20 August 2020

This week in PVD

3D cell culture technology used to develop model of arterial wall thickening in PAH enabling further study

Researchers at Okayama University, Japan, have developed a model that replicates the processes involved in pulmonary arterial hypertension (PAH) using 3D cell culture technology, allowing them to more carefully analyse the thickening of arterial walls that occurs in patients with PAH. The study, titled ‘3D in vitro Model of Vascular Medial Thickening in Pulmonary Arterial Hypertension’ was published in the Frontiers in Bioengineering and Biotechnology  journal.

The pulmonary arterial smooth muscle cells (PASMCs) of the arterial walls thicken in PAH, ultimately leading to heart failure and other symptoms. While these cells have been studied using 2D cell techniques in the lab, researchers have not been able to model the arterial wall thickening in these samples. Therefore, a 3D model of the arterial walls has been developed to investigate the thickening process more closely and in turn perhaps lead to the development of new PAH treatments.

“Given the importance of vascular medial thickening in the pathogenesis of PAH, novel therapeutics targeting this process might be beneficial in improving disease outcomes in PAH patients”, Mitsunobu Kano, PhD, a professor at Okayama University and co-supervisor of the study, said in a press release. “The lack of in vitro models that recapitulate vascular medial thickening led us to establish a new model to study this disease”. The model researchers developed not only enables the thickening process to be studied more thoroughly, but also how other factors may affect that process. For example, platelet-derived growth factor (PDGF) was found to “induce the proliferation of PASMCs and increased the thickness of the 3D tissues” according to Kano.

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The team used three medications approved for PAH, Tracleer (bosentan), Adcirca (tadalafil), and MRE-269, the active metabolite of Uptravi (selexipag), and investigated how they affect arterial wall thickening in the model, and thus, the usefulness of the 3D model in preclinical research. All three were found to reduce the thickening in the 3D model, with Tracleer and Adcirca showing a greater reduction than MRE-269. “We thus expect that our 3D-PAH medial thickening model can potentially be used in the future to screen novel compounds for their ability to suppress medial thickening for use against PAH,” the researchers concluded.

Study shows Interleukin-32 may serve as early biomarker for PAH in scleroderma patients

The protein, interlukin-32 (IL-32) has the potential to serve as a biomarker for pulmonary arterial hypertension (PAH) in scleroderma patients, study shows. The study published in the ‘Arthritis Research and Therapy journal was titled Interleukin-32 in systemic sclerosis, a potential new biomarker for pulmonary arterial hypertension’. The pro-inflammatory cytokine, IL-32 is thought to regulate many of the activities of endothelial cells that line the pulmonary artery, as well as being known to be activated in damaged vascular cells.

Researchers at the University of L’Aquila, Italy, tested serum levels of 18 systemic scleroderma–PAH (SSc-PAH) patients , 21 SSc patients without PAH, 15 patients with idiopathic PAH (iPAH,) and 14 healthy controls in order to analyse IL-32 as a potential new biomarker. The results showed that serum levels of IL-32 were significantly higher in SSc-PAH patients than in any of the other groups — 99.9 pg/ml. IL-32 was nearly undetectable in SSc patients without PAH, as well as in healthy controls. In the iPAH group, the mean levels of IL-32 were of 62.1 pg/ml. Furthermore, there was a strong correlation between IL-32 levels and other measures of PAH, such as mean and systolic pulmonary arterial pressure. The study also showed increased levels of IL-32 in SSc patients’ skin cells when compared to those without PAH. Further analysis suggested that a cut-off value of 11.12 pg/ml for IL-32 could predict patients with PAH.

Researchers concluded that “sera determination of IL-32 may be a promising approach to evaluate the presence of PAH in SSc patients and together with longitudinal future studies could help to increase the understanding how these biomarkers mirror the vascular changes and the inflammatory process during SSc”.

Ambrisentan treats patients with CTD-PAH according to new study

Volibris, also known as ambrisentan, has been given to patients in China with pulmonary arterial hypertension (PAH) caused by connective tissue disease (CTD-PAH). The study, titled “Efficacy and safety of ambrisentan in Chinese patients with connective tissue disease-pulmonary arterial hypertension: a post-hoc analysis,” was published in the journal BMC Cardiovascular Disorders. It shows that ambrisentan led to significant improvements in exercise capacity without signs of clinical worsening over 24 weeks. Furthermore, biomarker levels of heart function and breathing ability also showed positive advances.

