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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational

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

Brief Summary: 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.

Detailed Summary:
Sponsor: Imperial College London

Current Primary Outcome: Plasma growth and differentiation factor 15 levels in participants with and without muscle wasting [ Time Frame: 30 months ]

Muscle wasting will be defined by quadriceps cross sectional area measured by ultrasound


Original Primary Outcome: Same as current

Current Secondary Outcome:

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


Original Secondary Outcome: Same as current

Information By: Imperial College London

Dates:
Date Received: April 19, 2013
Date Started: October 2013
Date Completion: August 2016
Last Updated: May 9, 2016
Last Verified: February 2016