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

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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. Fact Checked By: Total Posts: 329 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. × 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. Latest Posts

Study identifies therapeutic target for high blood pressure in lungs - Mirage News Posted: 30 Sep 2019 12:52 PM PDT UCLA Health Gregoire Ruffenach (left) and Mansoureh Eghbali FINDINGS Researchers have identified a potential new therapeutic target for those who have high blood pressure in the lungs, or what is known as pulmonary hypertension secondary to pulmonary fibrosis, a lung disease in which lung tissue becomes damaged and scarred. The discovery helps explain the previously unknown mechanism behind the development of pulmonary hypertension in people with pulmonary fibrosis. BACKGROUND Pulmonary hypertension, a life-threatening disease, is a major complication of pulmonary fibrosis, yet it is poorly understood. Pulmonary fibrosis is a debilitating lung disease with limited treatments available. Characterized by an accumulation of scar tissue in the lung, it leads to shortness of breath, severe loss of quality of life and, often, an early death. Currently, an estimated 100,000 people in the United States have pulmonary fibrosis and about 40 percent of those eventually will develop high blood pressure in the lungs and require lung transplantation because of their resistance to drug therapies. A number of factors may contribute to developing pulmonary fibrosis, including autoimmune diseases, radiation and the environment. METHOD Researchers used tissues from whole lungs removed from transplant patients with pulmonary fibrosis and pulmonary hypertension, and found an unusually higher level of the protein known as Slug in their lungs. Researchers developed a new animal model of pulmonary fibrosis and pulmonary hypertension, which mimicked their findings in the lungs of human beings. By utilizing a commonly used synthetic molecule known as siRNA to inhibit the expression of Slug in the lungs of rats with pulmonary fibrosis and pulmonary hypertension, the blood pressure in the lungs was lowered. IMPACT The study suggests that people with pulmonary fibrosis who developed pulmonary hypertension also exhibit stiff blood vessels in the healthy, non-scarred areas of their lungs. Findings also indicated that by decreasing the Slug protein in diseased lungs, there is a potential to lower the severity of pulmonary hypertension in people with pulmonary fibrosis. Blocking that protein could become a potential novel therapy for pulmonary fibrosis-pulmonary hypertension, which currently has no approved treatment. AUTHORS The senior author is Mansoureh Eghbali, a professor of anesthesiology and perioperative medicine at the David Geffen School of Medicine at UCLA. The first author is postdoctoral fellow Gregoire Ruffenach and the second author is Dr. Soban Umar, an assistant professor of anesthesiology at the Geffen School and anesthesiologist at the Ronald Reagan UCLA Medical Center. Other authors are listed in the journal article. JOURNAL The research is published in the journal EMBO Molecular Medicine. FUNDING This study was supported by grants from the National Institutes of Health and the American Heart Association; and by the Foundation for Anesthesia Education and Research. /Public Release. View in full here.

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