Characterization of the pulmonary vascular bed and its coupling with the right ventricle.

摘要

Pulmonary arterial hypertension (PAH) is a disorder that directly affects the pulmonary circulation with significant clinical consequences on the performance of the right ventricle and its interactions with the pulmonary vasculature. The disease, which currently affects over 5,000 people each year in the U.S., can lead to severe heart dysfunction and death, and presents challenges in diagnosis and limited treatment choices. Furthermore, the lack of appropriate methods to measure changes in different components of the heart-lung system in humans and animal models limits our ability to establish correlation between those changes and the pathogenesis of the disease. The present work investigates the murine pulmonary vascular bed and its coupling with the right ventricle at three different scales. At the sub-organ level, we show that decreases in compliance of the arterial wall in hypoxia-induced pulmonary hypertension (HPH) is caused by a narrowing, thickening and increase in the elastic modulus of the artery wall but not persistent vasoconstriction. We also show that impedance metrics such as input impedance, characteristic impedance and index of wave reflection in live mice in vivo are sensitive indicators of the changes in the pulmonary vasculature with HPH. Finally, we demonstrate the utility of admittance technology for studying ventricular-vascular coupling in healthy and hypertensive mice. This study provides strong evidence that the current gold standard RV pressure-volume loop analysis can be performed to yield insight into alterations occurring with HPH. The techniques used in this dissertation work are novel in the field of cardiopulmonary research and provide new perspectives on the changes that occur in the cardiopulmonary system during HPH.