The pathophysiology of chronic thromboembolic pulmonary hypertension

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, progressive pulmonary vascular disease that is usually a consequence of prior acute pulmonary embolism. CTEPH usually begins with persistent obstruction of large and/or middle-sized pulmonary arteries by organised thrombi. Failure of thrombi to resolve may be related to abnormal fibrinolysis or underlying haematological or autoimmune disorders. It is now known that small-vessel abnormalities also contribute to haemodynamic compromise, functional impairment and disease progression in CTEPH. Small-vessel disease can occur in obstructed areas, possibly triggered by unresolved thrombotic material, and downstream from occlusions, possibly because of excessive collateral blood supply from high-pressure bronchial and systemic arteries. The molecular processes underlying small-vessel disease are not completely understood and further research is needed in this area. The degree of small-vessel disease has a substantial impact on the severity of CTEPH and postsurgical outcomes. Interventional and medical treatment of CTEPH should aim to restore normal flow distribution within the pulmonary vasculature, unload the right ventricle and prevent or treat small-vessel disease. It requires early, reliable identification of patients with CTEPH and use of optimal treatment modalities in expert centres.

FIGURE 1

Pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH). PH: pulmonary hypertension. Reproduced and modified from [4] with permission.

FIGURE 2

Natural history of chronic thromboembolic pulmonary hypertension (CTEPH). PE: pulmonary embolism. Reproduced and modified from [2] with permission.

FIGURE 3

Microvasculopathy in chronic thromboembolic pulmonary hypertension involving pulmonary arterioles, venules and capillaries. Schematic representation of anastomosis between systemic and pulmonary circulation through hypertrophic bronchial arteries and vasa vasorum. PA: pulmonary artery; PVOD: pulmonary veno-occlusive disease; PAH: pulmonary arterial hypertension. Reproduced and modified from [67] with permission.

FIGURE 4

Patient with inoperable chronic thromboembolic pulmonary hypertension showing a typical aspect of subpleural hypoperfusion at the capillary phase of pulmonary angiography. Image kindly provided by P. Dartevelle, French National Reference Centre of Pulmonary Hypertension, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

FIGURE 5

Relationship between pulmonary vascular obstruction (PVO) and pulmonary vascular resistance in chronic thromboembolic pulmonary hypertension (CTEPH) and acute pulmonary embolism (PE). a) Patient AL: 24-year-old female with CTEPH. Percentage of PVO estimated on perfusion lung scan at 75%. Total occlusion of left lung and occlusion of right middle and lower lobes. Haemodynamics: mean pulmonary arterial pressure (PAP) 32 mmHg; cardiac index 1.7 L·min^-1·m^-2; total pulmonary vascular resistance (TPR) 18.8 mmHg·L^-1·min·m². Despite 75% PVO, the TPR was only 18.8. b) Patient BJ: 54-year-old female with CTEPH. Percentage of PVO estimated on perfusion lung scan at 35%; multiple bilateral segmental and subsegmental perfusion defects. Haemodynamics: mean PAP 45 mmHg; cardiac index 1.4 L·min^-1·m^-2; TPR 32.1 mmHg·L^-1·min·m². c) Relationship between percentage of PVO assessed by perfusion lung scan and TPR in patients with acute PE (n=31). A strong hyperbolic correlation was found. d) For a given degree of PVO, most patients with CTEPH (n=45) have higher TPR values than patients with acute PE (n=31), suggesting that, in addition to mechanical obstruction by organised clots, they have small-vessel disease. Patient AL is located on the hyperbolic correlation (no microvasculopathy), whereas patient BJ has a disproportionate and very high level of TPR compared to mild PVO (severe microvasculopathy). Reproduced and modified from [86] with permission.