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Title: Cardiopulmonary exercise testing in congenital heart disease associated with pulmonary arterial hypertension : prognostic implications and exercise metabolic profiling
Author: Zhang, Hongda
ISNI:       0000 0004 6494 0042
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2017
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Background: Pulmonary arterial hypertension (PAH) is a currently incurable deadly disease characterized by progressively elevated pulmonary vascular resistance which leads to right heart failure and eventually death. Exercise intolerance is a major manifestation which severely affects the quality of life in patients with PAH. Exercise capacity can be objectively measured by cardiopulmonary exercise testing (CPET), which is also recommended by the latest PAH guideline. CPET also provides additional information on ventilatory efficiency and cardiovascular functions. The prognostic value of several CPET parameters has been demonstrated in patients with idiopathic PAH in previous studies, however, it is insufficiently demonstrated in congenital heart disease associated with PAH (CHD-PAH). Moreover, apart from prognostic evaluation of clinical exercise parameters, the underlying metabolic changes during exercise in PAH has yet to be investigated. Aims: We mainly aimed to: (1) evaluate the exercise capacity, ventilatory efficiency, and cardiovascular reserve using CPET in patients with CHD-PAH; (2) investigate whether CPET parameters have prognostic implications in these patients; (3) improve the understanding of metabolic perturbations in CHD-PAH through exercise-metabolomics profiling. Methods: We prospectively enrolled 171 consecutive patients with CHD-PAH and 30 age- and sex-matched healthy controls and performed CPET. Prognostic evaluation of CPET parameters was performed in the overall patient cohort. Of all the patients, we collected blood samples at baseline, peak exercise, and recovery period during CPET of 29 patients (Exercise metabolic cohort) and 20 age- and sex-matched healthy controls for measurement of 224 metabolites included in 3 targeted panels using liquid chromatography tandem-mass spectrometry. Results: The median age of patients at enrollment was 27.8 years, and 131 (76.6%) were female. Exercise capacity, ventilatory efficiency, and cardiovascular reserve were severely reduced in patients compared to healthy controls. In multivariate COX regression analysis, peak oxygen uptake (VO2) was identified as an independent predictor for both mortality (Hazard ratio = 0.579, 95% CI: 0.429, 0.781; p < 0.001) and clinical worsening (CW) (Hazard ratio = 0.842, 95% CI: 0.741, 0.958; p = 0.009). Patients with VO2 < 11.1 ml/kg/min were at increased risk of death (log-rank p < 0.001) and patients with peak VO2 < 13.0 ml/kg/min were more likely to have CW events (log-rank p = 0.004) in Kaplan-Meier analysis. Random survival forest analysis supported the prognostic value of peak VO2 for predicting both mortality and CW. Exercise-metabolomics profiling showed patients had significantly different baseline metabolic status and exercise-induced metabolic responses compared to controls. Linear regression analysis indicated that the reserve (difference between baseline and peak exercise) in some metabolites during exercise were significantly related to VO2 reserve in patients. Comprehensive analysis and screening identified spermine and spermidine not only of diagnostic value but also involved in the pathophysiological mechanisms in PAH. Conclusions: Patients with CHD-PAH have worse exercise capacity, ventilatory efficiency and cardiovascular reserve compared to healthy controls. Peak VO2 is a strong predictor for both mortality and CW in CHD-PAH. Patients with peak VO2 < 11.1 ml/kg/min are at higher risk of death and patients with peak VO2 < 13.0 ml/kg/min are more likely to have CW events. Altered spermidine/spermine metabolism might be involved in the pathophysiological mechanisms underlying the exercise intolerance in patients with CHD-PAH.
Supervisor: Lawrie, Allan ; Jing, Zhicheng Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available