Clinical trial NCT01520493: 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
Overall status: COMPLETED
Phase: NA
Conditions: Pulmonary Arterial Hypertension
Keywords: pulmonary arterial hypertension
skeletal muscle microcirculation
exercise induced blood flow
Lead sponsor: Laval University
Sponsor class: OTHER
First posted: 2012-01-30
Enrollment: 20
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

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.

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:

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.

Primary outcomes:
measure: Muscle microcirculation during submaximal exercise
timeFrame: day 3
measure: Cardiac output during submaximal exercise
timeFrame: day 3
measure: Muscle sympathetic nerve activity (MSNA)
timeFrame: day 2
measure: Quadriceps muscle function
timeFrame: day 2
measure: Relationship between in vivo muscle microcirculation and capillarity
timeFrame: day 1
Secondary outcomes:
Other outcomes:
Locations:
city: Québec
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ)
city: Québec
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec
Study officials:
affiliation: Fondation IUCPQ
name: Steeve Provencher, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: