Familial Pulmonary Arterial Hypertension Research Articles

Alu-mediated nonallelic homologous and nonhomologous recombination in the BMPR2 gene in heritable pulmonary arterial hypertension

The purpose of this study was to undertake thorough genetic analysis of the bone morphogenetic protein type 2 receptor (BMPR2) gene in patients with pulmonary arterial hypertension. We conducted a systematic analysis for larger gene rearrangements together with conventional mutation analysis in 152 pulmonary arterial hypertension patients including 43 patients diagnosed as having idiopathic pulmonary arterial hypertension and 10 diagnosed as having familial pulmonary arterial hypertension. Analysis of the BMPR2 gene revealed each of the four kinds of nonsense and frameshift mutations, one missense mutation, one splice-site mutation, and two types of exonic deletion. For cases in which exons 1-3 were deleted, the 5' and 3' break points were located in the AluY repeat sequences in the 5' side of the adjacent NOP58 gene and in the AluY repeat sequences in intron 3, suggesting an AluY-mediated nonallelic homologous recombination as the mechanism responsible for the deletion. For the case in which exon 10 was deleted, nonhomologous recombination took place between the AluSx site in intron 9 and a unique sequence in intron 10. Exonic deletions of BMPR2 account for at least part of BMPR2 mutations associated with heritable pulmonary arterial hypertension in Japan, as previously reported in other populations. One of our cases was mediated via Alu-mediated nonallelic homologous recombination and another was mediated via nonhomologous recombination.

Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare, severe disease resulting from progressive obliteration of small-caliber pulmonary arteries by proliferating vascular cells. PAH can occur without recognized etiology (idiopathic PAH), be associated with a systemic disease or occur as a heritable form, with BMPR2 mutated in approximately 80% of familial and 15% of idiopathic PAH cases. We conducted a genome-wide association study (GWAS) based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. We detected a significant association at the CBLN2 locus mapping to 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97 (1.59-2.45; P = 7.47 × 10(-10)). CBLN2 is expressed in the lung, and its expression is higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs.

Flecked retina, choroidopathy, and retinal pigment epithelial tear in familial pulmonary arterial hypertension.

Thanks to advancement in treatment modalities, the medial survival rate of patients with familial pulmonary arterial hypertension (FPAH) has been improved. Unfortunately, ocular complications because of the chronically elevated systemic venous pressure become more frequent. The authors report new FPAH-associated fundus changes in a 50-year-old male patient treated with sildenafil. The anomalies were studied with autofluorescence, fluorescein and indocyanine green angiography, and spectral optical coherence tomography including enhanced depth imaging. Loss of vision and cystoid macular edema were associated with a flecked retina, a thick choroid, central serous choroidopathy-like changes in both eyes and with retinal pigment epithelium detachments and a retinal pigment epithelium tear in the right eye. Treatment of ocular findings associated with FPAH mainly involves optimal control of pulmonary arterial hypertension and ophthalmic supportive treatment toward preventing acute ocular complications. The ocular complications occur as a result of enhanced pressure in the superior vena cava and in the ophthalmic veins, resulting in dilation of the ocular veins and congestion of the choroid. Sildenafil treatment in FPAH may enhance the congestion of the choroid and can induce central serous choroidopathy-like changes. A flecked retina, central serous choroidopathy-like changes, and retinal pigment epithelium tear are rare complications of FPAH.

Atherosclerosis and Vascular Biology

Atherosclerosis and Vascular Biology

Waiting in Anticipation

Waiting in Anticipation

Evolving Epidemiology of Pulmonary Arterial Hypertension

Evolving Epidemiology of Pulmonary Arterial Hypertension

Bone Morphogenetic Protein Signaling in Vascular Disease: ANTI-INFLAMMATORY ACTION THROUGH MYOCARDIN-RELATED TRANSCRIPTION FACTOR A

