Pulmonary arterial hypertension (PAH)

Patients with PAH usually present with non-specific symptoms such as fatigue, exhaustion, and exertional dyspnoea. Additional early symptoms include syncope, chest pain, palpitations, and oedema of the feet. Owing to the non-specific nature of these manifestations, diagnosis is often delayed by two to three years after symptom onset.

Pulmonary arterial hypertension comprises idiopathic (IPAH), heritable (HPAH), and disease- or drug-associated forms. Heterozygous pathogenic variants in BMPR2 are detected in approximately 75% of patients with heritable PAH and in about 15–20% of patients with idiopathic PAH. In rarer cases, pathogenic variants in other genes account for approximately 1–3% of cases.

PAH is characterised by a mean pulmonary arterial pressure (PAP) greater than 25 mmHg at rest, measured by right heart catheterisation, with normal pulmonary capillary occlusion pressure (wedge pressure ≥ 15 mmHg) and increased pulmonary vascular resistance (PVR). Structural changes in the pulmonary vasculature lead to progressive vasoconstriction, resulting in increasing strain on the right heart and potentially right heart failure.

Pathogenic variants in the BMPR2 gene, which encodes bone morphogenetic receptor 2, a member of the transforming growth factor beta (TGF-β) family, are the most common genetic cause of HPAH. In addition, causative variants have been identified less frequently in other genes, including ACVRL1, BMPR1B, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, SMAD1, SMAD4, SMAD9, and TBX4. These variants may occur de novo or be inherited.

Heritable pulmonary arterial hypertension is inherited in an autosomal dominant manner with incomplete penetrance. Penetrance differs markedly by sex, with approximately 42% in women and around 14% in men. As a result of incomplete penetrance, familial cases may remain unrecognised. Disease onset is highly variable and can range from early childhood to late adulthood.

Diagnosis of PAH is based on haemodynamic measurements obtained by right heart catheterisation. Because clinical symptoms are often non-specific, diagnosis is frequently delayed. Molecular genetic diagnostics serve as a complementary tool to standard diagnostic methods and are particularly relevant in suspected heritable or idiopathic cases. Early diagnosis is essential, as timely initiation of therapy significantly improves prognosis and quality of life.

Pulmonary arterial hypertension must be distinguished from other forms of pulmonary hypertension and from pulmonary hypertension secondary to underlying diseases such as connective tissue disorders, HIV infection, or liver disease, as well as drug-induced pulmonary hypertension.

Molecular genetic testing can complement conventional diagnostic approaches, particularly in patients with suspected heritable PAH or idiopathic PAH, and may support early diagnosis and family counselling.

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