What is the diagnosis, classification, signs and symptoms, pathophysiology, and treatment of pulmonary hypertension?

Pulmonary Hypertension: Comprehensive Clinical Overview

Definition and Diagnosis

Pulmonary hypertension is definitively diagnosed by right heart catheterization showing a mean pulmonary arterial pressure ≥25 mmHg at rest, though recent guidelines suggest lowering the threshold to >20 mmHg. 1, 2

Hemodynamic Criteria

• Right heart catheterization remains the gold standard for confirming PH diagnosis and is essential for accurate classification 2, 3
• Pre-capillary PH is defined by mean PAP ≥25 mmHg, pulmonary wedge pressure ≤15 mmHg, and pulmonary vascular resistance >3 Wood units 1, 2
• Post-capillary PH is characterized by mean PAP ≥25 mmHg with wedge pressure >15 mmHg 2, 4
• Combined pre- and post-capillary PH shows mean PAP >20 mmHg, PAWP >15 mmHg, and PVR ≥3 Wood units 2
• There is insufficient data to support the definition of "PH on exercise" and this is no longer recommended 1, 2

Diagnostic Algorithm

• Echocardiography is the initial screening study to estimate probability of PH based on tricuspid regurgitation velocity and systolic pulmonary artery pressure 3, 5
• All patients with suspected PH without confirmed left heart or lung disease must undergo ventilation-perfusion scanning to exclude chronic thromboembolic PH 6
• Routine workup includes electrocardiography, chest radiography, and pulmonary function tests 6

Classification

PH is classified into five major clinical groups based on etiology, pathophysiology, and therapeutic approaches. 1, 2

Group 1: Pulmonary Arterial Hypertension (PAH)

• Idiopathic PAH (no identifiable cause) 1
• Heritable PAH with BMPR2 mutations or other genetic mutations 1
• Drug and toxin-induced PAH 1
• Associated PAH including:
  • Connective tissue disease 1
  • HIV infection 1
  • Portal hypertension 1
  • Congenital heart disease (including Eisenmenger's syndrome) 1
  • Schistosomiasis 1
• Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis (with EIF2AK4 mutations) 1

Group 2: PH Due to Left Heart Disease

• Left ventricular systolic dysfunction (up to 60% of severe LV dysfunction patients develop PH) 1
• Left ventricular diastolic dysfunction (up to 70% of heart failure with preserved ejection fraction) 1
• Valvular disease (virtually all severe symptomatic mitral disease; up to 65% of symptomatic aortic stenosis) 1
• Congenital/acquired left heart inflow/outflow obstruction 1

Group 3: PH Due to Lung Diseases and/or Hypoxia

• Chronic obstructive pulmonary disease 1
• Interstitial lung disease 1
• Sleep-disordered breathing 1
• Alveolar hypoventilation disorders 1
• Chronic high altitude exposure 1

Group 4: Chronic Thromboembolic PH and Pulmonary Artery Obstructions

• Chronic thromboembolic pulmonary hypertension 1
• Angiosarcoma and other intravascular tumors 1
• Arteritis 1
• Congenital pulmonary artery stenoses 1

Group 5: PH with Unclear/Multifactorial Mechanisms

• Hematological disorders (chronic hemolytic anemia, myeloproliferative disorders, splenectomy) 1
• Systemic disorders (sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis) 1
• Metabolic disorders (glycogen storage disease, Gaucher disease, thyroid disorders) 1
• Chronic renal failure 1

Signs and Symptoms

Dyspnea on exertion is the cardinal symptom of PH, though symptoms are nonspecific and primarily reflect progressive right ventricular dysfunction. 7, 3

Common Presenting Symptoms

• Unexplained exertional dyspnea (most common) 7, 8
• Syncope or near-syncope (especially with exertion) 8
• Fatigue and weakness 7
• Chest pain (angina-like, reflecting RV ischemia) 7
• Palpitations 7

Physical Examination Findings

• Signs of right ventricular dysfunction and failure:
  • Elevated jugular venous pressure 7
  • Peripheral edema 7
  • Hepatomegaly and hepatic congestion 7
  • Ascites 7
• Cardiac auscultation findings:
  • Loud P2 (pulmonic component of second heart sound) 7
  • Right ventricular heave 7
  • Tricuspid regurgitation murmur 7

Clinical Pitfall

Diagnosis is commonly delayed because symptoms are attributed to underlying heart or lung disease rather than PH itself. 3 Maintain high clinical suspicion in patients with unexplained dyspnea on exertion, syncope, or signs of right ventricular dysfunction.

