Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 19, Pages -Publisher
MDPI
DOI: 10.3390/ijms21197024
Keywords
marfan syndrome; fibrillin-1; cardiac function; myocardial compaction; ventricular pseudoaneurysm; electrocardiogram; arrhythmia
Funding
- Special Research Fund (BOF) of Ghent University [01M01108]
- Foundation for Cardiac Surgery (VZW Fonds voor Hartchirurgie) [489644]
- Research Foundation Flanders (FWO)
- FWO
- European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant [794365]
- Marie Curie Actions (MSCA) [794365] Funding Source: Marie Curie Actions (MSCA)
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Patients with Marfan syndrome (MFS), a connective tissue disorder caused by pathogenic variants in the gene encoding the extracellular matrix protein fibrillin-1, have an increased prevalence of primary cardiomyopathy, arrhythmias, and sudden cardiac death. We have performed an in-depth in vivo and ex vivo study of the cardiac phenotype of Fbn1(mgR/mgR) mice, an established mouse model of MFS with a severely reduced expression of fibrillin-1. Using ultrasound measurements, we confirmed the presence of aortic dilatation and observed cardiac diastolic dysfunction in male Fbn1(mgR/mgR) mice. Upon post-mortem examination, we discovered that the mutant mice consistently presented myocardial lesions at the level of the right ventricular free wall, which we characterized as spontaneous pseudoaneurysms. Histological investigation demonstrated a decrease in myocardial compaction in the MFS mouse model. Furthermore, continuous 24 h electrocardiographic analysis showed a decreased heart rate variability and an increased prevalence of extrasystolic arrhythmic events in Fbn1(mgR/mgR) mice compared to wild-type littermates. Taken together, in this paper we document a previously unreported cardiac phenotype in the Fbn1(mgR/mgR) MFS mouse model and provide a detailed characterization of the cardiac dysfunction and rhythm disorders which are caused by fibrillin-1 deficiency. These findings highlight the wide spectrum of cardiac manifestations of MFS, which might have implications for patient care.
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