# Pulmonary Hypertension: Classification and Management

## Definition and Hemodynamic Classification

### Updated Hemodynamic Definitions (6th World Symposium, 2018; ESC/ERS 2022)

The hemodynamic definitions of pulmonary hypertension have undergone significant revision. Pulmonary hypertension is now defined as a mean pulmonary artery pressure exceeding 20 mmHg at rest, lowered from the previous threshold of 25 mmHg or greater, reflecting accumulating evidence that even mildly elevated pressures carry prognostic significance. Pre-capillary pulmonary hypertension requires a mean PAP greater than 20 mmHg, a PCWP of 15 mmHg or less, and a pulmonary vascular resistance exceeding 2 Wood units. Isolated post-capillary pulmonary hypertension is defined by a mean PAP greater than 20 mmHg, a PCWP exceeding 15 mmHg, and a PVR of 2 Wood units or less. Combined pre- and post-capillary pulmonary hypertension is characterized by a mean PAP greater than 20 mmHg, a PCWP exceeding 15 mmHg, and a PVR exceeding 2 Wood units. An emerging definition of exercise pulmonary hypertension uses a mean PAP/cardiac output slope greater than 3 mmHg/L/min during exercise.

| Hemodynamic Category | mPAP | PCWP | PVR |
|---|---|---|---|
| Pre-capillary PH | > 20 mmHg | <= 15 mmHg | > 2 Wood units |
| Isolated Post-capillary PH (IpcPH) | > 20 mmHg | > 15 mmHg | <= 2 Wood units |
| Combined Pre- and Post-capillary PH (CpcPH) | > 20 mmHg | > 15 mmHg | > 2 Wood units |
| Exercise PH | mPAP/CO slope > 3 mmHg/L/min | -- | -- |

### WHO Clinical Classification (5 Groups)

The World Health Organization clinical classification organizes pulmonary hypertension into five groups. Group 1 encompasses pulmonary arterial hypertension, which includes idiopathic, heritable, drug- and toxin-induced, connective tissue disease-associated, HIV-associated, portal hypertension-associated, congenital heart disease-associated, and schistosomiasis-related forms. Group 2 comprises pulmonary hypertension due to left heart disease, including HFpEF, HFrEF, and valvular disease, and represents the most common cause of pulmonary hypertension overall. Group 3 includes pulmonary hypertension due to lung disease or hypoxia, encompassing COPD, interstitial lung disease, combined pulmonary fibrosis and emphysema, sleep-disordered breathing, and high-altitude exposure. Group 4 represents chronic thromboembolic pulmonary hypertension and other pulmonary artery obstructions. Group 5 captures pulmonary hypertension with unclear or multifactorial mechanisms, including sarcoidosis, hematologic disorders such as myeloproliferative disease and post-splenectomy states, metabolic diseases including glycogen storage disease and Gaucher disease, systemic disorders, and chronic renal failure on dialysis.

| WHO Group | Category | Examples |
|---|---|---|
| 1 | Pulmonary Arterial Hypertension (PAH) | Idiopathic, heritable (BMPR2), CTD-associated, drug/toxin, HIV, portal HTN, CHD |
| 2 | PH due to Left Heart Disease | HFpEF, HFrEF, valvular disease (most common cause of PH overall) |
| 3 | PH due to Lung Disease/Hypoxia | COPD, ILD, CPFE, sleep-disordered breathing, high altitude |
| 4 | Chronic Thromboembolic PH (CTEPH) | Organized thromboemboli, pulmonary artery obstructions |
| 5 | Unclear/Multifactorial Mechanisms | Sarcoidosis, myeloproliferative, Gaucher, CKD on dialysis |

## Group 1: Pulmonary Arterial Hypertension (PAH)

### Pathobiology

The pathobiology of pulmonary arterial hypertension involves progressive vascular remodeling encompassing intimal fibrosis, medial hypertrophy, adventitial thickening, and the formation of plexiform lesions, which are pathognomonic but only observed on biopsy or at autopsy. Endothelial dysfunction lies at the core of the disease process, manifesting as reduced prostacyclin and nitric oxide production alongside increased endothelin-1 levels.

