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. / Experimental Medicine
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/822 |
| Date | 11 1900 |
| Creators | Nagendran, Jayan |
| Contributors | Michelakis, Evangelos (Medicine), Dyck, Jason (Pharmacology), Ross, David (Surgery), Adatia, Ian (Pediatrics), Anderson, Todd (Medicine, University of Calgary) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 2286222 bytes, application/pdf |
| Relation | Nagendran J, Archer SL, Gurtu V, Moudgil R, Webster L, Haromy A, Rebeyka IM, Ross DB, Michelakis ED. Phosphodiesterase type 5 (PDE5) is highly expressed in the hypertrophied human right ventricle and acute inhibition of PDE5 improves contractility. Circulation 2007,116(3):238-48., Nagendran J, Gurtu V, Fu DZ, Dyck JR, Ross DB, Rebeyka IM, Michelakis ED. A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted. Journal of Thoracic and Cardiovascular Surgery 2008, 136:168-178. |
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