In PAH, RNF213 Gene Variant a Risk Factor for Poor Outcomes, Study Says - Pulmonary Hypertension News

Posted: 30 Sep 2019 06:00 AM PDT

Patients with pulmonary arterial hypertension (PAH) who carry a specific mutation in the RNF213 gene have poor clinical outcomes and worse response to combination treatments, according to a study from Japan.

The study, "Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension," was published in The Journal of Heart and Lung Transplantation.

A 2018 study found that approximately 10% of the patients with idiopathic PAH have a specific variant in the RNF213 gene — rs112735431, or p.Arg4810Lys — consisting of an amino acid substitution of arginine to lysine in the RNF213 protein. This gene alteration has already been associated with Moyamoya disease and peripheral pulmonary stenosis.

In the current study, the scientists set out to characterize and assess the outcomes of PAH patients with this variant.

A total of 139 patients with idiopathic or possibly heritable PAH were included, all treated between April 2005 and August 2018. Patients with mutations in the BMPR2 gene — with a well-known link to PAH — were included as controls.

At both diagnosis and after combination treatment with prostaglandin I₂ (PGI₂) infusion, endothelin receptor antagonists (ERAs), and/or phosphodiesterase-5 inhibitors (PDE5i), the patients underwent assessments of their serum levels of B-type natriuretic peptide (BNP) — a marker of heart failure and other cardiac problems — World Health Organization (WHO) class, and six-minute walk distance (6MWD), a test of exercise capacity.

Whole-exome sequencing, which screens the DNA bits containing information to generate a protein, found the p.Arg4810Lys variant in 11 patients (7.9% of the patients, eight women), all in only one of the gene copies (heterozygous). No patient showed cerebral involvement suggestive of Moyamoya disease.

All 11 patients had clinically severe disease at diagnosis, as indicated by their BNP levels, cardiac output, mean pulmonary arterial pressure (mPAP), and pulmonary vascular resistance (PVR). Eight were treated with PGI₂.

Over a mean follow-up period of 30 months, both mPAP and PVR improved with combination treatment. In contrast, BNP levels, cardiac output, WHO class, and 6MWD scores did not change.

Two of these patients had both the studied variant in RNF213 and BMPR2 gene mutations, and did not respond favorably to treatment.

Compared with the 36 patients with BMPR2 gene mutations, the nine patients with the p.Arg4810Lys variant showed significantly inferior benefits with combination therapy, including in mPAP, cardiac output, BNP levels, and 6MWD scores. These patients also showed higher diastolic pressure gradients, suggesting worse response to treatment.

Four patients died, three of whom were in the group with the RNF213 gene variant. One patient in this group and two in the group with BMPR2 mutations underwent lung transplants. The RNF213 gene variant carrier who underwent this procedure experienced clinical improvements and did not require hospital admission for five years.

Event-free rates (no death or lung transplant) since diagnosis and the start of PGI₂ treatment were significantly better in patients with BMPR2 mutations. Specifically, at five years after diagnosis, all patients with BMPR2 mutation survived and did not require lung transplants, compared with 60% in the RNF213 variant group.

After introduction of PGI₂, none of the patients with the RNF213 variant were event-free, compared with 93% of controls who avoided these outcomes. A similar difference favoring the group without the variant in RNF213 was also found in terms of heart failure.

Patients with RNF213 variants other than p.Arg4810Lys showed better event-free rates after diagnosis than those with these gene alterations. A subsequent analysis showed that the p.Arg4810Lys variant was a risk factor for death, lung transplant, and heart failure.

Post-mortem analysis of lung samples from two patients with the p.Arg4810Lys variant found lesions in pulmonary arteries, and marked venous wall and arterial thickness, venous occlusion, dilated capillaries, and lymph accumulation.

"Patients with idiopathic PAH who have the RNF213 p.Arg4810Lys variant are associated with severe hemodynamics, poor reactivity to vasodilator drugs, and poor clinical outcomes," the scientists wrote.

"Our findings may suggest the importance of genetic stratification of PAH to provide clinically relevant information for therapeutic strategies, leading to a personalized approach," they added.

The researchers believe that earlier consideration of a lung transplant "might be required for RNF213 p.Arg4810Lys variant carriers who are developing PAH."

Author Details

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer's disease.

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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

Growth Differentiation Factor-15 Linked to Transplant-Free Survival in PH - Pulmonology Advisor

Posted: 27 Sep 2019 03:00 AM PDT

Growth differentiation factor-15 (GDF-15) could be a promising biomarker to identify low-risk patients with normal GDF-15 levels, potentially serving as a predictor for mortality in adults with pulmonary hypertension (PH), according to study results published in Heart.

This single-center, prospective, observational cohort study included adults diagnosed with PH at their tertiary-care center between May 2012 and October 2016 (N=103). Researchers defined diagnostic right heart catheterization as the baseline and defined PH as a mean pulmonary artery pressure ≥25 mm Hg. To assess the biomarker, they sampled venous blood during the diagnostic right heart catheterization for study purposes only. Investigators used an electrochemiluminescence assay to directly measure N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and GDF-15.

Growth differentiation factor-15 was elevated in 74% (n=76/103) of patients. It showed a significant moderate correlation with NT-proBNP (r =0.51, P <.001) and estimated glomerular filtration rate (r =−0.47, P <.001). Median follow-up was 3.4 years (interquartile range, 2.3-4.6). The primary endpoint of all-cause mortality or lung transplantation was reached in 31.1% of patients (n=32). The secondary endpoint, a composite that included the primary endpoint and heart failure, was reached in 39.8% (n=41) of patients. Causes of death in the 30 patients who died were end-stage heart failure (n=9), sudden death presumed cardiac (n=4), multiorgan failure (n=3), other diverse causes (n=13), and unknown cause (n=1).

Patients who had normal GDF-15 had a significantly higher transplant-free survival compared with patients with elevated GDF-15 (P =.007), which was specifically pronounced within the first 2 years of follow-up.

After adjusting for several clinical characteristics as well as age and NT-proBNP, GDF-15 was significantly associated with the primary endpoint.

The limitations of this study included the exclusion of patients with PH caused by left heart disease, which should be considered when extrapolating these results to other studies. This study consisted of a heterogeneous group of PH etiologies, so subgroup analysis could only be performed for pulmonary arterial hypertension. The clinical usefulness of GDF-15 might differ among PH etiologies. Because of limited statistical power, the additive value of GDF-15 could not be assessed.

Growth differentiation factor-15 was strongly associated with mortality in this study and specifically identified low-risk patients with PH at the time of diagnosis.

Measuring GDF-15 could be considered as a means to identify and reassure newly diagnosed patients with PH. Follow-up frequency can probably be lowered in these patients compared with patients at high risk.

More research is needed to validate these findings before integrating them into clinical practice and to further explore the potential of GDF-15 as a biomarker for predicting mortality.

Reference

Geenen LW, Baggen VJM, Kauling RM, et al. Growth differentiation factor-15 as candidate predictor for mortality in adults with pulmonary hypertension [published online September 6, 2019]. Heart. doi:10.1136/heartjnl-2019-315111

This article originally appeared on The Cardiology Advisor

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