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Michelle Buckman_Thesis_12-08-20251.64 MB
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Dissertation
Cancer prevalence and anthracycline-induced cardiovascular toxicity in the adult Down syndrome population
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2025
DOI: 10.25820/etd.008243
Abstract
The median life expectancy of individuals with Down syndrome (DS) has increased over the past 6 decades from 5 years to 53 years. DS is associated with metabolic disorders and accelerated aging. It is established that children with DS have a high risk of leukemia; however, the risk in adults remains unknown. Anthracycline treatment for leukemia is effective but has toxic side effects on the cardiovascular system. Children with DS are at a higher risk of anthracycline cardiotoxicity after chemotherapy, but the risk in adults has not been addressed due to the lack of studies on the cancer profile of adults with DS. Adults with DS have an elevated risk of cardiovascular diseases, which can exacerbate their risk of anthracycline cardiotoxicity. Traditional risk factors for cardiovascular diseases in the general population may not be predictive of chemotherapy-induced heart failure in the DS population. It is unknown if established mechanisms apply to individuals with DS.
We evaluated the cancer diagnosis profile of adolescent and young adults with DS, and the incidence of cardiovascular disease diagnoses after anti-neoplastic treatment. Adults with DS had a similar incidence of all malignancies, a significantly higher incidence of hematological malignancies, and a significantly lower incidence of solid malignancies compared to age and sex-matched adults without DS. Specifically, they had a significantly higher risk of myelodysplastic syndromes, leukemia, myeloma, and testicular cancer. Even though the risk of all solid tumors was low, they had a similar risk of endometrial and colon cancer compared to adults without DS. The risk of ischemic heart diseases, diseases of arteries, arterioles, and capillaries, and heart failure was higher in individuals with DS after anthracycline treatment compared to age and sex matched individuals without DS.
We leveraged the adult Ts65Dn mouse model of DS, which recapitulates several cardiovascular phenotypes associated with DS, to evaluate the pathophysiology of anthracycline cardiotoxicity. Four-month-old euploid wild-type Ts65Dn (WT, n=8) and Ts65Dn (n=12) mice were treated with two doses of 2mg/kg or 4mg/kg of daunorubicin, or saline over a period of two weeks. Following treatment, we serially assessed pulse wave velocity for 8 weeks and monitored the survival of mice. At the end of the experiment, we performed left ventricular catheterization, collected blood samples, and harvested tissues for ELISA and histological analyses.
Ts65Dn mice treated with 4mg/kg of daunorubicin had a significantly reduced survival compared to the saline control group. Due to the high mortality in the 4mg/kg group, all subsequent experiments were conducted with the 2mg/kg group (treated) and the saline group. Body weight, end-diastolic pressure, and left ventricular weight significantly decreased in the treated mice. Ejection fraction increased in WT-treated mice and decreased in Ts65Dn-treated mice. Cardiac fibrosis increased in WT-treated mice and decreased in Ts65Dn-treated mice. Pulse wave velocity significantly increased with time in both groups. Smooth muscle thickness and collagen decreased in the thoracic aorta of Ts65Dn-treated mice.
This work outlines the cancer profile of adults with DS, the prevalence of anthracycline-induced cardiotoxicity, and establishes a distinct cardiac and vascular remodeling phenotype in Ts65Dn mice after anthracycline treatment. Further research into the mechanisms of anthracycline cardiotoxicity will better inform surveillance, treatment strategies, and long-term follow-up recommendations for individuals with DS.
Details
- Title: Subtitle
- Cancer prevalence and anthracycline-induced cardiovascular toxicity in the adult Down syndrome population
- Creators
- Michelle Abena Buckman
- Contributors
- Michael H. Tomasson (Advisor)Barry London (Committee Member)David J. Gordon (Committee Member)Gary Beasley (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Cancer Biology)
- Date degree season
- Autumn 2025
- DOI
- 10.25820/etd.008243
- Publisher
- University of Iowa
- Number of pages
- xiv, 95 pages
- Copyright
- Copyright 2025 Michelle A. Buckman
- Language
- English
- Date submitted
- 12/08/2025
- Description illustrations
- Illustrations, graphs, charts, tables
- Description bibliographic
- Includes bibliographical references (pages 78-92).
- Public Abstract (ETD)
Down syndrome (DS) occurs in 1 in 772 live births and is characterized by a range of clinical risks, including life-threatening conditions affecting the heart and blood vessels, and childhood leukemia. Over the past 6 decades, advancements in medical and social care have greatly extended the lifespan of people with DS. One side effect of these successes is uncertainty about what to expect as individuals with DS age. Commonly diagnosed cancer seems to be rare in DS. However, it s only relatively recently that individuals with DS have lived long enough to develop age-related cancers. In this thesis, I explored heart and blood vessel diagnoses in adults with DS and how a common cancer chemotherapy drug affects their health.
I started by exploring the cancer profile of adults with DS using an electronic medical records database. Adults with DS had an increased risk of developing leukemia and myeloma, an age-related blood cancer. Adults with DS who previously received chemotherapy had an increased risk of heart failure compared to adults without DS.
To better understand exactly how heart failure might be occurring in DS patients after surviving chemotherapy, I studied heart and vascular function following chemotherapy using a well-known mouse model of DS. We found that heart function responds uniquely to chemotherapy in DS mice, suggesting that heart function may also respond differently in patients with DS who receive chemotherapy. Further research is needed to investigate this mechanism and help tailor screening guidelines for the growing adult DS population.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9985135148902771
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