06 October 2021

This week in PVD

Long noncoding RNAs may have role in PH onset, rat study finds

Seven long noncoding RNA molecules were found to be associated with the development of pulmonary hypertension (PH) in an early study in rats, scientists reported.

The researchers noted that some of these RNAs are known to regulate immune and inflammatory response pathways, which may participate in PH.

“Our study contributes to a better understanding of the [development of PH] and the role of [noncoding RNAs] in disease progression,” they wrote. “Further research is needed to determine the molecular mechanisms by which [noncoding RNAs] play a role in [PH] generation and development.”

The study, “Construction and analysis of the abnormal lncRNA–miRNA–mRNA network in hypoxic pulmonary hypertension,” was published in the journal Bioscience Reports.

Blood vessels that pass through the lungs narrow in PH, leading to abnormally high blood pressure, making it harder for the heart to pump blood. As a result, the heart becomes enlarged and gradually weakens. Although many studies have investigated PH, many of the underlying biological mechanisms that contribute to the disease have not been fully explored.

BETTER-B: new study wants to test treatment for breathlessness in COPD and ILD patients

A study called BETTER-B, led by Professor Irene Higginson, wants to test a new treatment. This is a medicine called mirtazapine. Mirtazapine is an antidepressant that has been used for many years. In small regular doses it may help to relieve severe breathlessness in people who are not depressed.

Breathlessness affects people with chronic obstructive pulmonary (COPD) or interstitial lung disease (ILD), often even after the underlying causes are treated. There are very few treatments for this symptom.

The study team plan to recruit 324 people across the UK, Germany, Ireland, Italy and Poland. They will compare treatment with either mirtazapine or a placebo (dummy drug) tablet.

May-Thurner anatomy common in patients with CTEPH, new study shows

Like highways, roads, and side streets, blood vessels in the human body come in different sizes, with a range of traffic-carrying capacities. These differences are critical to facilitating blood flow through tissues. But when it comes to blood clots – oversized vehicles on the blood cell highway – the risk of a traffic jam escalates with every turn into the increasingly narrow vessels supplying the heart and lungs. Eventually, large clots become stuck, holding up blood flow. When this happens in the lungs, a potentially dangerous condition known as chronic thromboembolic pulmonary hypertension (CTEPH) develops.

In many cases, the clots that cause CTEPH come from veins in the lower half of the body, usually due to deep vein thrombosis (DVT). A risk factor for DVT is compression of the iliac vein in the pelvis, which can be caused by an anatomical variant known as May-Thurner anatomy (MTA). While MTA is generally thought to be rare, a new study by researchers at the Lewis Katz School of Medicine at Temple University shows that the anomaly is very common in patients with CTEPH – in a sample of 148 patients referred to Temple's CTEPH program since 2016, nearly 30 percent were found to have MTA.

Potential PAH therapy, KER-012 also prevents bone loss in rat model

A lab version of an investigational treatment for bone disorders and pulmonary arterial hypertension (PAH), KER-012 prevented bone loss in a PAH rat model, its developer, Keros Therapeutics, reported.

Separate preclinical data in a PAH rat model, presented by the company earlier this year, also demonstrated that KER-012 worked to block increases in inflammation, fibrosis (scarring), and heart damage in the animals. As such, it showed a “potential to treat PAH in patients without dose-limiting increases in red blood cells,” the company said in a May release.

Bone findings were presented this month at the American Society for Bone and Mineral Research (ASBMR) 2021 Annual Meeting.

“The results of this study suggest that RKER-012 prevented bone loss in this PAH model, which we believe supports that KER-012 has the potential to treat bone loss resulting from secondary osteoporosis, such as in PAH,” Jasbir Seehra, PhD, Keros’ president and CEO, said in a press release. Secondary osteoporosis refers to bone loss that occurs due to a specific and well-defined health disorder like PAH.

KER-012 is designed to increase bone morphogenic protein (BMP) signaling. The BMP pathway plays important roles in promoting bone growth and health. Reduced BMP activity is also associated with PAH, according to Keros.

Triplet therapy for PAH may reduce disease progression vs doublet therapy

New data on treatment for newly diagnosed pulmonary arterial hypertension (PAH) show initial treatment for the progressive disease that includes macitentan has potential to reduce risk of disease progression.

Patients with newly diagnosed pulmonary arterial hypertension (PAH) who have yet to initiate treatment may find subsequent benefit in initial therapy with a triple- vs a double-drug combination, new data from the multicenter, double-blind, randomized phase 3b TRITON trial show.

This, and other findings, were recently published in Journal of the American College of Cardiology.

Oral triplet therapy with macitentan, tadalafil, and selexipag was compared with doublet therapy of macitentan, tadalafil, and placebo among treatment-naive patients, because “combination therapy to target multiple pathways is an essential part of PAH management [and] patients receiving double oral therapy, including initial double therapy, continue to experience PAH progression, providing a rationale for more intensive treatment.”

Previous studies, the authors added, have also shown initial triplet therapy to improve hemodynamic status, functional capacity, morbidity, and mortality. Participants in this study (aged 18 to 75 years) were randomized 1:1 to initial triple (n = 123) or double (n = 124) therapy by 28 days after study screening and had to have PAH confirmed in the 6 months leading up to this, a 6-minute walk distance (6MWD) of at least 50 meters, and pulmonary vascular resistance (PVR) of at least 6 WU; they were followed until week 26 for the last randomized patient.

Blocking specific PI3K protein prevents PH in animal models

Targeting a protein called p110a, a part of the PI3K family of enzymes, may be useful for preventing or even reversing pulmonary hypertension, research done in cells and rodent models showed.

“Targeted inhibition of [p110a] offers a disease-modifying treatment approach, which is readily accessible by small molecule inhibitors and warrants further evaluation in clinical trials,” the researchers wrote.

Results of the study “Disrupted PI3K subunit p110α signaling protects against pulmonary hypertension and reverses established disease in rodents,” were published in The Journal of Clinical Investigation.

Pulmonary hypertension (PH) is characterized by changes in the biological activity of pulmonary arterial smooth muscle cells (PASMCs), the cells that line the lung’s blood vessels. In PH, PASMCs tend to grow more than is normal and become resistant to apoptosis, a form of programmed cell death.

These phenomena are thought to be largely driven by the activation of certain protein receptors — specifically, receptors for growth factors — on the surface of pulmonary arterial smooth muscle cells. Growth factors, as its name suggests, are signaling molecules that can prompt cells to grow.

When a growth factor binds to its receptor, it sends biochemical signals into the cell that affect its activity, like prompting cell division and growth.

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