Daunorubicin Treatment Impairs Cardiac Function in the Ts65Dn Mouse Model of Down Syndrome
Physiology(2024)
摘要
Anthracycline treatment for leukemia is effective but has toxic side effects on the cardiovascular system. Few studies regarding the impact of anthracyclines on the heart in individuals with Down syndrome have been addressed although they are at a higher risk of developing leukemia. It is unknown if established mechanisms apply to individuals with Down syndrome. We hypothesize that anthracycline cardiotoxicity will lead to the enhanced impairment of cardiac function and initiate pronounced vascular dysfunction in a mouse model of Down syndrome. We used the Ts65Dn mouse model of Down syndrome to investigate the impact of daunorubicin chemotherapy on survival, arterial stiffness and left ventricular function. Four-month-old Ts65Dn (n=12) and wild-type control Ts65Dn (WT, n=8) mice were treated with 2mg/kg of daunorubicin or saline. Following treatment, left ventricular catheterization was performed to assess cardiac function. Serum cardiac troponin levels were evaluated using ELISA. Histological analysis was conducted on the heart and aorta of mice to assess the accumulation of elastin and collagen. We found decreased end-diastolic pressure (p=0.016) and ejection fraction (p=0.029) in Ts65Dn daunorubicin-treated mice compared to WT control. However, contractility (end-systolic pressure-volume relationship, p=0.221) and diastolic stiffness coeffcient (end-diastolic pressure-volume relationship, p=0.418) remained unchanged. Ts65Dn mice had a higher cardiac troponin concentration (p=0.02). Histological assessment showed no significant difference in collagen (p=0.841) and elastin (p=0.768) content. Daunorubicin negatively impacted end-diastolic pressure and ejection fraction of the Ts65Dn mouse model of Down syndrome. We demonstrated that we could recapitulate the findings of anthracycline cardiotoxicity in Ts65Dn mice indicating this is a good model to investigate toxicity. Continued work with this model will better elucidate the mechanisms underlying anthracycline cardiotoxicity in Down syndrome. This shows the need for constant screening after anthracycline treatment which will improve the survival of this population. NIH R21 HD099573. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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