Goal-oriented Combo Therapy Can Improves HRQoL in PAH patients - Pulmonary Hypertension News

Goal-oriented Combo Therapy Can Improves HRQoL in PAH patients - Pulmonary Hypertension News

Goal-oriented Combo Therapy Can Improves HRQoL in PAH patients - Pulmonary Hypertension News

Posted: 01 Jul 2019 12:00 AM PDT

Use of sequential combination therapy focused on changes in exercise capacity improves health-related quality of life (HRQoL) in patients with newly diagnosed pulmonary arterial hypertension (PAH), according to a new study.

The research, "Medium-term health-related quality of life in patients with pulmonary arterial hypertension treated with goal-oriented sequential combination therapy based on exercise capacity," was published in the journal Health and Quality of Life Outcomes.

Combination treatments in PAH patients have led to greater benefits in exercise capacity and risk of clinical worsening than standalone therapies. Still, the optimal combination approach for these patients remains unclear.

Addressing the impact of PAH treatment on HRQoL has been drawing increasing attention, with HRQoL scores being associated with disease prognosis. However, information on changes in quality of life in newly diagnosed patients undergoing goal-oriented sequential combination therapy remains scarce.

A research team from Japan addressed this knowledge gap by focusing on exercise capacity. They conducted a study at Nagoya University Hospital, from October 2012 through March 2015, which included 30 patients (22 of whom were women), mean age of 57 years, with newly diagnosed PAH and mild to severe physical limitation (World Health Organization (WHO) functional classes 2 to 4).

Two patients died during the study, one due to right heart failure at four months and the other to cardiac sudden death at seven months.

During the study period, all patients received tailored treatment designed to achieve a main goal of a peak VO2 — pulmonary oxygen uptake — greater than 15.0 mL/min/kg. This value has been associated with better prognosis, and a peak systolic blood pressure during exercise above 120 mmHg.

As first-line treatment, the patients received an endothelin receptor antagonist (ERA), either bosentan (sold under the brand name Tracleer) or ambrisentan (with the brand name Letairis). If with this approach the patient was sill able to achieved that targeted goal, they would switch to a second line of treatment, which included the addition of a phosphodiesterase-5 inhibitor (PDE-5I), either sildenafil (brand name Revatio) or tadalafil (marketed as Adcirca and ALYQ). If needed, epoprostenol (with brand names Flolan and Veletri) could also be added to the treatment regimen.

All patients underwent cardiac catheterization when they were first diagnosed and 12 months afterward, as well as cardiopulmonary exercise testing, laboratory measurements, and echocardiograms. They also completed the Japanese version of the Short Form (SF)-8 survey of HRQoL at the beginning of the study and at three, six, and 12 months.

At six months, 79% of the patients were taking both ERA and PDE-5 inhibitor, while at 12 months 82% were receiving the combo treatment. Compared with baseline, brain natriuretic peptide (BNP) — a biomarker of cardiovascular diseases — and the tricuspid regurgitation pressure gradient — used to determine pulmonary artery pressure — gradually dropped throughout the 12-month follow-up period.

In contrast, exercise capacity, assessed through the 6-minute walk distance (6MWD) test, significantly increased at three months, with no further improvements at six and 12 months. Peak VO2 was significantly higher at six months, while mean pulmonary arterial pressure and pulmonary vascular resistance (PVR) — an indicator of PAH severity — were lower at 12 months.

Sequential combination therapy gradually improved seven of the eight SF-8 domains, including general health perception, physical functioning, bodily pain, vitality, and mental health.

In general, the participants showed better physical health scores at three months, which remained stable during 12 months. In turn, mental health scores were found to be improved at six months.

Poorer physical health scores were found to be significantly correlated with higher PVR, plasma BNP level, and peak VO2, while mental health scores were significantly associated with only peak VO2. In turn, better social functioning was significantly linked with lower plasma BNP and higher peak VO2.

