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Permanent link (DOI): https://doi.org/10.7939/R33K92

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Experimental Therapies for the Hypertrophied Right Ventricle Open Access

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Other title
Subject/Keyword
Right Ventricular Hypertrophy
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Nagendran, Jayan
Supervisor and department
Michelakis, Evangelos (Medicine)
Dyck, Jason (Pharmacology)
Examining committee member and department
Anderson, Todd (Medicine, University of Calgary)
Adatia, Ian (Pediatrics)
Ross, David (Surgery)
Department
Department of Medicine
Specialization

Date accepted
2009-10-21T21:42:33Z
Graduation date
2009-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
The right ventricle (RV) of the heart is clearly an extremely important component of cardiovascular function and physiology. The RV is affected in many cardiovascular disease processes, including pulmonary arterial hypertension (PAH), congenital heart disease, and left ventricular failure. In PAH, the performance of the RV is the strongest predictor of morbidity and mortality. Several advances in PAH therapies have occurred over the past decade, including the use of phosphodiesterase-5 (PDE5) inhibitors, endothelin receptor antagonists (ETRAs), and experimental metabolic modulators (Dichloroacetate-DCA). Most therapies for PAH are focused on decreasing RV afterload by vasodilation of the pulmonary vasculature, though there is a surprising lack of focus on direct effects of therapies on the RV. In PAH, the RV compensates to the increase in afterload by hypertrophy, this hypertrophic defense mechanism eventual falls short and the RV progresses to failure and patient death. The specific aims of our investigations are to assess the effects of PAH therapies on RV in normal and hypertrophied states, as seen in PAH. We utilize human RV samples attained from cardiac surgical procedures to perform in-vitro analysis of protein and mRNA expression of the targets of PAH therapies. We also use a rat model of PAH and subsequent RV hypertrophy to verify human data and to also perform applied physiology experiments to isolate ex-vivo effects of PAH therapies on the RV. The experiments and data gathered in this thesis represent the insight into the importance of the RV in PAH therapies and how these therapies directly mediate the state of inotropy of the RV. A conclusion of greater importance is the better understanding of RV-specific changes in gene expression when the RV undergoes hypertrophy. By demonstrating the up-regulation of protein expression in RVH we are able to potentially tailor therapies to only improve performance of the diseased RV, while sparing the LV if it is otherwise normal. This is a true shift in paradigm as all current cardiac therapeutics effect both right and left ventricle.
Language
English
DOI
doi:10.7939/R33K92
Rights
License granted by Jayan Nagendran (jnagendr@ualberta.ca) on 2009-10-16T19:15:03Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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