Pulmonary Arterial Hypertension (PAH)


Pulmonary arterial hypertension (PAH) is a rare disease in which the arteries of the lungs present with high blood pressure.1 Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure higher than 20 mmHg at rest when measured with right heart catheterization.2 There are currently 5 defined clinical groups of PH, which are based on etiology, pathophysiology, symptoms, hemodynamic features, and therapeutic approaches.3 PAH corresponds to the first clinical group of this classification, in which PH develops due to pulmonary vascular disease following damage to small pulmonary arterioles.4 In PAH, the pulmonary vasculature is remodeled, increasing the pulmonary vascular load and leading to right ventricular overload and failure.2,5 This disease may be secondary to other medical conditions or it can be idiopathic.6 Symptoms of PAH include fatigue, exertional dyspnea, and chest discomfort.5

Pathophysiologic Mechanisms of PAH

An increase in pulmonary vascular resistance and an increase in pulmonary venous pressure are the 2 major processes involved in the development of PAH.5 Patients with PAH have pathological changes such as an angioproliferative vasculopathy in the pulmonary arterioles, endothelial and smooth muscle proliferation and dysfunction, inflammation, and the development of thrombosis.7 Patients with PAH present with abnormal endothelial cells, smooth muscle cells, fibroblasts, and inflammatory cells.4 Many inflammatory pathways are activated in these patients, with an increased infiltration of macrophages, lymphocytes, mast cells, and tumor necrosis factor (TNF) in the perivascular region and in the plasma.8 These changes to the patients’ normal physiology result in the thickening of the medial layer of the pulmonary arterial wall, an increase in connective tissue and elastic fibers, and partial blockages of small pulmonary arteries, promoting an increase in pulmonary vascular resistance and consequently triggering further cardiac events.8,9 

Underlying these vascular changes is the dysfunction of 3 signaling pathways: nitric oxide (NO), prostacyclin (PGI2) and thromboxane A2 (TXA2), and endothelin-1 (ET-1).10 PAH pathophysiology is multifactorial. Patients may have different risk factors that are responsible for pulmonary vascular remodeling. Environmental factors or different immune or inflammatory events may be also involved.11

Increase in Pulmonary Vascular Resistance

NO is a key player in the homeostasis of healthy pulmonary vasculature. It promotes pulmonary vasodilation and prevents platelet aggregation and thrombosis.6 In PAH, the availability of NO is decreased due to endothelial dysfunction,12 resulting in vasoconstriction, smooth cell proliferation, inflammation, and in situ thrombi.6

Prostacyclins that are produced by endothelial cells are also important in preventing platelet aggregation and thrombosis. The physiologic production of PGI2 and subsequent activation of adenylate cyclase results in the production of cyclic adenosine monophosphate (cAMP), responsible for smooth muscle relaxation and vasodilation. PGI2 also regulates cellular proliferation and inflammation.6 In PAH, there is a decreased expression of the prostacyclin receptor and prostacyclin synthase, with a lower amount of prostacyclin produced.13 An alternative product to PGI2 is then released, TXA2, which is involved in vasoconstriction, cellular proliferation, and thrombotic events.6 

ET-1 is responsible for activating 2 receptors found in vascular smooth muscle cells and endothelial cell surfaces, ETA and ETB. The activation of ETA results in vasoconstriction and fibrosis, while the activation of ETB can result in either vasoconstriction or vasodilation depending whether the cell target is vascular smooth cells or endothelial surfaces. Patients with PAH experience an increased amount of ET-1, which leads to higher expressions of ETA and smooth muscle ETB and a reduced expression of endothelial ETB, resulting in vasoconstriction.6

Increase in Pulmonary Venous Pressure

The increase in pulmonary vascular resistance can trigger responses of the right ventricle, including hypertrophy, fat deposition, and dilatation. The mechanisms underlying right ventricular remodeling still need to be fully elucidated, however, research points to potentially perturbed angiogenesis and mitochondrial bioenergetics with glycolysis and fatty acid oxidation.2 

Diseases that affect the left side of the heart can also increase the blood pressure in the pulmonary veins, with further damage to the alveolar-capillary walls and consequent edema. When high blood pressure remains constant for prolonged periods of time, the alveolar-capillary walls can remain thickened, compromising lung diffusion capacity.5

Therapeutic Targets in PAH

Different therapeutic options targeting the pathophysiology of PAH are available. These include phosphodiesterase-5 inhibitors and guanylate cyclase, which are stimulators for tackling the NO signaling pathway; prostacyclin analogues and prostacyclin receptor agonists for addressing PIG2-TXA2 dysfunction; and endothelin receptor antagonists for improving endothelin-related events.6 

References

1. Pulmonary arterial hypertension. National Organization for Rare Disorders (NORD). Accessed March 15, 2022.

2. Hassoun PM. Pulmonary arterial hypertension. N Engl J Med. 2021;385(25):2361-2376. doi:10.1056/NEJMra2000348

3. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913. doi:10.1183/13993003.01913-2018

4. Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018;360:j5492. doi:10.1136/bmj.j5492

5. Gladwin MT, Levine AR. Pulmonary hypertension. MSD Manual Professional Version. Updated September 2020. Accessed March 15, 2022.

6. Lan NSH, Massam BD, Kulkarni SS, Lang CC. Pulmonary arterial hypertension: pathophysiology and treatment. Diseases. 2018;6(2):38. doi:10.3390/diseases6020038

7. Tuder RM, Archer SL, Dorfmüller P, et al. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D4-D12. doi:10.1016/j.jacc.2013.10.025

8. Rafikova O, Al Ghouleh I, Rafikov R. Focus on early events: pathogenesis of pulmonary arterial hypertension development. Antioxid Redox Signal. 2019;31(13):933-953. doi:10.1089/ars.2018.7673

9. Dodson MW, Brown LM, Elliott CG. Pulmonary arterial hypertension. Heart Fail Clin. 2018;14(3):255-269. doi:10.1016/j.hfc.2018.02.003

10. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation. 2004;109(2):159-165. doi:10.1161/01.CIR.0000102381.57477.50

11. Coons JC, Pogue K, Kolodziej AR, Hirsch GA, George MP. Pulmonary arterial hypertension: a pharmacotherapeutic update. Curr Cardiol Rep. 2019;21(11):141. doi:10.1007/s11886-019-1235-4

12. Alp NJ, Channon KM. Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease. Arterioscler Thromb Vasc Biol. 2004;24(3):413-420. doi:10.1161/01.ATV.0000110785.96039.f6

13. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159(6):1925-1932. doi:10.1164/ajrccm.159.6.980405

Reviewed by Kyle Habet, MD, on 3/31/2022.

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