Woolley, R.J. (Rebecca Jane) (2019) Uncovering the molecular nexus of ischaemic heart failure : A systems biology approach. thesis, Medicine.
Full text available on request.Abstract
Background: The most common forms of heart failure (HF) are ischemic HF and nonischemic cardiomyopathy. Deciphering the molecular mechanisms underpinning these two types of HF may provide a rationale for differential diagnostics and treatment targets. Materials and Methods: A post-hoc analysis of a prospective study; the BIOSTAT-CHF project was done. The differential expression of 92 plasma protein-biomarkers between 715 HF patients with ischemic heart disease vs 445 with non-ischemic cardiomyopathy was investigated. An enriched protein-protein interaction network for the upregulated proteins was constructed. Pathway overrepresentation analyses and clinical significance of the proteins were assessed. An independent cohort of 765 ischemic vs 100 non-ischemic patients was used for validation of the differentially expressed proteins. Results: Patients in both groups were predominantly males with reduced left ventricular ejection fraction. Patients with ischemic HF were older and had more comorbidities. In ischemic HF patients, 21/92 proteins were upregulated and 2/92 downregulated relative to nonischemic cardiomyopathy patients. After adjustment for age and sex, galectin-4 and growth differentiation factor-15 remained upregulated and paraoxonase-3 downregulated. Pathway analyses of the 21 upregulated proteins yielded few hits. Nevertheless, the enriched network unveiled 6 interconnecting pathways (a molecular ischemic nexus) consisting of ‘Dissolution of fibrin clot’; ‘Bone resorption’; ‘Regulation of superoxide anion generation’; ‘Prostate cancer’; ‘Neuroinflammatory response’ and ‘Regulation of cardiac muscle hypertrophy’. Although the network was enriched, its clinical outcome-models performed similarly with those of the differentially expressed proteins. For CV-death, the area under the curves (AUCs) were 58.1, 77.5 and 76.9 for the unadjusted, differentially expressed proteins and network respectively. Conclusions: Pathophysiological pathways distinguishing ischemic HF from non-ischemic cardiomyopathy insinuate the role of atherosclerosis and inflammation.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | University Medical Centre Groningen, Department of Cardiolog and Supervisor: and Voors, Dr. Prof. A.A. Cardiologist and In cooperation with and Sama, Dr.I.E Medical scientist |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 10:53 |
| Last Modified: | 25 Jun 2020 10:53 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/1383 |
Actions (login required)
 |
View Item |