Mechanistic insights in mitral valve prolapse and associated left ventricular remodelling: Barlow*s Disease versus Fibroelastic Deficiency

Mitral valve prolapse (MVP) is a frequent valvular disorder which can be
associated with mitral regurgitation, heart failure, ventricular arrhythmias
and sudden cardiac death. Barlow's Disease (BD) and fibroelastic deficiency
(FED) present the 2 most common MVP subtypes and currently the same assessment
and treatment is recommended for both entities. Interestingly, recent evidence
points to the existence of a concomitant cardiomyopathy in BD, regardless of
mitral regurgitation severity, which could be caused by mutations in
cardiomyopathy genes. Furthermore risk at ventricular arrhythmias and sudden
cardiac death has been observed to be higher in patients with BD. We
hypothesize that mechanisms of left ventricular remodelling in BD include a
larger prolapse volume and underlying genetic substrate, beyond volume overload
related to mitral regurgitation. These will result in more severe left
ventricular remodelling and dysfunction in patients with BD compared to FED.

Primary Objective:
1) Assess different LV loading mechanisms in Barlow's Disease (BD) versus
Fibroelastic deficiency (FED), including transvalvular mitral regurgitant and
prolapse volume, both with echocardiography and cardiac magnetic resonance
imaging.

Secondary Objective(s):
2) Assess the prevalence of titin (and other) genetic variants and its impact
on left ventricular remodelling in BD versus FED.
3) Assess the arrhythmogenic potential of BD versus FED, and its relationship
with the severity of mitral regurgitation, the degree of left ventricular
remodelling and the presence of myocardial fibrosis.

This study is designed to be a multicentre, international prospective cohort
study in which we aim to enrol a total of 200 mitral valve prolapse patients,
100 with Barlow's Disease and 100 with fibroelastic deficiency.
To achieve an adequately powered cohort, patients will be recruited at the
Departments of Cardiology of 2 large volume centres, namely the Antwerp
University Hospital (UZA, Belgium) and the Maastricht University Medical Center
+ (MUMC+, The Netherlands), who already have an ongoing collaboration.

Participation in this study has a very low burden since several of the
investigations are frequently performed in clinical routine, such as
echocardiography, cardiac magnetic resonance imaging and 24h-holter. The
investigations are performed in an ambulatory setting.
* An in-dept 3D-echocardiography has a duration of 20-30 minutes, is
non-invasive and part of the routine cardiac follow-up.
* A cardiac magnetic resonance (CMR) scan has a duration of 30-40 minutes, is
non-invasive and uses no radiation. Exclusion criteria for CMR will be checked
to minimize the risk (e.g. pregnancy, severe chronic kidney disease, devices*).
A potential burden of claustrofobia, venous puncture and admission of a
contrast agent will be mentioned.
* For 24h-holter monitoring, the patient is asked to wear a small monitor which
is connected to chest electrodes for a duration of 24 hours. This is not
painful and has a low patient burden with potentially irritation from skin
electrodes and discomfort.
* Finally, after genetic counseling one blood sample is taken for genetic
testing. The inherent risk of genetic testing includes that certain variants of
unknown significance can be detected, but this risk will be limited since we
will focus on a specific set of cardiac genes. In case a potentially
significant genetic variant is detected, an appointment with a genetic
counselor will be scheduled.
Patients could benefit from this study based on the extensive risk assessment
regarding severity of mitral regurgitation, fibrosis, arrhythmias and genetic
burden. To conclude, participation in this observational study is associated
with a very low burden and very few risks and potential benefits can be
significant.