Pulmonary artery hypertension (PAH) patients exhibit elevated levels of inflammatory cytokines and infiltration of inflammatory cells in the lung. Concurrently, mutations of bmpr2, the gene encoding the type II receptor of bone morphogenetic proteins (BMP), are found in ∼75% of patients with familial PAH, but a possible nexus between increased inflammation and diminished BMP signaling has hitherto remained elusive. We previously showed that BMP4 triggers nuclear localization of the Myocardin-related transcription factor A (MRTF-A) in human pulmonary artery smooth muscle cells (PASMC), resulting in the induction of contractile proteins. Here we report the BMPR2-dependent repression of a set of inflammatory mediators in response to BMP4 stimulation of PASMC. Forced expression of MRTF-A precisely emulates the anti-inflammatory effect of BMP4, while MRTF-A depletion precludes BMP4-mediated cytokine inhibition. BMP4 and MRTF-A block signaling through NF-κB, the keystone of most pathways leading to inflammatory responses, at the level of chromatin recruitment and promoter activation. Moreover, MRTF-A physically interacts with RelA/p65, the NF-κB subunit endowed with a transcription activation domain. Interestingly, the MRTF-A-NF-κB interaction is mutually antagonistic: stimulation of NF-κB signaling by TNFα, as well as p65 overexpression, hinders MRTF-A activity and the expression of contractile genes. Thus, a molecular inhibitory pathway linking BMP4 signaling, activation of MRTF-A, and inhibition of NF-κB provides insights into the etiology of PAH and a potential focus of therapeutic intervention.

The Impact of Pulmonary Arterial Hypertension‐Targeted Therapy on Survival in Chinese Patients with Idiopathic Pulmonary Arterial Hypertension

The survival rates of Chinese patients with idiopathic pulmonary arterial hypertension (IPAH) and familial pulmonary arterial hypertension (PAH) on conventional therapy at 1 and 3 years were 68.0% and 38.9%, respectively. Our aim was to update recent knowledge on the demographics, clinical course, hemodynamic features, disease management, and survival of adult patients with IPAH. This retrospective and observational study was conducted at the largest tertiary referral center in China. Ninety patients with IPAH who underwent initial evaluation at Fu Wai Hospital from January 2006 through November 2009 were retrospectively enrolled. The primary outcome was death. Statistical analyses used included independent sample t test, nonparametric test, Kaplan-Meier method, and Cox proportional hazards analysis. Of the 90 patients enrolled, the median age was 32 years with female predominance. The median interval from onset of symptoms to diagnosis was 14 months. Patients exhibited severe exercise limitation and hemodynamic abnormalities at diagnosis. Only 10.6% had a positive vasoreactivity test, while calcium channel blockers were given to 22.2% of patients. Fifty-nine patients (65.6%) received PAH-targeted therapies during follow-up. Our survival rates of 84.1%, 73.7%, and 70.6% at 1-, 2-, and 3-years compared favorably with predicted survival based on the National Institutes of Health equation which showed 1-, 2-, and 3-years survival rates of 67.7%, 55.9%, and 47%, respectively. For the patients receiving conventional therapy solely, the 1- and 3-years survival rates were 67.0% and 49.3%, respectively. Younger age, lower body mass index, presence of pericardial effusion, and absence of PAH-targeted therapy were independently associated with mortality. We concluded that patients with IPAH were still diagnosed too late, and while survival rates have improved in the modern treatment era, there is still room for improvement.

Pre-implantation genetic diagnosis in pulmonary arterial hypertension due toBMPR2mutation: Figure 1–

To the Editors: Pulmonary arterial hypertension (PAH) is a rare and severe condition that may present as familial/heritable disease [1–3]. In recent years, there have been considerable advances in the management of PAH and disease-specific therapies have improved survival rates [3–5]. Nevertheless, PAH remains a devastating disease with progressively debilitating symptoms and high mortality even in the modern management era [6, 7]. Familial cases of PAH have been detected since the 1950s [1, 2]. Before the availability of modern genetic tools, studies of the genealogies demonstrated that familial PAH segregated as an autosomal dominant trait, thus leading to a 50% chance of inheriting the disease allele. More recently, mutations in the bone morphogenetic protein receptor 2 gene ( BMPR2 ) have been detected in 70–80% of familial cases [1, 8, 9]. The BMPR2 mutations have an incomplete but variable penetrance (on average, 10–20% of mutation carriers develop PAH, but it can be much higher in some families). A genetic anticipation phenomenon (characterised by a younger age at PAH diagnosis in subsequent generations) has been demonstrated in familial PAH, with an increased risk of cases occurring in children and young adults. Recently, we have shown that BMPR2 mutation carriers with PAH …

Estrogen Paradox in Pulmonary Hypertension

Although the incidence of pulmonary hypertension is higher in female patients, numerous experimental studies have demonstrated better outcome in female animals, exacerbation of the disease after ovariectomy, and a strong protective effect of estrogen: a phenomenon known as the "estrogen paradox" of pulmonary hypertension. On the other hand, some clinical studies have indirectly linked estrogen to increased risk of portopulmonary hypertension, whereas others implicate increased estrogen metabolism and high levels of certain estrogen metabolites in promoting pulmonary vascular remodeling in familial pulmonary arterial hypertension. In this review we investigate the estrogen paradox through highlighting the differential receptor-mediated effects of estrogen. Although estrogen and estrogen receptor-based therapies have shown promise in rescuing preexisting pulmonary hypertension in animals, their role is yet to be defined in humans.

