Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans

Abstract

Background: Mild intrinsic cardiomyopathy in patients with Marfan syndrome (MFS) has consistently been evidenced by independent research groups. So far, little is known about the long-term evolution and pathophysiology of this finding. Methods: To gain more insights into the pathophysiology of MFS-related cardiomyopathy, we performed in-vivo and ex-vivo studies of 11 Fbn1 C1039G/+ mice and 9 wild-type (WT) littermates. Serial ultrasound findings obtained in mice were correlated to the human phenotype. We therefore reassessed left ventricular (LV) function parameters over a 6-y follow-up period in 19 previously reported MFS patients, in whom we documented mild LV dysfunction. results: Fbn1C1039G/+ mice demonstrated LV contractile dysfunction. Subsequent ex-vivo studies of the myocardium of adult mutant mice revealed upregulation of TGFβ-related pathways and consistent abnormalities of the microfibrillar network, implicating a role for microfibrils in the mechanical properties of the myocardium. Echocardiographic parameters did not indicate clinical significant deterioration of LV function during follow-up in our patient cohort. conclusion: In analogy with what is observed in the majority of MFS patients, the Fbn1 C1039G/+ mouse model demonstrates mild intrinsic LV dysfunction. Both extracellular matrix and molecular alterations are implicated in MFS-related cardiomyopathy. This model may now enable us to study therapeutic interventions on the myocardium in MFS. M arfan syndrome (MFS, GenBank accession nos. L13923)is an autosomal dominant inherited connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1) encoding the extracellular matrix protein fibrillin-1. The clinical diagnosis of MFS relies on the identification of characteristic clinical manifestations, mainly occurring in the cardiovascular, musculoskeletal, and ocular system, as summarized in the ''Revised Ghent Nosology'' , and may be supplemented by the identification of a causal FBN1 mutation (1).Cardiovascular involvement in MFS is characterized by progressive dilatation of the ascending aorta at the level of the sinuses of Valsalva, ensuing a risk for type A aortic dissection or -rupture and aortic valve regurgitation (2). Other established cardiovascular manifestations of MFS include mitral valve prolapse and pulmonary artery dilatation. More recently, several independent studies demonstrated the presence ofmostly subclinical-intrinsic cardiomyopathy (CMP) with both left and right ventricular (LV and RV) systolic and diastolic dysfunction in MFS patients (3,4). The current knowledge of MFS-related CMP is based on cross-sectional studies, but little is known about the long-term evolution and pathophysiology of this finding.To unravel the underlying pathophysiology of MFS-related CMP, the knowledge obtained from the study of other MFS manifestations may at least be partly translated to the cardiac phenotype. Upregulation of TGFβ signaling, with activation of the canonical (SMAD2/3) and noncanonical (predominantly ERK1/2) pathways, i...

Sex, pregnancy and aortic disease in Marfan syndrome

“…This is in accordance with what has been observed in most other MFS mouse models, including Fbn1 mgN/mgN , Fbn1 mgR/mgR , and Fbn1 C1039G/+ mice [24],[37],[38]. The involvement of a large part of the thoracic aorta in MFS mice is different from the common aortic phenotype seen in MFS patients, in whom the aortic dilatation is usually restricted to the level of the sinuses of Valsalva.…”

Aortic and Cardiac Structure and Function Using High-Resolution Echocardiography and Optical Coherence Tomography in a Mouse Model of Marfan Syndrome

“…Since aortic dilation and stiffness also occurred in both 6-and 12-month groups, it is not clear whether the increased LV muscle mass and abnormal diastolic function in our study are due to the abnormal afterload caused by increased aortic stiffness or by abnormal myocardial connective tissue or a combination of both. A recent study also indicated that 14 month old Fbn1 C1039G/+ mice demonstrated mild intrinsic LV dysfunction [60]. Both extracellular matrix and molecular alterations appear to be implicated in MFS-related cardiomyopathy but further studies are required to resolve this controversy.…”

A 1D model of the arterial circulation in mice

“…Mice in particular are a common model in hypothesis-driven cardiovascular research (Treuting et al, 2012) due to their short lifespan, their small size, the similarity of their well-decrypted genome with the human one and, most importantly, the possibility to induce genetic modifications (Pennacchio, 2003). Genetically or pharmacologically altered mouse models have provided insight into (amongst many other cardiovascular applications) abdominal aortic aneurysm (Trachet et al, 2014a,b), stable and unstable atherosclerotic plaque (Van der Donckt et al, 2014;De Wilde et al, 2015), diabetes (Reed and Herold, 2015), hypertrophy (Yamaguchi et al, 2007) and Marfan syndrome (Campens et al, 2015). However, since mice have a much smaller (aortic dimensions are 10x smaller, Tab.…”