Pulmonary arterial hypertension: promising advances and remaining challenges
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* Karim El-Kersh
* John D Dickinson

*   hypertension
*   pulmonary

Pulmonary arterial hypertension (PAH) diagnosis and management have evolved over the years. Despite advances in management that resulted in an overall improvement of disease outcomes, there remain challenges to be addressed, including more accurate disease phenotyping, earlier diagnosis with better screening, and novel therapeutic approaches. In this issue of the *Journal of Investigative Medicine*, Deshwal1 review the changing landscape of PAH with a special emphasis on clinical risk assessment as a tool to guide treatment options.

Further disease phenotyping is needed beyond the current Sixth World Symposium on Pulmonary Hypertension subgroups to better understand the disease and response to therapies.2 The Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics program aims to compare ‘omics’ data to better phenotype patients with pulmonary vascular disease to advance a precision medicine approach.3 4 The lack of consistent response to multiple PAH-specific therapies across the PAH spectrum may be due to our lack of complete understanding of the heterogeneity of patients with PAH and disease subtypes. Using omics approaches to predict treatment responders would go a long way to increasing the benefit of drug treatment while limiting adverse effects.

Earlier diagnosis and referral to specialized pulmonary hypertension centers is still a challenge. A significant number of patients with PAH have symptoms for >2 years before diagnosis.5 Furthermore, the mean pulmonary artery pressure among the participants in the ABMITION trial, which focused on incident PAH, was about 49 mm Hg, reflecting a missed gap for earlier diagnosis.6 One barrier to earlier diagnosis is the non-specific symptoms associated with PAH onset which overlap with symptoms of other cardiopulmonary diseases. Recent advances in MRI using hyperpolarized 129Xe gas and dynamic spectroscopy showed promising results with the ability to identify unique signatures for PAH, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and left heart failure, and have the potential to be used as a possible non-invasive sensitive probe for earlier diagnosis.7 

Deshwal1 correctly point out that PAH risk stratification is a powerful management tool that is still underutilized partly due to the multitude and complexity of scoring systems.8 REVEAL Lite 2, an abridged version of REVEAL 2.0, may mitigate some potential barriers of risk assessment in clinical practice by only using six non-invasive modifiable variables that include functional class, 6 min walk distance, brain natriuretic peptide/N-terminal prohormone of brain natriuretic peptide level, vital signs (systolic blood pressure and heart rate), and renal insufficiency.9 Including right ventricular imaging data may augment current risk scores as these can possibly predict disease progression in seemingly clinically stable patients.10 More recently, risk stratification using Bayesian analysis was used to develop the Pulmonary Hypertension Outcomes Risk Assessment with improved discrimination of risk stratification that outperformed REVEAL 2.0.11 Risk stratification strategy can inform PAH clinical trials to ensure balanced randomization, to serve as a meaningful primary end point, and to help clinical trials enrichment to reduce sample size, trial length, and cost.12 

The area of therapeutics continues to evolve with several advances in treatment options and delivery methods. Intravenous selexipag was recently approved as a bridge for patients on oral selexipag who are temporarily unable to take oral therapy.13 A fully implantable system for treprostinil delivery can potentially improve the quality of life of patients with PAH.14 INSPIRE and BREEZE trials ([NCT03950739](/lookup/external-ref?link\_type=CLINTRIALGOV&access_num=NCT03950739&atom=%2Fjim%2F69%2F7%2F1268.atom)) are offering inhaled treprostinil in a dry powder formulation through newer delivery systems that are more portable and convenient to patients with PAH.15 A phase II/III study is currently evaluating a once-daily inhaled soluble guanylate cyclase stimulator (MK-5475-007) in patients with PAH ([NCT04732221](/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04732221&atom=%2Fjim%2F69%2F7%2F1268.atom)). The Remunity pump is a new delivery system for subcutaneous treprostinil that uses prefilled disposable cassettes with several safety features. As highlighted by Deshwal,1 sotatercept is a step forward on the right path to target novel treatment pathways in PAH.16 Finally, despite the advances in therapy and delivery systems, treatments that target the right ventricle to improve its function are urgently needed as the right ventricular function is a major determinant of PAH outcome.17 

## Ethics statements

### Patient consent for publication

Not required.

## Footnotes

*   Contributors KE-K wrote the editorial. JDD edited and revised the editorial.

*   Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

*   Competing interests KE-K served on advisory boards for United Therapeutics and Actelion and as consultant for Acceleron Pharma, and received institutional funded research from United Therapeutics and Actelion.

*   Provenance and peer review Commissioned; externally peer reviewed.

