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

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

Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension.

Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH

Erythroid-Specific Transcriptional Changes in PBMCs from Pulmonary Hypertension Patients

Gene expression profiling of peripheral blood mononuclear cells (PBMCs) is a powerful tool for the identification of surrogate markers involved in disease processes. The hypothesis tested in this study was that chronic exposure of PBMCs to a hypertensive environment in remodeled pulmonary vessels would be reflected by specific transcriptional changes in these cells.The transcript profiles of PBMCs from 30 idiopathic pulmonary arterial hypertension patients (IPAH), 19 patients with systemic sclerosis without pulmonary hypertension (SSc), 42 scleroderma-associated pulmonary arterial hypertensio patients (SSc-PAH), and 8 patients with SSc complicated by interstitial lung disease and pulmonary hypertension (SSc-PH-ILD) were compared to the gene expression profiles of PBMCs from 41 healthy individuals. Multiple gene expression signatures were identified which could distinguish various disease groups from controls. One of these signatures, specific for erythrocyte maturation, is enriched specifically in patients with PH. This association was validated in multiple published datasets. The erythropoiesis signature was strongly correlated with hemodynamic measures of increasing disease severity in IPAH patients. No significant correlation of the same type was noted for SSc-PAH patients, this despite a clear signature enrichment within this group overall. These findings suggest an association of the erythropoiesis signature in PBMCs from patients with PH with a variable presentation among different subtypes of disease.In PH, the expansion of immature red blood cell precursors may constitute a response to the increasingly hypoxic conditions prevalent in this syndrome. A correlation of this erythrocyte signature with more severe hypertension cases may provide an important biomarker of disease progression

α(1L)-Adrenoceptors in canine pulmonary artery

The aim of this study was to characterize theα1-adrenoceptors of the canine pulmonary artery. Arterial rings from lower lung lobes were suspended for isometric-tension recording in the presence of cocaine (5 x 10-6 M), hydrocortisone (3 x 10-5 M), propranolol (5 x 10-6 M), and rauwolscine (10-7 M) to inhibit neuronal uptake, extraneuronal uptake, and β- and α2-adrenoceptors, respectively. Prazosin was more potent against contractions evoked by phenylephrine (pA2 of 9.7) compared with methoxamine (pA2 of 8.4). SZL49 (10-8 and 3 x 10-8 M), an irreversible α1- adrenergic antagonist, inhibited responses to phenylephrine but not methoxamine. With norepinephrine, low concentrations of prazosin (3 x 10- 10 M and 10-9 M) caused inhibition of the concentration-response curve; a higher concentration (3 x 10-9 M) failed to produced further inhibition, whereas increasing the concentration of the antagonist (to 10-8 and 3 x 10-8 M) caused further rightward shifts in the concentration-response curve. The Arunlakshana and Schild plot revealed two components corresponding to pA2 values of 9.8 and 8.4. After SZL49 (3 x 10-8 M), the Arunlakshana and Schild plot for the interaction between norepinephrine and prazosin was linear and generated a pA2 of 8.3. Contractions evoked by phenylephrine were inhibited by the α(1B)/α(1D)adrenoceptor antagonist, chloroethylclonidine (10-5 M), or by the α(1B)-antagonist, risperidone (pA2 value of 8.5), but were relatively resistant to inhibition by the selective α(1D)-antagonist, BMY7378 (-log K(B) of 6.1). The results suggest that two α1-adrenoceptor subtypes mediate contraction of the canine pulmonary artery. One subtype has high affinity for prazosin (α(1H), likely to be α(1B)), is activated by phenylephrine, and is inhibited by SZL49. The other subtype has lower affinity for prazosin (α(1L)), is stimulated by methoxamine, and is relatively resistant to SZL49. The physiologic agonist, norepinephrine, causes contraction by activating both subtypes.link_to_subscribed_fulltex

[Treatment goals of pulmonary hypertension].

