Pulmonary Arteriovenous Malformations in BMPR2-Associated Pulmonary Arterial Hypertension

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Abstract Pulmonary arteriovenous malformations (PAVMs) are frequently associated with hereditary hemorrhagic telangiectasia (HHT) but may occur sporadically or in association with cyanotic congenital heart disease. Pulmonary arterial hypertension (PAH) is a multifactorial disease with both sporadic and inherited mutations in the bone morphogenic protein receptor 2 (BMPR2) gene well described in its pathogenesis. HHT and BMPR2-associated PAH share abnormalities in the bone morphogenic protein (BMP) signaling pathway. Despite this overlap, PAVMs in association with PAH are not commonly reported in the literature. Here, we report the case of multiple PAVMs in a patient without HHT but with PAH and a concomitant sporadic BMPR2 mutation. A 25-year-old woman was referred to our clinic after relocating from Texas. She was diagnosed with myasthenia gravis at age 17, followed by a diagnosis of PAH with genetic testing documenting sporadic heterozygosity for a pathogenic BMPR2 variant. She was born from an egg donor who tested negative for the mutation; her father also tested negative for a BMPR2 mutation. At the time of her relocation, she was on triple oral therapy with riociguat, selexipag, and macitentan with low-risk by REVEAL score and mildly decreased right ventricular function on echocardiography. Dual energy CT angiography obtained to complete PH evaluation was notable for multifocal bilateral ground glass opacities, as well as multiple PAVMs and aorto-pulmonary collaterals (Figure 1). Serial ambulatory oxygen assessments demonstrated progressive borderline exertional hypoxia. Additional genetic testing for HHT was negative. This case illustrates an example of PAVM in association with BMPR2-associated PAH. Growing evidence supports shared overlap in signaling pathways between PAH and HHT with the BMP signaling pathway thought to be important in both. It is known that patients with HHT may develop significant pulmonary hypertension, but only recently case reports have suggested an association between PAH and PAVMs. The recently approved drug sotatercept is an activin-receptor IIA (ActRIIA) analog acting as a ligand trap for multiple factors in the BMP signaling pathway, with 10% of patients on treatment developing telangiectasias. This further supports an overlapping role for BMP signaling in PAVM and PAH. This case illustrates the importance of remaining vigilant for comorbid PAVM in patients with PAH, particularly in the presence of heritable or sporadic BMPR2 mutations. Specific management including the role of antiplatelet therapy and prophylactic embolization in these patients remains to be determined. Whether sotatercept in these patients can worsen pre-existing AVMs is unknown. Figure 1.

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