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

Pulmonary Hypertension: Diagnostic and Treatment Approach

Diagnostic Evaluation

Right heart catheterization is mandatory to confirm the diagnosis of pulmonary hypertension, establish hemodynamic classification, and guide therapy selection. 1, 2 PH is defined as a mean pulmonary arterial pressure ≥25 mmHg at rest, though recent data suggest normal mean PAP is 14 ± 3 mmHg with an upper limit of 20 mmHg. 3

Initial Clinical Assessment

• Clinical suspicion should arise with unexplained dyspnea on exertion, particularly in patients without overt heart or lung disease, or with disproportionate symptoms relative to underlying cardiopulmonary conditions. 3 Additional symptoms include fatigue, syncope, angina, and signs of right heart failure (jugular venous distension, hepatomegaly, peripheral edema). 3

• Physical examination findings include left parasternal lift, accentuated P2, tricuspid regurgitation murmur, elevated jugular venous pressure, and in advanced cases, signs of right ventricular failure. 3 Lung sounds are typically normal, which helps distinguish PH from primary lung disease. 3

Stepwise Diagnostic Algorithm

The detection phase requires ECG, chest radiograph, and transthoracic Doppler echocardiography to confirm elevated pulmonary pressures. 3 However, echocardiography alone cannot definitively diagnose PH—it estimates probability and screens for underlying causes. 3, 4

Ventilation-perfusion (V/Q) scanning must be performed in all patients with suspected or confirmed PH to exclude chronic thromboembolic pulmonary hypertension (CTEPH). 1, 5 In pulmonary arterial hypertension (PAH), V/Q scans may be normal or show small peripheral non-segmental defects, whereas CTEPH shows segmental or larger perfusion defects. 3

Additional essential investigations include: 3

• High-resolution CT chest to assess for interstitial lung disease and identify features of pulmonary veno-occlusive disease (ground-glass opacities, septal thickening) 3
• Pulmonary function tests with diffusion capacity 5
• Serological testing for connective tissue disease (antinuclear antibodies, anti-centromere, anti-Scl-70), HIV, and hepatitis 3
• Thrombophilia screening in CTEPH (antiphospholipid antibodies, lupus anticoagulant) 3
• NT-proBNP or BNP for prognostic assessment 3
• Abdominal ultrasound to evaluate for portal hypertension 3

Right heart catheterization is essential to confirm diagnosis, measure precise hemodynamics (mean PAP, pulmonary wedge pressure, cardiac output, pulmonary vascular resistance), and perform vasoreactivity testing. 1, 2 This distinguishes pre-capillary PH (wedge pressure ≤15 mmHg) from post-capillary PH due to left heart disease (wedge pressure >15 mmHg). 3

Vasoreactivity testing with inhaled nitric oxide or IV epoprostenol is mandatory in idiopathic PAH, heritable PAH, and drug-induced PAH to identify calcium channel blocker responders. 1, 2 A positive response is defined as a reduction in mean PAP ≥10 mmHg to reach an absolute value <40 mmHg with increased or unchanged cardiac output. 1

Risk Stratification

All PAH patients must be risk-stratified using a multiparametric approach incorporating clinical, functional, biochemical, and hemodynamic variables. 3, 6 This determines prognosis and guides treatment intensity.

Low-risk patients (estimated 1-year mortality <5%) are characterized by: 3, 6

• WHO Functional Class I-II
• 6-minute walk distance >440 meters
• BNP <50 ng/L or NT-proBNP <300 ng/L
• Cardiac index ≥2.5 L/min/m²
• Right atrial pressure <8 mmHg
• No signs of right ventricular dysfunction on echocardiography

Intermediate-risk patients (1-year mortality 5-10%) have: 3, 6

• WHO Functional Class III
• 6-minute walk distance 165-440 meters
• BNP 50-300 ng/L or NT-proBNP 300-1400 ng/L
• Moderately impaired right ventricular function

High-risk patients (1-year mortality >10%) demonstrate: 3, 6

• WHO Functional Class III-IV with progression
• 6-minute walk distance <165 meters
• BNP >300 ng/L or NT-proBNP >1400 ng/L
• Cardiac index <2.0 L/min/m²
• Right atrial pressure >14 mmHg
• Severe right ventricular dysfunction or failure