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Volibris, marketed by GSK in Europe and by Gilead in the USA, is approved to treat the symptoms of PAH. While previous studies on the use of ambrisentan to treat CTD-PAH have been conducted, they have all predominantly included people of European descent and the use of the treatment in patients of Asian ethnicity was limited. Thus, researchers at the Peking Union Medical College & Chinese Academy of Medical Sciences sought to target this gap in research.

The research team also examined differences in treatment response between patients with CTD-PAH and those with either idiopathic PAH (IPAH) or heritable PAH (HPAH) for a comparison to be drawn.  Data were available 64 adult CTD-PAH patients (41 had PAH associated with systemic lupus erythematosus and 23 did not. Their median age was 40 and most were women). The patients received a 5 mg oral dose of Volibris once daily for 12 weeks, followed by a 12-week dose adjustment period in which doses were increased up to 10 mg depending on the patient’s tolerance. The average time of exposure to the therapy was about 164 days; additional medications to treat CTD included hydroxychloroquine, glucocorticoids, and immunosuppressants.  The primary endpoint was a change in exercise capacity over 12 weeks, as measured by the 6-minute walking test (6MWT).

Results showed that the use of Volibris led to a significant improvement in the 6MWT from baseline at 12 weeks, and of 73.2 meters at 24 weeks. The improvement in CTD-PAH patients was greater than that seen in IPAH or HPAH patients, but the difference was not statistically significant. Moreover, the NT-proBNP levels in CTD-PAH patients decreased significantly with treatment at both 12 and 24 weeks compared to baseline, the WHO functional classification improved by one class in 29 of the CTD-PAH patients by week 12, and heart rates . were significantly slower (a reduced change in heart rate recovery from baseline to week 24) with treatment. 

According to the team, “results of the current analysis provide substantial evidence regarding the efficacy of ambrisentan in CTD-PAH population and warrant further research in this direction”.

Uptravi as an add-on treatment for children with PAH

A study published in the Journal of Heart and Lung Transplantation, titled ‘Selexipag for the treatment of children with pulmonary arterial hypertension: First multicenter experience in drug safety and efficacy’ has found that Uptravi (selexipag), an approved treatment for adults with pulmonary arterial hypertension (PAH), may also be safe and effective in children. Uptravi is a a selective antagonist of the prostacyclin receptor, or a molecule that works like prostacyclin to regulate blood pressure.

Researchers in Europe conducted a study that included 15 patients aged 7 months to 17 years with pre-capillary pulmonary hypertension (PH) whose clinical, heart, and blood markers were not improving after at least six months on a dual oral combination therapy. Uptravi was given to the patients for eight months and a varying starting dose depending on their weight (50 – 200 mcg). This dose was then increased incrementally every two to three days until the final Uptravi dose was reached after four to eight weeks depending on the side effects the patients experienced.

After two years, responses to Uptravi were variable but no one had died. Researchers wrote “Overall, approximately 50% of our paediatric patients with PAH improved with add-on selexipag, 25% were stabilised, and 20% of the patients deteriorated during the observation period”. The ratios of mean pulmonary arterial pressure to mean systemic artery pressure (mPAP/mSAP), and diastolic pulmonary arterial pressure to diastolic pulmonary arterial pressure, both measures of PH, were lessened by 17%. Furthermore, patients also showed a 17% reduction in mean transpulmonary pressure gradient (mTPG), and a 5.8 mm Hg decrease in mean diastolic transpulmonary pressure gradient (dTPG).

The researchers also evaluated the response using the EPPVDN paediatric PH risk score, improvements were seen in seven patients and four other showed disease stabilisation, three patients progressed with Uptravi. The EPPVDN risk score significantly correlated with other measures of disease, such as NT-proBNP levels suggesting it can “reliably indicate a change of clinical status with medication,” the researchers wrote.

In conclusion, “oral add-on therapy with selexipag in children with PAH, although not approved in this age group to date, is well tolerated and appears to be safe when closely monitored”. “In children who underwent invasive cardiac catheterisation at baseline [study start] and follow-up, selexipag treatment was associated with the improvement or stabilisation of several outcome relevant variables,” researchers wrote.

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