Although cautioning that the study had a limited number of participants and a short follow-up period, the team believes that "goal-oriented sequential combination therapy based on exercise capacity improves HRQoL in patients with PAH."

Tiny RNA Molecule May Treat PAH by Slowing Pulmonary Vascular Remodeling, Study Says - Pulmonary Hypertension News

Posted: 19 Jul 2019 05:00 AM PDT

A tiny RNA molecule known as microRNA-410 (miR-410) was seen to slow the proliferation of endothelial cells in the lung and ease pulmonary vascular remodeling in a mouse model of pulmonary arterial hypertension (PAH).

These findings suggest that raising miR-410 levels in the lung may offer a way of treating people with this disease, researchers report.

The study, "MicroRNA410 Inhibits Pulmonary Vascular Remodeling via Regulation of Nicotinamide Phosphoribosyltransferase," was published in the journal Nature Scientific Reports.

Nicotinamide phosphoribosyltransferase (NAMPT) is a protein with proinflammatory activity outside cells and enzymatic activity inside cells. Higher than usual levels of NAMPT in pulmonary artery endothelial cells (PAECs) — which line the interior of blood vessels — are associated with PAH progression and vascular remodeling in the lung. Although it remains unclear exactly how elevated NAMPT levels aggravate PAH, suppressing this enzyme may be a treatment approach.

miRs are increasingly linked to cardiac and vascular diseases, including PAH, in scientific studies.

Researchers at University of Illinois at Chicago, University of Maryland School of Medicine, and Indiana University explored if miRs might help to regulate NAMPT levels, and so modulate the proliferation, migration, and death of PAECs.

The team used computer-based methods to find miRs targeting a specific region of the genetic coding sequence of NAMPT. They found five different miRs, of which miR-410 had the highest probability of being target specific. Prior research has associated this small RNA molecule with cell proliferation and survival.

Laboratory experiments with human PAECs that involved overproducing and suppressing miR-410 confirmed that this particular miR could effectively target NAMPT. Increased levels of miR-410 boosted NAMPT production, while miR-410 inhibition had the opposite effect.

Upon further analysis, the team also found that the presence of vascular endothelial growth factor (VEGF) — known to induce endothelial cell proliferation and drive PAH disease processes — was linked to lower miR-410 levels, and higher RNA and protein levels of NAMPT.

Subsequent analyzes using small molecules that either mimic or suppress miR-410 in PAECs confirmed the previous findings, with NAMPT showing an miR-410 dependent response.

High levels of the miR-410 mimics prevented basal and VEGF-induced proliferation and migration of human PAECs (hPAECs), while elevated levels of miR-410 inhibitors served to boost both processes. The data also revealed that overproduction of miR-410 led to the death of human PAECs in a dose-dependent manner, in contrast with NAMPT that is known to support hPAEC survival.

Exposing mice to low oxygen significantly dropped miR-410 levels in the lung by day seven, but they returned to previous (baseline) levels by days 14 and 28. During these same 28 days of low oxygen, NAMPT behaved in an opposite manner, with an increase followed by a reduction.

Administration of miR-410 mimics to these animals led to significant lessening of the right ventricular systolic pressure, prevented right ventricular hypertrophy (enlargement) and pulmonary vascular remodeling compared to placebo-treated mice. miR-410 mimics also lowered NAMPT levels in the lung while the mice were under low oxygen.

Neither of these effects were seen in mice on normal oxygen levels. But protein levels of NAMPT were lower than usual in lung endothelial cells in both hypoxia and normal oxygen conditions.

"Our results describe a novel role for miR-410 in controlling the proliferation, apoptosis, and migration of hPAECs, and affecting pulmonary vascular remodeling via regulation of NAMPT expression," the researchers wrote. "Overexpression of miR-410 in the pulmonary circulation may have a therapeutic effect in PAH."

However, the team cautioned that studies in samples from patients with PAH and animal models of severe disease are needed to validate these results.

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