Treatment of Pulmonary Arterial Hypertension in Connective Tissue Disease

Pulmonary arterial hypertension (PAH) is a group of distinct disorders that includes idiopathic PAH (IPAH), familial PAH and PAH associated with other conditions (APAH) such as connective tissue disease (CTD-APAH) or congenital heart disease. PAH is characterized by increased pulmonary arterial pressure and pulmonary vascular resistance. If left untreated, PAH can lead to right heart failure and premature death. CTD-APAH represents an important clinical subgroup of APAH that has a higher risk of death than IPAH. The European treatment guidelines advocate the use of PAH-targeted therapies including bosentan, ambrisentan, sildenafil, inhaled iloprost, intravenous epoprostenol (I-A recommendations), tadalafil or treprostinil (I-B recommendations) for patients in WHO functional class II-III. Not all randomized clinical studies of the approved PAH-targeted therapies have included patients with CTD-APAH. The purpose of this review is to describe the clinical characteristics of CTD-APAH and discuss the approved pharmacological treatments, with a focus on data specific to this subgroup where possible.

BuMPy road of delayed graft function

BuMPy road of delayed graft function

Incremental prognostic value of cardiopulmonary exercise testing and resting haemodynamics in pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a fatal disease despite recent treatment advances. Individual risk stratification is important. Exercise capacity and invasive haemodynamic data are both relevant, but data on the combined prognostic power are lacking. Methods226 consecutive patients with idiopathic or familial PAH were included at seven specialised tertiary centres. All patients underwent right heart catheterization and cardiopulmonary exercise testing (CPET). ResultsDuring follow-up (1508±1070days) 72 patients died and 30 underwent transplantation. On multivariate analysis percentage of predicted peak oxygen uptake (%predicted peak VO2 [risk ratio 0.95]), pulmonary vascular resistance (PVR [1.105,]) and increase in heart rate during exercise (ΔHR [0.974]) were independent prognostic predictors (all p<0.0001). Peak VO2 allowed for risk stratification with a survival of 100, 92.9, 87.4 and 69.6% at 1year and 97.7, 63.2, 41 and 23% at 5years for the 4th, 3rd, 2nd and 1st quartiles, respectively. Dichotomizing by median peak VO2 and intra-group median PVR showed a worse 1-year survival for patients with low peak VO2/higher PVR compared to patients with low peak VO2/low PVR, high peak VO2/high PVR and high peak VO2/low PVR (65 vs. 93, 93, 100%, p<0.001). At 10years survival was different for all 4 subgroups (19 vs. 25 vs. 48 vs. 75%, adjusted p<0.05). ConclusionsPeak VO2, PVR and ΔHR independently predict prognosis in patients with PAH. Low peak VO2, high PVR and low ΔHR refer to poor prognosis. Combined use of peak VO2 and PVR provides accurate risk stratification underlining the complementary prognostic information from cardiopulmonary exercise testing and resting invasive haemodynamic data.

Combinatorial inhibitory effects on VSV‐GtsO45GFP trafficking in human endothelial cells due to functional haploinsufficiency of BMPRII, eNOS, STAT5a and STAT5b

Lung lesions in idiopathic pulmonary arterial hypertension (PAH) contain enlarged “vacuolated” endothelial and smooth muscle cells with enlarged and fragmented Golgi apparatus and dilated endoplasmic reticulum (ER) cisternae. Familial PAH often involves mutations in or haploinsuffciency of BMPRII but with low penetrance (10–15%) setting up a search for “second‐hit” genes. Recently we observed that acute knockdown of STAT5a or STAT5b or both in HPAECs using siRNAs led to marked Golgi enlargement and fragmentation and cisternal dilatation of the ER. In the present study we used the VSV‐GtsO45GFP ER to Golgi to plasma membrane trafficking assay in EA.hy926 human endothelial cells to quantitatively assess the combinatorial effects of functional haploinsufficiency of BMPRII, eNOS, STAT5a and STAT5b using respective siRNAs. Knockdown of STAT5a, STAT5b, BMPRII, or eNOS one at a time did not significantly affect intracellular trafficking. However, down‐regulation of STAT5a plus STAT5b inhibited VSV‐G trafficking from the ER/Golgi apparatus to the cell surface by 60–70%. STAT5a or STAT5b combined with eNOS siRNA treatments had a similar inhibitory effect. STAT5a or STAT5b combined with BMPRII siRNA also inhibited VSV‐G trafficking. These observations suggest that combinatorial functional haploinsufficiency of BMPRII, eNOS, STAT5a and STAT5b may contribute to intracellular trafficking defects.

