Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension

<p>Abstract</p> <p>Background</p> <p>Autosomal dominant inheritance of germline mutations in the bone morphogenetic protein receptor type 2 (<it>BMPR2</it>) gene are a major risk factor for pulmonary arterial hypertension (PAH). While previous studies demonstrated a difference in severity between <it>BMPR2 </it>mutation carriers and noncarriers, it is likely disease severity is not equal among <it>BMPR2 </it>mutations. We hypothesized that patients with missense <it>BMPR2 </it>mutations have more severe disease than those with truncating mutations.</p> <p>Methods</p> <p>Testing for <it>BMPR2 </it>mutations was performed in 169 patients with PAH (125 with a family history of PAH and 44 with sporadic disease). Of the 106 patients with a detectable <it>BMPR2 </it>mutation, lymphocytes were available in 96 to functionally assess the nonsense-mediated decay pathway of RNA surveillance. Phenotypic characteristics were compared between <it>BMPR2 </it>mutation carriers and noncarriers, as well as between those carriers with a missense versus truncating mutation.</p> <p>Results</p> <p>While there was a statistically significant difference in age at diagnosis between carriers and noncarriers, subgroup analysis revealed this to be the case only for females. Among carriers, there was no difference in age at diagnosis, death, or survival according to exonic location of the <it>BMPR2 </it>mutation. However, patients with missense mutations had statistically significant younger ages at diagnosis and death, as well as shorter survival from diagnosis to death or lung transplantation than those with truncating mutations. Consistent with this data, the majority of missense mutations were penetrant prior to age 36 years, while the majority of truncating mutations were penetrant after age 36 years.</p> <p>Conclusion</p> <p>In this cohort, <it>BMPR2 </it>mutation carriers have more severe PAH disease than noncarriers, but this is only the case for females. Among carriers, patients with missense mutations that escape nonsense-mediated decay have more severe disease than those with truncating mutations. These findings suggest that treatment and prevention strategies directed specifically at <it>BMPR2 </it>pathway defects may need to vary according to the type of mutation.</p

Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension

<p>Abstract</p> <p>Background</p> <p>Previous studies indicate that patients with pulmonary arterial hypertension (PAH) carrying a mutation in the bone morphogenetic protein receptor type 2 (<it>BMPR2</it>) gene, develop the disease 10 years earlier than non-carriers, and have a more severe hemodynamic compromise at diagnosis. A recent report has suggested that this may only be the case for females and that patients with missense mutations in <it>BMPR2 </it>gene have more severe disease than patients with truncating mutations.</p> <p>Methods</p> <p>We reviewed data from all patients with PAH considered as idiopathic and patients with a family history of PAH, who underwent genetic counselling in the French PAH network between January, 1^st2004 and April, 1^st2010. We compared clinical, functional, and hemodynamic characteristics between carriers and non-carriers of a <it>BMPR2 </it>mutation, according to gender or <it>BMPR2 </it>mutation type.</p> <p>Results</p> <p>PAH patients carrying a <it>BMPR2 </it>mutation (n = 115) were significantly younger at diagnosis than non-carriers (n = 267) (35.8 ± 15.4 and 47.5 ± 16.2 respectively, p < 0.0001). The presence of a <it>BMPR2 </it>mutation was associated with a younger age at diagnosis in females (36.4 ± 14.9 in <it>BMPR2 </it>mutation carriers and 47.4 ± 15.8 in non-carriers, p < 0.0001), and males (34.6 ± 16.8 in <it>BMPR2 </it>mutation carriers and 47.8 ± 17.1 in non-carriers, p < 0.0001). <it>BMPR2 </it>mutation carriers had a more severe hemodynamic compromise at diagnosis, but this was not influenced by gender. No differences in survival and time to death or lung transplantation were found in male and female PAH patients carrying a <it>BMPR2 </it>mutation. No differences were observed in clinical outcomes according to the type of <it>BMPR2 </it>mutations (missense, truncating, large rearrangement or splice defect).</p> <p>Conclusion</p> <p>When compared to non-carriers, <it>BMPR2 </it>mutation carriers from the French PAH network are younger at diagnosis and present with a more severe hemodynamic compromise, irrespective of gender. Moreover, <it>BMPR2 </it>mutation type had no influence on clinical phenotypes in our patient population.</p

