Cardiac mechanoenergetics in health and in right-ventricular failure

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dc.contributor.advisor Loiselle, D en
dc.contributor.advisor Taberner, A en
dc.contributor.advisor Hickey, A en
dc.contributor.advisor Mellor, K en
dc.contributor.advisor Han, JC en Pham, Toan en 2018-05-22T04:26:03Z en 2018 en
dc.identifier.uri en
dc.description.abstract Aim Cardiac hypertrophy that occurs in response to pathological stress may become lethal if it eventually results in heart failure. In pulmonary arterial hypertension (PAH), the increased afterload on the right ventricle (RV) triggers RV hypertrophy and ultimately RV failure. In this disease, the left ventricle (LV) is also affected. The passive filling pressure in the LV reduces, thereby potentially resulting in LV atrophy. Clinical and experimental studies have shown a decrease in energetic efficiency of the RV myocardium in PAH patients as well as in a PAH rat model. However, an understanding of the mechanisms underlying reduced cardiac energy efficiency in PAH remains unclear. The aim of this PhD thesis was to investigate how structural remodelling in both ventricles affects their respective mechanoenergetic performance. Methods A flow-through calorimeter was employed to simultaneously measure force production, heat output and length change of ventricular cardiac trabeculae. These trabeculae were superfused with oxygenated Tyrode solution at 37 °C. Four studies were undertaken to achieve the ultimate aim. 1. To establish capabilities of the calorimeter to perform experiments under physiological experimental conditions, a study to compare interventricular differences of isometric stress and heat production as a function of stimulus frequency (0.1 Hz to 10 Hz) was carried out using a Latin Square experimental design. 2. To develop the methodology to accurately measure cardiac activation heat, experiments using isolated trabeculae from both ventricles were performed. Isometric stress and heat production, as functions of muscle length, were simultaneously measured in both the absence and presence of blebbistatin as a selective inhibitor of myosin II ATPase. 3. To develop the methodology to perform the first characterisation of work-loop contractions at 5 Hz and 37 °C, both RV and LV trabeculae were subjected to two experimental protocols: isotonic work-loop contractions at a range of afterloads, and isometric contractions at a variety of muscle lengths. Simultaneous measurements of force-length work and suprabasal heat output allowed calculation of suprabasal efficiency. 4. The ultimate study aimed to characterise the mechanoenergetics of trabeculae isolated from both ventricles of Wistar rats in which PAH had been induced by an injection of monocrotaline. The experimental protocols were adapted from study #3. Results 1. There was no difference in stress (force per muscle cross-sectional area) production or suprabasal heat output as a function of stimulus frequency between healthy RV and LV trabeculae undergoing isometric contractions. A decline of stress production was observed over the period of the experiments. A negative stress-radius relation was revealed in trabeculae from both ventricles. 2. Cardiac activation heat estimated from the intercept of heat-stress relation was not altered by the presence of blebbistatin. There was no difference in activation heat between ventricles. In the presence of blebbistatin, activation heat remained constant at all muscle lengths. 3. Both extent and velocity of shortening were higher in RV trabeculae. However, there was no difference in work, heat output, or suprabasal efficiency between ventricles. Shortening crossbridge heat was present and independent of ventricular origin. 4. RV trabeculae from PAH rats generated higher activation heat, but developed normal active stress. Their peak work output was lower due to reduced extent and velocity of shortening. Despite lower peak work output, suprabasal enthalpy was unaffected, thereby rendering suprabasal efficiency lower. Crossbridge efficiency, however, was unaffected. In contrast, LV trabeculae from PAH rats maintained normal mechanoenergetic performance. Conclusions Per unit mass, mechanoenergetic performance is homogeneously distributed throughout the ventricles in healthy hearts. However, the suprabasal energy efficiency of RV tissues is decreased in PAH hearts, as a consequence of the increased energy cost for Ca2+ cycling. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA99265065312902091 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.rights.uri en
dc.title Cardiac mechanoenergetics in health and in right-ventricular failure en
dc.type Thesis en Physiology en The University of Auckland en Doctoral en PhD en
dc.rights.holder Copyright: The author en
dc.rights.accessrights en
pubs.elements-id 740852 en Bioengineering Institute en
pubs.record-created-at-source-date 2018-05-22 en

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