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ENerGetIcs in hypertrophic cardiomyopathy: traNslation between MRI, PET and cardiac myofilament function (ENGINE
A Güçlü1, T Germans, E R Witjas-Paalberends
1Department of Cardiology, Institute for Cardiovascular Research (ICaR-VU, VU University Medical Center, ZH 5F-13, PO Box 7057, 1007MB, Amsterdam, the Netherlands, a.guclu@vumc.nl.
Insights
This study investigates how heart muscle energy metabolism is altered in hypertrophic cardiomyopathy (HCM). Researchers aim to understand if these energy disturbances worsen disease progression and if surgery can restore cardiac energetics in patients.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Hypertrophic cardiomyopathy (HCM) is an inherited heart condition causing left ventricular hypertrophy.
- Current treatments for HCM lack the ability to reverse cardiac dysfunction or hypertrophy.
- Sarcomere mutations in HCM are thought to increase the heart's energy demands, leading to dysfunction.
Purpose of the Study:
- To investigate the role of myocardial energy metabolism disturbances in HCM progression.
- To determine if sarcomere mutations directly increase ATP consumption in human myocardium.
- To assess the impact of surgery on cardiac energetics in HCM patients.
Main Methods:
- Positron emission tomography (PET) with acetate and cardiovascular magnetic resonance imaging (CMR) in hypertrophic obstructive cardiomyopathy (HOCM) and aortic valve stenosis (AVS) patients.
- In-vitro analysis of sarcomere contraction efficiency from myectomy or septal biopsy tissues.
- Comparison of in-vivo cardiac performance with in-vitro sarcomere function before and after surgical intervention.
Main Results:
- The study will determine if cardiac energetics decline during HCM progression.
- It will identify whether observed changes are due to cardiac remodeling or sarcomere mutations.
- In-vitro studies will clarify if sarcomere mutations elevate ATP consumption in hypertrophied myocardium.
Conclusions:
- This research will elucidate the relationship between cardiac energetics and HCM progression.
- Findings will clarify the contribution of sarcomere mutations versus remodeling to impaired energy metabolism.
- The study will provide insights into the potential for surgical restoration of cardiac energetics.
Introduction:
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease mostly due to mutations in genes encoding sarcomeric proteins. HCM is characterised by asymmetric hypertrophy of the left ventricle (LV) in the absence of another cardiac or systemic disease. At present it lacks specific treatment to prevent or reverse cardiac dysfunction and hypertrophy in mutation carriers and HCM patients. Previous studies have indicated that sarcomere mutations increase energetic costs of cardiac contraction and cause myocardial dysfunction and hypertrophy. By using a translational approach, we aim to determine to what extent disturbances of myocardial energy metabolism underlie disease progression in HCM.
Methods:
Hypertrophic obstructive cardiomyopathy (HOCM) patients and aortic valve stenosis (AVS) patients will undergo a positron emission tomography (PET) with acetate and cardiovascular magnetic resonance imaging (CMR) with tissue tagging before and 4 months after myectomy surgery or aortic valve replacement + septal biopsy. Myectomy tissue or septal biopsy will be used to determine efficiency of sarcomere contraction in-vitro, and results will be compared with in-vivo cardiac performance. Healthy subjects and non-hypertrophic HCM mutation carriers will serve as a control group.
Endpoints:
Our study will reveal whether perturbations in cardiac energetics deteriorate during disease progression in HCM and whether these changes are attributed to cardiac remodelling or the presence of a sarcomere mutation per se. In-vitro studies in hypertrophied cardiac muscle from HOCM and AVS patients will establish whether sarcomere mutations increase ATP consumption of sarcomeres in human myocardium. Our follow-up imaging study in HOCM and AVS patients will reveal whether impaired cardiac energetics are restored by cardiac surgery.
