Pulmonary hypertension (PH) is a serious condition characterised by elevated blood pressure within the pulmonary arteries. The pulmonary arteries are responsible for carrying blood from the right-hand side of the heart to the lungs. It has been estimated that PH may affect about 1% of the global population, and this may increase to 10% in those aged over 65 [1].
As PH progresses the walls of the pulmonary artery become thickened and stiffer, making it increasingly more difficult for blood to pass through to the lungs [2]. This reduced blood flow means the right side of the heart has to work harder [2]. Over time this can cause damage to the heart muscle and lead to right-sided heart failure [2]. Other symptoms of PH may include shortness of breath, chest pains, palpitations, fatigue, lightheadedness and swelling of the legs or feet and in the later stages the abdomen [2].
PH is a highly disabling condition that can have a significant impact on a sufferer's quality of life. A better understanding of the characteristics of PH is key for ensuring early identification and treatment of PH to deliver optimal patient outcomes. This article will provide an overview of our current understanding of the causes of PH and the complex pathophysiological mechanisms underlying the development of PH.
Causes of PH
A variety of conditions are known to contribute to the development of PH. Based on the underlying cause and clinical features cases of PH generally fall into one of the following groups:
- Group 1: Pulmonary arterial hypertension (PAH). Some causes include connective tissue disorders such as scleroderma, congenital heart problems, portal hypertension, HIV and certain medications. Some cases of PAH may be idiopathic with no known cause [2].
- Group 2: Pulmonary hypertension due to left-sided heart disease. Some causes include left-side heart failure and mitral or aortic valve disease [2].
- Group 3: Pulmonary hypertension due to lung disease and/or hypoxia. Some causes include COPD, interstitial lung disease and obstructive sleep apnea [2].
- Group 4: Pulmonary hypertension associated with chronic pulmonary artery obstruction. Some causes include chronic blood clots (pulmonary emboli) [2].
- Group 5: Pulmonary hypertension with unclear and/or multifactorial mechanisms. Some causes include inflammatory conditions such as sarcoidosis, metabolic disorders such as glycogen storage disease, blood disorders such as sickle cell disease and chronic kidney disease [2].
By far the most common type of PH is that caused by left-sided heart disease which may account for 34% of all cases of PH [3]. In addition to medical conditions other identified risk factors for PH include age, gender (being more common in women), a family history of the condition, lifestyle factors (e.g. smoking, being overweight) and exposure to hazardous substances (e.g. asbestos),
Mechanisms underlying PH
Much of what is known about the pathophysiology of PH comes from studies on PAH, which is thought to make up around 14% of all cases of PH [3]. While the mechanisms underlying the different types of PH may differ slightly, some common mechanisms include vasoconstriction, microthrombotic events, pulmonary vascular remodelling and inflammation.
- Vasoconstriction: Represents an early step in the pathogenesis of PH. It is thought that vasoconstriction is primarily mediated by an imbalance of vasoactive factors, i.e. an excess of vasoconstrictors and a concomitant deficiency of vasodilating mediators [4]. Some key vasoactive players likely include prostacyclins, endothelin-1 and nitric oxide, all of which are known to be dysregulated in PH [4].
- Microthrombotic events: Play an important role in the progression of PH and occur with increasing frequency in the more advanced stages of the disease [4]. Specifically, decreased levels of thrombomodulin and increased levels of plasminogen activator inhibitor, fibrinogen and von Willebrand antigen have been noted in patients with PH [5,6]. More research is needed to determine their true relevance as some of these proteins are acute-phase reactants and increase in response to inflammation [4].
- Pulmonary vascular remodelling: Another key event in the progression of PH. Vascular remodelling primarily involves the excessive proliferation and migration of pulmonary artery smooth muscle cells [4] A particularly notable molecule in vascular remodelling is bone morphogenetic protein receptor type II (BPM2)[4]. As many as 75% of patients with heritable PAH possess mutations in the BPM2 gene [7]. Dysfunctional BPM2 signalling may contribute to remodelling through an imbalance between proliferation and apoptosis [4].
- Inflammation: Helps drive vascular remodelling in PH. Numerous cellular factors including T‐ and B‐lymphocytes, dendritic cells, mast cells and macrophages have been observed in lung tissue samples from PH sufferers [8]. Additionally, many cytokines including the proinflammatory cytokines IL-6 and TGF-β have been shown to be dysregulated in PH patients [9].
Additional research is clearly needed to help identify more causative factors and shed more light on the pathophysiological mechanisms underlying the development of PH. This would enable the development of more tailored PH prevention strategies and novel treatment approaches with the potential to alter disease trajectory and improve patient outcomes.
References
[1] Hoeper MM, Humbert M, Souza R, et al. A global view of pulmonary hypertension. Lancet Respir Med. 2016;4:306–322.
[2] NHS. Pulmonary Hypertension [Internet]. [cited 2024 Apr 25]. Available from: https://www.nhs.uk/conditions/pulmonary-hypertension/#:~:text=Pulmonary%20hypertension%20is%20high%20blood,well%20to%20allow%20blood%20through.
[3] Wijeratne DT, Lajkosz K, Brogly SB, et al. Increasing Incidence and Prevalence of World Health Organization Groups 1 to 4 Pulmonary Hypertension. Circ Cardiovasc Qual Outcomes. 2018;11.
[4] Huber L, Bye H, Brock M. The pathogenesis of pulmonary hypertension – an update. Swiss Med Wkly. 2015;
[5] Hoeper M, Sosada M, Fabel H. Plasma coagulation profiles in patients with severe primary pulmonary hypertension. European Respiratory Journal. 1998;12:1446–1449.
[6] Welsh CH, Hassell KL, Badesch DB, et al. Coagulation and Fibrinolytic Profiles in Patients With Severe Pulmonary Hypertension. Chest. 1996;110:710–717.
[7] Ma L, Chung WK. The role of genetics in pulmonary arterial hypertension. J Pathol. 2017;241:273–280.
[8] Price LC, Wort SJ, Perros F, et al. Inflammation in Pulmonary Arterial Hypertension. Chest. 2012;141:210–221.
[9] Zhong Y, Yu PB. Decoding the Link Between Inflammation and Pulmonary Arterial Hypertension. Circulation. 2022;146:1023–1025.
