Pulmonary Arterial
Hypertension
Pulmonary Arterial
Hypertension
Incidence and Prevalence of Pulmonary Arterial Hypertension
Incidence and prevalence are reported to be ~6 and 48–55 cases/million adults, respectively.1,2 Idiopathic PAH is the most common subtype (50–60% of all cases), followed by PAH associated with connective tissue disease, congenital heart disease, and portal hypertension.1,3
Very Common
PH associated with left heart disease [WHO Group 2]
Common
PH associated with lung disease [WHO Group 3]
Rare
- Pulmonary Arterial Hypertension [WHO Group 1]
- PH associated with pulmonary artery obstructions [WHO Group 4]
- PH with unclear and/or multifactorial mechanisms [WHO Group 5]
PAH, Pulmonary Arterial Hypertension; PH, Pulmonary Hypertension; WHO, World Health Organization. References: 1. Humbert M, et al. Eur Heart J. 2022;43(38):3618–731. 2. Leber L, et al. Pulm Circ. 2021;11:2045894020977300. 3. Lau EMT, et al. Nat Rev Cardiol. 2017;14:603–14.
Pulmonary Hypertension is categorized into five groups according to the World Health Organization [WHO] classification
Group 1
PAH
Incidence and prevalence are reported to be ~6 and 48–55 cases/million adults, respectively.1,2 Idiopathic PAH is the most common subtype (50–60% of all cases), followed by PAH associated with connective tissue disease, congenital heart disease, and portal hypertension.1,3
Group 2
PH associated with left-sided heart disease
The prevalence of PH increases with severity of left-sided valvular diseases and can be found in 60–70% of patients with severe and symptomatic mitral valve disease4 and in up to 50% of those with symptomatic aortic stenosis.1,5
Group 3
PH associated with lung disease and/or hypoxia
~1–5% of patients with advanced COPD have an mPAP > 35–40 mmHg.1,6,7 8–15% of patients with idiopathic pulmonary fibrosis have an mPAP ≥ 25 mmHg, with prevalence increasing in advanced (30–50%) and end-stage disease (60%).1,7
Group 4
PH associated with chronic pulmonary artery obstruction
Incidence and prevalence of Chronic Thromboembolic Pulmonary Hypertension are reported to be 2–6 and 26–38 cases/million adults, respectively.1,2,8,9
Group 5
PH with unclear and/or multifactorial mechanisms
As the causes of this disorder are often multifactorial and can be secondary to increased pre- and post-capillary pressure, the incidence and prevalence in most cases are unknown.1
COPD, Chronic Obstructive Pulmonary Disease; mPAP, Mean Pulmonary Arterial Pressure; PAH, Pulmonary Arterial Hypertension; PH, Pulmonary Hypertension. References: 1. Humbert M, et al. Eur Heart J. 2022;43(38):3618–731. 2. Leber L, et al. Pulm Circ. 2021;11:2045894020977300. 3. Lau EMT, et al. Nat Rev Cardiol. 2017;14:603–14. 4. Tichelbacker T, et al. Herz. 2019;44:491–501. 5. Weber L, et al. Eur J Heart Fail. 2019;21:172–81. 6. Hurdman J, et al. Eur Respir J. 2013;41:1292–301. 7. Nathan SD, et al. Eur Respir J. 2019;53: 1801914. 8. Delcroix M, et al. Eur Respir J. 2021;57:2002828. 9. Kramm T, et al. Clin Res Cardiol. 2018;107:548–53.
What is Pulmonary Arterial Hypertension?
- Pulmonary Arterial Hypertension (PAH) has an estimated prevalence of 48–55 cases/million adults in economically developed countries1,2
- PAH is defined by the presence of mean Pulmonary Arterial Pressure (mPAP) > 20 mmHg with a pulmonary artery wedge pressure ≤15 mmHg and elevated pulmonary vascular resistance > 2 WU, in the absence of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and PH associated with lung diseases2
- PAH is a subcategory of PH that can be further divided into four sub-categories2
- The hallmark histopathologic lesions in PAH are called plexiform lesions. These are complex vascular malformations originating from remodeled pulmonary arteries and have been found to show upregulation of remodeling-associated genes and of markers associated with vascular sprouting3
APAH, Associated Pulmonary Arterial Hypertension; HIV, Human Immunodeficiency Virus; IPAH, Idiopathic Pulmonary Hypertension; PAH, Pulmonary Arterial Hypertension.
References: 1. Leber L, et al. Pulm Circ. 2021;11:2045894020977300. 2. Humbert M, et al. Eur Heart J. 2022;43(38):3618–731. 3. Jonigk D, et al. Am J Pathol. 2011;179:167–79.
Functional Classification of Disease Severity
- Clinical assessment provides valuable information for determining PAH severity, improvement, deterioration, and stability1
- Both the New York Heart Association and the World Health Organization (WHO) have developed classification systems for symptom severity in PH, defined in terms of functional status2
- WHO functional class is one of the strongest predictors of survival, both at diagnosis and follow-up1,3–5
References: 1. Humbert M, et al. Eur Heart J. 2022;43(38):3618–731. 2. Benza RL, et al. Circulation. 2010;122:164–172. 3. Barst RJ, et al. Chest. 2013;144:160–8. 4. Nickel N, et al. Eur Respir J. 2012;39:589–596. 5. Sitbon O, et al. J Am Coll Cardiol. 2002;40:780–8.
