Pulmonary arterial hypertension (PAH) is a devastating and life-threatening disease that is associated with high morbidity and mortality. The disease is characterised by increased pulmonary arterial pressure; the blood pressure of the arteries found in the lungs. This increase in pressure is due to the progressive narrowing and obliteration of these blood vessels, often leading in failure of the right ventricle of the heart.
Current treatments for PAH utilise vasodilators to lessen the effects of the narrowing of the blood vessels and reduce blood pressure. However, a major breakthrough in our understanding of the molecular basis of PAH has been the identification of mutations, or changes, in important genes involved in the normal function of the lung vasculature. Mutations in the gene encoding bone morphogenetic protein type II receptor (BMPR2) have, to date been the most important genetic mutation identified, present in the majority (75%) of heritable PAH cases and approximately 11-44% of idiopathic cases (Dunmore et al). Such mutations result in a significantly reduced amount of this receptor on key cells in the pulmonary vasculature, the result of which is disruption of the normal cellular events and the subsequent development of vascular disease. Extensive research now exists on the role of BMPR2 in the development of PAH and pre-clinical findings support the targeting of BMPR2 as a potential treatment, however there are currently no therapeutics targeting the receptor in development.
To define the optimal biological biomarker end point of BMPR2 target engagement we will assess two study populations over a longitudinal time-course using peripheral blood samples.
Samples will be taken from a patient population with idiopathic or hereditary pulmonary arterial hypertension (n=17) and healthy volunteers (n=30) who will act as a control group.
Recruitment of healthy volunteers will be targeted at female aged 30-40 years as this is in line with the demographics of a typical PAH patient cohort. Blood samples will be collected from the control group across a total of 6 time points; the first 5 samples will be offered on a weekly basis with a final blood sample taken at 4 months. Sampling on weeks 2, 3, 4 and 16 will be optional. The expected duration for healthy volunteers is a total of 5 weeks with no follow up.
PAH participants will be sampled during routine clinic reviews over a four-month time period. Sampling will occur at separate two distinct time-points, three to six months apart. IPAH/HPAH participants will be recruited based upon their diagnosis and will be in WHO functional class I-IV and on stable medication or have unchanged PAH for at least one month prior to screening. The total duration for participants in this group will be approximately 3-6 months (typically 4 months), dependent on scheduling of clinical visits.
This will provide critical information for a future RCT testing two novel therapies with the potential to improve survival and quality of life for people diagnosed with PAH by providing a personalised approach to treatment.
