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

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.

Cardiomyopathy in Genetic Aortic Diseases

“…In addition, the role of fibrillin-1 in providing elasticity to the myocardium is also observed in the fbn1 mgR/mgR Marfan mouse model. A decrease in passive filling properties of the left ventricle in this model suggests an impaired elastic recoil of the left ventricle (68). It is assumed that the underlying abnormality in the FBN1 gene in MFS results in an impaired signaling function of fibrillin microfibrils in the ECM and that mechanical factors such as volume-or pressure overload are not correctly compensated which in turn leads to myocardial dysfunction.…”

An Overview of Investigational and Experimental Drug Treatment Strategies for Marfan Syndrome

“… 21 On the other hand, recent results from our group did not show any dilated cardiomyopathy in these mice, but instead identified spontaneous right ventricular pseudoaneurysms as a new previously unreported cardiac manifestation in the Fbn1 mgR/mgR model. 22 The discrepancy between both studies can likely be explained by a difference in genetic background, which has previously been shown to strongly affect the clinical phenotype in a related MFS mouse model. 23 Table 1 provides an overview of the genetic backgrounds in which the MFS mouse models were originally generated when their cardiovascular phenotypes were first described.…”

“… 12 , 21 , 39 , 40 Disruption of cardiac microfibril structures due to fibrillin-1 deficiency has been suggested to lead to a loss of myocardial compaction, which is believed to affect myocardial signal conduction, leading to the development of arrhythmias. 22 , 41–43…”

“… 12 , 21 Interestingly, Fbn1 mgR/mgR mice backcrossed on a pure C57BL/6 genetic background, which did not show a similar cardiac phenotype as in the previous study, also did not show ERK1/2 activation. 22 …”

“…Interestingly, MFS mice with a C57BL/6 genetic background seem less susceptible to TAA, AAA and ventricular dysfunction compared to 129 mice. [22][23][24][25][26] These observations underscore the importance of taking into account the effects of potential genetic modifiers, which might complicate the interpretation of results obtained in specific inbred mouse strains.…”