Portopulmonary Hypertension: A Report From the US-Based REVEAL Registry

We evaluated survival and hospitalization rates in patients with group 1 portopulmonary hypertension (PoPH) in the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry). The REVEAL Registry is a multicenter, observational, US-based study evaluating demographics and management of patients with pulmonary arterial hypertension (PAH). Outcomes were examined using Kaplan-Meier time-to-event estimates and compared with patients with idiopathic PAH (IPAH) or familial PAH (FPAH). One hundred seventy-four patients with PoPH were enrolled in the REVEAL Registry (IPAH/FPAH; n = 1,478) from March 2006 to December 2009. Mean age was 53 ± 10 years, 52% were female, 32% were newly diagnosed, and 6% were New York Heart Association/World Health Organization functional class IV. Outcome parameters were worse for PoPH vs IPAH/FPAH, respectively: 2-year survival from enrollment (67% vs 85%, P < .001), 5-year survival from time of diagnosis (40% vs 64%, P < .001), and 2-year freedom from all-cause hospitalization (49% vs 59%, P = .019). However, despite worse outcomes, hemodynamic parameters at diagnosis were better for PoPH vs IPAH/FPAH, respectively: mean pulmonary artery pressure (49 mm Hg vs 53 mm Hg, P < .001), mean right atrial pressure (9 mm Hg vs 10 mm Hg, P = .005), pulmonary vascular resistance (8 Wood units vs 12 Wood units, P < .001), and cardiac output (5 L/min vs 4 L/min, P < .001). Compared with patients with IPAH/FPAH, patients with PoPH were less likely to be on a PAH-specific therapy at enrollment (P < .001), suggesting potential delays in therapy for patients with PoPH. Patients with PoPH had significantly poorer survival and all-cause hospitalization rates compared with patients with IPAH/FPAH, despite having better hemodynamics at diagnosis. Further studies should investigate such outcomes and differences in treatment patterns. ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Seeking the right targets: gene therapy advances in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a grave vascular disorder characterised by the obstruction and occlusion of the small pulmonary arteries, primarily through the abnormal proliferation of the endothelial and smooth muscle layers. A clinical diagnosis of pulmonary hypertension (PH) is made when the mean pulmonary arterial pressure ( P pa) is ≥25 mmHg at rest. An additional criterion to differentiate PAH from other forms of PH requires that pulmonary arterial wedge pressure be ≥15 mmHg [1, 2]. The disease is typically fatal due to right heart failure as a result of the pathological increases in pulmonary vascular resistance. While the majority of the patient population develop spontaneous or idiopathic PAH and PAH associated with other disorders, for example, HIV infection, connective tissue disease or exposure to risk factors such as appetite suppressants containing dex/fenfluramine (associated PAH), some 10% display familial transmission. In families, PAH is an autosomal dominant trait with a sex bias favouring females and penetrance as low as 20%, features that suggest that, while a Mendelian condition, PAH displays features of complex disease [1, 2]. Traditional positional cloning approaches identified the causative gene for familial PAH as BMPR2 , encoding a type-II receptor of the transforming growth factor (TGF)-β signalling family [3, 4]. Currently, deleterious germ-line mutations have been detected in ∼70% of families analysed and 25% of idiopathic cases [5, 6]. The recent re-classification of mutation carriers with or without a family history as heritable PAH (HPAH), at the 4th World symposium on Pulmonary Hypertension (Dana Point, CA, USA) in 2008, indicates the growing recognition of the central importance of BMPR2 dysfunction in pathogenesis [7]. The majority of BMPR2 mutation in HPAH predicts premature truncation of the transcript and, …