6zet\u2013 Pulmoner hipertansiyon alan\u131ndaki \uf6nemli geli\u15fmelerden sonra, en \uf6nemli g\uf6revlerden biri uzun d\uf6nem sonu\ue7larla ili\u15fkili kinik tedavi hedeflerini belirleme gereksinimidir. Modifiye New York Kalp Cemiyeti fonksiyonel s\u131n\u131f I veya II, 380 metreden fazla 6 dakika y\ufcr\ufcme mesafesine ula\u15fma, ekokardiyografide sa\u11f ventrik\ufcl boyutunun ve fonksiyonunun normalle\u15fmesi, B-tip natri\ufcretik peptit d\ufczeyinin azalmas\u131 ya da normalle\u15fmesi ve sa\u11f atriyal bas\u131nc\u131n\u131n 8 mmHg\u2019den d\ufc\u15f\ufck ve kardiyak indeksin 2,5 L/dk/m2 \u2019den b\ufcy\ufck olmas\u131 g\ufcncel hedeflerdir. Bununla birlikte, egzersiz kapasitesi ve sa\u11f kalp fonksiyonu gibi uzun d\uf6nem sonu\ue7larla daha fazla ili\u15fkili olan parametreleri hedefleyen daha g\ufc\ue7l\ufc ve net s\u131n\u131rlarla \ue7izen \u201ce\u15fi\u11fin\u201d daha y\ufcksek tutulmas\u131 gerekti\u11fi a\ue7\u131k hale gelmektedir; 6zellikle, manyetik rezonans g\uf6r\ufcnt\ufcleme ve BNP/N-terminal pro B tip natri\ufcretik peptit gibi do\u11fru ve noninvaziv olarak sa\u11f ventrik\ufcl fonksiyonunu belirleyen testler, temel belirleyiciler ve tedavi hedefleri olarak hizmet etmek i\ue7in umut verici g\uf6stergeler olarak ortaya \ue7\u131kmaktad\u131r. Ayr\u131ca, sonu\ue7lar \ufczerine odakl\u131 \ue7al\u131\u15fmalar tek ba\u15f\u131na hi\ue7bir testin g\ufcvenilir bir \u15fekilde uzun vadeli prognostik belirte\ue7 olarak kullan\u131lamayaca\u11f\u131n\u131 ve birle\u15fik tedavi hedeflerinin uzun d\uf6nem sonu\ue7lar\u131n\u131n daha iyi \uf6ng\uf6rd\ufcrece\u11fini g\uf6sterdi. Yeniden d\ufczenlenen tedavi hedeflerinin \u15funlar oldu\u11fu ileri s\ufcr\ufclm\ufc\u15ft\ufcr: Modifiye New York Kalp Cemiyeti fonksiyonel s\u131n\u131f I veya II, 65380 ve 440 m aras\u131ndaki 6 dakika y\ufcr\ufcme mesafesi, kardiyopulmoner egzersiz testi-15 ml/d/kg\u2019dan fazla tepe oksijen t\ufcketim \uf6l\ue7\ufcm\ufc ve 45 l/dak\u2019dan az karbondioksit i\ue7in solunum e\u15fde\u11feri, normale yak\u131n BNP de\u11feri, ile normal/normale yak\u131n sa\u11f ventrik\ufcl boyut ve fonksiyonlar\u131n\u131 g\uf6steren ekokardiyografi ve/veya kardiyak manyetik rezonans g\uf6r\ufcnt\ufcleme ve 8 mmHg\u2019den az sa\u11f atriyal bas\u131n\ue7la ve 2,5-3 l/dak/m\ub2\u2019den fazla kardiyak indeksle birlikte sa\u11f ventrik\ufcl fonksiyonunun normalle\u15fti\u11fini g\uf6steren hemodinamik parametreler. (J Am Coll Cardiol 2013;62:D73\u201381)With significant therapeutic advances in the field of pulmonary arterial hypertension, the need to identify clinically relevant treatment goals that correlate with long-term outcome has emerged as 1 of the most critical tasks. Current goals include achieving modified New York Heart Association functional class I or II, 6-min walk distance &gt;380 m, normalization of right ventricular size and function on echocardiograph, a decreasing or normalization of B-type natriuretic peptide (BNP), and hemodynamics with right atrial pressure &lt;8 mm Hg and cardiac index &gt;2.5 L/dk/m2. However, to more effectively prognosticate in the current era of complex treatments, it is becoming clear that the "bar" needs to be set higher, with more robust and clearer delineations aimed at parameters that correlate with long-term outcome; namely, exercise capacity and right heart function. Specifically, tests that accurately and noninvasively determine right ventricular function, such as cardiac magnetic resonance imaging and BNP/N-terminal pro-B-type natriuretic peptide, are emerging as promising indicators to serve as baseline predictors and treatment targets. Furthermore, studies focusing on outcomes have shown that no single test can reliably serve as a long-term prognostic marker and that composite treatment goals are more predictive of long-term outcome. It has been proposed that treatment goals be revised to include the following: modified New York Heart Association functional class I or II, 6-min walk distance 380 to 440 m, cardiopulmonary exercise test-measured peak oxygen consumption &gt;15 ml/min/kg and ventilatory equivalent for carbon dioxide &lt;45 l/min/l/min, BNP level toward "normal," echocardiograph and/or cardiac magnetic resonance imaging demonstrating normal/near-normal right ventricular size and function, and hemodynamics showing normalization of right ventricular function with right atrial pressure &lt;8 mm Hg and cardiac index &gt;2.5 to 3.0 l/min/m2. (J Am Coll Cardiol 2013;62:D73-81) \ua92013 by the American College of Cardiology Foundation