Three key therapeutic pathways are targeted by current pharmacotherapy. The prostacyclin pathway involves prostacyclin deficiency leading to reduced cyclic AMP levels and consequently vasoconstriction and vascular smooth muscle proliferation. The nitric oxide pathway involves reduced NO and cyclic GMP, with phosphodiesterase-5 degrading cGMP to cause vasoconstriction, or alternatively deficient stimulation of soluble guanylate cyclase. The endothelin pathway involves excess endothelin-1 signaling through ETA and ETB receptors, driving vasoconstriction, fibrosis, and cellular proliferation.

Mutations in BMPR2 represent the most common genetic cause, found in 70 to 80% of heritable PAH cases and 10 to 20% of idiopathic PAH. The inheritance pattern is autosomal dominant with incomplete penetrance of approximately 20%.

### Risk Stratification

Risk stratification in PAH guides therapeutic intensity and is based on estimated 1-year mortality. Low-risk status, with an estimated mortality below 5%, is characterized by NYHA functional class I to II, a 6-minute walk distance exceeding 440 meters, BNP below 50 pg/mL or NT-proBNP below 300, right atrial pressure below 8 mmHg, a cardiac index of 2.5 or greater, mixed venous oxygen saturation above 65%, no pericardial effusion, and TAPSE exceeding 20 mm. Intermediate risk, with a 5 to 20% estimated mortality, includes NYHA class III, a 6-minute walk distance between 165 and 440 meters, BNP between 50 and 800, NT-proBNP between 300 and 1400, right atrial pressure of 8 to 14, a cardiac index of 2.0 to 2.4, and mixed venous saturation between 60 and 65%. High-risk status, with mortality exceeding 20%, is defined by NYHA class IV, a 6-minute walk distance below 165 meters, BNP above 800, NT-proBNP above 1400, right atrial pressure exceeding 14, a cardiac index below 2.0, mixed venous saturation below 60%, and the presence of pericardial effusion. | Parameter | Low Risk (< 5% 1-yr mortality) | Intermediate Risk (5-20%) | High Risk (> 20%) |
| --- | --- | --- | --- | --- |
| NYHA FC | I - II | III | IV |  |
| 6MWD (m) | > 440 | 165 - 440 | < 165 |  |
| BNP (pg/mL) | < 50 | 50 - 800 | > 800 |  |
| NT-proBNP (pg/mL) | < 300 | 300 - 1400 | > 1400 |  |
| RAP (mmHg) | < 8 | 8 - 14 | > 14 |  |
| Cardiac Index (L/min/m²) | >= 2.5 | 2.0 - 2.4 | < 2.0 |  |
| SvO2 (%) | > 65 | 60 - 65 | < 60 |  |
| Pericardial Effusion | No | No | Yes |  |
| TAPSE (mm) | > 20 | -- | -- |  |

The REVEAL 2.0 risk calculator provides a validated multiparametric tool that additionally incorporates renal function and all-cause hospitalization history.

### PAH-Specific Pharmacotherapy

#### Endothelin Receptor Antagonists (ERA)

Ambrisentan is a selective ETA antagonist dosed at 5 to 10 mg daily, evaluated in the ARIES trials. It should be avoided in interstitial lung disease-associated pulmonary hypertension, as the ARTEMIS-IPF trial demonstrated harm. Bosentan is a dual ETA/ETB antagonist initiated at 62.5 mg twice daily for 4 weeks and then increased to 125 mg twice daily, as studied in the BREATHE-1 trial. Monthly liver function test monitoring is required due to an approximately 10% risk of hepatotoxicity. Macitentan, also a dual ERA, is dosed at 10 mg daily and was evaluated in the SERAPHIN trial, which demonstrated a 45% reduction in morbidity and mortality events compared with placebo, with less hepatotoxicity than bosentan.

