The results of genetic analysis and clinical outcomes after stent deployment in adult patients with isolated peripheral pulmonary artery stenosis

Extract

Peripheral pulmonary arterial stenosis (PPAS) is commonly observed in paediatric patients with associated congenital heart disease or systemic congenital syndromes, such as tetralogy of Fallot and Williams syndrome [1]. Meanwhile, isolated PPAS without other structural heart disease or systemic congenital syndromes is primarily reported in adulthood [2]. Recent genetic analyses have revealed that four cases of isolated PPAS in adulthood were homozygous for the ring finger protein 213 (RNF213) p.Arg4810Lys variant (also referred to as G to A alteration of rs112735431 and NM_001256071.3:c.14429G>A) [3]. RNF213 p.Arg4810Lys is a genetic determinant in moyamoya disease (MMD) in East Asians [4]. This genetic variant is unique to East Asians and is reported to have a frequency of approximately 0.8% in the general Japanese population [5, 6]. However, its prevalence in adult patients with isolated PPAS remains unknown.

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The RNF213 p.Arg4810Lys mutation is closely linked to the development of PPAS. Stent deployment might be a promising treatment option, but further investigation would be warranted. https://bit.ly/40t8Gmz

To the Editor:

Peripheral pulmonary arterial stenosis (PPAS) is commonly observed in paediatric patients with associated congenital heart disease or systemic congenital syndromes, such as tetralogy of Fallot and Williams syndrome [1]. Meanwhile, isolated PPAS without other structural heart disease or systemic congenital syndromes is primarily reported in adulthood [2]. Recent genetic analyses have revealed that four cases of isolated PPAS in adulthood were homozygous for the ring finger protein 213 (RNF213) p.Arg4810Lys variant (also referred to as G to A alteration of rs112735431 and NM_001256071.3:c.14429G>A) [3]. RNF213 p.Arg4810Lys is a genetic determinant in moyamoya disease (MMD) in East Asians [4]. This genetic variant is unique to East Asians and is reported to have a frequency of approximately 0.8% in the general Japanese population [5, 6]. However, its prevalence in adult patients with isolated PPAS remains unknown.

The treatment of choice for adult patients with PPAS has yet to be elucidated. Balloon angioplasty [7] and stent deployment [8] have shown effectiveness in patients with peripheral lesions involving segmental or subsegmental pulmonary arteries. However, further investigation would be warranted to determine the treatment for isolated PPAS, given the limited number of patients. In this study, we examined the genetic association of RNF213 with isolated PPAS by whole-genome sequencing analysis. We also investigated haemodynamic improvements before and after pulmonary angioplasty to reconsider the optimal treatment for isolated PPAS.

This single-centre, retrospective, observational study, including genetic analysis, was approved by the institutional review board of the NHO Okayama Medical Center (approval numbers: H29-RINKEN-077 and GAIKEN2020-001). This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement reporting guidelines [9]. Patients with isolated PPAS aged 18 years or older at diagnosis and who underwent pulmonary angioplasty at our hospital between July 2007 and March 2022 were included. Patients associated with other structural heart diseases or those considered part of a systemic congenital syndrome were excluded from this study. None of the participants in this study have been previously reported. Written informed consent was obtained from each patient before the procedure, encompassing the entire pulmonary angioplasty, including stent deployment. Clinical characteristics and haemodynamic parameters were investigated before and after pulmonary angioplasty. Differences between variables measured before and after pulmonary angioplasty were evaluated using the paired t-test or Wilcoxon signed-rank test, as appropriate. Long-term survival from the initiation of treatment at our hospital was evaluated using the Kaplan–Meier method, with all-cause death as the primary outcome, and the follow-up period ended in March 2022. Whole-genome sequencing was conducted on 20 of the 24 patients who provided written informed consent for genetic analysis. The analysis was performed using DNBSeq-G400RS, DNBSeq-T7 (MGI-Tech Inc., Shenzhen, China) and NovaSeq (Illumina Inc., San Diego, CA, USA), for 16, two and two patients, respectively.