## References

1.   Deshwal H , Weinstein T , Sulica R . Advances in the management of pulmonary arterial hypertension. J Investig Med 2021;69:1270–80.[doi:10.1136/jim-2021-002027](http://dx.doi.org/10.1136/jim-2021-002027) 
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiamltIjtzOjU6InJlc2lkIjtzOjk6IjY5LzcvMTI3MCI7czo0OiJhdG9tIjtzOjE5OiIvamltLzY5LzcvMTI2OC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

2.   Simonneau G , Montani D , Celermajer DS , et al . Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019;53:1801913.[doi:10.1183/13993003.01913-2018](http://dx.doi.org/10.1183/13993003.01913-2018) pmid:http://www.ncbi.nlm.nih.gov/pubmed/30545968 
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiZXJqIjtzOjU6InJlc2lkIjtzOjEyOiI1My8xLzE4MDE5MTMiO3M6NDoiYXRvbSI7czoxOToiL2ppbS82OS83LzEyNjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

3.   Hemnes AR , Beck GJ , Newman JH , et al . PVDOMICS: a multi-center study to improve understanding of pulmonary vascular disease through phenomics. Circ Res 2017;121:1136–9.[doi:10.1161/CIRCRESAHA.117.311737](http://dx.doi.org/10.1161/CIRCRESAHA.117.311737) pmid:http://www.ncbi.nlm.nih.gov/pubmed/29074534 
    
    [FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6ImNpcmNyZXNhaGEiO3M6NToicmVzaWQiO3M6MTE6IjEyMS8xMC8xMTM2IjtzOjQ6ImF0b20iO3M6MTk6Ii9qaW0vNjkvNy8xMjY4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

4.   Tang WHW , Wilcox JD , Jacob MS , et al . Comprehensive diagnostic evaluation of cardiovascular physiology in patients with pulmonary vascular disease: insights from the PVDOMICS program. Circ Heart Fail 2020;13:e006363. [doi:10.1161/CIRCHEARTFAILURE.119.006363](http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006363) pmid:http://www.ncbi.nlm.nih.gov/pubmed/32088984 
    
    [PubMed](/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fjim%2F69%2F7%2F1268.atom) 

5.   McGoon MD , Miller DP . Reveal: a contemporary us pulmonary arterial hypertension registry. Eur Respir Rev 2012;21:8–18.[doi:10.1183/09059180.00008211](http://dx.doi.org/10.1183/09059180.00008211) pmid:http://www.ncbi.nlm.nih.gov/pubmed/22379169 
    
    [FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NToiZXJyZXYiO3M6NToicmVzaWQiO3M6ODoiMjEvMTIzLzgiO3M6NDoiYXRvbSI7czoxOToiL2ppbS82OS83LzEyNjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

6.   Galiè N , Barberà JA , Frost AE , et al . Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 2015;373:834–44.[doi:10.1056/NEJMoa1413687](http://dx.doi.org/10.1056/NEJMoa1413687) pmid:http://www.ncbi.nlm.nih.gov/pubmed/26308684 
    
    [CrossRef](/lookup/external-ref?access_num=10.1056/NEJMoa1413687&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=26308684&link_type=MED&atom=%2Fjim%2F69%2F7%2F1268.atom) 

7.   Wang Z , Bier EA , Swaminathan A , et al . Diverse cardiopulmonary diseases are associated with distinct xenon magnetic resonance imaging signatures. Eur Respir J 2019;54:1900831.[doi:10.1183/13993003.00831-2019](http://dx.doi.org/10.1183/13993003.00831-2019) pmid:http://www.ncbi.nlm.nih.gov/pubmed/31619473 
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiZXJqIjtzOjU6InJlc2lkIjtzOjEyOiI1NC82LzE5MDA4MzEiO3M6NDoiYXRvbSI7czoxOToiL2ppbS82OS83LzEyNjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

8.   Wilson M , Keeley J , Kingman M , et al . Current clinical utilization of risk assessment tools in pulmonary arterial hypertension: a descriptive survey of facilitation strategies, patterns, and barriers to use in the United States. Pulm Circ 2020;10:2045894020950186. [doi:10.1177/2045894020950186](http://dx.doi.org/10.1177/2045894020950186) pmid:http://www.ncbi.nlm.nih.gov/pubmed/33062258 
    
    [PubMed](/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fjim%2F69%2F7%2F1268.atom) 

