# Chronic Thromboembolic Pulmonary Hypertension

## Definition and Epidemiology

### Definition

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of precapillary pulmonary hypertension defined by a mean pulmonary arterial pressure exceeding 20 mmHg, a pulmonary artery wedge pressure of 15 mmHg or less, and a pulmonary vascular resistance exceeding 2 Wood units, caused by organized thromboembolic obstruction of the pulmonary arteries persisting after at least 3 months of therapeutic anticoagulation. CTEPH is classified as WHO Group 4 pulmonary hypertension. The clinical spectrum extends beyond classic CTEPH to include chronic thromboembolic disease without pulmonary hypertension at rest (CTED), in which patients have organized thromboembolic material on imaging with exercise limitation but resting hemodynamics that do not meet the criteria for pulmonary hypertension.

### Epidemiology

The cumulative incidence of CTEPH among survivors of acute pulmonary embolism is 2-4%, though the condition is likely substantially underdiagnosed. Risk factors for developing CTEPH after PE include large or bilateral PE, residual perfusion defects on follow-up imaging, unprovoked PE, prior splenectomy, non-O blood group, the presence of lupus anticoagulant or antiphospholipid antibodies, chronic inflammatory conditions, myeloproliferative disorders, ventriculoatrial shunts, and infected pacemaker leads. Notably, approximately 25% of CTEPH patients have no documented history of acute PE, suggesting that in situ thrombosis within the pulmonary vasculature may be a contributing mechanism.

### Pathophysiology

The pathophysiology of CTEPH involves incomplete resolution of pulmonary emboli, resulting in organized fibrotic material within the pulmonary arteries. CTEPH is conceptualized as a dual-compartment disease. The proximal compartment consists of organized thrombi in the main, lobar, and segmental pulmonary arteries, which are surgically accessible through pulmonary endarterectomy. The distal compartment involves small-vessel arteriopathy in non-obstructed territories, driven by shear stress and overflow perfusion, producing microvasculopathy similar to that observed in pulmonary arterial hypertension. Without intervention, the natural history is one of progressive right ventricular failure and death.

## Diagnosis

### Clinical Presentation

Patients with CTEPH present with progressive exertional dyspnea and exercise intolerance. The condition is frequently misdiagnosed as deconditioning, COPD, or residual effects of the index PE event, resulting in a median delay from symptom onset to diagnosis of 14 months, a period that is unacceptably long and underscores the need for a high index of clinical suspicion. Physical examination in established disease reveals signs of pulmonary hypertension and right heart failure, including a loud pulmonary component of the second heart sound, a right ventricular heave, a tricuspid regurgitation murmur, jugular venous distension, peripheral edema, and hepatomegaly.

### Screening

Echocardiography should be performed in any patient with persistent dyspnea 3-6 months after acute PE, with elevated estimated right ventricular systolic pressure or RV dilation and dysfunction triggering further workup. The ESC 2019 guidelines recommend clinical reassessment at 3-6 months after PE, with echocardiography pursued in symptomatic patients.

### Diagnostic Workup

The ventilation-perfusion (V/Q) scan is the screening test of choice for CTEPH, with a sensitivity exceeding 96% and specificity of approximately 90% for detecting mismatched segmental or larger perfusion defects. A normal V/Q scan essentially excludes CTEPH. A critically important point is that CTPA has an unacceptable sensitivity of only 50-70% for detecting chronic organized thromboembolic disease, as chronic organized material can be difficult to distinguish from the vessel wall on CT, and CTPA should not be used as the sole screening test. When V/Q scan is abnormal, CTPA with ECG-gated protocol delineates the organized thrombus morphology including webs, bands, stenoses, and complete occlusions, and identifies proximal versus distal disease distribution for surgical planning. Right heart catheterization is mandatory for confirming pulmonary hypertension with the hemodynamic criteria of mPAP exceeding 20 mmHg, PAWP of 15 mmHg or less, and PVR exceeding 2 Wood units. Conventional pulmonary angiography remains the gold standard for anatomic delineation and is performed at expert CTEPH centers to define surgical accessibility. Dual-energy CT (DECT) is an emerging modality that provides both vascular anatomy and perfusion mapping in a single study.

