25 October 2019

This week in PVD

New trial shows Adcirca-Opsumit combo could be beneficial as treatment for newly diagnosed PAH patients

The results from a new clinical trial show that treatment with Adcirca plus Opsumit can reduce symptoms in newly diagnosed patients with pulmonary arterial hypertension (PAH) and provide functional benefits.

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Early treatment with an endothelin-receptor antagonist (ERA) and a phosphodiesterase type-5 inhibitor (PDE-5) is currently recommended for PAH sufferers. Opsumit is an ERA therapy, therefore it can reduce the production of endothelin, and so decrease blood vessel constriction, and lower the blood pressure in the pulmonary arteries in turn. Adcirca is a PDE-5 inhibitor that works by relaxing the smooth muscle cells of arteries, leading to vasodilation and a reduction of blood pressure.

The Phase 4 open-label OPTIMA trial — sponsored by Actelion, the developer of Opsumit — was designed to assess the impact of the Adcirca plus Opsumit combo treatment as a first-line therapy in newly diagnosed PAH patients. After 16 weeks of treatment, patients had reduced pulmonary resistance by roughly 47% compared with assessments from before the start of the therapy. Participants were also able to walk 36 meters more than before in the six-minute walk distance test, and approximately 63% of patients showed improved functional ability.

 “Our findings add new evidence to the benefit of initial oral double combination therapy in patients with pulmonary hypertension,” said Olivier Sitbon, MD, PhD, Université Paris–Sud, who will be discussing these recent findings at an upcoming meeting.

New study suggests that halting Slug protein may lessen the risk of PH in fibrotic lungs

The effects of increased blood pressure related to pulmonary hypertension (PH) may be reduced by halting a protein called Slug, a new study shows. The condition, PH secondary to pulmonary fibrosis, or PF-PH, is marked by scarring of the lung tissues.

The study, ‘Histological hallmarks and role of Slug/PIP axis in pulmonary hypertension secondary to pulmonary fibrosis’, examined scarred and non-scarred areas within lung tissue of PF and PH patients. They observed that the blood vessels had thicker walls in PF‐PH patient lungs, compared with those in people with just PF. Increased levels of a protein called Slug within the macrophages (cells of the immune system), was found to be linked to this increased thickening. The team therefore, could conclude that increased levels of the Slug protein might promote deposits of other proteins which are involved in tissue scarring.

The researchers developed a new rat model that developed PH after induction of PF in order to test this hypothesis. This new animal model represented the features of human PF‐PH, in particular, lung scarring and pulmonary vascular remodelling. Moreover, the animals also showed increased levels of Slug protein. “Slug inhibition in the presence of a PH stimulus decreases PH severity in rats with pre‐existing PF by decreasing vascular remodelling and vascular wall cell proliferation,” the researchers said.

This study demonstrates that Slug inhibition reduces PH severity in a pre‐clinical model of PF‐PH, which may eventually lead the way to a better understanding of this devastating disease.

Low blood levels of secretin hormone may trigger PH

Loss of a hormone called secretin (SCT) induces hypertension, scarring, and structural alterations in the heart and lungs, a study in mice reports.

SCT is released by cells in the intestine and the brain, and its receptors are found at high levels in both the heart and lungs. Prior studies showed that SCT reduces blood pressure in the heart, increases cardiac blood flow, and regulates water and salt balance. However, “no studies have clearly shown the significance of SCT in these systems and explained how SCT plays a role in regulating blood pressure,” the researchers wrote.

The study suggests that SCT can be an essential hormone for the cardiovascular and pulmonary systems in humans, since SCT deficiency can result in pulmonary and systemic hypertension in mice. Measuring SCT levels can also provide information as whether SCT deficiency has a role in pulmonary and systemic hypertension in humans.

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Higher levels of sST2 protein linked to poorer outcomes in PH, study finds

More severe pulmonary hypertension (PH) and heart dysfunction is associated with higher levels of a protein involved in certain immune responses, called soluble suppression of tumorigenicity-2 (sST2), a study found. PH is a rare disorder that is often coupled with heart dysfunction, leading to high pulmonary arterial pressure (PAP).

Alterations occurring in blood vessels in the lungs of patients with pulmonary arterial hypertension (PAH), have been found in previous studies to be linked with the protein sST2. In recent years sST2 has emerged as a biomarker of heart failure because its levels rise significantly when the heart is under stress. Other studies also found a direct correlation between sST2 levels and the degree of right heart dysfunction in PAH patients. This suggested that, in addition to being a valuable biomarker of heart failure, sST2 may also be a useful indicator of heart and lung blood vessel deterioration in PH.

To explore this further, researchers measured blood levels of sST2 in patients with different types of PH. The study’s main goal was to determine if there was a correlation between the levels of sST2 and poor clinical outcomes in PH, including the need for a lung transplant, signs of heart failure, or death. Results showed that high sST2 levels were associated with severe right heart disfunction, higher PAP values, and a worse exercise capacity.

Overall, data showed that “higher sST2 is associated with a worse exercise capacity, higher pulmonary and cardiac pressures, and with more severe right ventricular [heart] disfunction. Moreover, sST2 is significantly associated with the risk of death or lung transplantation,” the researchers wrote.

Our findings add new evidence to the benefit of initial oral double combination therapy in patients with pulmonary hypertension
Olivier Sitbon, MD, PhD Professor of Respiratory Medicine, University Paris-Sud

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