Home-based Exercise Training in Patients With Pulmonary Arterial Hypertension: Effect on Skeletal Muscular Function and Metabolism

Pulmonary Arterial Hypertension has gone from a disease that causes rapid death to a more chronic condition. Yet, improved survival is associated with major challenges for clinicians as most patients remain with poor quality of life and limited exercise capacity. The effects of exercise training on exercise capacity have been largely evaluated and showed an improvement in 6-minutes walking distance (6MWD), peak V'O2. It is also known that exercise program improves quality of life. Maximal volitional and nonvolitional strength of the quadriceps are reduced in patients with Pulmonary Arterial Hypertension and correlated to exercise capacity. Moreover, on the cellular level, alterations are observed in both the respiratory as well as the peripheral muscles. Muscle fiber size has been reported to be decreased in some studies or conversely unaltered in human and animal models. Reduction in type I fibers and a more anaerobic energy metabolism has also been reported, but not in all studies. Likewise, a loss in capillary density in quadriceps of patients with Pulmonary Arterial Hypertension and rats has been reported, but could not be confirmed in other studies. While the impact of exercise training on clinical outcomes such as exercise capacity or quality of life is well known, this data highlight the fact that the underlying causes of peripheral muscle weakness as well as the mechanisms underlying the clinical improvements observed with exercise programs are not completely understood. Improvement of muscle cell metabolism in part via the enhancement of oxidative cellular metabolism and decrease in intracellular lipid accumulation may play a role in improving muscle function and exercise capacity.

In this study, we intend to evaluate the impact of a 12 weeks home-based rehabilitation program on peripheral muscle function and metabolism, focusing on lipid infiltration, oxidative metabolism and epigenetic factors that can be involved in metabolic syndrome, in patients with Pulmonary Arterial Hypertension.

Study Overview

• Status: Unknown
• Conditions: Pulmonary Arterial Hypertension; Exercise Training; Exercise Capacity; Muscle Function; Home-based Rehabilitation; Muscle Metabolism; Lipid Infiltration; Oxidative Metabolism
• Intervention / Treatment: Behavioral: Home-based rehabilitation

Detailed Description

The 12 weeks home-based rehabilitation program is detailed as follows:

• 1st sessions at the hospital, in the presence of a physiotherapist/kinesiologist
• 3 weeks of supervised home-based rehabilitation (using a telemonitoring system) 3 times a weeks
• 9 weeks of unsupervised home-based rehabilitation (one phone call a week)

Patients will be evaluated at baseline and at endpoint (12 weeks)

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Québec, Canada, QC G1V 4G5
    • University Institute of Cardiology and Respirology of Quebec

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men or women > 18 years old
• Pulmonary Arterial Hypertension group 1: idiopathic, genetics, drug or toxin-induced, associated with connective tissue, HIV, portal hypertension, congenital heart disease.
• Diagnosis performed by right heart catheterization with Pulmonary Arterial Pressure⩾ 20 mmHg, pulmonary artery occlusion pressure <15 and pulmonary vascular resistance >3 Wood units
• New York Heart Association II or III and a 6-Minute Walk Test < 500m
• Patient stable without therapeutic modification within the last 3 months
• Patient having wireless internet at home
• Consciously informed and written by the patient

Exclusion Criteria:

• Syncope within the last 6 month
• Metabolic comorbidity (eg Diabetes)
• Musculoskeletal impairment that does not allow physical exercise
• Patient unable or with contraindications to perform a cardio pulmonary exercise testing
• Patient with pulmonary veno-occlusive disease
• Presence of a permanent pacemaker or other contraindication to MRI
• Pregnant or breastfeeding woman
• Age <18 years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Patients with Pulmonary Arterial Hypertension; 12 weeks home-based rehabilitation	Behavioral: Home-based rehabilitation; 1 supervised exercise session at the hospital; 3 weeks of supervised home-based exercise training (3x/week); 9 weeks of unsupervised home-based exercise training (3x/week)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Epigenetic factors influencing muscle metabolism	Transcriptome analysis using RNA-seq	Changes between baseline and 12 weeks of exercise rehabilitation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intramyocellular lipid accumulation	H-magnetic resonance spectroscopy and Oil red O technique	Changes between baseline and 12 weeks of exercise rehabilitation
Muscular mitochondrial phosphorylation (ATP synthesis)	phosphorus-31 Magnetic resonance spectroscopy saturation transfer	Changes between baseline and 12 weeks of exercise rehabilitation
Proportion of muscle fiber types	Ethanol modified technique	Changes between baseline and 12 weeks of exercise rehabilitation
HbA1c	Serum HbA1c	Changes between baseline and 12 weeks of exercise rehabilitation
Insulin	Serum Insulin	Changes between baseline and 12 weeks of exercise rehabilitation
Glucose	Serum glucose	Changes between baseline and 12 weeks of exercise rehabilitation
Apolipoprotein A1	Serum Apolipoprotein A1	Changes between baseline and 12 weeks of exercise rehabilitation
Adiponectin	Serum Adiponectin	Changes between baseline and 12 weeks of exercise rehabilitation
Leptin	Serum leptin	Changes between baseline and 12 weeks of exercise rehabilitation
Volitional strength quadriceps	Maximal Voluntary force using isometric force meter	Changes between baseline and 12 weeks of exercise rehabilitation
Non-volitional strength of the quadriceps	Maximal non-Voluntary force using isometric force meter and magnetic stimulation of the femoral neve	Changes between baseline and 12 weeks of exercise rehabilitation
Maximal exercise capacity	Cardio-pulmonary exercise testing on a cycloergometer	Changes between baseline and 12 weeks of exercise rehabilitation
Functional Exercise capacity	6-MWD	Changes between baseline and 12 weeks of exercise rehabilitation
Quality of life (QOL)	Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire. The CAMPHOR questionnaire contains 65 items in total, 25 relating to symptoms, 15 relating to activities, and 25 relating to QoL. It is negatively weighted; a higher score indicates worse QoL and greater functional limitation. Symptom and QoL items are both scored out of 25: "yes/true" scores 1 and "no/not true" scores 0. Activity items have three possible responses (score 0-2), giving a score out of 30. Each CAMPHOR assessment takes an average of 10 min	Changes between baseline and 12 weeks of exercise rehabilitation

