Assuntos
Síndrome Coronariana Aguda/etiologia , Anomalias dos Vasos Coronários/induzido quimicamente , Moduladores de Receptor Estrogênico/efeitos adversos , Estrogênios/efeitos adversos , Progesterona/efeitos adversos , Progestinas/efeitos adversos , Doenças Vasculares/congênito , Síndrome Coronariana Aguda/epidemiologia , Adulto , Angiografia Coronária/métodos , Anomalias dos Vasos Coronários/complicações , Anomalias dos Vasos Coronários/diagnóstico por imagem , Anomalias dos Vasos Coronários/genética , Vasos Coronários/patologia , Feminino , Hematoma , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Gravidez , Complicações Cardiovasculares na Gravidez/epidemiologia , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/complicações , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/genéticaRESUMO
BACKGROUND: The anthracycline doxorubicin is an effective chemotherapeutic agent used to treat pediatric cancers but is associated with cardiotoxicity that can manifest many years after the initial exposure. To date, very little is known about the mechanism of this late-onset cardiotoxicity. METHODS AND RESULTS: To understand this problem, we developed a pediatric model of late-onset doxorubicin-induced cardiotoxicity in which juvenile mice were exposed to doxorubicin, using a cumulative dose that did not induce acute cardiotoxicity. These mice developed normally and had no obvious cardiac abnormalities as adults. However, evaluation of the vasculature revealed that juvenile doxorubicin exposure impaired vascular development, resulting in abnormal vascular architecture in the hearts with less branching and decreased capillary density. Both physiological and pathological stress induced late-onset cardiotoxicity in the adult doxorubicin-treated mice. Moreover, adult mice subjected to myocardial infarction developed rapid heart failure, which correlated with a failure to increase capillary density in the injured area. Progenitor cells participate in regeneration and blood vessel formation after a myocardial infarction, but doxorubicin-treated mice had fewer progenitor cells in the infarct border zone. Interestingly, doxorubicin treatment reduced proliferation and differentiation of the progenitor cells into cells of cardiac lineages. CONCLUSIONS: Our data suggest that anthracycline treatment impairs vascular development as well as progenitor cell function in the young heart, resulting in an adult heart that is more susceptible to stress.