What are the diagnostic steps and treatment options for a patient with suspected pulmonary hypertension?

Pulmonary Hypertension: Diagnostic Steps and Treatment

Diagnostic Evaluation

All patients with suspected pulmonary hypertension require a systematic stepwise diagnostic approach beginning with non-invasive testing, followed by right heart catheterization for definitive diagnosis and classification. 1

Clinical Suspicion and Initial Presentation

• Suspect PH in any patient with unexplained dyspnea on exertion, particularly when breathlessness occurs without overt signs of specific heart or lung disease 1
• Additional symptoms include fatigue, weakness, angina, syncope, and abdominal distension; symptoms at rest occur only in advanced cases 1
• Physical examination findings include left parasternal lift, accentuated pulmonary component of S2, pansystolic murmur of tricuspid regurgitation, jugular vein distension, hepatomegaly, peripheral edema, and ascites in advanced disease 1
• Lung sounds are typically normal, which helps distinguish PH from primary lung disease 1

Non-Invasive Diagnostic Testing

Electrocardiography (ECG):

• Perform ECG in all patients with suspected PH to detect right ventricular hypertrophy and strain patterns 1

Chest Radiography:

• Obtain chest X-ray to exclude moderate-to-severe lung disease or pulmonary venous hypertension, though a normal radiograph does not exclude mild post-capillary PH 1

Transthoracic Echocardiography:

• Echocardiography is the recommended initial non-invasive test for suspected PH 1
• Assess right ventricular systolic pressure (RVSP), right and left ventricular dimensions and function, tricuspid regurgitation, inferior vena cava dimensions, and pericardial effusion 1
• Echocardiography alone cannot definitively diagnose PH; false negatives can occur with high clinical suspicion 1
• Echocardiography also helps identify left heart valvular disease, myocardial disease, and congenital heart defects 1

Ventilation-Perfusion (V/Q) Lung Scan:

• V/Q scanning is mandatory in all patients with suspected or confirmed PH to exclude chronic thromboembolic pulmonary hypertension (CTEPH), as this is a potentially curable form 1, 2
• V/Q scan has 96-97% sensitivity and 90-95% specificity for CTEPH diagnosis 1
• In pulmonary arterial hypertension (PAH), V/Q scans may be normal or show small peripheral non-segmental perfusion defects 1

High-Resolution CT Chest:

• CT pulmonary angiography confirms CTEPH by identifying ring-like stenoses, webs/slits, and chronic total occlusions 1
• High-resolution CT assesses lung parenchyma for interstitial lung disease, emphysema, or bronchial disease 1

Laboratory Testing:

• Obtain routine biochemistry, complete blood count, thyroid function tests, liver function tests, and renal function in all patients 1
• Serological testing for connective tissue disease (antinuclear antibodies, anti-centromere, anti-Ro, U3-RNP), HIV, and hepatitis is required 1
• Measure NT-proBNP or BNP as prognostic biomarkers 1
• In suspected CTEPH, perform thrombophilia screening including antiphospholipid antibodies, anticardiolipin antibodies, and lupus anticoagulant 1

Abdominal Ultrasound:

• Consider abdominal ultrasound to evaluate for portal hypertension in patients with PAH 1

Definitive Diagnosis: Right Heart Catheterization

Right heart catheterization is essential to confirm the diagnosis of PH, establish hemodynamic classification, determine severity, and guide therapy selection. 1, 2, 3

• PH is defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest 1
• Pre-capillary PH: mPAP ≥25 mmHg, pulmonary wedge pressure (PWP) ≤15 mmHg, cardiac output normal or reduced 1
• Post-capillary PH: mPAP ≥25 mmHg, PWP >15 mmHg 1
• RHC distinguishes between pulmonary arterial hypertension (Group 1), PH due to left heart disease (Group 2), and other forms 1

Vasoreactivity Testing:

• Vasoreactivity testing during RHC is mandatory for patients with idiopathic PAH, heritable PAH, and drug-induced PAH to identify candidates for calcium channel blocker therapy 1, 2, 3
• Approximately 5-10% of idiopathic PAH patients are vasoreactive 4

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Treatment Approach

Classification-Based Treatment Strategy

Treatment must be tailored to the specific PH classification, with Group 1 (PAH) and Group 4 (CTEPH) having approved targeted therapies, while other groups require treatment of underlying conditions. 1, 2

Group 1: Pulmonary Arterial Hypertension (PAH)

For Vasoreactive Patients (Positive Acute Vasodilator Response):

• High-dose calcium channel blockers are first-line therapy for the approximately 5-10% of idiopathic PAH patients who demonstrate acute vasoreactivity 2, 4

For Non-Vasoreactive Patients - Risk-Stratified Approach:

The European Society of Cardiology and European Respiratory Society recommend risk stratification using clinical parameters, exercise capacity (6-minute walk distance), biomarkers (NT-proBNP/BNP), and echocardiographic/hemodynamic variables to guide treatment intensity 1, 2, 3

Low-Risk Patients (estimated 1-year mortality <5%):

