The 3 treatment pathways in Pulmonary arterial hypertension (PAH)
Treatment for Pulmonary arterial hypertension (PAH) centres around three substances that are produced by the inner layer of the smaller blood vessels in the lungs. These three substances are nitric oxide, endothelin, and prostacyclin. When you have the right amount of each of these substances, they keep your blood vessels healthy. This allows red blood cells to flow freely through the lungs and transport oxygen to the rest of the body.
Nitric Oxide, Endothelin and Prostacyclin
- Nitric oxide, the first of the three important substances, helps ensure blood vessels stay open and that blood is flowing properly. People with PAH have too little nitric oxide.
- Endothelin is the second important substance related to PAH. Endothelin causes blood vessels to contract. However, people with PAH have too much endothelin.
- Prostacyclin is the third important substance in PAH. It helps blood vessels stay open, helps prevent clotting, and slows down the rapid cell growth, which can prevent vessels from becoming too thick. People with PAH have too little prostacyclin.
When all of these substances are at the correct levels, blood flows normally, but if there is excess endothelin and too little prostacyclin or nitric oxide, the natural balance is disrupted and causes the blood vessels to thicken and narrow.
Researchers have used knowledge about how these substances work to develop medicines that mimic what a healthy body does naturally.
Each medication class treats one of the three pathways: the nitric oxide pathway, the endothelin pathway, or the prostacyclin pathway.
Medications that treat the nitric oxide pathway, Phosphodiesterase Inhibitors (PDE 5 Inhibitors), help keep the blood vessels open and blood flowing freely. These medications include:
- Sildenafil (Revatio™)
- Sildenafil (Revatio™) for Pediatric Use
- Tadalafil (Adcirca®)
Medications that treat the endothelin pathway block the extra endothelin in patients with PAH to help stop the blood vessels from contracting. These medications include:
- Ambrisentan (Letairis®)
- Bosentan (Tracleer®)
- Bosentan (Tracleer®) for Pediatric Use
- Macitentan (Opsumit®)
Medications that treat the prostacyclin pathway help keep the blood vessels open and prevent clotting. These medications are available in tablet, inhaled, and Intravenous forms. Medications include:
- Iloprost (Ventavis®)
- Inhaled Treprostinil (Tyvaso®)
- Intravenous Treprostinil (Remodulin®)
- Epoprostenol (Flolan®)
- Room Temperature Stable Epoprostenol (Veletri®)
Currently there is no test to see which treatment pathway would be best for patients. Unfortunately, for many patients, treating PAH with only one of the three drug therapies is not sufficient. Using treatments from the different pathways in combination is usually recommended by experts for patients who are just starting treatment as well as for those who are already being treated with one of the three classes.
Lung or Heart Transplant
Lung or heart transplants are treatment options for patients who are not improving on other medical treatments.
While transplants can prolong life and improve quality of life, a transplant also offers a potential cure for PAH. It does, however, carry the risk of significant complications. There are many factors to be considered before proceeding with a transplant.
Potts shunt procedure
Children with severe PH, who have not responded to medical treatment have limited treatment options and can die from right heart failure. A surgical procedure known as a Potts shunt is an old technique that shows promise as an alternative therapy for treating children with severe, drug-resistant PH, possibly delaying or even negating the need for lung transplantation.
A Potts shunt is a side-to-side connection from the left pulmonary artery to the descending aorta, this diverts some of the high pressure pulmonary blood to escape out to the body without having to go through the damaged lungs. A Potts shunt provides a pressure release for the right ventricle, hopefully preserving its function.
Research & new developments in treatments for Pulmonary arterial hypertension (PAH)
BMPR2 Gene Mutation
Scientists are now looking at genetic ways to treat the disease. This is where the Dinosaur Trust is heavily focusing funding. We work in particular with the BMPR2 gene mutation which is often found in patients that have idiopathic pulmonary arterial hypertension. More information on the research projects we have been involved can be found here.
CrispR Cas9
The real promise of CrispR cas9 is for treating diseases caused by genetic mutations, there is ongoing research into inherited, rare gene mutations and PAH including a project through the University of Giessen, funded by The Dinosaur Trust. To read more about the CRISPR/Cas9 research study we are funding click here
Acceleron – Sotatercept
Sotatercept is an investigational product being studied in patients with pulmonary arterial hypertension (PAH).
Sotatercept is a ligand trap with high selectivity for multiple proteins within the TGF-beta superfamily, including activins, GDFs, and others. With its believed ability to block the TGF-beta superfamily signaling pathway, sotatercept could promote a rebalancing of bone morphogenetic protein receptor type II (BMPR-II) signaling and, potentially, restore vascular homeostasis. In preclinical research published in Science Translational Medicine, sotatercept exhibited consistent effects across multiple components of disease, including suppressed proliferation of pulmonary arterial smooth muscle and microvascular endothelial cells, reduced pulmonary pressures, lessened right ventricular hypertrophy, improved right ventricular function, and attenuated vascular remodelling.
Sotatercept studies are ongoing.
To read the full article about Sotatercept please click here to visit Acceleron’s website.
Working with Great Ormond Street Hospital
At The Dinosaur Trust we realise how essential communication is between institutions and researchers around the world.
To aid this communication, we fund two research posts at Great Ormond Street Hospital.
Our aim is to speed up and improve the quality of information about specific treatments for pulmonary arterial hypertension and pulmonary hypertension together with scientific advances, making best use of research being done. This allows the patients at GOSH to benefit from global research and cutting edge treatments.
Disclaimer: It is not the intention of The Dinosaur Trust to provide medical advice, diagnosis or treatment. This content is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your Doctor or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on our pages or on a website.