifice 8 weeks after fifth injection (ExPr. 5). All groups were assessed by serial cardiac magnetic resonance (CMR) to quantify perfusion and invasive measurement of coronary flow reserve (CFR). At the end of each protocol, animals were sacrificed for ex vivo analyses. Vascular function was further evaluated by myography in explanted coronary arteries of pigs undergoing ExPr. 3 and controls.A single doxorubicin injection had no impact on microcirculation status, excluding a direct chemical toxicity. A series of five fortnightly doxorubicin injections (high cumulative dose) triggered a progressive decline in microcirculation status, evidenced by reduced CMR-based myocardial perfusion and CFR-measured impaired functional microcirculation. In the high cumulative dose regime (ExPr. 5), microcirculation changes appeared long before any contractile defect became apparent. Low cumulative doxorubicin dose (3 biweekly injections) was not associated with any contractile defect across long-term follow-up, but provoked persistent microcirculation damage, evident soon after third dose injection. Histological and myograph evaluations confirmed structural damage to arteries of all calibers even in animals undergoing low cumulative dose regimes. Conversely, arteriole damage and capillary bed alteration occurred only after high cumulative dose regime. Serial in vivo evaluations of microcirculation status using state-of-the-art CMR and invasive CFR show that anthracyclines treatment is associated with progressive and irreversible damage to the microcirculation. This long-persisting damage is present even in low cumulative dose regimes, which are not associated with cardiac contractile deficits. Microcirculation damage might explain some of the increased incidence of cardiovascular events in cancer survivors who received anthracyclines without showing cardiac contractile defects.es_ES
dc.description.sponsorshipThis study was supported by a European Research Council grant MATRIX (ERC-COG-2018- ID: 819775) to B.I.; the ERA-CVD Joint Translational Call 2016 (funded through the Instituto de Salud Carlos III (ISCIII), and the European Regional Development Fund (ERDF); ID: AC16/00021); a Health Research Project from the ISCIII-FIS (ID: PI16/02110); The BBVA foundation grant (ID: BIO CAR 0265). This study forms part of a Master Research Agreement between the CNIC and Philips Healthcare. C.G. and R.V-G. are P-FIS fellows (Instituto de Salud Carlos III). E.O. is recipient of funds from the Programa de Atracción de Talento (2017-T1/BMD-5185) of the Comunidad de Madrid. This study was partially supported by the Comunidad de Madrid (S2017/BMD-3867 RENIM-CM) and cofunded with European Union structural and investment funds. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU), and the Pro CNIC Foundation.es_ES
dc.publisherOxford University Press es_ES
dc.titleCoronary microcirculation damage in anthracycline cardiotoxicity.es_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderInstituto de Salud Carlos III 
dc.contributor.funderComunidad de Madrid (España) 
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (España) 
dc.contributor.funderFundación ProCNIC 
dc.identifier.journalCardiovascular researches_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Laboratorio Traslacional para la Imagen y Terapia Cardiovasculares_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Fisiopatología Cardiovascular Molecular y Genéticaes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Arritmias Cardíacases_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Imagen Cardiovascular y Estudios Poblacionaleses_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Medicina Comparativaes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/S2017/BMD-3867 RENIM-CMes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BIO CAR 0265es_ES
dc.rights.accessRightsopen accesses_ES

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