Assessment of myocardial function, endothelial function 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 or valve disease. The genetic mutation underlying HCM sets in
motion a cascade of functional and metabolic changes ultimately leading to
disease. In addition to energy deficiency, studies have also shown reduced
cardiac perfusion, diastolic dysfunction, and microvascular dysfunction, even
before the onset of hypertrophy. We propose that mutation-induced energy
deficiency triggers metabolic and mitochondrial changes causing diastolic
dysfunction, and hypoperfusion of the heart before hypertrophy occurs. Whether
these genetic mutation directly causes microvascular remodeling and thereby
microvascular dysfunction or it is a consequence of diastolic dysfunction and
thereby reduced cardiac perfusion, has not been elucidated. The causality and
sequence of these cardiovascular changes need to be defined to develop targeted
preventive therapies.
A comparison will be made between mutation carriers without signs of cardiac
hypertrophy (septal thickness <12 mm), mutation carriers with a mild phenotype
(asymmetric septal thickness >=12 until <15mm) and patients with advanced HCM
(>=15mm). As the thick filament mutations represent the majority of all HCM
cases, we will include 25 individuals with a MYBPC3 mutation or a MYH7 mutation
per disease stage (minimal age 18 years). Imaging studies will also be
performed in healthy control individuals to define the normal (healthy) cardiac
characteristics.
As the pathomechanism of HCM is thought to be a cascade of changes, all
measures of cardiac perfusion, endothelial (dys)function, and cardiac function
will be measured in the different stages of disease as described above.

In different stages of HCM, to measure the:
- Myocardial perfusion
- Myocardial function
- Volume parameters of the heart
- Fibrosis
- Function of the small vessels (endothelial (dys)function)
- Diastolic function and strain of the heart

Observational with invasive measurements.

Participants will have to come to the hospital for two separate days, one day
for 6 hours and the second day for 2 hours. They have to lie still for long
periods in scanners, intravenous lines will be inserted which can be painful
and unpleasant. Adverse reactions to dotarem are rare. The side effects of
adenosine can be unpleasant. There is always a doctor present to terminate the
test if this is considered necessary. The radiation exposure of the PET/CT scan
is 1.8-4.8 mSv, which falls in category llb and is associated with low risk.
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 perfusion of
the heart, and endothelial (dys)function in different stages of HCM. The
implications of this study involve predictvie 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. Because we compare different techniques in this
study, we also gain knowledge about the usage of less
invasive/burdensome/expensive methods to predict the onset of disease. FO rthis
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 risk can
be considered negligible because the Amsterdam UMC has much experience with the
procedures performed in this study and specialists (cardiologists, nuclear
radiologists) are involved in all aspects of the study. All procedures except
the Laser Speckle Contrast Analysis and Oxygenation-Sensitve Cardiac Magnetic
Resonance Imaging (a novel sequence during the MRI scan) are routinely
performed in the Amsterdam UMC for clinical and/or research purposes.