#### PDE5 Inhibitors and sGC Stimulators

Sildenafil, studied in the SUPER-1 trial, is FDA-approved at 20 mg three times daily, though some centers use higher off-label doses of 40 to 80 mg three times daily. Tadalafil at 40 mg daily was evaluated in the PHIRST trial and offers the advantage of once-daily dosing due to its longer half-life. Riociguat is a soluble guanylate cyclase stimulator dosed at 0.5 to 2.5 mg three times daily, studied in the PATENT-1 trial for PAH and the CHEST-1 trial for CTEPH. It is contraindicated with PDE5 inhibitors due to the risk of severe hypotension, and is also contraindicated with nitrates. Riociguat holds the distinction of being the only approved oral therapy for inoperable or persistent CTEPH.

#### Prostacyclin Pathway Agents

Epoprostenol administered intravenously as a continuous infusion via central line and pump remains the gold standard for severe PAH in NYHA class IV. Its half-life of only 3 to 5 minutes means that abrupt interruption can be fatal due to rebound pulmonary hypertension. Dosing begins at 2 to 4 ng/kg/min and is titrated upward, with typical maintenance ranging from 25 to 40 ng/kg/min. Side effects include jaw pain, flushing, diarrhea, line infection, and thrombocytopenia. Treprostinil is available in intravenous, subcutaneous, inhaled, and oral formulations. The subcutaneous formulation is delivered via continuous infusion pump, with infusion site pain being the dose-limiting side effect. The inhaled formulation is dosed at 6 to 12 breaths four times daily. Iloprost is an inhaled prostacyclin analog dosed at 2.5 to 5 mcg delivered 6 to 9 times daily, studied in the STEP trial, though its impractical dosing frequency limits clinical use. Selexipag is an oral prostacyclin IP receptor agonist evaluated in the GRIPHON trial, which demonstrated a 40% reduction in morbidity and mortality events. It is titrated from 200 mcg twice daily to the maximum tolerated dose up to 1600 mcg twice daily, with side effects similar to prostacyclin class agents.

| Drug | Pathway | Route | Dose | Key Trial | Notable Considerations |
|---|---|---|---|---|---|
| Ambrisentan | Endothelin (ETA selective) | Oral | 5-10 mg daily | ARIES | Avoid in ILD-PH (ARTEMIS-IPF) |
| Bosentan | Endothelin (dual ETA/ETB) | Oral | 125 mg BID | BREATHE-1 | Monthly LFTs; ~10% hepatotoxicity |
| Macitentan | Endothelin (dual ETA/ETB) | Oral | 10 mg daily | SERAPHIN | 45% morbidity/mortality reduction; less hepatotoxic |
| Sildenafil | NO-cGMP (PDE5i) | Oral | 20 mg TID | SUPER-1 | Off-label higher doses used |
| Tadalafil | NO-cGMP (PDE5i) | Oral | 40 mg daily | PHIRST | Once-daily dosing advantage |
| Riociguat | NO-cGMP (sGC stimulator) | Oral | 0.5-2.5 mg TID | PATENT-1, CHEST-1 | Contraindicated with PDE5i and nitrates; approved for CTEPH |
| Epoprostenol | Prostacyclin | IV continuous | 25-40 ng/kg/min | -- | Gold standard for severe PAH; fatal if interrupted |
| Treprostinil | Prostacyclin | IV/SC/inhaled/oral | Variable | INCREASE (inhaled) | SC site pain dose-limiting |
| Selexipag | Prostacyclin (IP receptor) | Oral | Up to 1600 mcg BID | GRIPHON | 40% morbidity/mortality reduction |