Collaborators and Investigators

• Sponsor: Laval University

Publications and helpful links

General Publications

• Grunig E, Lichtblau M, Ehlken N, Ghofrani HA, Reichenberger F, Staehler G, Halank M, Fischer C, Seyfarth HJ, Klose H, Meyer A, Sorichter S, Wilkens H, Rosenkranz S, Opitz C, Leuchte H, Karger G, Speich R, Nagel C. Safety and efficacy of exercise training in various forms of pulmonary hypertension. Eur Respir J. 2012 Jul;40(1):84-92. doi: 10.1183/09031936.00123711. Epub 2012 Feb 9.
• Ehlken N, Lichtblau M, Klose H, Weidenhammer J, Fischer C, Nechwatal R, Uiker S, Halank M, Olsson K, Seeger W, Gall H, Rosenkranz S, Wilkens H, Mertens D, Seyfarth HJ, Opitz C, Ulrich S, Egenlauf B, Grunig E. Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial. Eur Heart J. 2016 Jan 1;37(1):35-44. doi: 10.1093/eurheartj/ehv337. Epub 2015 Jul 31.
• Grunig E, Eichstaedt C, Barbera JA, Benjamin N, Blanco I, Bossone E, Cittadini A, Coghlan G, Corris P, D'Alto M, D'Andrea A, Delcroix M, de Man F, Gaine S, Ghio S, Gibbs S, Gumbiene L, Howard LS, Johnson M, Jureviciene E, Kiely DG, Kovacs G, MacKenzie A, Marra AM, McCaffrey N, McCaughey P, Naeije R, Olschewski H, Pepke-Zaba J, Reis A, Santos M, Saxer S, Tulloh RM, Ulrich S, Vonk Noordegraaf A, Peacock AJ. ERS statement on exercise training and rehabilitation in patients with severe chronic pulmonary hypertension. Eur Respir J. 2019 Feb 28;53(2):1800332. doi: 10.1183/13993003.00332-2018. Print 2019 Feb.
• Potus F, Malenfant S, Graydon C, Mainguy V, Tremblay E, Breuils-Bonnet S, Ribeiro F, Porlier A, Maltais F, Bonnet S, Provencher S. Impaired angiogenesis and peripheral muscle microcirculation loss contribute to exercise intolerance in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2014 Aug 1;190(3):318-28. doi: 10.1164/rccm.201402-0383OC.
• Malenfant S, Brassard P, Paquette M, Le Blanc O, Chouinard A, Nadeau V, Allan PD, Tzeng YC, Simard S, Bonnet S, Provencher S. Compromised Cerebrovascular Regulation and Cerebral Oxygenation in Pulmonary Arterial Hypertension. J Am Heart Assoc. 2017 Oct 12;6(10):e006126. doi: 10.1161/JAHA.117.006126.
• Malenfant S, Potus F, Fournier F, Breuils-Bonnet S, Pflieger A, Bourassa S, Tremblay E, Nehme B, Droit A, Bonnet S, Provencher S. Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension. J Mol Med (Berl). 2015 May;93(5):573-84. doi: 10.1007/s00109-014-1244-0. Epub 2014 Dec 30.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): March 1, 2020
• Primary Completion (ANTICIPATED): March 1, 2021
• Study Completion (ANTICIPATED): March 1, 2021

Study Registration Dates

• First Submitted: January 22, 2020
• First Submitted That Met QC Criteria: January 22, 2020
• First Posted (ACTUAL): January 27, 2020

Study Record Updates

• Last Update Posted (ACTUAL): January 28, 2020
• Last Update Submitted That Met QC Criteria: January 24, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: HTAP A DOM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No