Pulmoner Hipertansiyonun Patofizyolojisi
Özet
Pulmoner hipertansiyon (PH), pulmoner vasküler direnç ve pulmoner arter basıncında progresif artış ile karakterize, sağ ventrikül yetmezliği ve erken mortaliteye yol açabilen kompleks bir pulmoner vasküler hastalıktır.Hastalığın patofizyolojisinin temelinde endotel disfonksiyonu, vazokonstriksiyon, vasküler yeniden şekillenme, inflamasyon, trombotik süreçler ile genetik ve moleküler mekanizmaların karşılıklı etkileşimi yer almaktadır. Bu mekanizmaların birlikte etkisi, hastalığın gelişimi ve ilerlemesinden sorumludur.Endotel disfonksiyonu ile birlikte nitrik oksit ve prostasiklin yolaklarında azalma, endotelin yolunda ise artış meydana gelerek vazokonstriksiyon ve vasküler proliferasyon gelişmektedir. Pulmoner vasküler yeniden şekillenme; medial hipertrofi, intimal proliferasyon, fibrozis ve pleksiform lezyon oluşumu ile karakterizedir ve pulmoner vasküler direncin ilerleyici artışına neden olmaktadır.İnflamatuvar hücre infiltrasyonu, sitokin aktivasyonu ve trombotik süreçler vasküler hasarı derinleştirirken, artan afterloada karşı gelişen sağ ventrikül adaptasyonu zamanla maladaptasyona ve sağ kalp yetmezliğine dönüşmektedir.Son yıllarda BMPR2 başta olmak üzere TGF-β sinyal yolundaki bozukluklar ve diğer genetik değişiklikler, hastalığın moleküler temelinin daha iyi anlaşılmasını sağlamış; sotatercept gibi hastalık mekanizmasını hedefleyen yeni tedavilerin geliştirilmesine öncülük etmiştir.Patofizyolojik mekanizmaların ayrıntılı olarak anlaşılması, erken tanı, risk sınıflaması ve hedefe yönelik tedavi yaklaşımlarının geliştirilmesi açısından büyük önem taşımaktadır.
Pulmonary hypertension (PH) is a complex pulmonary vascular disorder characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, ultimately leading to right ventricular failure and premature mortality.The pathophysiology of PH is based on the interaction of endothelial dysfunction, vasoconstriction, vascular remodeling, inflammation, thrombosis, and genetic and molecular mechanisms. The combined effects of these mechanisms drive disease initiation and progressionEndothelial dysfunction is associated with reduced nitric oxide and prostacyclin signaling and increased endothelin activity, promoting vasoconstriction and vascular cell proliferation. Pulmonary vascular remodeling is characterized by medial hypertrophy, intimal proliferation, fibrosis, and plexiform lesion formation, leading to a progressive increase in pulmonary vascular resistance.Inflammatory cell infiltration, cytokine activation, and prothrombotic processes further accelerate vascular injury, while persistent pressure overload initially induces adaptive right ventricular remodeling that eventually progresses to maladaptation and right heart failure.Advances in molecular biology have identified abnormalities in the BMPR2/TGF-β signaling pathway and several additional susceptibility genes, providing important insights into disease pathogenesis and enabling the development of mechanism-based therapies such as sotatercept.A comprehensive understanding of these pathophysiological mechanisms is essential for improving early diagnosis, risk stratification, and targeted therapeutic strategies in patients with pulmonary arterial hypertension.
