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Peripheral Muscle Microcirculation and Exercise-induced Blood Flow Distribution in Pulmonary Arterial Hypertension

Primary Purpose

Pulmonary Arterial Hypertension

Status
Completed
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
Submaximal exercises
Sponsored by
Laval University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Pulmonary Arterial Hypertension focused on measuring pulmonary arterial hypertension, skeletal muscle microcirculation, exercise induced blood flow

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • WHO functional class II-III idiopathic PAH patients;
  • WHO functional class II-III PAH-SSc patients with hemodynamic assessment <6 months;
  • sedentary healthy subjects;
  • subjects with limited SSc (without PAH) individually matched for age, gender, height and weight.

Exclusion Criteria:

  1. unstable clinical condition (e.g. recent syncope, WHO functional class IV);
  2. a six-minute walked distance < 300 meters during routine follow-up at the pulmonary hypertension clinic;
  3. left ventricular ejection fraction < 40%;
  4. restrictive (lung fibrosis on CT scan or total lung capacity < 80% of predicted) or obstructive lung disease (FEV1/FVC < 70%);
  5. contraindication for MRI;
  6. body mass index > 30 kg/m2;
  7. known locomotor abnormality.

Sites / Locations

  • Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ)
  • Institut universitaire de cardiologie et de pneumologie de Québec

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Exercise

Arm Description

All patients are subject to this Arm.

Outcomes

Primary Outcome Measures

Muscle microcirculation during submaximal exercise
Thigh muscles overall perfusion and perfusion heterogeneity will be assessed by pulsed arterial spin labeling magnetic resonance imaging (ASL MRI). MRI allows the acquisition of both spatially and temporally localized perfusion measurements within working muscle.
Cardiac output during submaximal exercise
Cardiac MRI. Right after muscles perfusion heterogeneity assessment by MRI (both at rest and following the same exercise protocol), cardiac MRI will be performed with the same 1.5 Tesla MRI.
Muscle sympathetic nerve activity (MSNA)
MSNA will be assessed by microneurography and measures sympathetic nerve traffic directed to muscle circulation. All measurements will be performed under quiet resting supine conditions before non-MRI exercise.
Quadriceps muscle function
Quadriceps muscle function will be assessed using voluntary and non-volitional measurements: Strength of the dominant quadriceps will be evaluated using the Biodex System 4 Pro (Biodex Medical Systems, 20 Ramsay Road, Shirley, New York). Non-volitional dominant quadriceps endurance will be evaluated by magnetic stimulation of the femoral nerve using the Magstim Rapid 2 system (Magstim Co. Ltd., Whitland, Dyfed, Wales, UK) coupled with the Biodex System 4 Pro, allowing measurements of intrinsic muscle endurance properties independent of central drive.
Relationship between in vivo muscle microcirculation and capillarity
Capillarity and angiogenesis-related gene expression in muscle biopsy. In order to explore the relationship between in vivo muscle microcirculation and capillarity, percutaneous biopsy specimens of the vastus lateralis muscle of the nondominant leg will be taken at midthigh as described by Bergström.

Secondary Outcome Measures

Full Information

First Posted
January 25, 2012
Last Updated
March 6, 2018
Sponsor
Laval University
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1. Study Identification

Unique Protocol Identification Number
NCT01520493
Brief Title
Peripheral Muscle Microcirculation and Exercise-induced Blood Flow Distribution in Pulmonary Arterial Hypertension
Official Title
Peripheral Muscle Microcirculation and Exercise-induced Blood Flow Distribution in Pulmonary Arterial Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
March 2018
Overall Recruitment Status
Completed
Study Start Date
June 2011 (undefined)
Primary Completion Date
August 2013 (Actual)
Study Completion Date
March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Laval University

