Cardiovascular medicine : towards a molecular classification of pulmonary hypertension

• Main Author: Wilkins, Martin
• Format: Dissertation
• Language: English
• Published: Imperial College London 2023

Introduction: The healthy adult pulmonary circulation is a low resistance vascular bed, with a mean resting pulmonary artery pressure (mPAP) of 14.0±3.3 mmHg. The first world symposium on the subject in 1973 accepted a mPAP =25mmHg as an arbitrary definition of pulmonary hypertension. This was revised to >20mmHg in 2018, in part recognising that elevated mPAP represents a continuum of risk, with measured evidence of increased mortality beginning at 19mmHg relative to 10mmHg². The 1973 symposium acknowledged that pulmonary hypertension occurs most commonly in association with lung and left heart disease, but the focus of the meeting was the pathology, clinical features and epidemiology of the more rare presentation of pulmonary hypertension of unknown cause, termed primary pulmonary hypertension. A clinical classification of chronic pulmonary heart disease was provided in Annex 1 of the symposium record, with 3 categories based on diseases primarily affecting airways, the thoracic cage and the pulmonary vasculature, respectively. This was revisited and developed further 25 years later at what is recognised as the second world symposium. Here the clinical presentations of pulmonary hypertension were sorted into 5 main categories and the term pulmonary arterial hypertension or PAH was introduced to replace primary pulmonary hypertension. At the third world symposium in 2003, the classification was widely regarded as useful for clinical and epidemiological purposes, less so for research. The current clinical classification, visited in 2018, still holds to the 5 major category structure but is increasingly challenged by observations from molecular science. Patients do not always fit easily into one of the main categories. Not only is there overlap between them, but clinical heterogeneity is present within each category. This lack of precision arises from a lack of understanding of the molecular drivers of pulmonary hypertension and impairs novel drug development. For the past 20 years, my research has been directed at discovering and exploiting the molecular drivers of pulmonary hypertension and has tested the established clinical classification, with a view to providing a better tailored, more personalised approach to the management of the condition. Over-arching hypothesis: The hypothesis that underpins my research is that deep molecular phenotyping of patients presenting with a clinical diagnosis of pulmonary hypertension will identify subgroups that share one or more druggable disease-associated pathways and accessible biomarkers of response to treatment.