Discovery of a new biomarker for pulmonary arterial hypertension

by Adrienne Mueller, PhD
August 4, 2021

Your pulmonary artery carries blood that is low in oxygen from your heart to your lungs, where gas exchange can occur – removing the CO2 and replenishing the oxygen. Pulmonary arterial hypertension (PAH) is a chronic disorder in which the walls of your pulmonary artery progressively thicken, making it harder for blood to reach your lungs and for you to renew the oxygen supply to your body. As your right heart struggles to meet the lung’s demands, the heart tissue is increasingly taxed, and PAH often culminates in right heart failure and, ultimately, death.

What causes PAH? Research to answer this question is ongoing, but a well-recognized feature of the disease is persistent inflammation. Prolonged activation of your immune response, inflammation, can ultimately trigger the release of growth factors that cause vascular cells to grow and multiply. Proliferation of the vascular cells of the pulmonary artery cause the artery to thicken. Previous work has shown that some of the immune cells active in the inflammatory response release a protein called neutrophil elastase (NE). Additional studies suggest that NE is a likely candidate for triggering the vascular changes underlying PAH.

If NE is contributing to PAH, blocking it may help relieve symptoms. Elafin is a protein that does just that – it inhibits NE. In order to better understand the relationship between NE, Elafin, and PAH, a collaboration of labs from Stanford, Cambridge and Imperial College London, led by Roham Zamanian MD, recently conducted a study to determine whether circulating NE and Elafin levels are abnormal in individuals with PAH, and, if so, whether the levels are correlated with clinical severity. This study is part of program project grant given to Marlene Rabinovitch, MD as lead PI to bring Elafin to the clinic for pulmonary arterial hypertension. PAH consensus statements have called for the development of biomarkers relevant to drug mechanisms and disease states during the early investigation phases of new therapies, so as to promote the design of efficient, biomarker-informed later phase clinical trials.  The findings of the current study, first authored by Andrew Sweatt, MD, were recently reported in Chest.

In the first ever analysis of NE and Elafin in PAH, Sweatt et al compared NE and Elafin levels in a cohort of almost 249 Stanford PAH patients and 106 healthy controls - and related those levels to clinical features of the disease. The findings of the Stanford cohort were further validated in two additional cohorts in the United Kingdom. The investigators discovered that higher levels of NE were associated with worse PAH symptoms and a higher risk of mortality – meaning NE is an ideal biomarker for PAH severity. The investigators further showed that levels of Elafin, an NE inhibitor, were significantly lower in PAH patients – no matter which type of PAH the patient suffered from. The combination of excessive NE coupled with an Elafin deficiency suggests that in PAH patients excessive NE is not being adequately counterbalanced by Elafin.

Figure 1: PAH patients have significantly higher levels of NE (neutrophil elastase) and significantly lower levels of Elafin, an NE inhibitor.

Sweatt et al have now shown that NE levels are associated with disease severity and progression, making it an ideal candidate as a biomarker for testing for this disease, evaluating disease severity, and developing new therapies. The Zamanian and Rabinovitch labs are currently engaged in a phase 1 clinical trial to test Elafin therapy for PAH and NE will be an invaluable means of predicting treatment not only in this clinical trial, but other therapeutic trials for PAH that follow.  

Additional Cardiovascular Institute-affiliated authors who contributed to this study include Kazuya Miyagawa, Shalina Taylor, Patricia A Del Rosario, Andrew Hsi, Francois Haddad, Edda Spiekerkoetter, Michal B Roof, Richard D Bland, Mark R Nicolls, and Marlene Rabinovitch.

Dr. Andrew Sweatt

Dr. Marlene Rabinovitch

Dr. Roham Zamanian