Assessment of myocardial function, metabolism, and perFUSION in early and advanced disease stages of Hypertrophic CardioMyopathy: FUSION-HCM

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by
asymmetric hypertrophy of the heart in absence of loading conditions like
hypertension. The genetic mutation underlying HCM sets in motion a cascade of
functional and metabolic changes ultimately leading to disease. The theory of
energy deficiency currently is the leading theory of the pathomechanism of HCM.
Based on inefficient contraction of the heart, heart muscle cells become energy
deficient and cannot regulate their metabolism properly. To find evidence to
support this theory, this study will measure cardiac metabolism in vivo by
measuring which ratio of substrates (free fatty acids/glucose) the heart uses
to generate energy. As the pathomechanism of HCM is thought to be a cascade of
changes, cardiac substrate metabolism and perfusion will be measured in
different stages of disease: no symptoms, mild symptoms, and advanced HCM

In different stages of HCM:
- To measure myocardial fatty acid oxidation, uptake and esterification
- To measure myocardial glucose uptake en oxidation
- To measure myocardial perfusion
- To measure myocardial function
- To measure volume parameters of the heart
- biomarker analysis

Observational with invasive measurements

Participants will have to spend two full days in the hospital and lie still for
long periods in scanners. Intravenous lines will be inserted which can be
painful and unpleasant. Averse reaction of dotarem are rare. The side-effects
of docutamine and adenosine can be unpleasant. A doctor will always be present
to terminate the test if necessary. The radiation exposure is 7,1 mSv, which
falls in category IIb and is associated with low risk. It corresponds with a
maximum risk om 1 in 10.000 and is comparable to the average background
radiation in some parts of the world (Dutch Committe for Radiation Dosimetry, 6
september 2015). Performing this research in this population is justified
because this research will thoroughly examine the sequence of events leading to
HCM and aims to find ways to better predict progression of disease in mutation
carriers and/or find targets for preventative therapy.
This study with capacitated adults will yield a tremendous amount of knowledge
about the sequence of events driving HCM. This study is the first to do
extensive measurements of function and metabolism in HCM in different stages of
disease. The implications of this study involve predictive and prognostic
strategies for HCM which currently do not exist. Additionally, findings of this
study may lead to new therapeutic targets for HCM or verification of
therapeutic strategies that are currently being researched.
For this study it is essential to involve both MYBPC3 and MYH7 mutation
carriers because these two groups form the vast majority of HCM-causing
mutations. The risks can be considered negligible because the VU has much
experience with the procedures performed in this study and specialists
(cardiologists, internists, nuclear radiologists) are involved in all aspects
of the study. All procedures except the 11C-palmitate PET/CT scan are routinely
performed in the VUmc for clinical and/or research purposes.