#### Combination and Upfront Therapy

The AMBITION trial established that upfront combination therapy with ambrisentan and tadalafil reduced clinical failure by 50% compared with monotherapy, making initial combination therapy the standard of care for newly diagnosed PAH. For low- to intermediate-risk patients, initial dual combination therapy with an ERA plus a PDE5 inhibitor or an ERA plus a soluble guanylate cyclase stimulator is recommended. For high-risk patients, initial triple therapy including an intravenous or subcutaneous prostacyclin analog combined with an ERA and a PDE5 inhibitor is warranted, along with early referral for lung transplant evaluation. Follow-up risk assessment at 3 to 6 months should target achievement of a low-risk profile, with therapy escalation if intermediate or high risk persists.

<image>
A detailed treatment algorithm for Group 1 PAH. At top: "Newly Diagnosed PAH -- Confirm Group 1 with RHC." First decision: "Acute vasoreactivity testing positive?" (positive criteria: >= 10 mmHg fall in mPAP to <= 40 mmHg with normal/increased CO). If yes: "Trial of high-dose CCB (nifedipine 120-240 mg, diltiazem 240-720 mg, amlodipine 20 mg); reassess at 3-6 months; ~5-10% of PAH patients." If no or CCB failure: Risk stratify into three columns. Low/Intermediate Risk (green/yellow): "Initial dual oral combination: ERA (macitentan 10 mg) + PDE5i (tadalafil 40 mg) or sGC stimulator (riociguat)." High Risk (red): "Triple therapy: IV/SC prostacyclin (epoprostenol or treprostinil) + ERA + PDE5i; Lung transplant referral." Bottom section: "Reassess at 3-6 months -- if inadequate response: add sequential therapy (selexipag, switch PDE5i to riociguat, add parenteral prostacyclin); consider atrial septostomy or transplant listing." Include the three therapeutic pathways (prostacyclin, NO, endothelin) as a small inset diagram with drug classes mapped to each pathway.
</image>

## Group 2: PH Due to Left Heart Disease

### Pathophysiology

Group 2 pulmonary hypertension begins with passive transmission of elevated left atrial pressure to the pulmonary vasculature, producing isolated post-capillary pulmonary hypertension. With chronic pressure elevation, reactive pulmonary vascular remodeling occurs, leading to combined pre- and post-capillary pulmonary hypertension characterized by increased PVR. The distinction between IpcPH and CpcPH is made using the diastolic pressure gradient, calculated as the difference between the pulmonary artery diastolic pressure and the PCWP, along with the PVR, where a PVR exceeding 2 Wood units defines CpcPH.

### Management

The cornerstone of managing Group 2 pulmonary hypertension is treatment of the underlying left heart disease. This includes optimizing volume status, implementing guideline-directed medical therapy for HFrEF, administering SGLT2 inhibitors for HFpEF, and pursuing valvular intervention when indicated. PAH-specific therapies are not recommended for Group 2 pulmonary hypertension, as multiple negative trials including MELODY-1, SoPHIE, and SIOVAC have failed to demonstrate benefit. An exception may exist for carefully selected patients with a severe CpcPH component and PVR exceeding 5 Wood units evaluated at experienced centers, though this remains controversial and is not guideline-endorsed.

## Group 3: PH Due to Lung Disease

### Key Features

In COPD, the mean PAP is typically in the 20 to 35 mmHg range, with severe pulmonary hypertension defined as a mean PAP of 35 mmHg or greater, or 25 mmHg or greater with a low cardiac index, occurring in only 1 to 5% of patients with severe COPD. In interstitial lung disease, pulmonary hypertension prevalence ranges from 30 to 80% in advanced disease and portends a poor prognosis. Combined pulmonary fibrosis and emphysema is associated with a disproportionately high prevalence of pulmonary hypertension.