Treatment Strategy

Treatment Based on Vasoreactivity and Risk Status

For the small subset of vasoreactive patients (approximately 10% of idiopathic PAH), high-dose calcium channel blockers are first-line therapy. 1, 2 These patients require long-term follow-up to confirm sustained response, as many lose responsiveness over time. 1

For non-vasoreactive low or intermediate-risk PAH patients, initial oral combination therapy is the preferred approach. 1, 2, 6 The combination of ambrisentan (endothelin receptor antagonist) plus tadalafil (phosphodiesterase-5 inhibitor) significantly delays clinical failure compared to monotherapy. 6

For high-risk PAH patients, continuous intravenous epoprostenol must be initiated immediately, as it is the only therapy proven to reduce mortality. 1, 2, 6, 7 Epoprostenol has a half-life of approximately 6 minutes and requires continuous infusion via central venous catheter. 7 Common side effects include flushing, headache, jaw pain, diarrhea, and catheter-related complications. 7

Sequential combination therapy targeting multiple pathways (prostacyclin pathway, endothelin pathway, nitric oxide pathway) is recommended for patients with inadequate response to initial therapy. 1, 2, 6 Achievement or maintenance of intermediate-risk status should be considered inadequate for most patients, prompting therapy escalation. 3, 6

Treatment for CTEPH

Surgical pulmonary endarterectomy performed in deep hypothermia with circulatory arrest is the treatment of choice for operable CTEPH patients. 2 This is potentially curative and should be performed at experienced centers. 2

For inoperable CTEPH or persistent/recurrent PH after surgery, riociguat (soluble guanylate cyclase stimulator) is the only approved targeted therapy. 2, 5 Balloon pulmonary angioplasty is an emerging option for selected inoperable patients. 2

Lifelong anticoagulation is mandatory for all CTEPH patients. 2

Supportive Care Measures

Diuretics are essential for managing right ventricular failure and fluid overload, with careful monitoring of electrolytes and renal function. 1, 6 Loop diuretics are typically required, often in combination with aldosterone antagonists. 6

Oxygen supplementation should maintain arterial oxygen saturation >90% to prevent hypoxic pulmonary vasoconstriction. 1, 6 Continuous long-term oxygen therapy is recommended when arterial PO₂ is consistently <60 mmHg. 6

Supervised exercise training should be considered for physically deconditioned PAH patients already on medical therapy, as it improves functional capacity and quality of life. 1, 2, 6

Pregnancy must be avoided in PAH patients due to 30-50% maternal mortality risk. 2 Effective contraception counseling is mandatory, avoiding estrogen-containing methods. 2

Monitoring and Follow-Up

Regular follow-up assessments every 3-6 months are required in stable patients, including WHO functional class, 6-minute walk distance, BNP/NT-proBNP, and echocardiography. 3, 1, 6 Right heart catheterization should be considered at regular intervals or when clinical status changes. 3

The primary treatment goal is achieving and maintaining low-risk status (WHO FC I-II, 6MWD >440m, normal or near-normal BNP, preserved RV function). 3, 1, 6 This translates to improved survival and quality of life. 3

Advanced Therapies

Lung transplantation should be considered for patients with inadequate response to maximal medical therapy, including combination therapy. 1, 6 Early referral to transplant centers is critical, as waiting times are prolonged. 1

Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal therapy, creating a right-to-left shunt to decompress the right ventricle. 6 This is a high-risk procedure reserved for experienced centers. 6

Critical Management Considerations

All PAH and CTEPH patients must be managed at specialized pulmonary hypertension centers with multidisciplinary expertise. 1, 2 These centers have experience with advanced therapies, hemodynamic monitoring, and complex decision-making. 1, 2

Common pitfalls include:

• Misdiagnosing PH due to left heart disease (Group 2) as PAH—this requires careful assessment of wedge pressure and left ventricular function, as targeted PAH therapies are not indicated and may worsen outcomes in Group 2 PH 3
• Failing to perform V/Q scanning and missing potentially curable CTEPH 1, 5
• Delaying referral to expert centers, particularly in high-risk patients who require immediate IV prostacyclin therapy 1, 6
• Using ACE inhibitors, ARBs, or beta-blockers in PAH without specific comorbidity indications, as these are not beneficial and may be harmful 1
• Inadequate anticoagulation in CTEPH patients 2

For PH due to left heart disease (Group 2) or lung disease (Group 3), treatment focuses on optimizing the underlying condition rather than targeted PAH therapies. 5, 8 Targeted therapies may worsen pulmonary edema in left heart disease. 5