Pathogenesis of Pulmonary Arterial Hypertension
- The pathogenesis of PAH is multifactorial
- PAH is a vasculopathy in which structural changes are driven by excessive vascular cell growth and inflammation, with recruitment and infiltration of circulating cells
- The subcategories of PAH differ in their underlying causes, but all are characterized by excessive pulmonary vasoconstriction and abnormal vascular remodeling that affects all vessel layers
- Plexiform lesions — complex vascular formations originating from remodeled pulmonary arteries
ALK1, Activin Receptor-Like Kinase 1; BMPR2, Bone Morphogenetic Protein Receptor type 2; ET, Endothelin; HIV, Human Immunodeficiency Virus; IL, Interleukin; NO, Nitric Oxide; PDGF, Platelet-Derived Growth Factor; PGI2, Prostacyclin I2.
Reference: Schermuly R, et al. Nat Rev Cardiol. 2011;8:443–55.
Symptoms of Pulmonary Hypertension: Patients’ Perspective
- Shortness of breath and fatigue during normal day-to-day activities are the most obvious physical burdens of PH1,2
- PH can also impact patients emotionally due to decreased ability to connect with friends and psychological distress, and financially due to decreased ability to work1,2
References: 1. Braley K, et al. Pulm Circ. 2023;12:e12247. 2. Armstrong I, et al. BMJ Open. 2012;2:e000806.
Pulmonary Hypertension Diagnostic Workup
- A multi-step, pragmatic approach to diagnosis should be considered in patients with unexplained dyspnea or symptoms/signs raising suspicion of Pulmonary Hypertension (PH)
Suspicion
- Symptom assessment, medical and family history, physical examination (including blood pressure, heart rate, and pulse oximetry)
Detection
- Laboratory testing including brain natriuretic peptide/N-terminal probrain natriuretic peptide
- Resting electrocardiogram
- Non-invasive lung and cardiac testing, to include pulmonary function testing, echocardiography, VQ scan, and in some cases cardiopulmonary exercise testing
Confirmation
- Referral to PH center when an intermediate/high probability of PH is established, or in the presence of risk factors for Pulmonary Arterial Hypertension (PAH) or a history of pulmonary embolism
- Comprehensive workup to establish differential diagnoses and distinguish between PH etiologies
- Invasive hemodynamic assessment via right heart catheterization (RHC) is required to confirm a diagnosis of PAH
PAH, Pulmonary Arterial Hypertension; PH, Pulmonary Hypertension; RHC, Right Heart Catheterization; VQ, Ventilation/Perfusion Scan.
Reference: Humbert M, et al. Eur Heart J. 2022;43(38):3618–731.
The diagnosis of Group 1 PAH is a diagnosis of exclusion where other common causes of Pulmonary Hypertension such as underlying left heart and/or lung disease must be ruled out.
CTEPH, Chronic Thromboembolic Pulmonary Hypertension; PAH, Pulmonary Arterial Hypertension; PH, Pulmonary Hypertension.
Reference: Humbert M, et al. Eur Heart J. 2022;43(38):3618–731.
Diagnostic Assessments for Pulmonary Hypertension
CTEPH, Chronic Thromboembolic Pulmonary Hypertension; ECG, Electrocardiogram; PH, Pulmonary Hypertension.
Reference: Humbert M, et al. Eur Heart J. 2022;43(38):3618–731.
Gold Standard Diagnostic Assessment for Pulmonary Hypertension
- Right Heart Catheterization (RHC) is the gold standard for diagnosing and classifying PH as it accurately determines hemodynamic parameters1,2
- As RHC is a procedure requiring expertise and meticulous methodology, it is recommended to be performed at expert PH centers1,2
PH, Pulmonary Hypertension; RHC, Right Heart Catheterization.
References: 1. Humbert M, et al. Eur Heart J. 2022;43(38):3618–731. 2. Hoeper MM, et al. J Am Coll Cardiol. 2006;48:2546–52.
PH, Pulmonary Hypertension; RHC, Right Heart Catheterization.
References: 1. Humbert M, et al. Eur Heart J. 2022;43(38):3618–731. 2. Hoeper MM, et al. J Am Coll Cardiol. 2006;48:2546–52.
Treatment of Pulmonary Arterial Hypertension
- Drugs for Pulmonary Arterial Hypertension (PAH) target the vasoconstriction–vasodilation balance of endothelial dysfunction and vascular smooth muscle cell proliferation1
- They do this by targeting one of the three major signaling pathways in PAH: nitric oxide, endothelin, or prostacyclin1–3:
PAH, Pulmonary Arterial Hypertension.
References: 1. Humbert M, et al. Lancet Respir Med. 2023;11(9):804–19. 2. Humbert M and Ghofrani HA. Thorax. 2016;71(1):73–83. 3. Tettey A, et al. Front Pharmacol. 2021;12:767002.
Drug Target Pathways1-3
cAMP, Cyclic Adenosine Monophosphate; cGMP, Cyclic Guanosine Monophosphate; ER, Endothelin Receptor; PAH, Pulmonary Arterial Hypertension; PDE5i, Phosphodiesterase Type 5 Inhibitor; sGC, soluble guanylate cyclase.
References: 1. Humbert M, et al. Lancet Respir Med. 2023;11(9):804–19. 2. Humbert M and Ghofrani HA. Thorax. 2016;71(1):73–83. 3. Tettey A, et al. Front Pharmacol. 2021;12:767002.
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