The effects of energetic substrate manipulation on myocardial metabolism and cardiac function
<p>The healthy human heart uses fat and glucose as its predominant metabolic substrates, approximately in a ratio of 70% to 30%. In heart failure, substrate oxidation is decreased as is ATP production. Free fatty acid uptake and oxidation is reduced, while glucose uptake and glycolysis are inc...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2021
|
| Subjects: |
| _version_ | 1797103442033901568 |
|---|---|
| author | Watson, WD |
| author2 | Rider, O |
| author_facet | Rider, O Watson, WD |
| author_sort | Watson, WD |
| collection | OXFORD |
| description | <p>The healthy human heart uses fat and glucose as its predominant metabolic substrates, approximately in a ratio of 70% to 30%. In heart failure, substrate oxidation is decreased as is ATP production. Free fatty acid uptake and oxidation is reduced, while glucose uptake and glycolysis are increased, although pyruvate oxidation falls. This thesis set out to establish the links between myocardial substrate metabolism and function in the healthy and the failing human heart, at rest and at stress.</p>
<p>In chapter 3, an inhibitor of lipolysis, nicotinic acid, is compared to a lipid infusion in normal human subjects and in rats. While the lipid infusion increases cardiac contractility, a decline in both contractility and PCr/ATP ratio is shown with the nicotinic acid. This is revealed to result from inhibition in lipolysis combined with reduction in glucose stimulated insulin secretion, hence the heart is starved of energetic substrate, revealing metabolism’s importance and close link to contractile function.</p>
<p>In chapters 4 and 5, lipid infusion is further shown in the failing human heart to increase contractility and PCr/ATP ratio at rest as well as increasing maximum available cardiac work. It is demonstrated that the failing heart displays substrate flexibility with an ability to take up higher amounts of free fatty acids when their availability is increased and increase their uptake during rapid pacing stress. In addition, the failing heart is not shown to be oxygen starved and oxygen consumption increases during the lipid infusion without deleterious consequence.</p>
<p>In chapter 6, in normal human subjects, vasodilator stress with glyceryl trinitrate is shown to greatly increase myocardial ATP demand while inhibiting mitochondrial ATP production, creating a mismatch between supply and demand and resulting in a fall in PCr/ATP ratio. A higher baseline PCr/ATP is shown to be protective against stress induced changes, confirming the importance of PCr/ATP as a target for interventions.</p>
<p>Together, these data show myocardial metabolism is an important target for heart failure therapeutics and that it may be manipulated via increasing availability of free fatty acids.</p> |
| first_indexed | 2024-03-07T06:20:10Z |
| format | Thesis |
| id | oxford-uuid:f274e34f-4525-4951-8003-52626d0b0b10 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:20:10Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:f274e34f-4525-4951-8003-52626d0b0b102022-03-27T12:03:56ZThe effects of energetic substrate manipulation on myocardial metabolism and cardiac functionThesishttp://purl.org/coar/resource_type/c_db06uuid:f274e34f-4525-4951-8003-52626d0b0b10Heart--MetabolismHeart failureEnglishHyrax Deposit2021Watson, WDRider, OHerring, NNeubauer, SEvans, RWiggers, H<p>The healthy human heart uses fat and glucose as its predominant metabolic substrates, approximately in a ratio of 70% to 30%. In heart failure, substrate oxidation is decreased as is ATP production. Free fatty acid uptake and oxidation is reduced, while glucose uptake and glycolysis are increased, although pyruvate oxidation falls. This thesis set out to establish the links between myocardial substrate metabolism and function in the healthy and the failing human heart, at rest and at stress.</p> <p>In chapter 3, an inhibitor of lipolysis, nicotinic acid, is compared to a lipid infusion in normal human subjects and in rats. While the lipid infusion increases cardiac contractility, a decline in both contractility and PCr/ATP ratio is shown with the nicotinic acid. This is revealed to result from inhibition in lipolysis combined with reduction in glucose stimulated insulin secretion, hence the heart is starved of energetic substrate, revealing metabolism’s importance and close link to contractile function.</p> <p>In chapters 4 and 5, lipid infusion is further shown in the failing human heart to increase contractility and PCr/ATP ratio at rest as well as increasing maximum available cardiac work. It is demonstrated that the failing heart displays substrate flexibility with an ability to take up higher amounts of free fatty acids when their availability is increased and increase their uptake during rapid pacing stress. In addition, the failing heart is not shown to be oxygen starved and oxygen consumption increases during the lipid infusion without deleterious consequence.</p> <p>In chapter 6, in normal human subjects, vasodilator stress with glyceryl trinitrate is shown to greatly increase myocardial ATP demand while inhibiting mitochondrial ATP production, creating a mismatch between supply and demand and resulting in a fall in PCr/ATP ratio. A higher baseline PCr/ATP is shown to be protective against stress induced changes, confirming the importance of PCr/ATP as a target for interventions.</p> <p>Together, these data show myocardial metabolism is an important target for heart failure therapeutics and that it may be manipulated via increasing availability of free fatty acids.</p> |
| spellingShingle | Heart--Metabolism Heart failure Watson, WD The effects of energetic substrate manipulation on myocardial metabolism and cardiac function |
| title | The effects of energetic substrate manipulation on myocardial metabolism and cardiac function |
| title_full | The effects of energetic substrate manipulation on myocardial metabolism and cardiac function |
| title_fullStr | The effects of energetic substrate manipulation on myocardial metabolism and cardiac function |
| title_full_unstemmed | The effects of energetic substrate manipulation on myocardial metabolism and cardiac function |
| title_short | The effects of energetic substrate manipulation on myocardial metabolism and cardiac function |
| title_sort | effects of energetic substrate manipulation on myocardial metabolism and cardiac function |
| topic | Heart--Metabolism Heart failure |
| work_keys_str_mv | AT watsonwd theeffectsofenergeticsubstratemanipulationonmyocardialmetabolismandcardiacfunction AT watsonwd effectsofenergeticsubstratemanipulationonmyocardialmetabolismandcardiacfunction |