Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations

Abstract

BackgroundMutations in the bone morphogenetic protein receptor 2 (BMPR2) gene can lead to idiopathic pulmonary arterial hypertension (IPAH). This study prospectively screened for BMPR2 mutations in a large cohort of PAH-patients and compared clinical features between BMPR2 mutation carriers and non-carriers.MethodsPatients have been assessed by right heart catheterization and genetic testing. In all patients a detailed family history and pedigree analysis have been obtained. We compared age at diagnosis and hemodynamic parameters between carriers and non-carriers of BMPR2 mutations. In non-carriers with familial aggregation of PAH further genes/gene regions as the BMPR2 promoter region, the ACVRL1, Endoglin, and SMAD8 genes have been analysed.ResultsOf the 231 index patients 22 revealed a confirmed familial aggregation of the disease (HPAH), 209 patients had sporadic IPAH. In 49 patients (86.3% of patients with familial aggregation and 14.3% of sporadic IPAH) mutations of the BMPR2 gene have been identified. Twelve BMPR2 mutations and 3 unclassified sequence variants have not yet been described before. Mutation carriers were significantly younger at diagnosis than non-carriers (38.53 ± 12.38 vs. 45.78 ± 11.32 years, p < 0.001) and had a more severe hemodynamic compromise. No gene defects have been detected in 3 patients with HPAH.ConclusionThis study identified in a large prospectively assessed cohort of PAH- patients new BMPR2 mutations, which have not been described before and confirmed previous findings that mutation carriers are younger at diagnosis with a more severe hemodynamic compromise. Thus, screening for BMPR2 mutations may be clinically useful.

Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH

“…Moreover, several STAT3-related proteins have been implicated in RhoA/ROCK activation [52], along with IL-6 expression [11]. This not only demonstrates the importance of the STAT3 axis in PAH but also shows that STAT3 can be considered as an integrator of the multiple pathways implicated in PAH, including NFAT activation, BMPR2 downregulation RhoA/ROCK activation and IL-6 expression [39,53]. We therefore believe that the PLB-dependant inhibition of STAT3 could explain how a single drug such as PLB can affect so many pathophysiological pathways and be efficient in several experimental models (figs 5, 6 and 7).…”

“…In addition to both the Kv/calcium axis and DYm, other pathways are known to be implicated in PAH-PASMC proliferation and resistance to apoptosis, including: BMPR2 protein and mRNA expression [39]; ROCK1 activation [40]; and mRNA interleukin (IL)-6 expression [41]. Although the importance of each pathway in the aetiology of PAH remains to be established (and is likely to be different among the different forms of PAH), we provide evidence that PLB can affect all of them.…”

Bone Morphogenetic Protein Signaling in Pulmonary Arterial Hypertension

“…BMPR2 mutation carriers are diagnosed with PAH approximately 10 years earlier than BMPR2 mutation-negative patients [69,158,194]. Patients with BMPR2 mutations also present worse clinical phenotypes at diagnosis, including higher mean pulmonary artery pressure, lower cardiac index, higher pulmonary vascular resistance, and lower mixed venous oxygen saturation compared to mutation-free patients [194].…”

Epigenetik und Genetik der pulmonal arteriellen Hypertonie – neue Erkenntnisse der letzten Jahre

“…Die Korezeptoren receptor type II-like kinase-1(ACVRL1, auch bekannt als ALK1) [30] sowie Endoglin sind weitere wichtige Gene, die für die Entstehung der mit einem Morbus Osler einhergehenden PAH verantwortlich sind [31]. Exonische BMPR2-Mutationen wurden bei > 80 % der Patienten mit hereditä-rer PAH (HPAH) sowie bei bis zu 25 % der Patienten mit sporadischer Form nachgewiesen [32,33]. Inzwischen wurden mehr als 300 verschiedene exonische Mutationen beschrieben [28].…”

“…Keine BMPR2-Mutationen wurden bislang bei anderen assoziierten PAH-Formen gefunden. [33,49]. Die regelmäßige klinische Untersuchung Betroffener und zumindest deren erstgradiger Familienmitglieder mittels Echokardiographie können beitragen, die Erkrankung bei Betroffenen zu einem früheren Zeitpunkt zu diagnostizieren [34].…”