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Title: β1-adrenoceptor blockade treatment of right ventricular dysfunction caused by pulmonary hypertension
Author: Fowler, Ewan Douglas
ISNI:       0000 0004 5369 9513
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2015
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Failure of the right ventricle (or ventricular) (RV) is the leading cause of death in patients with pulmonary arterial hypertension (PAH), however no treatments specifically target the failing RV. β1-adrenoceptor blockers (β-blockers, BB) reduce mortality in left heart failure but current clinical guidelines caution against their use in PAH. Recent studies suggest β-blockers may be beneficial in PAH however the mechanisms remain unknown. The present study sought to establish whether the β1- blocker metoprolol (10 mg/kg/day) improved survival and function in a rat model of PAH induced by monocrotaline (60 mg/kg, MCT), and to elucidate the mechanisms responsible. Daily metoprolol or placebo was administered 15 days post-monocrotaline injection. PAH resulted in severe RV hypertrophy, dysfunction and heart failure by median day 23 in placebo treated rats (FAIL), whereas metoprolol extended the median survival to day 31 (MCT+BB). RV function measured by echocardiography and catheterisation was severely impaired in FAIL, but was partially restored in MCT+BB on day 23±1. Metoprolol appeared to act primarily on the myocardium and not the vasculature. Contractile abnormalities in isolated FAIL RV cardiomyocytes included increased cell volume, negative force and Ca2+ transient response to faster pacing, increased stiffness to stretch and shorter resting sarcomere length. Reduced creatine kinase activity was found in FAIL; creatine kinase inhibition reproduced characteristics of FAIL in healthy cells, whereas exogeneous creatine kinase reversed the shorter sarcomere length in FAIL cells. Contractile and Ca2+ handling properties of MCT+BB cells were partially or fully restored relative to healthy cells. Capillary density was reduced in FAIL and partially restored in MCT+BB; computer modelling indicated fewer areas of hypoxia in MCT+BB RV. Assessment of FAIL RV mitochondria revealed reduced creatine-coupled respiration but no other detectable defects. Metoprolol improved survival, Ca2+-handling, contractility, oxygen delivery and diastolic properties of PAH rats. β-blockers represent a novel myocardium-specific therapy to target the failing RV in PAH.
Supervisor: White, Ed Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available