Inhaled treprostinil demonstrated improved 6-minute walk distance in the INCREASE trial for Group 3 pulmonary hypertension due to interstitial lung disease and has received FDA approval for this indication. Management should focus on optimizing the underlying lung disease through supplemental oxygen, CPAP or BiPAP for obstructive sleep apnea, and disease-specific treatment for COPD and ILD. Other PAH-specific therapies should be avoided in Group 3 as systemic vasodilators may worsen ventilation-perfusion matching.

## Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

### Pathophysiology and Diagnosis

CTEPH develops from organized thromboembolic material in the pulmonary arteries combined with secondary small-vessel arteriopathy. It occurs in 2 to 4% of patients following acute pulmonary embolism and can develop even without a recognized prior embolic event.

The ventilation-perfusion scan remains the gold standard screening test, with a sensitivity of 96 to 97% for CTEPH and characteristic mismatched perfusion defects. CT pulmonary angiography may underestimate proximal disease but demonstrates webs, bands, stenoses, and post-stenotic dilation. Conventional pulmonary angiography provides the definitive imaging assessment for surgical planning, revealing webs, pouching defects, and intimal irregularities. Right heart catheterization confirms hemodynamic severity, with a PVR exceeding 2 Wood units required for diagnosis.

### Treatment

Lifelong anticoagulation is fundamental, with warfarin traditionally preferred, though direct oral anticoagulants are increasingly used despite less supporting evidence. Pulmonary endarterectomy is the treatment of choice for surgically accessible disease involving the main, lobar, or proximal segmental arteries, and is potentially curative. Operative mortality at experienced centers ranges from 2 to 4%, with dramatic hemodynamic improvement in the majority of patients. Balloon pulmonary angioplasty provides an alternative for patients with inoperable disease or residual pulmonary hypertension following PEA, delivered in staged procedures over 3 to 6 sessions, with improvements in hemodynamics and functional capacity that are expertise-dependent. Riociguat is the only FDA-approved medical therapy for inoperable CTEPH or persistent pulmonary hypertension after PEA, based on the CHEST-1 and CHEST-2 trials. Multidisciplinary evaluation at an expert CTEPH center involving a surgeon, interventionalist, and pulmonary hypertension specialist is essential for operability assessment.

<image>
A comparison illustration of pulmonary vascular pathology across PH groups. Four panels arranged horizontally. Panel 1 (Group 1 - PAH): cross-section of a small pulmonary arteriole showing medial hypertrophy (thickened smooth muscle layer in red), intimal fibrosis (blue layer narrowing lumen), and a plexiform lesion (complex vascular tuft with multiple channels, labeled). Panel 2 (Group 2 - Left Heart Disease): pulmonary venous congestion with dilated pulmonary veins, interstitial edema shown as pink fluid in perivascular space, and secondary arteriolar medial hypertrophy. Panel 3 (Group 3 - Lung Disease): pulmonary arteriole with hypoxic vasoconstriction (contracted smooth muscle), surrounded by emphysematous lung parenchyma with destroyed alveolar walls. Panel 4 (Group 4 - CTEPH): large pulmonary artery with organized thrombus (dark red with fibrous bands/webs), recanalization channels, and post-stenotic dilation. Each panel labeled with Group number, name, and key pathological features. Use consistent color coding: vessel wall in red/pink, lumen in white, pathological changes in blue/purple.
</image>

## Right Heart Catheterization: Technical Considerations

### Vasoreactivity Testing

Acute vasoreactivity testing is indicated in idiopathic, heritable, and drug-associated PAH to identify the small subset of patients who may respond to calcium channel blocker therapy. Testing agents include inhaled nitric oxide at 10 to 20 ppm, intravenous epoprostenol, and intravenous adenosine. A positive response is defined as a fall in mean PAP of 10 mmHg or greater to an absolute mean PAP of 40 mmHg or less with maintained or increased cardiac output. Only approximately 10% of idiopathic PAH patients are true responders, and even fewer maintain a long-term response to calcium channel blockers, necessitating retesting at 3 to 12 months. Vasoreactivity testing is not indicated in Group 2, 3, 4, or 5 pulmonary hypertension, nor in connective tissue disease-associated PAH where positive responses are rare.

### Fluid Challenge During RHC

A rapid saline infusion of 500 mL can unmask occult Group 2 pulmonary hypertension in patients with borderline PCWP values between 12 and 15 mmHg. A post-fluid PCWP exceeding 18 mmHg suggests occult left heart disease contributing to the pulmonary hypertension. This maneuver is particularly valuable in obese patients, those with a history of atrial fibrillation, or patients with multiple Group 2 risk factors.

### Exercise Hemodynamics

Supine bicycle ergometry performed during right heart catheterization allows assessment of exercise hemodynamics. An exercise mean PAP/cardiac output slope exceeding 3 mmHg/L/min indicates exercise pulmonary hypertension. An exercise PCWP of 25 mmHg or greater suggests an exercise-induced Group 2 pulmonary hypertension component.

## Monitoring and Follow-Up

### Serial Assessments

Regular monitoring is essential for guiding therapy and detecting clinical deterioration. The 6-minute walk distance should be assessed every 3 to 6 months, with a minimal clinically important difference of 33 meters. BNP and NT-proBNP trending reveals right ventricular decompensation when values rise. Echocardiography evaluates right ventricular size and function, TAPSE, tricuspid regurgitation severity, and the presence of pericardial effusion. Right heart catheterization should be performed at diagnosis, 3 to 6 months after therapy initiation, and with clinical worsening. Cardiopulmonary exercise testing provides peak VO2, the VE/VCO2 slope, and assessment for exercise oscillatory ventilation. Cardiac MRI serves as the gold standard for right ventricular volumes and ejection fraction and has an increasing role in longitudinal follow-up.

### Supportive Measures

Supplemental oxygen should maintain SpO2 above 90%, with some guidelines recommending above 92%, as even mild hypoxia worsens pulmonary vasoconstriction. Diuretics address right ventricular volume overload, though over-diuresis must be avoided given that the right ventricle is preload-dependent. Supervised exercise rehabilitation improves 6-minute walk distance and quality of life. Pregnancy carries a 30 to 50% maternal mortality rate in severe PAH, making contraception counseling absolutely essential. Influenza, pneumococcal, and COVID-19 vaccinations should be administered. Psychosocial support deserves attention, as the prevalence of depression and anxiety in pulmonary hypertension is high at 40 to 55%.

## Key Clinical Pearls

- V/Q scan should be performed in ALL patients with unexplained PH to screen for CTEPH -- CTPA alone misses up to 50% of operable CTEPH cases
- Group 2 PH is the most common cause of PH; always exclude left heart disease before diagnosing PAH -- a PCWP of 16-18 mmHg in an obese patient may represent occult HFpEF, especially with fluid challenge
- Pulmonary endarterectomy for CTEPH is potentially curative and dramatically underutilized -- all CTEPH patients should be evaluated at an expert surgical center
- Acute vasoreactivity testing is ONLY for Group 1 PAH patients being considered for CCB therapy; a positive test does not apply to other PH groups
- Pericardial effusion in PH is an ominous sign of RV failure and elevated RAP; high-risk feature that should prompt urgent therapy escalation
- Abrupt discontinuation of IV prostacyclin (epoprostenol) can cause fatal rebound PH -- patients on continuous infusion must have backup pump and emergency plan

## References

- Humbert M, et al. 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. Eur Heart J. 2022;43:3618-3731.
- Galie N, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension (AMBITION). NEJM. 2015;373:834-844.
- Ghofrani HA, et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension (CHEST-1). NEJM. 2013;369:319-329.
- Waxman A, et al. Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease (INCREASE). NEJM. 2021;384:325-334.
- Sitbon O, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension (GRIPHON). NEJM. 2015;373:2522-2533.