Pulmonary arterial hypertension: an update

Dear Sir, We read with interest the article by Hoendermis [1] concerning an update on pulmonary arterial hypertension (PAH). This paper pays particular attention to the diagnosis and treatment of PAH; however, we would like to highlight the role of stress echocardiography to detect pulmonary vascular disease (PVD) prior to a rise of pulmonary arterial pressure (PAP) at rest. In fact, stress echocardiography has been successfully used on relatives of patients with idiopathic and familial PAH in a large multicentre study [2] and in patients with systemic sclerosis [3, 4]. It seems to be a useful tool to detect PVD early, but it requires further validation because of the lack of standardisation in the exercise protocol and because the cut-off value of PAP as in these cases has not been established; neither, to our knowledge, has the influence of age, gender, and body mass index on PAP been clearly defined. Stress echocardiography, despite MRI and CT, is more available and less expensive, and it might give more information on the functionality. However, today, it is not yet recommended as a routine method for the early detection of PVD, but we do hope that future research would fill the existing gaps and allow an extended use.

Early Recognition and Management of Pulmonary Arterial Hypertension: ACase for Profiling

Early Recognition and Management of Pulmonary Arterial Hypertension: ACase for Profiling

Survival in Childhood Pulmonary Arterial Hypertension

Background— Pulmonary arterial hypertension (PAH) is a rare but important cause of morbidity and mortality in children. Methods and Results— We analyzed data from 216 patients ≤18 years of age at diagnosis who were enrolled in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Median age at diagnosis and enrollment was 7 and 15 years, respectively. The most frequent presenting symptom was dyspnea (idiopathic/familial PAH, 53%; PAH associated with congenital heart disease, 30%). Presyncope/syncope was more frequent in patients with idiopathic PAH/familial PAH (36%) than in those with PAH associated with congenital heart disease (4%). At diagnosis, mean pulmonary artery pressure and pulmonary vascular resistance index were 56 mm Hg and 17 Wood units · m 2 , respectively. Five-year survival from diagnosis for the overall cohort was 74±6%, with no significant difference between the idiopathic PAH/familial PAH (n=122, 75±7%) and PAH associated with congenital heart disease (n=77, 71±13%) cohorts ( P =0.53). Older age at diagnosis was the only variable significantly associated with decreased survival from diagnosis. Variables at enrollment that were significantly associated with decreased survival from enrollment included higher pulmonary vascular resistance index, lower-weight z scores, and familial PAH. Additional variables at enrollment, identified in a secondary analysis, that were marginally associated with increased survival from enrollment included acute vasoreactivity (adaptation of conventional pediatric definition; P =0.087) and lower brain natriuretic peptide ( P =0.060). None of the 22 patients who were acute responders treated with high-dose calcium channel blockade as monotherapy or combination therapy died within 5 years of diagnosis. Conclusion— Using REVEAL, we identified key predictors of survival in childhood PAH. Refining these prognostic parameters should help clinicians improve outcomes. Clinical Trial Registration— URL: www.clinicaltrials.gov . Unique identifier: NCT00370214.

A Novel Mutation in BMPR2 in Patients with Congenital Heart Disease and Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is caused by intensive remodeling of small pulmonary arteries. The main pathological characteristic is proliferation of endothelial and smooth muscle cells. PAH is clinically characterized by a sustained increase in pulmonary arterial pressure, right-sided heart failure and death. Genetic studies in patients of familial PAH (FPAH), idiopathic pulmonary arterial hypertension (IPAH) and congenital heart disease with pulmonary arterial hypertension (CHD/PAH) have identified heterozygous mutations in the bone morphogenetic protein type receptor II ( BMPR2 ) gene. To date, only six distinct missense mutations have been identified in patients with CHD/ PAH. Methods: The protein-coding region and intron/exon boundaries of the BMPR2 gene were amplified by PCR using DNA samples from 80 Chinese Han patients with CHD/PAH and 80 matched controls. Direct sequencing of PCR products was conducted on both the sense and antisense strands. Mutations were excluded if present in a panel of chromosomes from 80 normal individuals. Results: A novel missense mutation, a G-to-A transition at position 1042 in exon 8, which encodes a Val348Ile mutation, of the BMPR2 gene, was identified in a female pediatric patient with atrioventricular septal defect/anterior mitral valve cleft/pulmonary arterial hypertension (AVSD/ AMVC/PAH). A single nucleotide polymorphisms (SNP), c. 2811G>A, in the BMPR2 gene was identified in nine patients and ten controls. However, no significant difference was found in the frequency distribution of the SNP between patients with CHD/PAH and controls. Conclusions: We identified a novel missense mutation occurring at a valine located in the kinase domain of BMPR2 . The Val348Ile mutation may be responsible for the development of CHD/PAH.