Referanslar
Kovacs G, Bartolome S, Denton CP, et al. Definition, classification and diagnosis of pulmonary hypertension. Eur Respir J. 2024;64(4):2401324. Published 2024 Oct 31. doi:10.1183/13993003.01324-2024
Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731. doi:10.1093/eurheartj/ehac237
Evans CE, Cober ND, Dai Z, Stewart DJ, Zhao YY. Endothelial cells in the pathogenesis of pulmonary arterial hypertension. Eur Respir J. 2021;58(3):2003957. Published 2021 Sep 2. doi:10.1183/13993003.03957-2020
Benza RL, Grünig E, Sandner P, Stasch JP, Simonneau G. The nitric oxide-soluble guanylate cyclase-cGMP pathway in pulmonary hypertension: from PDE5 to soluble guanylate cyclase. Eur Respir Rev. 2024;33(171):230183. Published 2024 Mar 20. doi:10.1183/16000617.0183-2023
Mandras S, Kovacs G, Olschewski H, et al. Combination Therapy in Pulmonary Arterial Hypertension-Targeting the Nitric Oxide and Prostacyclin Pathways. J Cardiovasc Pharmacol Ther. 2021;26(5):453-462. doi:10.1177/10742484211006531
Manzi G, Mariani MV, Filomena D, et al. Comparative effectiveness of oral therapies targeting the prostacyclin pathway in pulmonary arterial hypertension: A systematic review and network meta-analysis. Vascul Pharmacol. 2024;154:107280. doi:10.1016/j.vph.2024.107280
Olsson KM, Fuge J, Park DH, Kamp JC, Hoeper MM. Withdrawal of prostacyclin pathway therapies after initiation of sotatercept treatment in patients with pulmonary arterial hypertension. Eur Respir J. 2025;65(6):2500064. Published 2025 Jun 5. doi:10.1183/13993003.00064-2025
Feriel B, Alessandra C, Deborah GJ, et al. Exploring the Endothelin-1 pathway in chronic thromboembolic pulmonary hypertension microvasculopathy. Sci Rep. 2024;14(1):28308. Published 2024 Nov 16. doi:10.1038/s41598-024-79623-5
Boucly A, Gerges C, Savale L, et al. Pulmonary arterial hypertension. Presse Med. 2023;52(3):104168. doi:10.1016/j.lpm.2023.104168
Mocumbi A, Humbert M, Saxena A, et al. Pulmonary hypertension. Nat Rev Dis Primers. 2024;10(1):1. Published 2024 Jan 4. doi:10.1038/s41572-023-00486-7
Dai J, Chen H, Fang J, Wu S, Jia Z. Vascular Remodeling: The Multicellular Mechanisms of Pulmonary Hypertension. Int J Mol Sci. 2025;26(9):4265. Published 2025 Apr 30. doi:10.3390/ijms26094265
Lai YC, Potoka KC, Champion HC, Mora AL, Gladwin MT. Pulmonary arterial hypertension: the clinical syndrome. Circ Res. 2014;115(1):115-130. doi:10.1161/CIRCRESAHA.115.301146
Correale M, Mercurio V, Bevere EML, et al. Pathophysiology of Pulmonary Arterial Hypertension: Focus on Vascular Endothelium as a Potential Therapeutic Target. Int J Mol Sci. 2025;26(19):9631. Published 2025 Oct 2. doi:10.3390/ijms26199631
Humbert M, Guignabert C, Bonnet S, et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J. 2019;53(1):1801887. Published 2019 Jan 24. doi:10.1183/13993003.01887-2018
Tello K, Richter MJ, Axmann J, et al. More on Single-Beat Estimation of Right Ventriculoarterial Coupling in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2018;198(6):816-818. doi:10.1164/rccm.201802-0283LE
Vonk Noordegraaf A, Chin KM, Haddad F, et al. Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update. Eur Respir J. 2019;53(1):1801900. Published 2019 Jan 24. doi:10.1183/13993003.01900-2018
Morrell NW, Aldred MA, Chung WK, et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J. 2019;53(1):1801899. Published 2019 Jan 24. doi:10.1183/13993003.01899-2018
Southgate L, Machado RD, Gräf S, Morrell NW. Molecular genetic framework underlying pulmonary arterial hypertension. Nat Rev Cardiol. 2020;17(2):85-95. doi:10.1038/s41569-019-0242-x
Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2023;388(16):1478-1490. doi:10.1056/NEJMoa2213558
