None listed
Conditions
Brief summary
HCM is the most common cardiovascular genetic disorder and can cause significant morbidity and mortality, including the most serious complications of heart failure and sudden death. At present, there are no proven pharmacological therapies that either prevent or cause regression of clinical features. This is largely due to a lack of knowledge in our understanding of the molecular and functional consequences of the disease-causing gene mutations leading to the clinical disease. The proposed study will aim to test whether cardiac energetic compromise is a central pathophysiological mechanism in HCM. We will investigate potentially beneficial treatments based on our hypothesis, by trialling the use of metformin in an HCM group. If the results from this ‘proof of concept study’ are confirmatory, it could pave the way for larger multi-centre randomised studies (with longer duration of treatment) with either metformin or facilitators of fatty acid oxidation such as ranolazine. If realised, these treatments could prevent the vicious cycle of cardiac hypertrophy and myocardial dysfunction seen in hypertrophic cardiomyopathy, leading to improved morbidity and mortality. These investigations will establish early phenotype changes in HCM patients and provide insights into potential therapeutic interventions for a condition that currently has little therapeutic evidence base. This therapeutic sub-study is linked to the main study ACTRN12611000479909.
Interventions
From the main study criteria (ACTRN12611000479909), patients with reduced PCR/ATP ratio of < 1.7 will be eligible to participate in the therapeutic metformin sub-study. They will have a baseline 10ml blood sample before having 12 weeks treatment of either metformin 1g orally 3 x daily or placebo orally 3 x daily before crossing over to the other treatment after a 4 week drug wash-out period. At the end of each 12 week treatment phase they will have another 10ml blood sample, cardiac magnetic r
From the main study criteria (ACTRN12611000479909), patients with reduced PCR/ATP ratio of < 1.7 will be eligible to participate in the therapeutic metformin sub-study. They will have a baseline 10ml blood sample before having 12 weeks treatment of either metformin 1g orally 3 x daily or placebo orally 3 x daily before crossing over to the other treatment after a 4 week drug wash-out period. At the end of each 12 week treatment phase they will have another 10ml blood sample, cardiac magnetic resonance imaging with gadolinium contrast (0.025mmol/kg body weight), cardiac magnetic resonance spectroscopy with adenosine intravenously (140mcg/kg/min) for 3-6 mins and echocardiography.
Sponsors
Professor Joseph Selvanayagam
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Blinded (masking used)
Eligibility
Sex/Gender
All
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Hypertrophic cardiomyopathy patients aged between 18 and 75; phenotype positive (established by echocardiography or cardiac magnetic resonance scan); genotype positive for cardiac myosin binding protein-C gene mutations or cardiac beta-myosin heavy chain gene mutations; patients with reduced baseline PCR/ATP ratio of <1.7
Exclusion criteria
Impaired LV systolic function (EF <50%) as detected on echocardiography or cardiac magnetic resonance scan; history of diabetes mellitus, calculated GFR <30mls/hr; significant derranged liver function defined as liver enzymes of 3 x ULN; current therapy with metformin or amiodarone; absolute contraindication of having MRI scan.
Outcome results
None listed