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Pulmonary artery hypertension (PAH) is a rare, severe disease, characterized by a progressive increase in pulmonary vascular resistance ultimately leading to right ventricular (RV) failure and premature death. PAH may be idiopathic (IPAH) or may be also related to various conditions like portal hypertension, HIV infection, left to right shunt, connective tissue diseases such as scleroderma (PAHSSc). Symptoms include dyspnea and fatigue resulting in restricted exercise capacity and poor quality of life. The therapies currently approved have been shown to improve survival. Indeed, recent studies described a three year survival higher than 80%. This improved survival is associated with major challenges for clinicians as most patients remain with limited exercise capacity and poor quality of life. A clear understanding of exercise physiopathology is thus mandatory to specifically address mechanisms responsible for this exercise limitation and eventually improve patients' management. In order to better characterize the exercise physiopathology in PAH, the general objective of this research is to systematically examine blood flow distribution and limb muscles microcirculation at rest and during submaximal exercise in PAH.
Detailed Description
Pulmonary artery hypertension (PAH) is a rare, severe disease, characterized by a progressive increase in pulmonary vascular resistance ultimately leading to right ventricular (RV) failure and premature death. PAH may be idiopathic (IPAH) or may be also related to various conditions like portal hypertension, HIV infection, left to right shunt, connective tissue diseases such as scleroderma (PAHSSc). PAH is defined as a mean pulmonary artery pressure (mPAP) of > 25 mmHg at rest. Symptoms include dyspnea and fatigue resulting in restricted exercise capacity and poor quality of life. The agents currently approved for treatment of PAH are prostanoids (i.v. epoprostenol or s.c./i.v. treprostinil), endothelin-receptor antagonists (ambrisentan, bosentan and sitaxsentan), and phosphodiesterase type 5-inhibitors (sildenafil and tadalafil). These therapies have been shown to improve pulmonary hemodynamics, exercise capacity, quality of life and survival. Indeed, recent studies described a three year survival higher than 80%. This improved survival is associated with major challenges for clinicians as most patients remain with limited exercise capacity and poor quality of life. A clear understanding of exercise physiopathology is thus mandatory to specifically address mechanisms responsible for this exercise limitation and eventually improve patients' management. In order to better characterize the exercise physiopathology in PAH, the general objective of this research is to systematically examine blood flow distribution and limb muscles microcirculation at rest and during submaximal exercise in PAH. The limited link between traditional measures of pulmonary hemodynamic impairment and functional capacity confirms that exercise physiopathology in PAH is not well understood. Although peripheral muscle dysfunction and exercise intolerance are certainly multifactorial in origin and are unlikely to be explained by a single mechanism, an altered skeletal muscle microcirculation could represent a unifying mechanism to explain similarities in skeletal muscle dysfunction and exercise intolerance in PAH. The investigators plan to use a multimodality approach to provide comprehensive information regarding skeletal muscle perfusion in PAH. For example, the investigators will be able to know if there is some relationship between muscle perfusion heterogeneity (arterial spin labeling MRI) and microvascular oxygenation or muscle oxygen consumption (NIRS). Muscle oxygen delivery could also be influenced by cardiac function or hypoxemia. These methods should thus be viewed as complimentary and will help to separate differences in cardiac function, quadriceps global perfusion, perfusion heterogeneity and oxygenation and their consequences on skeletal muscle function and exercise tolerance in PAH versus controls.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension
Keywords
pulmonary arterial hypertension, skeletal muscle microcirculation, exercise induced blood flow

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Exercise
Arm Type
Experimental
Arm Description
All patients are subject to this Arm.
Intervention Type
Other
Intervention Name(s)
Submaximal exercises
Intervention Description
Consists of a 3-min unloaded exercise, followed by a progressive RAMP protocol (10 watts/min) up to 70% of peak workload followed by 3 min. of cycling at constant workload (70% peak workload) (total exercise duration of 25 min.).
Primary Outcome Measure Information:
Title
Muscle microcirculation during submaximal exercise
Description
Thigh muscles overall perfusion and perfusion heterogeneity will be assessed by pulsed arterial spin labeling magnetic resonance imaging (ASL MRI). MRI allows the acquisition of both spatially and temporally localized perfusion measurements within working muscle.
Time Frame
day 3
Title
Cardiac output during submaximal exercise
Description
Cardiac MRI. Right after muscles perfusion heterogeneity assessment by MRI (both at rest and following the same exercise protocol), cardiac MRI will be performed with the same 1.5 Tesla MRI.
Time Frame
day 3
Title
Muscle sympathetic nerve activity (MSNA)
Description
MSNA will be assessed by microneurography and measures sympathetic nerve traffic directed to muscle circulation. All measurements will be performed under quiet resting supine conditions before non-MRI exercise.
Time Frame
day 2
Title
Quadriceps muscle function
Description
Quadriceps muscle function will be assessed using voluntary and non-volitional measurements: Strength of the dominant quadriceps will be evaluated using the Biodex System 4 Pro (Biodex Medical Systems, 20 Ramsay Road, Shirley, New York). Non-volitional dominant quadriceps endurance will be evaluated by magnetic stimulation of the femoral nerve using the Magstim Rapid 2 system (Magstim Co. Ltd., Whitland, Dyfed, Wales, UK) coupled with the Biodex System 4 Pro, allowing measurements of intrinsic muscle endurance properties independent of central drive.
Time Frame
day 2
Title
Relationship between in vivo muscle microcirculation and capillarity
Description
Capillarity and angiogenesis-related gene expression in muscle biopsy. In order to explore the relationship between in vivo muscle microcirculation and capillarity, percutaneous biopsy specimens of the vastus lateralis muscle of the nondominant leg will be taken at midthigh as described by Bergström.
Time Frame
day 1

10. Eligibility

Sex
All
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: WHO functional class II-III idiopathic PAH patients; WHO functional class II-III PAH-SSc patients with hemodynamic assessment <6 months; sedentary healthy subjects; subjects with limited SSc (without PAH) individually matched for age, gender, height and weight. Exclusion Criteria: unstable clinical condition (e.g. recent syncope, WHO functional class IV); a six-minute walked distance < 300 meters during routine follow-up at the pulmonary hypertension clinic; left ventricular ejection fraction < 40%; restrictive (lung fibrosis on CT scan or total lung capacity < 80% of predicted) or obstructive lung disease (FEV1/FVC < 70%); contraindication for MRI; body mass index > 30 kg/m2; known locomotor abnormality.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Steeve Provencher, MD, MSc
Organizational Affiliation
Fondation IUCPQ
Official's Role
Principal Investigator
Facility Information:
Facility Name
Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ)
City
Québec
ZIP/Postal Code
G1V 4G5
Country
Canada
Facility Name
Institut universitaire de cardiologie et de pneumologie de Québec
City
Québec
ZIP/Postal Code
G1V 4G5
Country
Canada

12. IPD Sharing Statement

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Peripheral Muscle Microcirculation and Exercise-induced Blood Flow Distribution in Pulmonary Arterial Hypertension

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