The clinical characteristics, treatment with pulmonary vasodilators, haemodynamic data, and presence of MMD in the 24 patients are summarised in table 1. Although dual antiplatelets were basically continued, patients deemed to be at high risk for bleeding were switched to single antiplatelets. The mean±sd age at diagnosis was 33±12 years, with a higher age of diagnosis tendency in patients homozygous for the reference allele of RNF213 p.Arg4810Lys. MMD was identified in four patients. There were no significant differences in haemodynamic severity, clinical presentation or treatment response between pathogenic variants of RNF213. In total, 347 pulmonary angioplasty procedures were performed, with an average of 14 procedures per patient. 22 of 24 patients underwent stent deployment, resulting in 414 stents being deployed, averaging 19±9 stents per patient. Significant improvements were observed after pulmonary angioplasty, including a decrease in mean pulmonary arterial pressure (PAP) and pulmonary vascular resistance and an improvement in 6-min walk distance. Regarding complications, haemosputum was observed in 91 procedures (26.2%), and severe lung injury requiring mechanical ventilation was observed in five procedures (1.4%). Two patients required mechanical ventilation and extracorporeal membrane oxygenation support; only case 4 died 2 days after the 19th pulmonary angioplasty. Additionally, three patients died, due to pulmonary artery rupture 42 months after the sixth intervention (n=1), haemoptysis 29 months after the fourth intervention (n=1), and unknown sudden death 11 months after the 11th intervention (n=1). Four patients (16.6%) died during the observation period, and the 1- and 5-year cumulative survival rates for patients with isolated PPAS were 100% and 86%, respectively.

TABLE 1.

Characterisation of patients with isolated peripheral pulmonary artery stenosis

Case	Age (years)	Sex	Survival status	MMD	RNF 213 p.Arg4810Lys (G>A)	Before pulmonary angioplasty				After pulmonary angioplasty
						PH medication	6MWD (m)	mPAP (mmHg)	PVR (WU)	PH medication	6MWD (m)	mPAP (mmHg)	PVR (WU)
1	23	M	Alive	−	A/A	None	NA	57	8	Single	400	34	3.9
2	33	F	Alive	−	G/G	Single	120	43	7.4	Triple	240	38	10.8
3	24	F	Dead	+	NA	Triple	230	67	17.6	Triple	270	68	NA
4	36	F	Dead	−	A/A	Dual	300	101	20	Dual	200	74	22.4
5	18	M	Alive	−	A/A	Dual	432	48	6.9	Triple	535	41	3.6
6	18	F	Alive	−	A/A	Dual	340	53	7.6	Single	270	34	5.1
7	50	M	Dead	−	NA	None	NA	45	7.7	None	640	28	5.5
8	37	F	Dead	+	NA	None	NA	49	15.3	Single	NA	41	4.7
9	34	M	Alive	−	A/A	Dual	420	65	10.1	Single	700	29	3.5
10	33	M	Alive	+	G/G	Dual	350	50	7.1	None	549	31	4.5
11	29	F	Alive	−	A/A	Dual	130	56	10.7	Dual	430	44	5.7
12	30	M	Alive	−	A/A	Dual	445	61	11	Dual	540	31	4.5
13	51	M	Alive	−	G/G	Single	450	54	9.5	None	490	29	5.4
14	19	F	Alive	−	NA	Dual	390	67	14.7	Dual	460	57	13.3
15	24	M	Alive	−	A/A	Dual	555	36	9.1	Dual	550	35	6.2
16	48	M	Alive	−	A/A	None	585	33	6.4	None	524	26	3.2
17	51	F	Alive	−	G/A	Single	360	35	5	None	505	15	3.2
18	23	M	Alive	−	G/A	Triple	570	54	6.7	Dual	745	38	4.8
19	22	M	Alive	−	A/A	None	415	30	4.2	Single	410	21	3
20	56	F	Alive	−	G/G	Single	365	43	7.4	Single	390	35	5.9
21	30	F	Alive	−	A/A	None	540	55	11.3	None	585	39	8.8
22	18	M	Alive	−	G/A	Triple	380	39	6.3	Dual	415	39	6.3
23	40	F	Alive	−	A/A	None	330	83	14.7	Single	345	34	5.3
24	44	M	Alive	+	A/A	None	240	37	10.7	None	367	27	6.4
Total	33±12	13/11	20/4	4/20	24	8/4/9/3	378±129	53±16	9.8±4.0	7/7/7/3	459±142*	37±13**	6.3±4.3**
A/A	31±10	8/5	12/1	1/12	13	6/0/7/0	394±134	55±20	10.1±4.0	3/5/4/1	451±138	36±13*	6.3±5.1*
G/A	31±18	2/1	3/0	0/3	3	0/1/0/2	437±116	43±10	6.0±0.9	1/0/2/0	555±171	31±14	4.8±1.6
G/G	43±12	2/2	4/0	1/3	4	0/3/1/0	321±141	48±5	7.9±1.1	2/1/0/1	417±135	33±4	6.7±2.8

