Pulmonary hypertension (PH) is a life-threatening disease. The current PAH therapy can improve the survival and quality of life for PH patients, however, it is unable to reverse the pulmonary vascular remodeling, which will eventually lead to right heart failure and premature death. Therefore, more in-depth knowledge of the underlying mechanisms in the development and progression of PH are needed to facilitate the discovery of potential novel therapeutic targets.
In Part I of this thesis, two different porcine models of early-stage PH, i.e. chronic thromboembolic pulmonary hypertension and combined pre- and post- capillary pulmonary hypertension (CpcPH), were used to investigate the cardiac pathophysiology of PH.
The main findings are that:
1) mild right ventricular (RV) dysfunction characterized by reduced RV-PA coupling with preserved cardiac index is a common phenomenon at early-stage PH. This uncoupling was particularly present during exercise.
2) RV O2 delivery is a determinant of RV function during exercise at early-stage CpcPH.
3) TGF-β1 signaling might contribute to the onset of RV dysfunction. In part II of this thesis, a cohort of PH patients was followed to investigate the prognostic values of tryptophan metabolites, including kynurenine metabolites and melatonin.
The main findings are that:
1) Abnormal circulating levels of tryptophan metabolites were correlated with long-term survival in PAH patients.
2) Pro-inflammatory cytokines, especially IL-6/IL-6Ra, induced kynurenine pathway activation similar to that seen in PAH patients in pulmonary vascular cells.
3) Melatonin levels were increased in PAH patients.
However, PAH patients with lower levels of melatonin showed worse long-term survival, which likely was due to the loss of protective properties of melatonin.

Pulmonary Hypertension, Cardiac Pathophysiology, Tryptophan Metabolism, Survival
D.J.G.M. Duncker (Dirk) , D. Merkus (Daphne)
Erasmus University Rotterdam
The studies in this thesis were financially supported by China Scholarship Council (CSC 201606230252); Netherlands Cardiovascular Research Initiative, Dutch Heart Foundation, Dutch Federation of University Medical Centers, Netherlands Organization for Health Research and Development, Royal Netherlands Academy of Science (CVON2012-08, PHAEDRA); Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-11, RECONNECT), Sophia Foundation for Medical Research Grant (S1312, 2012, SSWO, The Netherlands); German Center for Cardiovascular Research (DZHK81Z0600207).
For copyright reasons there is a partial embargo for this dissertation
Laboratory of Experimental Cardiology

Cai, Z. (2020, June 26). Pulmonary Hypertension: Cardiac Pathophysiology and Tryptophan Metabolism. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/127711