Abstract

Mitral valve degeneration is a key component of the pathophysiology of Marfan syndrome. The biomechanical consequences of aging and genetic mutation in mitral valves are poorly understood because of limited tools to study this in mouse models. Our aim was to determine the global biomechanical and local cell-matrix deformation relationships in the aging and Marfan related Fbn1 mutated murine mitral valve. To conduct this investigation, a novel stretching apparatus and gripping method was implemented to directly quantify both global tissue biomechanics and local cellular deformation and matrix fiber realignment in murine mitral valves. Excised mitral valve leaflets from wild-type and Fbn1 mutant mice from 2 weeks to 10 months in age were tested in circumferential orientation under continuous laser optical imaging. Mouse mitral valves stiffen with age, correlating with increases in collagen fraction and matrix fiber alignment. Fbn1 mutation resulted in significantly more compliant valves (modulus 1.34±0.12 vs. 2.51±0.31 MPa, respectively, P<.01) at 4 months, corresponding with an increase in proportion of GAGs and decrease in elastin fraction. Local cellular deformation and fiber alignment change linearly with global tissue stretch, and these slopes become more extreme with aging. In comparison, Fbn1 mutated valves have decoupled cellular deformation and fiber alignment with tissue stretch. Taken together, quantitative understanding of multi-scale murine planar tissue biomechanics is essential for establishing consequences of aging and genetic mutations. Decoupling of local cell-matrix deformation kinematics with global tissue stretch may be an important mechanism of normal and pathological biomechanical remodeling in valves.

Highlights

  • Marfan syndrome (MFS) is an autosomal-dominant systemic disorder of connective tissue, with an estimated prevalence of 1 in 5,000 individuals [1]

  • Despite its significant public health and clinical burden, very little is known about the biomechanical remodeling of mitral valves with age or genetic mutations, which lie at the core of its pathophysiology

  • We were able to visualize a correlation between the effective tissue modulus and slope of circularity index (CI), which suggests that cellular deformation increases with both stretch and tissue stiffness

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Summary

Introduction

Marfan syndrome (MFS) is an autosomal-dominant systemic disorder of connective tissue, with an estimated prevalence of 1 in 5,000 individuals [1]. It is associated with mutations in Fbn, encoding fibrillin-1, the principal component of extracellular microfibrils, leading to severe cardiovascular, ocular, and skeletal defects [2]. Of these consequences, mitral valve disease is one of the leading indications for surgery and causes of death in young children with MFS. Despite its significant public health and clinical burden, very little is known about the biomechanical remodeling of mitral valves with age or genetic mutations, which lie at the core of its pathophysiology

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