Pulmonary Arterial Hypertension Disease Background

Introduction

Pulmonary arterial hypertension (PAH) is part of the spectrum of pulmonary hypertension which is a hemodynamic and pathophysiological condition. Pulmonary hypertension is defined by a mean PA pressure (mPAP) of >20 mmHg at rest. Pre-capillary pulmonary hypertension is defined as an increase in mPAP >20 mmHg, PA wedge pressure (PAWP) of ≤15 mmHg, and pulmonary vascular resistance (PVR) of >2 Wood Units (WU), with all measurements taken at rest. Isolated post-capillary pulmonary hypertension (IpcPH) is defined as mPAP >20 mmHg, PAWP >15 mmHg and PVR ≤2 WU. Combined pre- and post-capillary pulmonary hypertension (CpcPH) is defined as mPAP >20 mmHg, PAWP >15 mmHg and PVR >2 WU. Exercise pulmonary hypertension is defined as mPAP/cardiac output (CO) slope between rest and exercise of >3 mmHg/L/min.

Pulmonary Arterial Hypertension_Disease Background

Epidemiology

Pulmonary hypertension affects approximately 1% of the global population. It affects all age groups with higher prevalence in individuals >65 years old. In Asia, the prevalence of PAH is higher in females than in males and highest among individuals aged 50-59 years old.  

Left heart disease is the most common cause of pulmonary hypertension while lung disease, particularly chronic obstructive pulmonary disease (COPD), represents the second most frequent cause of pulmonary hypertension with estimated prevalence of 50-70% and 30-50%, respectively. The prevalence of pulmonary hypertension increases with severity of left-sided valvular diseases. The incidence and prevalence of PAH is approximately 6 cases/million adults and 48 to 55 cases/million adults, respectively. Idiopathic PAH (IPAH) is the most common subtype affecting 50-60% of cases, followed by PAH associated with connective tissue disease (CTD), congenital heart disease (CHD), and portal hypertension. Groups 2 and 3 pulmonary hypertension represent the most common types worldwide, making up approximately 90-95% of all pulmonary hypertension cases.

Pathophysiology

PAH is a syndrome resulting from restricted flow through the pulmonary arterial (PA) circulation, resulting in increased pulmonary vascular resistance and remodeling, and ultimately leading to right heart failure.

Risk Factors

Risk Factors and Associated Conditions for PAH

Drugs and Toxins

• Definite association: Aminorex, Fenfluramine, Benfluorex, Carfilzomib, Dasatinib, Dexfenfluramine, Fenfluramine, methamphetamines, Mitomycin-C, toxic rapeseed oil
• Possible association: Alkylating agents, amphetamines, Bevacizumab, Bosutinib, chemotherapeutic agents (eg Cyclophosphamide), cocaine, Diazoxide, direct-acting antiviral agents against hepatitis C virus infection (eg Sofosbuvir), indigo naturalis (Chinese herb Qing-Dai), Interferon α and β, Leflunomide, L-tryptophan, Phenylpropanolamine, Ponatinib, selective protease inhibitors (eg Bortezomib), solvents (eg Trichloroethylene) and St John’s wort
• Unlikely associated with PAH: Oral contraceptives, Estrogen therapy, cigarette smoking

Demographic Factors

• Definite association: Gender
• Possible association: Pregnancy, systemic hypertension
• Unlikely associated with PAH: Obesity

Medical Conditions

• Definite association: Human immunodeficiency virus (HIV) infection, severe symptomatic mitral or aortic valve disease
• Likely association: Portal hypertension or liver disease, collagen vascular diseases, congenital systemic-to- pulmonary cardiac shunts
• Possible association: Thyroid disorders, hematological conditions (eg asplenia secondary to surgical splenectomy, sickle cell disease, β-thalassemia, chronic myeloproliferative disorders), rare genetic or metabolic diseases (eg type 1a glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia)

Classification

Clinical Classification of Pulmonary Hypertension  

Group 1 consists of all causes of PAH while groups 2 to 5 consist of all causes of non-PAH.  

Updated Clinical Classification of Pulmonary Hypertension from the 7th World Symposium on Pulmonary Hypertension (Barcelona, 2024)  

Group 1 PAH

1.1 Idiopathic PAH (IPAH)
            1.1.1 Non-responders at vasoreactivity testing 
            1.1.2 Acute responders at vasoreactivity testing
1.2 Heritable PAH (HPAH)
            1.2.1 Bone morphogenic receptor type 2 (BMPR2)
            1.2.2 Other mutations
1.3 Drug- and toxin-induced PAH (DPAH) - The diagnosis is made by excluding other causes of pulmonary hypertension in patients with exposure to drugs associated with PAH development.
1.4 PAH associated with:
            1.4.1 CTD
            1.4.2 HIV infections
            1.4.3 Portal hypertension
            1.4.4 CHD
            1.4.5 Schistosomiasis
1.5 PAH with overt features of venous/capillary (PVOD/PCH) involvement
1.6 Persistent pulmonary hypertension of the newborn syndrome

Group 2 Pulmonary Hypertension Associated with Left Heart Disease 

2.1 Pulmonary hypertension due to heart failure
            2.1.1 With preserved left ventricular ejection fraction (LVEF)
            2.1.2 With reduced (≤40%) or mildly reduced LVEF (41-49%)
            2.1.3 Cardiomyopathies with specific etiologies
2.2 Valvular disease
2.3 Congenital/acquired cardiovascular (CV) conditions leading to post-capillary pulmonary hypertension

Group 3 Pulmonary Hypertension Associated with Lung Diseases and/or Hypoxia  

3.1 Chronic obstructive lung disease or emphysema 
3.2 Interstitial lung disease (ILD) 
3.3 Combined pulmonary fibrosis and emphysema 
3.4 Other parenchymal lung diseases
3.5 Non-parenchymal lung diseases
            3.5.1 Hypoventilation syndromes
            3.5.2 Pneumonectomy
3.6 Hypoxia without lung disease (eg high altitude)
3.7 Developmental lung diseases

Group 4 Pulmonary Hypertension Associated with PA Obstructions

4.1 CTEPH
4.2 Other PA obstructions
            4.2.1 Sarcoma (high or intermediate grade) or angiosarcoma
            4.2.2 Other malignant tumors (renal carcinoma, uterine carcinoma, testicular germ cell tumors, other tumors)
            4.2.3 Non-malignant tumors (uterine leiomyoma)
            4.2.4 Arteritis without CTD
            4.2.5 Congenital PA stenoses
            4.2.6 Parasites (hydatidosis)

Group 5 Pulmonary Hypertension with Unclear and/or Multifactorial Mechanisms  

5.1 Hematological disorders: Inherited and acquired chronic hemolytic anemia, chronic myeloproliferative disorders
5.2 Systemic disorders: Pulmonary Langerhans cell histiocytosis, neurofibromatosis, sarcoidosis
5.3 Metabolic disorders: Gaucher disease, glycogen storage diseases
5.4 Chronic renal failure with or without hemodialysis
5.5 Pulmonary tumor thrombotic microangiopathy
5.6 Fibrosing mediastinitis
5.7 Complex congenital heart disease