9.   Benza RL , Kanwar MK , Raina A , et al . Development and validation of an abridged version of the reveal 2.0 risk score calculator, reveal Lite 2, for use in patients with pulmonary arterial hypertension. Chest 2021;159:337–46.[doi:10.1016/j.chest.2020.08.2069](http://dx.doi.org/10.1016/j.chest.2020.08.2069) pmid:http://www.ncbi.nlm.nih.gov/pubmed/32882243 
    
    [PubMed](/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fjim%2F69%2F7%2F1268.atom) 

10.  van de Veerdonk MC , Marcus JT , Westerhof N , et al . Signs of right ventricular deterioration in clinically stable patients with pulmonary arterial hypertension. Chest 2015;147:1063–71.[doi:10.1378/chest.14-0701](http://dx.doi.org/10.1378/chest.14-0701) pmid:http://www.ncbi.nlm.nih.gov/pubmed/25376008 
    
    [CrossRef](/lookup/external-ref?access_num=10.1378/chest.14-0701&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=25376008&link_type=MED&atom=%2Fjim%2F69%2F7%2F1268.atom) 

11.  Kanwar MK , Gomberg-Maitland M , Hoeper M , et al . Risk stratification in pulmonary arterial hypertension using Bayesian analysis. Eur Respir J 2020;56:2000008.[doi:10.1183/13993003.00008-2020](http://dx.doi.org/10.1183/13993003.00008-2020) pmid:http://www.ncbi.nlm.nih.gov/pubmed/32366491 
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiZXJqIjtzOjU6InJlc2lkIjtzOjEyOiI1Ni8yLzIwMDAwMDgiO3M6NDoiYXRvbSI7czoxOToiL2ppbS82OS83LzEyNjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

12.  Scott JV , Garnett CE , Kanwar MK , et al . Enrichment benefits of risk algorithms for pulmonary arterial hypertension clinical trials. Am J Respir Crit Care Med 2021;203:726–36.[doi:10.1164/rccm.202002-0357OC](http://dx.doi.org/10.1164/rccm.202002-0357OC) pmid:http://www.ncbi.nlm.nih.gov/pubmed/32937078 
    
    [PubMed](/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fjim%2F69%2F7%2F1268.atom) 

13.  Klose H , Chin KM , Ewert R , et al . Temporarily switching from oral to intravenous selexipag in patients with pulmonary arterial hypertension: safety, tolerability, and pharmacokinetic results from an open-label, phase III study. Respir Res 2021;22:34. [doi:10.1186/s12931-020-01594-8](http://dx.doi.org/10.1186/s12931-020-01594-8) pmid:http://www.ncbi.nlm.nih.gov/pubmed/33536021 
    
    [PubMed](/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fjim%2F69%2F7%2F1268.atom) 

14.  Shapiro S , Bourge RC , Pozella P , et al . Implantable system for treprostinil: a real-world patient experience study. Pulm Circ 2020;10:2045894020907881. [doi:10.1177/2045894020907881](http://dx.doi.org/10.1177/2045894020907881) pmid:http://www.ncbi.nlm.nih.gov/pubmed/32363029 
    
    [PubMed](/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fjim%2F69%2F7%2F1268.atom) 

15.  Roscigno R , Vaughn T , Anderson S , et al . Pharmacokinetics and tolerability of LIQ861, a novel dry-powder formulation of treprostinil. Pulm Circ 2020;10:2045894020971509. [doi:10.1177/2045894020971509](http://dx.doi.org/10.1177/2045894020971509) pmid:http://www.ncbi.nlm.nih.gov/pubmed/33282202 
    
    [PubMed](/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fjim%2F69%2F7%2F1268.atom) 

16.  Humbert M , McLaughlin V , Gibbs JSR , et al . Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med 2021;384:1204–15.[doi:10.1056/NEJMoa2024277](http://dx.doi.org/10.1056/NEJMoa2024277) pmid:http://www.ncbi.nlm.nih.gov/pubmed/33789009 
    
    [PubMed](/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fjim%2F69%2F7%2F1268.atom) 

17.  van de Veerdonk MC , Kind T , Marcus JT , et al . Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 2011;58:2511–9.[doi:10.1016/j.jacc.2011.06.068](http://dx.doi.org/10.1016/j.jacc.2011.06.068) pmid:http://www.ncbi.nlm.nih.gov/pubmed/22133851 
    
    [FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6MzoiUERGIjtzOjExOiJqb3VybmFsQ29kZSI7czo0OiJhY2NqIjtzOjU6InJlc2lkIjtzOjEwOiI1OC8yNC8yNTExIjtzOjQ6ImF0b20iO3M6MTk6Ii9qaW0vNjkvNy8xMjY4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==)