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pathophysiological mechanisms. In spherocytosis, splenectomy is a risk factor for CTEPH.819 Multiple causes of PH have been described in patients with chronic myeloproliferative disorders.820 In chronic myelogenous leukaemia, spleen enlargement and anaemia can give rise to hyperkinetic syndrome. Hepatosplenic enlargement can also cause PoPH. Cases of potentially reversible DPAH have been described with dasatinib, bosutinib, and ponatinib. In polycythaemia vera and essential thrombocythaemia, there is an increased risk of venous thrombo-embolic disease and CTEPH; moreover, a blood clot within the hepatic veins can lead to Budd–Chiari syndrome and subsequent PoPH. Pulmonary extramedullary haematopoiesis complicating idiopathic or secondary myelofibrosis may also contribute to dyspnoea and PH. Group 5 PH may be described in other haematological disorders, such as common variable immunodeficiency; immunoglobulin G4 (IgG4)-related disease; Castleman disease; and polyneuropathy, organomegaly, endocrinopathy, monoclonal immunoglobulin, skin changes (POEMS) syndrome.821–823

11.2 Systemic disorders

The reported prevalence of PH in patients with sarcoidosis is 6– 20%.824 The causes are multifactorial, including fibrosing lung disease, granulomata in the PAs and/or pulmonary veins, fibrosing mediastinitis and/or extrinsic compression by lymph nodes, pulmonary vasculitis, CTEPH, and PoPH.58,825 It is associated with significant morbidity and increased mortality compared with sarcoidosis without PH.58,825 In a registry, factors independently associated with outcomes included physiological (forced expiratory volume in 1 s/FVC ratio and DLCO) and functional (6MWD) parameters.58 In a large study of severe, sarcoidosis-associated PH, PAH drugs improved short-term pulmonary haemodynamics without improving 6MWD.59 Small RCTs have suggested efficacy of PAH drugs in these patients, which requires confirmation in larger studies.826 Corticosteroids or immunosuppressive therapy may improve haemodynamics in selected patients with active granulomatous disease. Of note, when pulmonary vascular compression is suspected (fibrosing mediastinitis and/or extrinsic compression by lymph nodes), results from pulmonary angiography and PET scans provide additional information justifying endovascular and/or antiinflammatory approaches. Long-term survival remains poor in sarcoidosis-associated PH, which makes LTx a reasonable option for selected severe cases. In pulmonary Langerhans’s cell histiocytosis, diminished exercise capacity does not appear to be due to ventilatory limitation but may be related to pulmonary vascular dysfunction. In 29 patients with PH associated with pulmonary Langerhans’s cell histiocytosis, PAH drugs improved haemodynamics without worsening oxygen levels.827 Pulmonary hypertension associated with neurofibromatosis type 1 is a rare but severe complication characterized by female predominance (female/male ratio 3.9:1).828 Specific pulmonary vascular involvement exists in these patients, and despite a potential short-term benefit of PAH drugs, prognosis remains poor, and LTx should be considered in selected patients with severe disease. In the presence of dyspnoea, screening for ILD by non-contrast CT and for PH by echocardiography is required.828 11.3 Metabolic disorders

Glycogen storage diseases are caused by genetic alterations of glycogen metabolism, and PH case reports have been related to glycogen storage disease type 1 and 2.829 The occurrence of PH has predominantly been described in glycogen storage disease type 1, where it may partly be due to vasoconstrictive amines such as serotonin. Drugs for PAH have been used in some cases.830 Untreated patients with Gaucher disease may develop PH, which is caused by a combination of factors, including asplenia, plugging of the vasculature by abnormal macrophages, and pulmonary vascular remodelling. Treatment with enzyme-replacement therapy may improve PH.

11.4 Chronic kidney failure

Although commonly recognized in chronic renal failure, the pathogenesis of PH remains poorly understood and PH is observed in patients prior to and while receiving different dialysis modalities.831 A recent RHC study of 3504 patients with chronic kidney disease found that CpcPH was the most common phenotype, and the phenotype with the highest mortality.832 Post-capillary PH has been described in 65% of patients receiving haemodialysis and 71% of patients without kidney replacement.833

11.5 Pulmonary tumour thrombotic

microangiopathy Pulmonary tumour thrombotic microangiopathy describes tumourcell microemboli with occlusive fibrointimal remodelling in small PAs, pulmonary veins, and lymphatics. It is a rare cause of PH, which arises due to multiple mechanisms, but probably remains under-diagnosed, as evidenced by autopsy findings.834 The disorder is associated with carcinomas, notably gastric carcinoma. Progressive vessel occlusion ultimately results in PH, which is often severe, of sudden onset, rapidly progressive, and accompanied by progressive hypoxaemia. Chest CT may show patchy ground-glass and septal markings (masquerading as PVOD).

11.6 Fibrosing mediastinitis

Fibrosing mediastinitis is caused by fibrous tissue proliferating in the mediastinum, encasing mediastinal viscera and compressing mediastinal bronchovascular structures.835 Pre- or post-capillary PH can complicate the course of fibrosing mediastinitis due to extrinsic compression of the PAs and/or pulmonary veins. Fibrosing mediastinitis can be idiopathic or caused by irradiation, infection (tuberculosis, histoplasmosis), and systemic diseases, such as sarcoidosis and IgG4-related disease, a fibroinflammatory disease characterized by elevated serum IgG4 levels with infiltration of IgG4+ plasma cells and severe fibrosis in affected tissues.821 Treatment should be directed to the underlying condition. No clear clinical improvement has been described with PAH drugs. Surgical and endovascular procedures have been proposed to de-obstruct or bypass the arterial and/or venous compressions. In the absence of positive RCTs studying the use of PAH drugs for treating group 5 PH, treating the underlying disorder remains the standard of care.836 Importantly, some of the diseases described in Table 24 may have a pulmonary venous component that could be made worse with PAH drugs, implying that off-label use of drugs approved for PAH should be considered with great caution, if at all. Downloaded from academic.oup.com/eurheartj/article/43/38/3618/6673929 by guest on 07 October 2026