Pulmonary Arterial Hypertension With Moyamoya Disease Harboring the RNF213 p.Arg4810Lys Variant Presenting a Favorable Response to Monotherapy: A Case Report

ABSTRACT

Pulmonary arterial hypertension (PAH) harboring the heterozygous ring finger protein 213 (RNF213) p.Arg4810Lys variant responds poorly to PAH treatment and has a poor prognosis. Here, we present a case of severe PAH and moyamoya disease (MMD) harboring a heterozygous RNF213 p.Arg4810Lys variant that responded well to PAH monotherapy. A 23‐year‐old woman with cerebral infarction due to MMD was referred to our center for MMD bypass surgery and treatment of severe PAH. Genetic analysis revealed a heterozygous RNF213 p.Arg4810Lys variant. We initiated PAH‐targeted therapy before MMD bypass surgery, as bypass surgery was considered high‐risk in the presence of severe PAH. Despite a positive response to acute vasoreactivity testing with nitric oxide (NO) inhalation, calcium channel blockers were avoided due to the risk of hypotension‐induced cerebral ischemia. We initiated endothelin receptor antagonist (macitentan, 10 mg/day) monotherapy because upfront combination therapy may also cause hypotension. Endothelin receptor antagonist monotherapy improved symptoms and pulmonary hemodynamics, reducing vascular resistance from 11.4 to 7.1 Wood Units after 1 month. Bilateral cerebral bypass surgery was performed after hemodynamic improvement. The clinical spectrum of RNF213‐associated PAH may be broader than previously reported. This case highlights the importance of personalized medicine that considers patient conditions and comorbidities when selecting treatment options for patients with PAH harboring the RNF213 p.Arg4810Lys variant.

1. Case Description

A 23‐year‐old woman experienced a headache and a transient ischemic attack (TIA). She presented to a local hospital, where cerebral angiography (Figure 1A) led to a diagnosis of bilateral moyamoya disease (MMD). Further evaluation revealed coexisting pulmonary hypertension (PH). Given the need for cerebral revascularization and treatment of PH, the patient was referred to our hospital. At presentation, she was in NYHA functional class III, with a BNP level of 175.0 pg/ml. The 6‐min walk test was not performed because of crescendo transient ischemic attacks and concern that exertion could precipitate cerebral ischemia.

Figure 1.

(A) Cerebral angiography showing the characteristic abnormal vascular network at the base of the brain, commonly referred to as the “puff of smoke sign” (white arrows), consistent with Moyamoya disease. (B) Lung perfusion scintigraphy (anterior view) revealed diffusely reduced pulmonary perfusion, which was more pronounced in the lower lobes, with no apparent segmental defects. (C) Pulmonary angiography showing no evidence of peripheral pulmonary artery stenosis or chronic thromboembolism. (D) Transthoracic echocardiography showing marked right ventricular enlargement before pulmonary arterial hypertension (PAH)‐targeted treatment. (E) Transthoracic echocardiography showing a decrease in right ventricular size after PAH‐targeted treatment.

Right heart catheterization (RHC) at presentation showed a mean pulmonary artery pressure (mPAP) of 46 mmHg, pulmonary artery wedge pressure (PAWP) of 6 mmHg, cardiac index (CI) of 2.33 L/min/m², and pulmonary vascular resistance (PVR) of 11.4 Wood Units (WU). Acute vasoreactive test (AVT) was performed with 20 ppm nitric oxide (NO) administered for 10 min, which showed a positive response (hemodynamics during AVT: mPAP, 30 mmHg, PAWP, 8 mmHg, CI of 2.62 L/min/m², and PVR 5.6 WU). Computed tomography and spirometry ruled out lung disease. Patients with peripheral pulmonary artery stenosis or chronic thromboembolic pulmonary hypertension were excluded using lung perfusion scintigraphy (Figure 1B). Pulmonary angiography revealed no signs of chronic thromboembolism or peripheral pulmonary artery stenosis (Figure 1C). Transthoracic echocardiography revealed right ventricular dilatation (Figure 1D). The patient was diagnosed with idiopathic pulmonary arterial hypertension (PAH). Genetic testing revealed a heterozygous variant of RNF213 p.Arg4810Lys, a known gene associated with both PH and MMD.

Medical treatment for PAH is prioritized to reduce the perioperative risk of subsequent revascularization surgeries. Although calcium channel blockers (CCBs) are a treatment option owing to their positive response to AVT, CCBs were avoided because they can lower blood pressure and precipitate cerebral ischemia in the context of MMD. Therefore, we initiated endothelin receptor antagonist (ERA) monotherapy with macitentan 10 mg/day since it has a lower potential to cause blood pressure reduction and headaches than other drugs. Subsequently, an urgent right superficial temporal artery‐middle cerebral artery bypass surgery was performed because the crescendo TIAs were refractory to medical treatment.

