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Peer-reviewedCC BY 4.0Journal of Clinical Medicine

Beyond Vasodilation in Pulmonary Arterial Hypertension: Integrating Remodeling-Directed Therapies into Risk-Guided Management

  • Ahmad Kharoufeh1
  • Ahmad Omari1
  • Bassam Awad1
  • Mohamedanas Mohamedfaruk Patni2
  • Shadha Nasser BaHutair3
  • Haidy Alzaghal1
  • Hammad Alqedrh1
  • Ashfaq Ahmad Shah Bukhari4
  • Hafiz Ahmad5
5 affiliations
  1. 1RAK College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
  2. 2Department of Community Medicine, RAK College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
  3. 3Department of Obstetrics and Gynecology, RAK College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
  4. 4Department of Physiology, RAK College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
  5. 5Department of Microbiology, RAK College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
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Abstract

Background/Objectives: Pulmonary arterial hypertension (PAH) management is evolving beyond conventional vasoactive therapies toward strategies targeting pathways implicated in pulmonary vascular remodeling. Despite advances in combination therapy, substantial residual risk persists. The clinical introduction of sotatercept, targeting activin signaling, has expanded the therapeutic landscape. This narrative review critically evaluates the evidence supporting remodeling-directed treatment and examines how established recommendations, individualized therapeutic considerations, and investigational strategies can be distinguished within risk-guided PAH management. Methods: Clinical, translational, and mechanistic evidence was narratively synthesized, prioritizing randomized controlled trials, prospective investigations, major guidelines, and relevant mechanistic studies. Particular attention was given to differences in trial populations, endpoints, background treatment, safety, and evidence maturity. Results: Sotatercept has demonstrated incremental clinical benefits across functional, hemodynamic, and clinical-outcome measures in studied PAH populations, although trial heterogeneity limits indirect comparisons and long-term disease modification remains unproven. Other remodeling-directed approaches, including growth-factor inhibition, BMPR2 restoration, immune modulation, and metabolic targeting, remain investigational, with variable and frequently preliminary evidence. The proposed synthesis distinguishes guideline-supported therapeutic escalation from individualized clinical considerations and research hypotheses, emphasizing residual risk, treatment tolerability, and demonstrated incremental benefit. Conclusions: Remodeling-directed therapy expands the treatment options for PAH but does not replace established vasoactive treatment or risk-based escalation. Future priorities include defining optimal therapeutic sequencing, identifying responsive patient populations, and determining whether sustained clinical improvements translate into modification of disease progression.

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Cite

BibTeXRIS
BibTeX
@article{kharoufeh2026beyond,
  title = {{Beyond Vasodilation in Pulmonary Arterial Hypertension: Integrating Remodeling-Directed Therapies into Risk-Guided Management}},
  author = {Ahmad Kharoufeh and Ahmad Omari and Bassam Awad and Mohamedanas Mohamedfaruk Patni and Shadha Nasser BaHutair and Haidy Alzaghal and Hammad Alqedrh and Ashfaq Ahmad Shah Bukhari and Hafiz Ahmad},
  journal = {Journal of Clinical Medicine},
  year = {2026},
  month = nov,
  doi = {10.3390/jcm15218621},
  url = {https://www.mdpi.com/2077-0383/15/21/8621},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Beyond Vasodilation in Pulmonary Arterial Hypertension: Integrating Remodeling-Directed Therapies into Risk-Guided Management
AU  - Ahmad Kharoufeh
AU  - Ahmad Omari
AU  - Bassam Awad
AU  - Mohamedanas Mohamedfaruk Patni
AU  - Shadha Nasser BaHutair
AU  - Haidy Alzaghal
AU  - Hammad Alqedrh
AU  - Ashfaq Ahmad Shah Bukhari
AU  - Hafiz Ahmad
PY  - 2026
DA  - 2026/11/05
JO  - Journal of Clinical Medicine
DO  - 10.3390/jcm15218621
UR  - https://www.mdpi.com/2077-0383/15/21/8621
AB  - Background/Objectives: Pulmonary arterial hypertension (PAH) management is evolving beyond conventional vasoactive therapies toward strategies targeting pathways implicated in pulmonary vascular remodeling. Despite advances in combination therapy, substantial residual risk persists. The clinical introduction of sotatercept, targeting activin signaling, has expanded the therapeutic landscape. This narrative review critically evaluates the evidence supporting remodeling-directed treatment and examines how established recommendations, individualized therapeutic considerations, and investigational strategies can be distinguished within risk-guided PAH management. Methods: Clinical, translational, and mechanistic evidence was narratively synthesized, prioritizing randomized controlled trials, prospective investigations, major guidelines, and relevant mechanistic studies. Particular attention was given to differences in trial populations, endpoints, background treatment, safety, and evidence maturity. Results: Sotatercept has demonstrated incremental clinical benefits across functional, hemodynamic, and clinical-outcome measures in studied PAH populations, although trial heterogeneity limits indirect comparisons and long-term disease modification remains unproven. Other remodeling-directed approaches, including growth-factor inhibition, BMPR2 restoration, immune modulation, and metabolic targeting, remain investigational, with variable and frequently preliminary evidence. The proposed synthesis distinguishes guideline-supported therapeutic escalation from individualized clinical considerations and research hypotheses, emphasizing residual risk, treatment tolerability, and demonstrated incremental benefit. Conclusions: Remodeling-directed therapy expands the treatment options for PAH but does not replace established vasoactive treatment or risk-based escalation. Future priorities include defining optimal therapeutic sequencing, identifying responsive patient populations, and determining whether sustained clinical improvements translate into modification of disease progression.
SN  - 2077-0383
ER  -