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Title: Metabolic phenotype analysis in patients with pulmonary hypertension
Author: Ghataorhe, Pavandeep Kaur
ISNI:       0000 0004 6348 3863
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Pulmonary hypertension (PH) is a heterogeneous and progressive disorder leading to right ventricular dysfunction, and carries significant mortality. Diagnosis requires invasive cardiac catheterisation and the pathogenesis of the vascular biology is poorly understood. Metabolic dysregulation has been implicated in PH but there have been no high-throughput analyses of circulating metabolites in these patients. Using nuclear magnetic resonance spectroscopy, abnormal plasma metabolite levels were identified in patients with pulmonary arterial hypertension (PAH), relating to energy metabolism and lipid regulation, with decreased large high-density lipoprotein subtypes associated with poor survival. These findings were expanded using unbiased ultra-performance liquid chromatography mass spectrometry methodologies (including lipidomics), which identified novel changes including increased circulating fatty acid acylcarnitines and reduced sphingomyelins and phosphocholines. To extend the identification of metabolites, samples were also analysed using a commercial metabolomics approach. Semi-quantitative assessment of 1416 metabolites in three cohorts of PAH patients identified metabolites that discriminated PAH patients from controls. These included increased levels of tRNA-specific modified nucleosides, tricarboxylic acid (TCA) cycle intermediates, glutamate, tryptophan and polyamine metabolites and decreased levels of steroids metabolites. The largest differences correlated with increased risk of death and correction of several metabolites over time was associated with better outcomes. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to healthy controls. Metabolic profiling also discriminated patients with other sub-diagnoses of PH from controls. Variant-metabolite associations published in control populations were validated in PAH patients using data from whole genome sequencing. Mendelian randomisation studies found that these variants did not relate to outcomes in PAH. In conclusion, this study comprehensively describes metabolic abnormalities in patients with PAH and demonstrates alterations in pathophysiologically-relevant metabolites. Metabolic profiles are strongly related to outcomes and may be used to distinguish patients with poor prognosis or response to therapy and identify potential therapeutic targets.
Supervisor: Wilkins, Martin ; Zhao, Lan Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral