LIFE COURSE INTERVENTIONS THAT MODULATE SHORT- AND LONG-TERM CARDIOVASCULAR FUNCTION

• Author / Creator

  Noble, Ronan M N

• The Developmental Origins of Health and Disease (DOHaD) theory posits that insults during critical developmental periods can cause permanent structural and functional changes in key organ systems and thereby predispose an individual to chronic disease later in life. During gestation, iron deficiency (ID) is one insult which can increase risks of non-communicable diseases in the offspring, including cardiovascular disease. However, others who develop even under ideal circumstances will still experience chronic disease, particularly as they age. Cardiovascular disease alone is the leading cause of death worldwide, and accounts for a third of all mortality in Canada. Cardiovascular disease is associated with an enormous economic burden, accounting for more than $18 billion per year in Canada. Preventing even a small fraction of cardiovascular disease cases, either by discovering new mechanisms by which it develops, or by developing novel treatments which decrease its incidence, could result in substantial healthcare savings. Here we investigated the how perinatal ID affects offspring cardiovascular health in the neonatal period, as well as how broccoli sprout (BrSp) supplementation improves cardiovascular health throughout adulthood.
  To accomplish this female Sprague Dawley rats were fed either an iron restricted (3 or 10 mg/kg ferric citrate) or iron replete (37 mg/kg ferric citrate) purified diet prior to and throughout gestation; dams were fed an iron-replete diet at birth. Offspring were studied either during gestation or in the early neonatal period (postnatal days 0 through 28).
  In the early postnatal period, perinatal ID resulted in anemia and asymmetric growth restriction, as well as changes in cardiac function which occurred in a sex-specific manner. Proteomic analysis revealed ID down regulated structural components and elevated proteins associated with cellular stress response, and histology revealed a reduction in cardiomyocyte endowment. While the functional changes recovered, cellular differences persisted, implying ID may lead to long-term alterations in cardiac function.
  When ID dams were supplemented with an exogenous ketone, the previously mentioned cardiac dysfunction was partially mitigated. ID increased expression of Il-1β whereas ketone supplementation further altered Il-1β, Sod2, and Cat expression, indicating oxidative stress and inflammation may be relevant pathways for future study.
  We also assessed fetal and placental oxygen saturation (sO2) in ID and control offspring throughout gestation using photoacoustic imaging. We observed regional differences in sO2 within the placenta and between the placenta and fetus, however, ID had minimal effects on sO2 suggesting ID fetuses may require less oxygen during gestation when compared to controls.
  To study the long-term effects of nutritional supplementation, male and female Long-Evans rats were fed a control diet with or without dried BrSp from four months of age until death. Here, various parameters of cardiometabolic syndrome were assessed periodically across their lifespan. BrSp feeding reduced female bodyweight and visceral adiposity while improving glucose tolerance and reducing blood pressure in males. Finally, broccoli sprouts improved lifespan in females and in the oldest 25% of males.
  The studies herein show how perinatal ID affects fetal and neonatal circulatory physiology and provide two noteworthy therapies; ketones and BrSp, which may improve cardiovascular function in these models. Given the high incidence of perinatal ID as well as cardiovascular disease in adulthood, this work could have substantial implications for both the short- and long-term health of our population.

• Subjects / Keywords

  • Iron Deficiency
  • DOHaD
  • Photoacoustic

• Graduation date

  Fall 2023

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-w82q-3z03

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.