Introduction
Pulmonary arterial hypertension is part of the spectrum of pulmonary
hypertension (PH) which is a hemodynamic and pathophysiological condition. PH is defined by a mean PA pressure
(mPAP) of >20 mmHg at rest. Pre-capillary PH 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 PH (IpcPH) is defined as mPAP >20 mmHg, PAWP >15
mmHg and PVR ≤2 WU. Combined pre- and post-capillary PH (CpcPH) is defined as
mPAP >20 mmHg, PAWP >15 mmHg and PVR >2 WU. Exercise PH is defined as
mPAP/cardiac output (CO) slope between rest and exercise of >3 mmHg/L/min.
Pulmonary Arterial Hypertension_Disease BackgroundEpidemiology
Pulmonary hypertension (PH) 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 PH and lung disease,
particularly chronic obstructive pulmonary disease (COPD), is the second
leading cause of PH with estimated prevalence of 50-70% and 30-50%,
respectively. The prevalence of PH 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.
Pathophysiology
Pulmonary arterial hypertension 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 Pulmonary Arterial Hypertension
Drugs and Toxins
- Definite association: Aminorex, Fenfluramine, Benfluorex, Dasatinib, Dexfenfluramine, Fenfluramine, methamphetamines, toxic grapeseed oil
- Possible association: Amphetamines, Bosutinib, chemotherapeutic agents (eg Mitomycin C, Cyclophosphamide), Cocaine, Diazoxide, direct-acting antiviral agents against hepatitis C virus infection (eg Sofosbuvir), Indirubin, Interferon α and β, Leflunomide, L-tryptophan, Phenylpropanolamine, Ponatinib, selective protease inhibitors (eg Carfilzomib), 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 6th World Symposium on Pulmonary Hypertension (Nice, 2018)
Group 1 Pulmonary Arterial Hypertension
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
PH 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 PH of
the newborn syndrome
Group 2 Pulmonary Hypertension Due to Left Heart Disease
2.1 PH due to heart
failure
2.1.1 WITH preserved
LV ejection fraction (LVEF)
2.1.2 WITH reduced
(≤40%) or mildly reduced LVEF (41-49%)
2.2 Valvular disease
2.3 Congenital/acquired
cardiovascular (CV) conditions leading to post-capillary PH
Group 3 Pulmonary Hypertension Due to Lung Diseases and/or Hypoxia
3.1
Obstructive lung disease or emphysema
3.2
Restrictive lung disease
3.3
Other pulmonary disease with mixed restrictive and obstructive pattern
3.4
Hypoventilation syndromes
3.5
Hypoxia without lung disease (eg high altitude)
3.6
Developmental pulmonary abnormalities
Group 4 Pulmonary Hypertension Due to 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