At the summary lines, number of patients are counted as follows. Sex: males/females; survival status: alive/dead; moyamoya disease (MMD): +/−; pulmonary hypertension (PH) medication: none/single/dual/triple. The other continuous numbers are summarised as mean±sd. 6MWD: 6-min walk distance; mPAP: mean pulmonary arterial pressure; PVR: pulmonary vascular resistance; WU: Wood unit; NA: not applicable. *: p<0.05; **: p<0.01; respectively, compared to before pulmonary angioplasty.

Using their whole-genome sequencing results, we investigated the presence of RNF213 pathogenic variants in the 20 patients. We identified RNF213 p.Arg4810Lys at a surprisingly high frequency (72.5%) compared to the general Japanese population (0.8%) [5, 6]. 13 (65%) were homozygous, and three (15%) were heterozygous for RNF213 p.Arg4810Lys, strongly suggesting RNF213 p.Arg4810Lys is the major genetic determinant for isolated PPAS. A large-scale meta-analysis of sporadic MMD in the East Asian population showed that allele frequency and prevalence of homozygosity for RNF213 p.Arg4810Lys were 18.1% and 1.6%, respectively [10], which is much lower than the current study. Of note, four patients (20%) were homozygous for the reference allele of RNF213 p.Arg4810Lys. Among them, case 13 was heterozygous for a rare missense genetic variant, RNF213 p.Pro4250Thr (rs138029774, NM_001256071: c.12748C>A, 0.6% in Japanese) [6]; however, its functional relevance is yet to be clarified. We did not identify other reported RNF213 pathogenic variants. We further examined if these 20 patients carry any of the 51 reported pathological genetic variations for MMD in the other 37 genes registered in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/). None of them had any such variants. Further genomic analysis is essential to fully understand the underlying molecular mechanism of the disease.

In this study, two were treated with simple balloon dilation, while 22 underwent stent deployment. After treatment, mean PAP decreased from 53±16 to 37±13 mmHg. Tonelli et al. [7] reported that mean PAP decreased from 46.8 to 35.6 mmHg after simple balloon dilation in six adult patients with PPAS. Yanagisawa et al. [11] reported that mean PAP decreased from 46 mmHg to 34 mmHg after simple balloon dilation in seven patients with PPAS and four with Takayasu arteritis. However, patient characteristics varied widely in each study, including age and presence of congenital heart disease or systemic congenital syndrome. In addition, the efficacy of evidence-based medical therapies, such as antithrombotic therapy and pulmonary vasodilators, has not yet been established. A further investigation may be necessary to determine the optimal treatment for adult patients with isolated PPAS. This study has some limitations. First, it was retrospectively conducted at a single centre with a small number of patients. Second, the patients in this study were all Japanese, limiting the generalisability of the data. Third, the number of patients used for genetic analysis is small. Further genomic studies recruiting more patients will return more precise information on allele frequency and prevalence of RNF213 p.Arg4810Lys.

In conclusion, genetic analysis revealed the involvement of the RNF213 p.Arg4810Lys variant in the development of isolated PPAS, even in patients heterozygous for this variant. Our findings will contribute to the definitive diagnosis and a better understanding of the pathogenesis of isolated PPAS. Notably, stent deployment emerged as an effective and safe treatment option in adult patients with isolated PPAS. However, further investigations are necessary to elucidate the pathogenesis and determine the optimal treatment for adult patients with isolated PPAS.

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