Role of pulmonary intravascular macrophages in endotoxin-induced lung inflammation and mortality in a rat model

<p>Abstract</p> <p>Background</p> <p>Bile-duct ligated (BDL) rats recruit pulmonary intravascular macrophages (PIMs) and are highly susceptible to endotoxin-induced mortality. The mechanisms of this enhanced susceptibility and mortality in BDL rats, which are used as a model of hepato-pulmonary syndrome, remain unknown. We tested a hypothesis that recruited PIMs promote endotoxin-induced mortality in a rat model.</p> <p>Methods</p> <p>Rats were subjected to BDL to induce PIM recruitment followed by treatment with gadolinium chloride (GC) to deplete PIMs. Normal and BDL rats were treated intravenously with <it>E. coli </it>lipopolysaccharide (LPS) with or without GC pre-treatment followed by collection and analyses of lungs for histopathology, electron microscopy and cytokine quantification.</p> <p>Results</p> <p>BDL rats recruited PIMs without any change in the expression of IL-1β, TNF-α and IL-10. GC caused reduction in PIMs at 48 hours post-treatment (P < 0.05). BDL rats treated intravenously with <it>E. coli </it>LPS died within 3 hours of the challenge while the normal LPS-treated rats were euthanized at 6 hours after the LPS treatment. GC treatment of rats 6 hours or 48 hours before LPS challenge resulted in 80% (1/5) and 100% (0/5) survival, respectively, at 6 hours post-LPS treatment. Lungs from BDL+LPS rats showed large areas of perivascular hemorrhages compared to those pre-treated with GC. Concentrations of IL-1β, TNF-α and IL-10 were increased in lungs of BDL+LPS rats compared to BDL rats treated with GC 48 hours but not 6 hours before LPS (P < 0.05).</p> <p>Conclusion</p> <p>We conclude that PIMs increase susceptibility for LPS-induced lung injury and mortality in this model, which is blocked by a reduction in their numbers or their inactivation.</p

A Novel BMPR2 Mutation Associated with Pulmonary Arterial Hypertension in an Octogenarian

We describe the case of an 83-year-old man with a family history of pulmonary hypertension (PH) who presented with severe pulmonary arterial hypertension (PAH) and later tested positive for a novel bone morphogenetic protein receptor 2 (BMPR2) gene mutation. To our knowledge, this may be the oldest reported patient with PAH in whom a BMPR2 mutation was initially identified

Year in review in Intensive Care Medicine 2011: III. ARDS and ECMO, weaning, mechanical ventilation, noninvasive ventilation, pediatrics and miscellanea

SCOPUS: re.jinfo:eu-repo/semantics/publishe

The genetics of pulmonary arterial hypertension in the post-BMPR2 era

Pulmonary arterial hypertension (PAH) is a rapidly progressive and fatal disease for which there is an ever-expanding body of genetic and related pathophysiological information on disease pathogenesis. The most common single culprit gene known is BMPR2, and animal models of the disease in several forms exist. There is a wealth of genetic data regarding modifiers of disease expression, penetrance, and severity. Despite the rapid accumulation of data in the last decade, a complete picture of the molecular pathogenesis of PAH leading to novel therapies is lacking. In this review, we attempt to summarize the current understanding of PAH from the genetic perspective. The most recent PAH demographics are discussed. Heritable PAH in the post-BMPR2 era is examined in detail as the most robust model of PAH genetics in both animal models and human pedigrees. Important downstream molecular pathways and modifiers of disease expression are reviewed in light of what is known about PAH pathogenesis. Current and emerging therapies are examined in light of genetic data. The role of genetic testing in PAH in the post-BMPR2 era is discussed. Finally, directions for future investigations that ideally will fulfill the promise of novel therapeutic or preventive strategies are discussed