Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor

BACKGROUND: Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-beta (TGF-beta) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH). METHODS AND RESULTS: Because the sites of expression of BMPR-II in the normal and hypertensive lung are unknown, we studied the cellular localization of BMPR-II and the related type I and II receptors for TGF-beta by immunohistochemistry in lung sections from patients undergoing heart-lung transplantation for PPH (n=11, including 3 familial cases) or secondary pulmonary hypertension (n=6) and from unused donor lungs (n=4). In situ hybridization was performed for BMPR-II mRNA. Patients were screened for the presence of mutations in BMPR2. In normal lungs, BMPR-II expression was prominent on vascular endothelium, with minimal expression in airway and arterial smooth muscle. In pulmonary hypertension cases, the intensity of BMPR-II immunostaining varied between lesions but involved endothelial and myofibroblast components. Image analysis confirmed that expression of BMPR-II was markedly reduced in the peripheral lung of PPH patients, especially in those harboring heterozygous BMPR2 mutations. A less marked reduction was also observed in patients with secondary pulmonary hypertension. In contrast, there was no difference in level of staining for TGF-betaRII or the endothelial marker CD31. CONCLUSIONS: The cellular localization of BMPR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension

The promise of recombinant BMP ligands and other approaches targeting BMPR-II in the treatment of pulmonary arterial hypertension.

Human genetic discoveries offer a powerful method to implicate pathways of major importance to disease pathobiology and hence provide targets for pharmacological intervention. The genetics of pulmonary arterial hypertension (PAH) strongly implicates loss-of-function of the bone morphogenetic protein type II receptor (BMPR-II) signalling pathway and moreover implicates the endothelial cell as a central cell type involved in disease initiation. We and others have described several approaches to restore BMPR-II function in genetic and non-genetic forms of PAH. Of these, supplementation of endothelial BMP9/10 signalling with exogenous recombinant ligand has been shown to hold considerable promise as a novel large molecule biopharmaceutical therapy. Here, we describe the mechanism of action and discuss potential additional effects of BMP ligand therapy

Prediction of cardiovascular disease risk by cardiac biomarkers in 2 United Kingdom cohort studies: does utility depend on risk thresholds for treatment?

We tested the predictive ability of cardiac biomarkers N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T, and midregional pro adrenomedullin for cardiovascular disease (CVD) events using the British Regional Heart Study (BRHS) of men aged 60 to 79 years, and the MIDSPAN Family Study (MFS) of men and women aged 30 to 59 years. They included 3757 and 2226 participants, respectively, and during median 13.0 and 17.3 years follow-up the primary CVD event rates were 16.6 and 5.3 per 1000 patient-years, respectively. In Cox models adjusted for basic classical risk factors, 1 SD increases in log-transformed NT-proBNP, high-sensitivity troponin T, and midregional pro adrenomedullin were generally associated with increased primary CVD risk in both the studies (P<0.006) except midregional pro adrenomedullin in MFS (P=0.10). In BRHS, QRISK2 risk factors yielded a C-index of 0.657, which was improved by 0.017 (P=0.005) by NT-proBNP, but not by other biomarkers. Using 28% 14-year risk as a proxy for 20% 10-year risk, NT-proBNP improved risk classification for primary CVD cases (case net reclassification index, 5.9%; 95% confidence interval, 2.8%–9.2%), but only improved classification of noncases at a 14% 14-year risk threshold (4.6%; 2.9%–6.3%). In MFS, ASSIGN risk factors yielded a C-index of 0.752 for primary CVD; none of the cardiac biomarkers improved the C-index. Improvements in risk classification were only seen using NT-proBNP and high-sensitivity troponin T among cases using the 28% 14-year risk threshold (4.7%; 1.0%–9.2% and 2.6%; 0.0%–5.8%, respectively). In conclusion, the improvement in treatment allocation gained by adding cardiac biomarkers to risk scores seems to depend on the risk threshold chosen for commencing preventative treatments

Standardized Field Sobriety Test: False Positive Test Rate among Sober Subjects

The Standardized Field Sobriety Test (SFST) is a series of exercises that a law enforcement officer gives to a driver suspected of driving under the influence of alcohol. The original research that demonstrated a high correlation between failure of the SFST and a high blood alcohol concentration did not utilize a standard control group to validate that the failure of the SFST was not a characteristic of the population at large. This study examined a series of drug naive subjects to determine the rate of failure of the SFST to accurately distinguish a suspect with high blood alcohol content from the general public. Of the 185 subjects tested, 26% of the drug naïve subjects failed the SFST

An exploratory qualitative investigation of course-fee funding for students on a full-time MSc pathway in Medical Ultrasound

Background: Students reading for a full-time MSc in Medical Imaging (Ultrasound) are graduates from a variety of demographic backgrounds, many with family commitments. Unlike other UK healthcare courses, students are not entitled to a bursary nor assistance with course-related costs. In previous years, a lack of financial support has been cited by prospective students as the chief reason for not accepting an offer of a place on the course. Course fees for students in the cohort beginning January 2023 were fully-financed by a key external agency to improve recruitment and retention on this pathway. This study explored the financial challenges experienced, and whether such funding enabled students to accept their place on the programme. Method: Semi-structured online interviews were undertaken with full-time medical ultrasound students (n=7) prior to starting clinical placement. Reflexive thematic analysis (Braun and Clarke, 2019) identified three global themes which describe participants’ experiences. Results: Three themes emerged from the data analysis. These were: (a) Enabling students to study: Full course-fee funding made it financially feasible for some participants to accept their place on the programme. Additionally, it reduced the necessity for students to undertake paid part-time work, allowing more time to focus on their learning; (b) Study-life balance: Reduced part-time working helped to support family-life and student mental health; (c) Ongoing financial challenges: Despite the positive outcomes of course-fee funding, students experienced continuing difficulties associated with increasing living costs. Conclusion: The intervention has had positive outcomes on enabling students to study and supporting students in their family-life and mental health

The lysosomal inhibitor, chloroquine, increases cell surface BMPR-II levels and restores BMP9 signalling in endothelial cells harbouring BMPR-II mutations.

Pulmonary arterial hypertension (PAH) is characterized by dysregulated pulmonary artery endothelial cell (PAEC) proliferation, apoptosis and permeability. Loss-of-function mutations in the bone morphogenetic protein receptor type-II (BMPR-II) are the most common cause of heritable PAH, usually resulting in haploinsufficiency. We previously showed that BMPR-II expression is regulated via a lysosomal degradative pathway. Here, we show that the antimalarial drug, chloroquine, markedly increased cell surface expression of BMPR-II protein independent of transcription in PAECs. Inhibition of protein synthesis experiments revealed a rapid turnover of cell surface BMPR-II, which was inhibited by chloroquine treatment. Chloroquine enhanced PAEC expression of BMPR-II following siRNA knockdown of the BMPR-II transcript. Using blood outgrowth endothelial cells (BOECs), we confirmed that signalling in response to the endothelial BMPR-II ligand, BMP9, is compromised in BOECs from patients harbouring BMPR-II mutations, and in BMPR-II mutant PAECs. Chloroquine significantly increased gene expression of BMP9-BMPR-II signalling targets Id1, miR21 and miR27a in both mutant BMPR-II PAECs and BOECs. These findings provide support for the restoration of cell surface BMPR-II with agents such as chloroquine as a potential therapeutic approach for heritable PAH