Balloon Pulmonary Angioplasty in Heterozygous RNF213 p.Arg4810Lys Variant Carriers Diagnosed With Chronic Thromboembolic Pulmonary Hypertension

Abstract

Background: The heterozygous ring finger protein 213 (RNF213) p.Arg4810Lys variant has been identified in patients with chronic thromboembolic pulmonary hypertension (CTEPH). This study aimed to clarify the influence of the RNF213 p.Arg4810Lys variant on the response to balloon pulmonary angioplasty (BPA) in patients with CTEPH.

Methods: We retrospectively analyzed 93 patients with CTEPH who underwent BPA by analyzing the RNF213 p.Arg4810Lys variant. Clinical parameters and hemodynamics following BPA were compared between RNF213 p.Arg4810Lys variant carriers and noncarriers, along with BPA-related complications.

Results: Among 93 patients, 7 (8%) were heterozygous RNF213 p.Arg4810Lys variant carriers and 86 (92%) were noncarriers. Both groups showed significant improvements in mean pulmonary artery pressure and pulmonary vascular resistance following BPA. However, the 6-minute walk distance, symptoms, cardiac index, and right ventricular function did not significantly improve in heterozygous RNF213 variant carriers, whereas noncarriers showed notable improvements. Group differences in mean change from baseline to follow-up were significant in cardiac index (0.4 L/min per m² [95% CI, 0.1-0.8]; P=0.019), 6-minute walk distance (70 m [95% CI, 6-135]; P=0.036), and right ventricular ejection fraction (9% [95% CI, 5-12]; P<0.001), all favoring noncarriers. Of the 515 BPA procedures, complications were significantly higher in variant carriers than in noncarriers (25% versus 8%; P<0.001). Multivariate logistic regression analysis indicated a significant association between the RNF213 p.Arg4810Lys variant and BPA complications (adjusted odds ratio, 7.0 [95% CI, 1.1-44.4]; P=0.038).

Conclusions: Heterozygous RNF213 p.Arg4810Lys variant carriers exhibited a poor response to BPA, suggesting that the RNF213 p.Arg4810Lys variant could be a risk factor for BPA complications.

Keywords: balloon pulmonary angioplasty; chronic thromboembolic pulmonary hypertension; ring finger protein 213.

Figure 1. Study protocol.

BPA indicates balloon pulmonary angioplasty; CTEPH, chronic thromboembolic pulmonary hypertension; and RNF213, ring finger protein 213.

Figure 2. Comparison of clinical parameters and hemodynamics at baseline and follow‐up after balloon pulmonary angioplasty.

A, mPAP, (B) PVR, (C) cardiac index, (D) 6MWD, and (E) RVEF. Values represent the group differences in the mean change from baseline to follow‐up. 6MWD indicates 6‐minute walk distance; BPA, balloon pulmonary angioplasty; mPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; RNF213, ring finger protein 213; and RVEF, right ventricular ejection fraction.

Figure 3. Representative case of BPA complications in a heterozygous RNF213 p.Arg4810Lys variant carrier diagnosed with CTEPH.

A, Pulmonary angiogram. B, Computed tomography pulmonary angiogram showing webs and bands (red arrowhead) in the pulmonary arteries. C, Selective pulmonary angiogram obtained before BPA treatment (left panel). After 2.0‐mm balloon inflation (middle panel), the pulmonary artery was ruptured (right panel). Hemostasis was achieved by using a hemostatic absorbable gelatin sponge. BPA indicates balloon pulmonary angioplasty; CTEPH, chronic thromboembolic pulmonary hypertension; and RNF213, ring finger protein 213.