Spontaneous Right Ventricular Pseudoaneurysms and Increased Arrhythmogenicity in a Mouse Model of Marfan Syndrome

Felke Steijns,Marine Vanhomwegen,Jana Desloovere,Robrecht Raedt,Lars E Larsen,Patrick Sips,Petra Vermassen,Julie De Backer,Marjolijn Renard,Máté I Tóth

doi:10.3390/ijms21197024

Felke Steijns, Marine Vanhomwegen + Show 8 more

Open Access

https://doi.org/10.3390/ijms21197024

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Abstract

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 Fbn1mgR/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 Fbn1mgR/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 Fbn1mgR/mgR mice compared to wild-type littermates. Taken together, in this paper we document a previously unreported cardiac phenotype in the Fbn1mgR/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.

Highlights

The myocardial extracellular matrix (ECM) is a complex fibrous meshwork in close contact with cardiac myocytes, fibroblasts, leukocytes, and endothelial cells [1], which plays an important role in myocardial structure and function, thereby continuously adapting to local cell signaling
A marked dilatation was observed at all levels of the thoracic aorta in the Fbn1mgR/mgR (MFS) mice compared to wild-type (WT) mice, as a hallmark of the Marfan syndrome (MFS) phenotype (Table 1)
As no difference could be observed in the values of the A wave velocity between the MFS and WT mice, this decrease in E wave peak amplitude resulted in a decreased E/A ratio in the MFS mice (Table 1)

Summary

Introduction

The myocardial extracellular matrix (ECM) is a complex fibrous meshwork in close contact with cardiac myocytes, fibroblasts, leukocytes, and endothelial cells [1], which plays an important role in myocardial structure and function, thereby continuously adapting to local cell signaling. Together with the fibrillar proteins collagen, elastin, and fibronectin, fibrillin-1 is an important component of the myocardial ECM and is believed to be involved in the transmission of forces from the myocardial ECM to the cardiac myocytes, based on its specific spatial arrangement in the myocardial tissue [2,3,4]. Pathogenic FBN1 variants resulting in defective fibrillin-1 cause Marfan syndrome (MFS). In order to explore these MFS-related cardiac manifestations, several studies have already been performed in Fbn1C1039G/+ and Fbn1mgR/mgR MFS mouse models [17]. The Fbn1C1039G/+ mouse model is an antimorphic model resulting from the substitution of a conserved cysteine to a glycine in a calcium-binding EGF-like domain of Fbn. The Fbn1mgR/mgR mouse model, on the other hand, is a hypomorphic model. Homozygous Fbn1mgR/mgR mice show an early-onset, severe MFS phenotype

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