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Reviews in Cardiovascular Medicine  2020, Vol. 21 Issue (2): 163-179     DOI: 10.31083/j.rcm.2020.02.597
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Current and emerging therapeutic approaches to pulmonary hypertension
Malik Bisserier1, *(), Natasha Pradhan1, Lahouaria Hadri1
1Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Pulmonary arterial hypertension (PAH) is a progressive and fatal lung disease of multifactorial etiology. Most of the available drugs and FDA-approved therapies for treating pulmonary hypertension attempt to overcome the imbalance between vasoactive and vasodilator mediators, and restore the endothelial cell function. Traditional medications for treating PAH include the prostacyclin analogs and receptor agonists, phosphodiesterase 5 inhibitors, endothelin-receptor antagonists, and cGMP activators. While the current FDA-approved drugs showed improvements in quality of life and hemodynamic parameters, they have shown only very limited beneficial effects on survival and disease progression. None of them offers a cure against PAH, and the median survival rate remains less than three years from diagnosis. Extensive research efforts have led to the emergence of innovative therapeutic approaches in the area of PAH. In this review, we provide an overview of the current FDA-approved therapies in PAH and discuss the associated clinical trials and reported-side effects. As recent studies have led to the emergence of innovative therapeutic approaches in the area of PAH, we also focus on the latest promising therapies in preclinical studies such as stem cell-based therapies, gene transfer, and epigenetic therapies.

Key words:  Pulmonary hypertension      FDA      clinical trial      treatment      gene therapy      epigenetics     
Submitted:  19 November 2019      Revised:  22 May 2020      Accepted:  25 May 2020      Published:  30 June 2020     
Fund: NIH R01 HL133554;AHA Innovative Project Award 18IPA34170321;NIH 5T32HL007824-22;Cardiovascular Medical Research and Education Fund (CMREF)
*Corresponding Author(s):  Malik Bisserier     E-mail:

Cite this article: 

Malik Bisserier, Natasha Pradhan, Lahouaria Hadri. Current and emerging therapeutic approaches to pulmonary hypertension. Reviews in Cardiovascular Medicine, 2020, 21(2): 163-179.

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Figure 1.  Updated classification of pulmonary hypertension. This classification is based on recommendations from the 5th World Symposium on Pulmonary Hypertension in Nice, France, 2013. The World Health Organization classifies PAH into five broad groups of pulmonary hypertension based on the clinical similarities. The five groups of PH are: 1-PAH, 2-PH associated with left heart disease, 3- PH associated with chronic lung disease and/or hypoxia, 4- chronic thromboembolic PH (CTEPH) and 5- PH with unclear or multifactorial mechanisms.

Figure 2.  Pathogenesis of pulmonary hypertension. PAH is characterized by a vascular remodeling of distal pulmonary arteries, vasoconstriction, endothelial dysfunction, inflammation and thrombosis leading to the formation of plexiform lesions. Proliferation and migration of pulmonary endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) contribute to the vascular muscularization and obstruction, which progressively increase vascular resistance in PAH and induce right ventricle (RV) hypertrophy and ultimately RV dysfunction.

Figure 3.  Pathways targeted by the current FDA-approved PAH therapies. FDA-approved PAH therapies target mostly three major pathways: prostacyclin, endothelin (ET), nitric oxide (NO). They fall into four categories: 1- Prostacyclin Analogues and receptor agonists (epoprostenol, tetroprostinil, iloprost, selexipag), 2- Phosphodiesterase 5 inhibitors (sildenafil, tadalafil), 3- ET receptor antagonists (ambrisentan, bosentan, macitentan), 4- cGMP activators (riociguat).

Figure 4.  Stem cell-based therapy, gene transfer and epigenetic therapy as promising innovative strategies for treating pulmonary hypertension. Recent preclinical studies suggested that stem cell-based therapies, gene transfer and epigenetic-based therapies may offer a new perspective in the treatment of PAH. Administration of endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), intratracheal administration of inhaled-adenovirus encoding for BMPR2 or gene delivery of adeno-associated virus (AAV) serotype 1 encoding for human SERCA2a prevented and reversed the development of PH in preclinical animal models of PAH by blocking cardiac/arterial remodeling and improving hemodynamic abnormalities (RVSP, mPAP). Increasing evidence suggests that epigenetic-based therapies, such as DNMT, HDAC and BET inhibitors, may be of great therapeutic potential for treating PAH.

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