miRNA and Myokines in Patients With PAH

Not Applicable

Withdrawn

• Conditions: Pulmonary Arterial Hypertension
• Interventions: Other: Exercise Rehab

• Registration Number: NCT03905083
• Lead Sponsor: University of Pittsburgh

Brief Summary

The overall objective of this study is to fulfill the Pilot study (miRNA and Myokines Acutely-expressed During Exercise) goal to Investigate the excretion of skeletal muscle-derived miRNA and myokines in patients with pulmonary arterial hypertension during acute exercise that are biologically active and modulate skeletal muscle function during exercise.

Pulmonary arterial hypertension (PAH), is characterized by the proliferation of endothelial and smooth muscle cells within the precapillary pulmonary vasculature, if untreated results in increased pulmonary vascular resistance and death. The hallmark perivascular infiltrates in PAH contain inflammatory macrophages and lymphocytes resulting in endothelial dysfunction and involves the dysregulation of distinct inflammatory mechanisms. Idiopathic PAH (iPAH) and scleroderma-associated PAH (SSc-PAH), are related by similar clinical and pathophysiologic features. Patients with PAH experience a central cardiovascular limitation to exercise. Despite effective treatment with pulmonary vasodilators, many resting PAH (rPAH) patients continue to experience exercise intolerance. PAH is increasingly acknowledged as a systemic disease, beyond abnormalities of the pulmonary vasculature. Although other contributions to exercise intolerance in PAH exist, skeletal muscle dysfunction significantly impacts exercise tolerance. The molecular mechanisms behind skeletal muscle dysfunction in PAH remain unclear. Provocative testing with invasive cardiopulmonary exercise testing challenges the cardio-pulmonary-vascular and skeletal muscle systems and elicits a cascade of physiologic events not measurable at rest. Myokines are circulating mediators released from skeletal muscle in an endocrine-like fashion in disease and health influencing many factors but not limited to systemic inflammation, immunity and endothelial function. Myokines have not been well described in PAH. Preliminary data indicate that myokines play important, yet still undescribed, roles in this disease. MicroRNAs (miRNAs) are small non-coding RNA molecules, which negatively regulate gene expression via repressing translation and degrading messenger RNAs through sequence-specific binding. There is a growing literature regarding the biological activity of extracellular miRNAs in PAH and in aerobic exercise. miR-126 has been implicated in skeletal muscle dysfunction in PAH, while miR-133 is skeletal muscle-specific but unlike miR-126 it is not yet implicated in skeletal muscle dysfunction in PAH.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-02-25
• Study First Submitted QC: 2019-04-02
• Study First Posted: 2019-04-05
• Status Verified: 2021-02
• Study Start: 2021-12
• Last Update Submitted: 2022-02-15
• Last Update Posted: 2022-03-03
• Primary Completion: 2023-03-15
• Study Completion: 2023-06-15

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• Patients undergoing a RHC/iCPET procedure at the UPMC Presbyterian Hospital Catheterization Lab.
• 18 years of age or older
• Able to read and understand the informed consent.
• Subjects who have signed the iCPET registry consent.

Exclusion Criteria

• Pregnant women
• people under 18
• Who are unable to read and understand the informed consent.
• Subjects prescribed anticoagulant therapy

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Exercise rehab	Exercise Rehab	Investigators aim to evaluate how exercise training may provide beneficial effects on the skeletal muscle and/or pulmonary vasculature in select subjects with pulmonary arterial hypertension, scleroderma or mixed connective tissue disease or patients with exercise pulmonary arterial hypertension

Primary Outcome Measures

Name	Time	Method
To evaluate the impact of released miRNA/myokines on the skeletal muscle in PAH patients.	At the time of the procedure	We will be able to measure the levels of miRNA by doing RNA sequencing and then To evaluate the impact of released miRNA/myokines on the skeletal muscle in PAH patients.Protein and transcript levels will be confirmed using Western blots and real-time PCR
To evaluate the impact of formal exercise training on the skeletal muscle	At the time of the procedure	Muscle biopsy for miRNA and myokine assessment will be performed for this outcome. Total RNA and protein extracted from quadriceps muscle biopsies will be used to measure RNA and protein expression. We will perform a secretome analysis utilizing the Mass Spectrometry Lab at the University of Pittsburgh for an unbiased assessment of muscle-secreted myokines in our subjects.; RNA sequencing and then Protein and transcript levels will be confirmed using Western blots and real-time PCR
To evaluate the impact of formal exercise training on the pulmonary vasculature system	At the time of the procedure	This will be done by measuring hemodynamics during invasive cardiopulmonary exercise test. We will correlate miRNA and myokines released from the skeletal muscle with measures of oxygen delivery and extraction in the muscle and oxygen consumption - calculated from arterial and pulmonary artery blood gasses and invasive hemodynamics. Oxygen delivery to peripheral tissues is determined by (Q ) ̇x CaO2. Oxygen extraction is Ca-vO2. Oxygen consumption is continuously measured by iCPET as( V) ̇O2. Systemic oxygen extraction ratio is determined by (Ca-vO2)/ CaO2

Trial Locations

Locations (1)

Division of Pulmonary, Allergy and Critical Care Medicine; 🇺🇸 Pittsburgh, Pennsylvania, United States