An unexpected therapeutic overlap: long-term control of KCNK3-associated pulmonary arterial hypertension during treatment of systemic hypertension—a case report

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by obliterative pulmonary vascular remodelling. Pathogenic variants in KCNK3 represent a recognized cause of heritable PAH (hPAH). Loss-of-function mutations lead to membrane depolarization, increased calcium influx, and enhanced pulmonary vasoconstriction. Calcium channel blockers (CCBs) are recommended for patients demonstrating a positive acute vasoreactivity test.

A 50-year-old man carrying a pathogenic KCNK3 (E34K) mutation was referred to a tertiary PAH centre during familial screening after two of his children were diagnosed with PAH and were non-responders to acute vasoreactivity testing. He was mildly symptomatic, World Health Organization functional class (WHO-FC) II, with preserved exercise capacity, 6-min walk distance (6MWD) of 580 m, and normal NT-proBNP levels. Echocardiography showed mild right ventricular dilatation with preserved systolic function. Right heart catheterization (RHC) confirmed mild pre-capillary pulmonary hypertension with a positive acute vasoreactivity testing response. Considering the mild haemodynamic impairment, the underlying KCNK3 mutation, and prior clinical improvement during amlodipine therapy for systemic hypertension, high-dose amlodipine was initiated. At 6-month follow-up, the patient improved to WHO-FC I, with increased 6MWD and haemodynamic improvement on repeat RHC.

This case describes a favourable clinical and haemodynamic response to CCB therapy in KCNK3-associated PAH. It highlights phenotypic variability within familial KCNK3-related disease and indicates that longitudinal data may help identify patients who could benefit from targeted therapies despite borderline haemodynamic profiles.