Transforming Growth Factor Beta Signalling in the Development of Muscle Weakness in Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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Pulmonary arterial hypertension (PAH) is a disease that causes raised blood pressure in blood vessels that pick up oxygen from the lungs. It has a life expectancy similar to some cancers. There is treatment available but there is no cure. We now know that PAH is associated with weakness in the muscles in the legs, which contributes to the symptoms patients' experience. Researchers believe that certain proteins found in high levels in the blood of patients with other chronic diseases can affect muscle function and growth. One of these proteins is called growth differentiating factor (GDF) 8, high levels of which are associated with muscle weakness in chronic obstructive pulmonary disease(COPD) and heart failure (HF). Interestingly there are drugs available which block the actions of GDF-8 on muscle cells which has been shown in animals to result in increased muscle size. A related protein called GDF-15 is found in elevated levels in patients PAH, and is linked to prognosis. Our preliminary data suggests that GDF-15 can also directly influence muscle size in a number of situations. We aim to investigate the role of GDF-15 and related molecules in the development of muscle weakness in patients with PAH. We will do this by measuring certain markers of muscle weakness and taking blood and muscle samples in patients and controls. We will then compare the levels of GDF-15 in these tissues in those with and without muscle wasting. We hope this work will lead to a greater understanding of the role of GDF-15 in the development of muscle weakness in patients with PAH. GDF-15 levels may be important in allowing us to define which patients have muscle weakness. In the future we aim to perform a clinical trial of drugs which block the actions of GDF-15.

Official Title
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Transforming Growth Factor Beta Signalling in the Development of Muscle Weakness in Pulmonary Arterial Hypertension

Conditions
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Muscle Weakness, Pulmonary Arterial Hypertension

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with pulmonary arterial hypertension with New York Heart Association stage II - III disease will be eligible for recruitment in the patient portion of the trial. Interested healthy age matched volunteers will also be recruited. Exclusion Criteria: Patients and volunteers will be excluded if they have significant co-morbidities including other cardiorespiratory disease, metabolic abnormalities including diabetes or thyroid disorders. They will be excluded if they cannot safely exercise and perform a six minute walk test or if they are wheelchair bound.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| PH with wasting<br>This group of patients with idiopathic pulmonary arterial hypertension exhibit quadriceps wasting | |
| PH no wasting<br>This groups of patients with idiopathic pulmonary arterial hypertension exhibit no evidence of muscle wasting | |
| Controls<br>This group of volunteers does not have pulmonary arterial hypertension and would not be expected to have muscle wasting | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma growth and differentiation factor 15 levels in participants with and without muscle wasting | Muscle wasting will be defined by quadriceps cross sectional area measured by ultrasound | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of plasma Growth and differentiation factor 15 levels with muscle strength | Muscle strength will be measured by quadriceps maximal volitional capacity percent predicted | 30 months | 
| Change in fibre type in muscle biopsy |  | 30 months | 
| GDF-15 levels in biopsy specimens |  | 30 months | 
| Correlation of plasma Growth and differentiation factor 15 levels with brain natriuretic protein levels |  | 30 months | 
| Correlation of plasma Growth and differentiation factor 15 levels with fat free mass index | Fat free mass index will be measured by bioelectrical impedence | 30 months | 
| Correlation of plasma Growth and differentiation factor 15 levels with quality of life | Quality of life will be measured by St. George's respiratory questionnaire | 30 months | 
| Correlation of plasma Growth and differentiation factor 15 levels with exercise tolerance | Exercise tolerance will be measured by six minute walk test | 30 months | 
| Correlation of plasma Growth and differentiation factor levels 15 with physical activity levels | Physical activity will be measured by Sensewear armband | 30 months | 
| Correlation of plasma Growth and differentiation factor levels 15 with echocardiographic measures of severity of pulmonary hypertension |  | 30 months | 
| Correlation of GDF-15 levels in biopsy specimens with muscle wasting and weakness | Wasting will be measured by quadriceps cross sectional area and weakness will be defined by quadriceps maximal volitional capacity | 30 months | 
| Determine the contribution of atrophy and autophagy to muscle wasting in PAH | Muscle biopsy specimens will be evaluated using microscopy and real time polymerase chain reaction | 30 months | 
| Determine the contribution of SMAD and non-SMAD signalling pathways to the development of muscle weakness and wasting in PAH | Phosphorylation of SMAD and non-SMAD signalling will be determined by western blot | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Growth and differentiation factor 15, Muscle weakness, Pulmonary arterial hypertension, Transforming growth factor beta