<image>A diagnostic pathway for CTEPH. Start with post-PE patient with persistent dyspnea at 3-6 months. Step 1: Echocardiography (estimated RVSP, RV function). If elevated RVSP or RV dysfunction: Step 2: V/Q scan (screening test of choice). If mismatched perfusion defects present: Step 3: CTPA with angiographic protocol (define proximal vs. distal disease). Step 4: Right heart catheterization (confirm PH: mPAP > 20, PAWP <= 15, PVR > 2). Step 5: Conventional pulmonary angiography at expert center. Final: CTEPH multidisciplinary team assessment for operability. Show key diagnostic criteria at each step. Highlight that CTPA alone can miss CTEPH (sensitivity 50-70%) and V/Q scan is the proper screening test. Include common pitfalls: CTEPH misdiagnosed as PAH due to skipping V/Q scan.</image>

## Treatment

### Lifelong Anticoagulation

All patients with CTEPH require lifelong anticoagulation regardless of whether they undergo surgical or interventional treatment. Warfarin with a target INR of 2.0-3.0 has been traditionally preferred, though DOACs are increasingly used in clinical practice despite limited data specific to CTEPH.

### Pulmonary Endarterectomy (PEA)

Pulmonary endarterectomy is the gold standard and potentially curative treatment for CTEPH. The operation involves surgical removal of organized thromboembolic material from the pulmonary arteries via median sternotomy under deep hypothermic circulatory arrest. It requires a true endarterectomy performed through dissection in the medial plane of the vessel wall, not a simple embolectomy. Operability assessment is performed by an expert CTEPH surgical team and considers the accessibility of disease (main, lobar, or segmental arteries), hemodynamic severity, and comorbidities. Outcomes at expert centers are excellent: perioperative mortality ranges from 2-5%, hemodynamic improvement is achieved in 85-90% of patients, near-normalization of PVR occurs in many, and 10-year survival is approximately 75%. Persistent or recurrent pulmonary hypertension after PEA occurs in 10-35% of patients and is managed with medical therapy with or without balloon pulmonary angioplasty.

### Balloon Pulmonary Angioplasty (BPA)

Balloon pulmonary angioplasty is a percutaneous catheter-based intervention developed for patients with surgically inaccessible distal disease or those who are not candidates for surgery. Multiple serial sessions are typically required, generally 3-6 sessions performed 2-4 weeks apart, with different vascular segments targeted at each session. The technique was pioneered and refined in Japan by Matsubara and Mizoguchi using the wire perforation technique. Outcomes demonstrate significant improvement in mean PAP (reduction of approximately 10-15 mmHg), PVR (reduction of approximately 50%), six-minute walk distance, and WHO functional class. Complications include reperfusion pulmonary edema (the most common, reduced with refined technique), vessel perforation, and hemoptysis. BPA may be combined with medical therapy and used after PEA for residual disease.

### Medical Therapy

Riociguat, a soluble guanylate cyclase stimulator, is the only FDA-approved medication for CTEPH. The CHEST-1 trial demonstrated improved six-minute walk distance (+46 meters), PVR, and WHO functional class compared to placebo in patients with inoperable CTEPH or persistent pulmonary hypertension after PEA. The CHEST-2 long-term extension confirmed sustained benefits at 2 years. Dosing begins at 1 mg three times daily with titration to a maximum of 2.5 mg three times daily. Riociguat cannot be combined with PDE5 inhibitors due to the risk of severe hypotension. Side effects include hypotension, headache, and gastrointestinal symptoms. Off-label medical therapies used in practice with limited RCT evidence include PDE5 inhibitors (sildenafil, tadalafil), endothelin receptor antagonists (bosentan, macitentan), and prostacyclin analogues for severe inoperable disease. Subcutaneous treprostinil demonstrated improved PVR and six-minute walk distance in severe inoperable CTEPH in the CTREPH trial published in 2024.

### Treatment Modality Comparison

| Modality | Indication | Mechanism | Key Outcomes | Limitations |
|----------|-----------|-----------|-------------|-------------|
| PEA (surgery) | Accessible proximal disease | Endarterectomy under DHCA | 85-90% hemodynamic improvement; 2-5% mortality; 10-yr survival ~75% | Requires expert center; not all patients operable |
| BPA | Distal disease or inoperable | Serial balloon dilation | ~50% PVR reduction; multiple sessions needed | Reperfusion edema; vessel perforation risk |
| Riociguat | Inoperable or residual PH post-PEA | sGC stimulator | +46m 6MWD (CHEST-1) | Cannot combine with PDE5i; not curative |
| Combined approach | Complex disease | PEA + BPA + medical | Optimizes outcomes; individualized | Requires expert MDT |

### Multimodal Approach

Contemporary CTEPH management is best guided by an expert multidisciplinary team comprising a surgeon, interventional pulmonologist or cardiologist, pulmonary hypertension specialist, and radiologist. Sequential or combined therapeutic approaches optimize outcomes: PEA followed by postoperative BPA for residual disease, BPA combined with medical therapy for inoperable patients, and medical therapy as a bridge to PEA or BPA.