Postoperatively, the patient developed bilateral cerebral infarction and presented with mild right lower limb weakness and motor aphasia. Follow‐up RHC after 1 month of PAH treatment demonstrated improved hemodynamics: mPAP, 34 mmHg, PAWP, 5 mmHg, CI of 2.73 L/min/m², and PVR 7.1 WU. At this assessment, NYHA functional class was II, and BNP was 25.4 pg/ml. After hemodynamic improvement, elective left‐sided bypass surgery was performed. No hypotension or new perioperative cerebral infarction occurred during the second surgery. The patient underwent rehabilitation and was discharged 2 months after initiation of PAH treatment. Furthermore, PAH‐targeted treatment was deferred because of concerns that escalating PH therapy might negatively affect MMD. At 1‐year follow‐up, NYHA functional class was II, 6‐min walk distance was 380 m, and BNP was 6.2 pg/ml. Right heart catheterization showed no worsening of pulmonary hemodynamics: mPAP, 28 mmHg, PAWP, 9 mmHg, CI of 3.35 L/min/m², and PVR 3.9 WU. Transthoracic echocardiography showed a reduction in right ventricular size (Figure 1E).

2. Discussion

We describe a patient with severe PAH harboring a heterozygous RNF213 p.Arg4810Lys variant who showed a short‐term clinical and hemodynamic response to endothelin receptor antagonist (ERA) monotherapy. RNF213 p.Arg4810Lys variant, initially identified as a susceptibility gene for MMD [1], has also been linked with the pathogenesis of PAH [2]. PAH associated with RNF213 mutations has been reported to exhibit poor responsiveness to PH therapies, worse prognosis, and, in some cases, the need for early lung transplantation [3]. Currently, PAH guidelines recommend upfront combination therapy for PAH patients [4]. However, careful consideration of systemic blood pressure was required in this case. Hypotension itself may increase the risk of cerebral ischemic events, particularly in patients with underlying cerebrovascular vulnerabilities such as MMD. ERA monotherapy was selected owing to its minimal effect on systemic blood pressure. Pulmonary hemodynamics and symptoms improved after 1 month; however, residual PH remained, and bilateral cerebral infarction occurred after the first bypass surgery, so the cerebrovascular safety of this strategy cannot be inferred from this single case.

The patient responded positively to AVT with nitric oxide inhalation. There have been no reports on AVT in patients with PAH harboring the RNF 213 variant. To our knowledge, this is the first report of an AVT‐positive PAH with an RNF213 mutation. AVT positivity is observed in approximately 8.5% of patients with idiopathic or heritable PAH [5] and identifies candidates for high‐dose CCB therapy [6]. However, AVT positivity alone does not establish long‐term CCB responsiveness and has not been shown to predict response to non‐CCB PAH‐specific drugs. Therefore, the favorable short‐term response to macitentan in this patient should not be attributed solely to AVT positivity.

High‐dose CCB treatment is the first‐line therapy for patients with idiopathic PAH who are positive for AVT because some are long‐term CCB responders [4]. However, hypotension can precipitate cerebral ischemia in patients with MMD [7]. Therefore, high‐dose CCB therapy was avoided in this patient. In our previous cohort, some AVT‐positive patients who were already receiving PAH‐specific therapy showed marked additional clinical and hemodynamic improvement after initiation of high‐dose CCBs, suggesting that PAH‐specific therapy alone may be insufficient in some acute vasoresponders [8]. Although hemodynamic improvement was observed in this patient, residual pulmonary hypertension remained, with a PVR of 7.1 WU, warranting careful follow‐up.

This is a case of severe PAH in a patient with MMD harboring the heterozygous RNF213 p.Arg4810Lys variant. Patients with this variant have been reported to be refractory to PAH treatment and have a poor prognosis. Because high‐dose CCB therapy was considered clinically unsafe, macitentan monotherapy was used as an individualized exception and was associated with short‐term clinical and hemodynamic improvement, although residual PH remained. A single case cannot establish ERA monotherapy as an alternative to CCB therapy. This case implies that the clinical spectrum of RNF213‐associated PAH may be broader than previously recognized, and that treatment decisions should be tailored to individual patients. Therefore, it is necessary to examine the relationship between the RNF213 gene variant and the PAH phenotype in more detail.

Author Contributions

Atsushi Kuraishi contributed to the first draft of the manuscript. All authors contributed to the data interpretation. Takatoyo Kiko, Shinya Fujisaki, Ryo Takano, Hiroya Hayashi, Ryotaro Asano, Eika Hamano, Hiroharu Kataoka, and Takeshi Ogo critically reviewed the manuscript, provided substantive comments, and approved the final draft for submission.

Funding

The authors have nothing to report.

Ethics Statement

Written informed consent was obtained from the patient for the publication of this case report. All procedures were conducted in accordance with the standards approved by the Institutional Review Board and the principles of the Declaration of Helsinki.

Conflicts of Interest

T.O. is a member of the Editorial Team of Circulation Reports. T.O. reports receiving lecture fees from Nippon Shinyaku Co., Janssen Pharmaceutical K.K., MSD, Bayer Yakuhin Ltd., and Mochida Pharmaceutical Co. Ltd. outside the submitted work. The other authors declare no conflicts of interest.

Guarantor

The guarantor of the study is Dr. Takeshi Ogo.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.