Metabolomic analysis of human plasma during acute myocardial ischemia and reperfusion. A non-targeted and targeted approach.
| dc.contributor.author | Surendran, Arun | |
| dc.contributor.examiningcommittee | Pierce, Grant (Physiology and Pathophysiology) | en_US |
| dc.contributor.examiningcommittee | Aukema, Harold (Food and Human Nutritional Sciences) | en_US |
| dc.contributor.examiningcommittee | Tuana, Balwant S (University of Ottawa) | en_US |
| dc.contributor.supervisor | Ravandi, Amir | |
| dc.contributor.supervisor | Aliani, Michel | |
| dc.date.accessioned | 2023-05-25T15:54:37Z | |
| dc.date.available | 2023-05-25T15:54:37Z | |
| dc.date.copyright | 2023-05-24 | |
| dc.date.issued | 2023-05-24 | |
| dc.date.submitted | 2023-05-24T13:14:18Z | en_US |
| dc.degree.discipline | Physiology and Pathophysiology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Revascularization of the infarct vessel by the primary percutaneous coronary intervention (PCI) is the treatment of choice for patients presenting with ST-segment elevation myocardial infarction (STEMI). However, myocardial reperfusion can paradoxically augment the injury to the myocardium through a process known as ischemia/reperfusion (IR) injury, which reduces the benefits of blood flow restoration. The pathophysiological mechanism underlying the development of I/R injury remains poorly understood. Herein, we employed a comprehensive metabolomics platform integrating non-targeted and targeted approaches to help us better understand the metabolic and lipid pathways impacted during I/R. Our non-targeted metabolomics analysis discovered 130 circulating metabolites that were significantly altered (p<0.001) in the setting of I/R injury during the first 48 hours post-reperfusion. Lipid molecules formed the largest pool of metabolites changing over the first 48 h after reperfusion. The pathway enrichment analysis identified the altered metabolic pathways indicative of the early reaction to reperfusion and late response to reperfusion. Also, we identified a select group of lipid species that can predict the extent of myocardial infarction based on the initial blood sample. Based on our above findings, we selected a targeted lipidomics approach to confirm our findings from the initial untargeted metabolomic analysis regarding the changes in plasma lipidome following reperfusion. We found that except for oxidized phospholipids (OxPL), the total amount of most of the lipid classes was markedly reduced immediately after reperfusion. The circulating free fatty acids (FA) exhibited the most extensive change in the first 24 h after PCI. We found that specific lipid species (acylcarnitine 18:2, TG 51:0, and LPC 17:1) could also distinguish STEMI patients with less cardiac injury from those with sizeable cardiac injury. These lipids were also associated with future cardiovascular events. Given the vital role played by lipids in the onset and progression of reperfusion injury, we next explored the role of lipids in the no-reflow phenomenon, which sets out during the ischemic period and then progresses during the reperfusion phase. Our analysis showed that the baseline levels of specific lipid species mainly belonging to the phosphatidylcholine (PC), alkylphosphatidylcholine (PC(O)), and sphingomyelin (SM) species were elevated in no-reflow patients. The fatty acid levels were markedly reduced (p<0.05) in no-reflow patients following reperfusion. We also found that sphingomyelin species (SM 41:1 and SM 41:2) were positively correlated with markers of no-reflow at pre-PCI and post-PCI. To summarize, we have developed the most detailed metabolomics and lipidomics atlas of human plasma during I/R injury. The results from this study will move us closer to our ultimate goal of devising therapeutic options to mitigate myocardial damage following acute myocardial infarction. | en_US |
| dc.description.note | October 2023 | en_US |
| dc.description.sponsorship | Mr. Surendran is supported by Research Manitoba Master’s Studentship (2018), Bank of Montreal/Institute of Cardiovascular Sciences Studentship (2019), and Singal, Pawan K. Graduate Scholarship in Cardiovascular Sciences (2019). | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/37354 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | metabolomics | en_US |
| dc.subject | lipidomics | en_US |
| dc.subject | acute coronary syndrome | en_US |
| dc.subject | ischemia/reperfusion injury | en_US |
| dc.subject | myocardial infarction | en_US |
| dc.subject | mass spectrometry | en_US |
| dc.subject | No-reflow | en_US |
| dc.subject | STEMI | en_US |
| dc.title | Metabolomic analysis of human plasma during acute myocardial ischemia and reperfusion. A non-targeted and targeted approach. | en_US |
| dc.type | doctoral thesis | en_US |
| local.subject.manitoba | no | en_US |