• Present in WHO Functional Class I-II with 6-minute walk distance >440m and preserved right ventricular function 1, 2
• Initial oral combination therapy targeting multiple pathways is recommended 1, 2, 3

Intermediate-Risk Patients (estimated 1-year mortality 5-10%):

• Present in WHO Functional Class III with moderately impaired exercise capacity 1, 4
• Initial oral combination therapy is recommended 1, 2, 3

High-Risk Patients (estimated 1-year mortality >10%):

• Present in WHO Functional Class III-IV with progressive disease and severe right ventricular dysfunction 1, 4
• Intravenous prostacyclin analogues (epoprostenol) are recommended as they improve survival 2, 3, 5
• Epoprostenol infusion should be initiated at 2 ng/kg/min and increased in increments of 2 ng/kg/min every 15 minutes until dose-limiting effects occur 5

Sequential Combination Therapy:

• For patients with inadequate response to initial monotherapy or dual combination therapy, sequential addition of drugs targeting different pathways is recommended 1, 2, 3

Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Surgical pulmonary endarterectomy in deep hypothermia circulatory arrest is the treatment of choice for operable CTEPH patients and should be performed at expert centers. 1, 3

• Assessment of operability and treatment decisions must be made by a multidisciplinary team of experts 1
• Lifelong anticoagulation is mandatory for all CTEPH patients 3
• For inoperable CTEPH or persistent/recurrent PH after surgery, riociguat is the only approved targeted therapy 3

Groups 2,3, and 5: Other Forms of PH

PAH-approved therapies are NOT recommended for patients with PH due to left heart disease (Group 2) or lung diseases (Group 3). 1, 2

• Treatment focuses on optimizing management of the underlying cardiac or pulmonary condition 1
• For Group 2, treat the underlying left heart disease (systolic dysfunction, diastolic dysfunction, or valvular disease) 1
• For Group 3, optimize treatment of lung disease and provide long-term oxygen therapy for chronic hypoxemia 1

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General Measures and Supportive Care

Pregnancy Avoidance:

• Pregnancy is contraindicated in PAH patients due to 30-50% maternal mortality risk 2, 3, 4

Diuretics:

• Diuretics are recommended for managing fluid overload with careful monitoring of electrolytes and renal function 2, 3

Oxygen Supplementation:

• Maintain arterial oxygen saturation >90% with supplemental oxygen 2, 3

Exercise Training:

• Supervised exercise training should be considered for physically deconditioned PAH patients under medical therapy 2, 4

Immunizations:

• Immunization against influenza and pneumococcal infection is recommended for all PAH patients 4

Psychosocial Support:

• Psychosocial support is recommended as part of comprehensive care 4

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Monitoring and Follow-Up

Regular follow-up assessments every 3-6 months in stable patients are mandatory, using a comprehensive panel including WHO functional class, 6-minute walk test, NT-proBNP/BNP, echocardiography, and consideration of repeat right heart catheterization. 1, 2, 3

Treatment Goal:

• The primary goal is to achieve and maintain low-risk status (WHO FC I-II, 6-minute walk distance >440m, preserved RV function, low NT-proBNP), which is associated with estimated 1-year mortality <5% 1, 2, 4

Follow-up Testing Schedule:

• Clinical assessment, ECG, 6-minute walk test, basic laboratory tests: every 3-6 months 1
• Echocardiography, extended laboratory tests, blood gas analysis: every 6-12 months 1
• Right heart catheterization: should be considered at regular intervals, particularly 3-6 months after treatment changes 1

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Advanced Therapies

Lung Transplantation:

• Consider lung transplantation for patients with inadequate response to maximal medical therapy 2, 3

Intensive Care Management:

• Hospitalization in intensive care unit is recommended for PH patients with hemodynamic compromise (high heart rate, low blood pressure, low urine output, rising lactate) 2

Balloon Atrial Septostomy:

• May be considered after failure of maximal medical therapy in select cases 2

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Critical Pitfalls and Caveats

Referral to Expert Centers:

• All patients with confirmed PAH or CTEPH must be referred to specialized pulmonary hypertension centers with multidisciplinary expertise 1, 3, 4

Avoid Abrupt Discontinuation:

• Never abruptly lower the dose or withdraw PAH-specific medications, particularly intravenous prostacyclins, as this can lead to rapid clinical deterioration and death 5

Drug Interactions:

• Epoprostenol may cause reduction in blood pressure when combined with diuretics, antihypertensives, or vasodilators 5
• Antiplatelet agents or anticoagulants combined with epoprostenol increase bleeding risk 5
• Monitor digoxin levels closely as epoprostenol may elevate digoxin concentrations 5

Contraindications to PAH Therapies:

• Do not use PAH-approved drugs in patients with congestive heart failure due to severe left ventricular systolic dysfunction or pulmonary edema 5

Avoid Inappropriate Medications:

• Angiotensin-converting enzyme inhibitors, angiotensin-2 receptor antagonists, and beta-blockers are not recommended in PAH patients unless required for comorbidities 2