<image>A treatment decision algorithm for CTEPH showing the multimodal approach. Start with confirmed CTEPH diagnosis. First decision node: multidisciplinary team assessment of operability. If operable (accessible proximal disease, acceptable surgical risk): PEA (gold standard). Post-PEA: reassess at 3-6 months; if residual PH: add riociguat +/- BPA. If inoperable (distal disease or high surgical risk): BPA series + riociguat. If BPA not feasible: riociguat + other medical therapy. Show outcomes at each pathway: PEA (85-90% hemodynamic improvement, 2-5% mortality), BPA (50% PVR reduction, multiple sessions), riociguat (+46m 6MWD). Include a central box showing that ALL patients receive lifelong anticoagulation. Use green for optimal pathway (PEA), yellow for alternative (BPA), orange for medical-only. Show the concept of combined/sequential therapy with connecting arrows between modalities.</image>

## CTED (Chronic Thromboembolic Disease without PH)

### Definition

Chronic thromboembolic disease without pulmonary hypertension (CTED) describes patients with organized thromboembolic material on imaging and exercise limitation but resting hemodynamics that do not meet the criteria for pulmonary hypertension, with mPAP of 20 mmHg or less at rest. Some patients demonstrate exercise-induced pulmonary hypertension, defined as an mPAP/cardiac output slope exceeding 3 mmHg/L/min during exercise right heart catheterization. CTED is increasingly recognized and may represent early CTEPH or a distinct pathophysiologic entity.

### Management

Lifelong anticoagulation is mandatory. PEA may be considered in symptomatic patients at expert centers, though outcomes data are mixed, with some studies showing worsening of exercise hemodynamics postoperatively despite symptom improvement. BPA has an emerging role, with case series demonstrating symptomatic improvement. Exercise rehabilitation complements interventional approaches.

## Prognosis

### Outcomes Without Treatment

The natural history of untreated CTEPH is one of progressive right ventricular failure and death, with a 3-year survival of approximately 70% when mPAP exceeds 30 mmHg. Outcomes are significantly worse with higher PVR and WHO functional class III-IV.

### Post-Treatment Outcomes

Following PEA, 10-year survival is approximately 75%, with near-normalization of hemodynamics and dramatic improvement in quality of life in many patients. BPA outcomes continue to improve with refined technique, with 5-year survival exceeding 95% in recent Japanese cohorts. Medical therapy alone provides stabilization and modest improvement but does not remove the mechanical obstruction.

## Key Clinical Pearls

- V/Q scan is the screening test of choice for CTEPH; a normal V/Q essentially excludes the diagnosis; CTPA has unacceptable sensitivity (50-70%) for CTEPH screening and should NOT be used as the sole screening test
- CTEPH is the only form of pulmonary hypertension that is potentially curable with PEA; all patients should be assessed for operability at an expert CTEPH center
- Up to 25% of CTEPH patients have no documented prior acute PE; absence of PE history does NOT exclude CTEPH in a patient with unexplained pulmonary hypertension
- Riociguat is the only FDA-approved medical therapy for CTEPH; it CANNOT be combined with PDE5 inhibitors (risk of severe hypotension)
- BPA is an evolving intervention that complements PEA and medical therapy; the multimodal approach (PEA + BPA + medical therapy) optimizes outcomes in complex CTEPH

## References
1. Kim NH, Delcroix M, Jais X, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J. 2019;53(1):1801915.
2. Ghofrani HA, D'Armini AM, Grimminger F, et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension. N Engl J Med. 2013;369(4):319-329. (CHEST-1)
3. Madani MM, Auger WR, Pretorius V, et al. Pulmonary endarterectomy: recent changes in a single institution's experience of more than 2,700 patients. Ann Thorac Surg. 2012;94(1):97-103.
4. Kawakami T, Ogawa A, Miyaji K, et al. Novel Angiographic Classification of Each Vascular Lesion in Chronic Thromboembolic Pulmonary Hypertension Based on Selective Angiogram and Results of Balloon Pulmonary Angioplasty. Circ Cardiovasc Interv. 2016;9(10):e003318.
5. Delcroix M, Torbicki A, Gopalan D, et al. ERS statement on chronic thromboembolic pulmonary hypertension. Eur Respir J. 2021;57(6):2002828.