Editorial - June 2021

Dear friends and colleagues,

Unmet needs in PAH in 2021

Pulmonary hypertension (PH) is a progressive clinical condition characterized by an elevated pulmonary arterial pressure and pulmonary vascular resistance leading finally to right heart failure and death. Patients with pulmonary arterial hypertension (PAH = group 1 PH) are hemodynamically characterized by precapillary PH in the absence of other causes, such as lung diseases, chronic thromboembolic disease, or other rare conditions. Obstructive remodelling of the pulmonary vascular bed is the hallmark of PAH which has poor prognosis if left untreated. Some of the major unmet needs in PH in 2021 are listed below:

1. Earlier diagnosis PAH has an insidious onset and course and therefore, reducing time to diagnosis is extremely important. Unfortunately, the time from symptom initiation to diagnosis has remained unchanged at about 2 years. Screening strategies of high-risk populations, such as specific patients with connective tissue disease, use clinical, imaging and biochemical tools to detect early the presence of PAH. However, these screening programs are mostly based in expert centers, performed by a few physicians globally and there is a need to transfer them to primary care and to a broader pool of potential patients. Novel screening tools, such as artificial intelligence with the use of deep learning or novel biomarkers, such as metabolomics may help towards this direction and address the unmet need for earlier PAH detection.
2. Genetics The number of genes associated with PAH has broadened, and therefore, it is difficult to test each of them individually. This issue may be solved by the use of next-generation sequencing which has enabled the development of gene panels which offers testing of numerous genes simultaneously. Studies using genetics/genomics from biobanks are needed in order to generate large-scale genetic data for patients with PAH. Genetic classification of PAH may promote prevention strategies for PAH and prediction of prognosis. Ideally, this will finally lead to the description of additional novel targets for new compounds.
3. Phenotyping in PAH Patient risk assessment and especially their response to therapy is not homogeneous. In specific, the majority of the incident patients with “classical” PAH present a significant improvement with initial double oral combination therapy, however there is a subset of patients who are not responders and require escalation of therapy with oral and even more aggressive therapy with parenteral drugs. It is an urgent need to improve the phenotyping of PAH patients and predict their clinical outcome earlier from the onset of their disease.
4. Better risk stratification using information from the right ventricle. It is known that right ventricle is the main determinant of patient's prognosis in PAH. However, the evaluation of right ventricular function in routine clinical practice has not been integrated into specific imaging parameters that will help to risk stratify patients more accurately. Further studies may shed light on specific cutoff values regarding right ventricular size and function especially using echocardiography.
5. New pathways in the pathophysiology and treatment. Although treatment advances with the use of combination therapy and overall expert care have lengthened survival in PAH, there is a need for the identification of novel pathogenic pathways that may be targeted in the future. Current and future design of more rigorous clinical trials will better define the efficacy and safety of potential new treatments and their position in the PAH treatment algorithms.
6. Drug therapy in mild PAH The updated proposed haemodynamic definition of PH has revised and lowered the threshold of mean pulmonary artery pressure from ≥25 mmHg to >20 mmHg. However, it remains to be seen whether providing targeted medical treatment in “mild PAH” early in the course of the disease improves long-term outcome.
7. Reinforce the patient perspective The engagement of PAH patients in decision making, their education and support of their needs will definitely improve holistic care and their health-related quality of life.

Stay strong and stay safe

On behalf of the Working Group Nucleus

George Giannakoulas & Piotr Pruszczyk