Pulmonary Hypertension: Diagnostic Work-Up and Treatment Approach
All patients with suspected pulmonary hypertension must undergo transthoracic echocardiography as the initial screening test, followed by mandatory right heart catheterization to confirm the diagnosis and establish hemodynamic classification before any PAH-specific therapy is initiated. 1
Initial Diagnostic Evaluation
Clinical Presentation to Recognize
- Exertional dyspnea is the cardinal symptom that worsens progressively; additional symptoms include syncope (especially in children), angina pectoris, palpitations, dry cough, and exertional nausea/vomiting 2, 3
- Lack of response to conventional dyspnea treatment should trigger suspicion for PH 2
- Signs of right heart failure appear in advanced stages 3
First-Line Screening Tests
- Transthoracic echocardiography with Doppler is the mandatory first-line screening test to estimate pulmonary artery systolic pressure, assess right ventricular function, detect right atrial/ventricular enlargement, pericardial effusion, and identify left-sided cardiac abnormalities 1
- Use contrast echocardiography to detect intracardiac shunting 1
- Obtain ECG, chest radiograph, complete blood count, renal/liver/thyroid function tests 2
- Check (NT-pro-)BNP concentration; if both BNP and ECG are normal, PH is unlikely 3
Essential Diagnostic Testing Algorithm
Step 1: Confirm PH and Classify Hemodynamically
- Right heart catheterization is mandatory in all patients with suspected PH to confirm diagnosis (mean pulmonary artery pressure >20 mmHg defines PH), establish specific hemodynamic classification, determine severity, and guide therapy 1, 4
- Must include full saturation run to detect intracardiac shunts, measurement of mean pulmonary artery pressure, pulmonary artery wedge pressure (PAWP), cardiac output, and calculation of pulmonary vascular resistance 1, 4
Step 2: Identify the Underlying Cause
- Ventilation-perfusion (V/Q) scanning must be performed in all patients with pulmonary arterial hypertension to rule out chronic thromboembolic pulmonary hypertension (CTEPH); a normal V/Q scan effectively excludes CTEPH 1, 5
- Do not rely on CT pulmonary angiography alone to exclude CTEPH, as it has insufficient sensitivity and may miss the diagnosis 1
- Perform spirometry, lung volumes, and DLCO measurement to evaluate for underlying lung disease (Group 3 PH) 1
- Obtain arterial blood gas analysis to assess oxygenation 1
- Perform abdominal ultrasound to screen for portal hypertension in patients with unexplained pulmonary arterial hypertension 1
Step 3: Specialized Testing
- Perform 6-minute walk test with Borg dyspnea score to establish baseline exercise capacity and provide prognostic information 1
- Offer genetic testing and counseling to relatives of patients with familial/heritable pulmonary arterial hypertension 1
Critical Referral Requirements
All patients with suspected PH must be promptly evaluated at a specialized pulmonary hypertension center with expertise in PH diagnosis before initiating any PAH-specific therapy 4. Referral should be urgent if the patient is syncopal, has rapidly progressing symptoms, or is in heart failure 2.
Expert Center Requirements
- Referral centers must provide care by a multiprofessional team including cardiology and respiratory medicine physicians, clinical nurse specialists, radiologists with PH imaging expertise, cardiologists with echocardiography and right heart catheterization expertise, and access to psychological/social work support 6
- Centers must have access to echocardiography, CT scanning, nuclear scanning, MRI, exercise testing, lung function testing, cardiac catheterization laboratory, and the full range of PAH and CTEPH drug therapies 6
Treatment Approach Based on PH Classification
Group 1: Pulmonary Arterial Hypertension (PAH)
Vasoreactivity Testing is Mandatory
- Vasoreactivity testing must be performed during right heart catheterization in patients with idiopathic, heritable, or drug-induced PAH to identify those who may respond to calcium channel blockers 7
- High-dose calcium channel blockers are first-line therapy only for patients demonstrating acute vasoreactivity during testing 7
- Never use calcium channel blockers empirically without documented acute vasoreactivity, as this can be harmful 1
Initial Therapy for Non-Vasoreactive Patients
- Initial oral combination therapy with ambrisentan plus tadalafil is recommended for low or intermediate risk patients, as it has proven superior to monotherapy in delaying clinical failure 7
- Initial monotherapy with approved drugs is recommended for treatment-naïve, low or intermediate risk patients 6
- Initial combination therapy including intravenous prostacyclin analogs should be prioritized for high-risk patients 7
- Sequential combination therapy is recommended for patients with inadequate response to initial monotherapy or double combination therapy 6
Group 2: PH Due to Left Heart Disease
- PAH-specific therapies are not recommended and may be harmful in patients with PH due to left heart disease 7, 4
- Management primarily involves treatment of the underlying left heart condition 5
Group 3: PH Due to Lung Disease
- Long-term oxygen therapy is recommended to maintain saturations >90% and has been shown to partially reduce PH progression 7
- Treatment primarily targets the underlying lung disease 5
Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
Surgical Treatment is First-Line
- Surgical pulmonary endarterectomy in deep hypothermia with circulatory arrest is the treatment of choice for patients with CTEPH 6, 7, 4
- All patients with CTEPH must have assessment of operability and treatment decisions made by a multidisciplinary team including at least one experienced PEA surgeon 6
- Life-long anticoagulation is mandatory in all patients with CTEPH 6
Medical Therapy for Inoperable or Persistent CTEPH
- Riociguat is recommended in symptomatic patients classified as having persistent/recurrent CTEPH after surgical treatment or inoperable CTEPH by a CTEPH team 6, 5
- Off-label use of drugs approved for PAH may be considered in symptomatic patients classified as having inoperable CTEPH 6
- Interventional balloon pulmonary angioplasty may be considered in patients who are technically non-operable or carry an unfavorable risk:benefit ratio for PEA 6
Essential Supportive Care Measures
- Diuretics (such as furosemide) are recommended for all PAH patients with signs of right ventricular failure and fluid retention; monitor electrolytes, renal function, and daily weights during active diuresis 7, 4
- Continuous long-term oxygen is recommended when arterial oxygen pressure is consistently <60 mmHg or to maintain saturations >90% 7
- Anticoagulation should be considered in idiopathic PAH, heritable PAH, and anorexigen-induced PAH, targeting INR 1.5-2.5 (2-3 for CTEPH) 7
- Pregnancy must be avoided in patients with PAH 6
Monitoring and Follow-Up
- Regular assessments every 3-6 months should include WHO functional class, 6-minute walk distance, BNP/NT-proBNP, and echocardiography 7
- The primary goal is achieving and maintaining low-risk status (typically WHO functional class I-II) 7
- Target 6-minute walk distance >440 meters for most patients, though lower values may be acceptable in elderly patients or those with significant comorbidities 7
Advanced Therapies and Rescue Options
- Consider eligibility for lung transplantation after inadequate response to initial monotherapy or combination therapy 7
- Refer for transplantation soon after inadequate response is confirmed on maximal combination therapy 7
- Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy 7
Critical Pitfalls to Avoid
- Do not start PAH-specific drugs empirically without confirming diagnosis and classification via right heart catheterization, as this can delay appropriate treatment and cause harm, particularly in Group 2 PH 7, 4
- Do not delay referral to a specialist center; attempting to complete the entire workup locally without specialist input often results in incomplete phenotyping and inappropriate therapy initiation 4
- Do not perform lung biopsy routinely due to high risk; reserve only for cases where tissue diagnosis is essential 1
- Avoid ACE inhibitors, ARBs, and beta-blockers in PAH unless specifically required for comorbidities, as they lack proven benefit 7