dc.contributor.advisor | Aasum, Ellen | |
dc.contributor.author | Pedersen, Tina Myhre | |
dc.date.accessioned | 2023-10-13T12:13:48Z | |
dc.date.available | 2023-10-13T12:13:48Z | |
dc.date.issued | 2019-10-21 | |
dc.description.abstract | Heart failure is associated with altered myocardial substrate utilization and reduced cardiac efficiency - changes that are hallmarks in heart failure independent of disease aetiology. This thesis describes remodelling in two distinct models of heart failure, namely obesity-mediated cardiomyopathy and early failure induced using a low dose angiotensin II (AngII).
The reported cardiac phenotype in obese mouse models varies, and methods used for cardiac functional assessment may influence these discrepancies. This thesis shows that ex vivo cardiac examination (isolated perfused working hearts) using prediabetic and diabetic mice, reveals a more severe dysfunction than in vivo measurements (echocardiography), suggesting that systemic changes contribute to sustain cardiac function in vivo. Hence, the ex vivo heart preparation provides valuable additional information in cardiac phenotyping, unmasking changes that might be compensated in vivo. Furthermore, when exposing obese mouse hearts to high fatty acid levels (mimicking stressful conditions, such as myocardial infarction), they did not display the adverse effects that were seen in hearts from normal mice. In fact, ischemic tolerance was increased with high fat in obese hearts. This suggests that, despite contributing to the progression of diabetic cardiomyopathy, chronic hyperlipidaemia induces cardiac adaptation making these hearts able to handle an acute exposure to high levels of fat.
Conversely, a low-dose of AngII did not change cardiac metabolism or efficiency, despite causing hypertrophy. However, the same dose of AngII induced cardiac dysfunction in mice with cardiac-specific NOX2 overexpression, with a concomitant change in substrate utilization. Thus, in AngII-induced heart failure, substrate utilization is not altered prior to dysfunction and NOX2 aggravates AngII-mediated effects.
In conclusion, although both obesity and early angiotensin II-induced heart failure are associated with altered substrate metabolism, these changes might be beneficial adaptations. | en_US |
dc.description.doctoraltype | ph.d. | en_US |
dc.description.popularabstract | In heart disease, the ability to adapt to the available substrate supply is reduced, leading to energetic imbalance and inefficiency, and subsequent heart failure. Cardiac metabolism may thus be a target for new treatment strategies, particularly in obesity and diabetes. This thesis describes that the use of multiple techniques is valuable when assessing function in hearts from obese mice. Additionally, although chronic elevation of circulating fat contributes to failure, we show that obese hearts also undergo adaptation, making them less sensitive to an acute fat exposure. The hormone angiotensin II also induces heart failure. While metabolic changes occur prior to dysfunction in obesity, this thesis describes that angiotensin II does not alter the substrate consumption prior to functional failure. This work elucidates changes in metabolism in two models of heart failure, thus improving our understanding of these processes, which is essential when developing new treatment strategies. | en_US |
dc.description.sponsorship | This project was funded by The Norwegian Heart Foundation (Nasjonalforeningen for Folkehelsen), with additional funding from the University of Tromsø. | en_US |
dc.identifier.uri | https://hdl.handle.net/10037/31549 | |
dc.language.iso | eng | en_US |
dc.publisher | UiT The Arctic University of Norway | en_US |
dc.publisher | UiT Norges arktiske universitet | en_US |
dc.relation.haspart | Paper I: Pedersen TM, Boardman NT, Hafstad AD, Aasum E. Isolated perfused working hearts provide valuable additional information during phenotypic assessment of the diabetic mouse heart. PLOS ONE. 13: e0204843, 2018. Available in Munin at <a href=https://hdl.handle.net/10037/15015>https://hdl.handle.net/10037/15015</a>. <p> <p>Paper II: Boardman NT*, Pedersen TM*, Rossvoll L, Hafstad AD, Aasum E. Dietinduced obese mouse hearts show metabolic adaptation that enhances tolerance to acute high fatty acid exposure and reduces susceptibility to ischemic injury. *Authors contributed equally (Submitted manuscript). Also available in Munin at <a href=https://hdl.handle.net/10037/29504>https://hdl.handle.net/10037/29504</a>. Final version published in <I>American Journal of Physiology, 2020,319</i>(3), H682-H693, is available at <a href=https://doi.org/10.1152/ajpheart.00284.2020 >https://doi.org/10.1152/ajpheart.00284.2020 </a>. <p> <p>Paper III: Pedersen TM, Hansen SS, Boardman NT, Aasum E, Hafstad AD. Overexpression of NOX2 exacerbates AngII-mediated cardiac remodelling and dysfunction in male, but not female mice. (Submitted manuscript). Final version published in <i>Antioxidants. 2022;11</i>(1), is available in Munin at <a href=https://hdl.handle.net/10037/25474>https://hdl.handle.net/10037/25474</a>. | en_US |
dc.rights.accessRights | openAccess | en_US |
dc.rights.holder | Copyright 2019 The Author(s) | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-sa/4.0 | en_US |
dc.rights | Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) | en_US |
dc.subject | VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Human and veterinary science physiology: 718 | en_US |
dc.subject | Cardiac metabolism | en_US |
dc.subject | Obesity and diabetes | en_US |
dc.subject | Cardiac efficiency | en_US |
dc.subject | Heart failure | en_US |
dc.title | Cardiac remodelling in obesity- and angiotensin II-mediated heart failure: Morphological, functional and metabolic alterations | en_US |
dc.type | Doctoral thesis | en_US |
dc.type | Doktorgradsavhandling | en_US |