What causes pulmonary hypertension?

What Causes Pulmonary Hypertension

Pulmonary hypertension results from five distinct pathophysiological categories, each with specific underlying mechanisms: Group 1 (pulmonary arterial hypertension from genetic mutations, drugs, or associated conditions), Group 2 (left heart disease), Group 3 (chronic lung disease and hypoxia), Group 4 (chronic thromboembolic disease), and Group 5 (unclear or multifactorial mechanisms). 1

Group 1: Pulmonary Arterial Hypertension (PAH)

Genetic and Molecular Causes

• BMPR2 mutations are present in 75% of familial PAH cases and up to 25% of idiopathic cases, causing loss of function in SMAD signaling pathways that normally regulate vascular cell growth 2
• Other genetic mutations include ALK1 (associated with hereditary hemorrhagic telangiectasia), EIF2AK4 (causing pulmonary veno-occlusive disease), and polymorphisms in serotonin transporter, nitric oxide synthase, and carbamyl-phosphate synthase genes 1, 2
• Endothelial dysfunction creates an imbalance with increased vasoconstrictors (endothelin-1, thromboxane A2) and decreased vasodilators (prostacyclin, nitric oxide), promoting vasoconstriction and cell proliferation 2

Drug and Toxin Exposures

• Definite risk: Aminorex, fenfluramine, dexfenfluramine, toxic rapeseed oil, benfluorex, and selective serotonin reuptake inhibitors 1, 2
• Likely risk: Amphetamines, dasatinib, L-tryptophan, and certain chemotherapeutic agents 1
• Possible risk: Cocaine, phenylpropanolamine, St. John's Wort, amphetamine-like drugs, and interferon alpha/beta 1

Associated Medical Conditions

• Connective tissue diseases: Particularly limited cutaneous systemic sclerosis (CREST syndrome), systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis 1, 2
• Congenital heart disease: Left-to-right shunts (atrial septal defects, ventricular septal defects, patent ductus arteriosus) causing increased pulmonary blood flow and eventual Eisenmenger syndrome 1, 3, 2
• HIV infection: Occurs in approximately 0.5% of HIV-infected individuals, independent of CD4 count but related to duration of infection 1, 2
• Portal hypertension: Portopulmonary hypertension develops with increasing severity of liver disease 1, 2
• Schistosomiasis: An important cause in endemic regions 1
• Hematological disorders: Chronic hemolytic anemias (sickle cell disease, thalassemia, hereditary spherocytosis), myeloproliferative disorders, and post-splenectomy states 1, 2

Group 2: Left Heart Disease

• Left ventricular systolic dysfunction: Up to 60% of patients with severe LV systolic dysfunction develop PH 1
• Left ventricular diastolic dysfunction: Up to 70% of patients with heart failure with preserved ejection fraction present with PH 1
• Valvular disease: Virtually all patients with severe symptomatic mitral valve disease and up to 65% with symptomatic aortic stenosis develop PH 1
• Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 1
• Congenital/acquired pulmonary vein stenosis 1

Group 3: Lung Diseases and Hypoxia

• Chronic obstructive pulmonary disease (COPD): Chronic airflow limitation leads to hypoxic vasoconstriction 1
• Interstitial lung disease: Parenchymal destruction and hypoxia contribute to elevated pulmonary pressures 1
• Sleep-disordered breathing: Obstructive sleep apnea causes intermittent hypoxia and may be an independent risk factor 1
• Obesity hypoventilation syndrome (OHS): Associated with pulmonary hypertension in 30-88% of cases and cor pulmonale 1
• Alveolar hypoventilation disorders and chronic exposure to high altitude 1
• Developmental lung diseases 1

Group 4: Chronic Thromboembolic Disease

• Chronic thromboembolic pulmonary hypertension (CTEPH): Results from organized thrombi causing proximal and distal pulmonary artery obstruction 1, 4
• Other pulmonary artery obstructions: Angiosarcoma, other intravascular tumors, arteritis, congenital pulmonary artery stenoses, and parasites (hydatidosis) 1

Group 5: Unclear or Multifactorial Mechanisms

• Hematological disorders: Chronic hemolytic anemia, myeloproliferative disorders, splenectomy 1
• Systemic disorders: Sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, neurofibromatosis 1
• Metabolic disorders: Glycogen storage disease, Gaucher disease, thyroid disorders 1
• Other conditions: Pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis, chronic renal failure (with/without dialysis), segmental pulmonary hypertension 1

Pathophysiological Mechanisms Common to All Groups

• Vascular remodeling involves intimal hyperplasia, medial hypertrophy, adventitial proliferation, and plexiform arteriopathy that progressively narrows pulmonary vessel lumens 2
• Altered cellular phenotype with decreased apoptosis/proliferation ratio in pulmonary artery smooth muscle cells leads to excessive proliferation 2
• Thrombosis in situ occurs with elevated fibrinopeptide A and plasminogen activator inhibitor-1, creating a procoagulant state 2
• Potassium channel dysfunction with downregulation of voltage-gated potassium channels (Kv1.5) causes membrane depolarization and increased intracellular calcium 2

Critical Clinical Pitfalls

• Delayed diagnosis is common because symptoms (dyspnea, fatigue, exercise intolerance) are nonspecific and mimic other conditions 1, 5
• Distinguishing PAH (Group 1) from other groups is essential because PAH-specific therapies are only appropriate for Group 1 and should not be used for Groups 2-5 without specialist guidance 3, 4
• Screening high-risk populations is crucial: patients with BMPR2 mutations, scleroderma spectrum diseases, portal hypertension undergoing liver transplant evaluation, and patients with congenital heart disease require periodic echocardiographic screening 1, 2
• Right heart catheterization is mandatory for definitive diagnosis and classification, measuring mean pulmonary arterial pressure (≥25 mmHg defines PH) and pulmonary capillary wedge pressure (≤15 mmHg defines pre-capillary PH) 1