Pathophysiology

PH results from progressive increases in pulmonary vascular resistance leading to right ventricular hypertrophy and ultimately right heart failure as the terminal consequence. 7, 4

Group-Specific Mechanisms

• Group 1 (PAH): Pulmonary arterial remodeling with endothelial dysfunction, smooth muscle proliferation, and in-situ thrombosis causing increased PVR 4
• Group 2 (Left Heart Disease): Backward transmission of elevated left atrial pressure into pulmonary circulation 7, 4
• Group 3 (Lung Disease/Hypoxia): Alveolar hypoxia triggers pulmonary vasoconstriction and subsequent vascular remodeling 4
• Group 4 (CTEPH): Persistent pulmonary artery obstruction from organized thrombi following pulmonary embolism 4
• Group 5: Complex, multifactorial mechanisms involving hematological, systemic, or metabolic derangements 4

Pathophysiological Progression

• Initial increase in pulmonary vascular resistance 4
• Right ventricular hypertrophy as compensatory mechanism 4
• Progressive right ventricular dilation and dysfunction 4
• Right ventricular failure (the primary cause of death) 7, 4

Treatment

All patients with PAH (Group 1) or CTEPH (Group 4) must be referred to specialized pulmonary hypertension centers with multidisciplinary teams. 7, 6

Group 1: Pulmonary Arterial Hypertension

PAH-Specific Therapies

• Prostacyclin analogues:

  • Epoprostenol (IV) is FDA-approved for PAH (WHO Group 1) to improve exercise capacity in NYHA Class III-IV patients 9
  • Initiated at 2 ng/kg/min and increased by 2 ng/kg/min increments every 15 minutes until dose-limiting effects or tolerance established 9
  • Administered via continuous IV infusion through central venous catheter with ambulatory pump 9
  • Critical warning: Do not abruptly lower dose or withdraw—can cause rapid deterioration and death 9
  • Treprostinil and iloprost are alternative prostanoids 5

• Endothelin receptor antagonists:

  • Bosentan and ambrisentan 6, 5

• Phosphodiesterase type 5 inhibitors:

  • Sildenafil and tadalafil 6, 5

• Soluble guanylate cyclase stimulators:

  • Riociguat (also approved for inoperable CTEPH) 6

General Supportive Measures

• Anticoagulation is recommended for PAH patients 7, 5
• Target INR 1.5-2.5 for PAH; 2-3 for CTEPH 5
• Diuretics are essential for managing right heart failure with fluid retention, hepatic congestion, ascites, and peripheral edema 5
• Oxygen therapy for hypoxemia 6

Group 4: Chronic Thromboembolic PH

• Surgical pulmonary endarterectomy is the treatment of choice for eligible CTEPH patients 6
• Riociguat for inoperable or persistent/recurrent CTEPH 6

Groups 2,3, and 5

• Primary management targets the underlying condition (left heart disease, lung disease, or systemic disorder) 6, 10
• No approved PAH-specific therapies for these groups 6

Critical Drug Interactions and Precautions

• Epoprostenol with diuretics, antihypertensives, or vasodilators: Risk of hypotension 9
• Epoprostenol with antiplatelet agents or anticoagulants: Increased bleeding risk 9
• Epoprostenol with digoxin: May elevate digoxin levels (significant in toxicity-prone patients) 9

Contraindications to Epoprostenol

• Congestive heart failure due to severe left ventricular systolic dysfunction 9
• Pulmonary edema 9
• Hypersensitivity to drug or structurally related compounds 9

Special Populations and Situations

• Pregnancy: Counsel patients of childbearing age to prevent pregnancy—PH worsens during pregnancy with high risk of fetal loss and maternal mortality 3
• Perioperative management: Patients have high risk of perioperative complications; require detailed specialty preoperative evaluation 3
• Patients on pulmonary vasodilators: May rapidly develop right ventricular failure and death if therapies interrupted 8

Emergency Management Principles

• Avoid intubation if possible (positive pressure ventilation worsens RV function), though hypoxemia and hypercapnia also worsen RV function 8
• Volume management is critical: Patients are often volume overloaded but require careful fluid administration 8
• In shock, use vasopressors and inotropes rather than fluid boluses to augment cardiac output and reduce RV ischemia risk 8
• Early consultation with PH specialist and transfer to tertiary center with invasive monitoring and mechanical support (RVAD, ECMO) capabilities 8

Prognosis

The median life expectancy for idiopathic PAH without disease-specific therapy is only 2.8 years from diagnosis. 7, 2, 4

• Right ventricular failure is the final cause of death in most PH patients 7, 4
• Prognosis is primarily determined by hemodynamic profile and right ventricular function 7
• Update immunization status, screen for mental health conditions, and discuss goals of care and advance directives given the severe, chronic, progressive nature of disease 3