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.
Study Type
OBSERVATIONAL
Enrollment
33
Royal Brompton Hospital
London, United Kingdom
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
Time frame: 30 months
Correlation of plasma Growth and differentiation factor 15 levels with muscle strength
Muscle strength will be measured by quadriceps maximal volitional capacity percent predicted
Time frame: 30 months
Change in fibre type in muscle biopsy
Time frame: 30 months
GDF-15 levels in biopsy specimens
Time frame: 30 months
Correlation of plasma Growth and differentiation factor 15 levels with brain natriuretic protein levels
Time frame: 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
Time frame: 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
Time frame: 30 months
Correlation of plasma Growth and differentiation factor 15 levels with exercise tolerance
Exercise tolerance will be measured by six minute walk test
Time frame: 30 months
Correlation of plasma Growth and differentiation factor levels 15 with physical activity levels
Physical activity will be measured by Sensewear armband
Time frame: 30 months
Correlation of plasma Growth and differentiation factor levels 15 with echocardiographic measures of severity of pulmonary hypertension
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 30 months
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