Defense Date

2022

Document Type

Thesis

Degree Name

Master of Science

Department

Physiology and Biophysics

First Advisor

Dr. Stefano Toldo

Abstract

The prevalence of heart failure (HF) has increased over the years and remains high. Although the incidence of HF is thought to no longer increase, the mortality rate and hospitalizations associated with HF remain high. Due to HF being an endpoint for many cardiovascular diseases and stemming from a variety of risk factors and comorbidities, there have been continued efforts to provide various effective treatments for HF patients. Even though both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) make up similar percentages of HF cases, there are currently several treatments approved for HFrEF but only a few approved for HFpEF. HFrEF is characterized by a reduced systolic and diastolic function, and HFpEF is mainly characterized by diastolic dysfunction. Angiotensin II (AngII) is elevated in virtually all HF patients, including HFpEF. It leads to hypertension, cardiac hypertrophy, fibrosis, and diastolic dysfunction. AngII induces a pro-inflammatory response independent from hypertension. IL-18 is a pro-inflammatory cytokine regulated by AngII, and causes the activation of many immune cells, including T helper 1 lymphocytes (Th1). Considering the literature connecting the effects of AngII and IL-18 on Th1 cells, together with data generated in my laboratory, we hypothesized that AngII activates Th1 cells to mediate diastolic dysfunction in an animal model of HFpEF.

By utilizing osmotic pumps delivering a subpressor dose of AngII in WT or TCR--/- mice, we found that the absence of mature T cells in TCR--/- mice protects from developing diastolic dysfunction. In addition, the adoptive transfer of WT Th1 cells into the TCR--/- mice re-induces diastolic dysfunction in TCR--/- mice. These findings suggest that AngII signaling, independent of hypertension, promotes Th1 cell-mediated diastolic dysfunction. The results of this study provide information that may help guide future experiments on determining how Th1 cells contribute to HFpEF and possible new therapies.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-3-2022

Available for download on Sunday, May 02, 2027

Included in

Cardiology Commons

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