Ischemic mitral regurgitation (IMR), a frequent complication of myocardial infarction, is characterized by regurgitation of blood from the left ventricle back into the left atrium. Physical interventions via surgery or less-invasive techniques are the only available therapies for IMR, with valve repair via undersized ring annuloplasty (URA) generally preferred over valve replacement. However, recurrence of IMR after URA occurs frequently and is attributed to continued remodeling of the MV and infarct region of the left ventricle. The mitral valve interstitial cells (MVICs) that maintain the tissue integrity of the MV leaflets are highly mechanosensitive, and altered loading post-URA is thought to lead to aberrant MVIC-directed tissue remodeling. Although studies have investigated aspects of mechanically directed VIC activation and remodeling potential, there remains a substantial disconnect between organ-level biomechanics and cell-level phenomena. Herein, we utilized an extant multiscale computational model of the MV that linked MVIC to organ-level MV biomechanical behaviors to simulate changes in MVIC deformation following URA. A planar biaxial bioreactor system was then used to cyclically stretch explanted MV leaflet tissue, emulating the in vivo changes in loading following URA. This simulation-directed experimental investigation revealed that post-URA deformations resulted in decreased MVIC activation and collagen mass fraction. These results are consistent with the hypothesis that URA failures post-IMR are due, in part, to reduced MVIC-mediated maintenance of the MV leaflet tissue resulting from a reduction in physical stimuli required for leaflet tissue homeostasis. Such information can inform the development of novel URA strategies with improved durability.

Mechanical stress is one of the major aetiological factors underlying soft-tissue remodelling, especially for the mitral valve (MV). It has been hypothesized that altered MV tissue stress states lead to deviations from cellular homeostasis, resulting in subsequent cellular activation and extracellular matrix (ECM) remodelling. However, a quantitative link between alterations in the organ-level in vivo state and in vitro-based mechanobiology studies has yet to be made. We thus developed an integrated experimental-computational approach to elucidate MV tissue and interstitial cell responses to varying tissue strain levels. Comprehensive results at different length scales revealed that normal responses are observed only within a defined range of tissue deformations, whereas deformations outside of this range lead to hypo- and hyper-synthetic responses, evidenced by changes in α-smooth muscle actin, type I collagen, and other ECM and cell adhesion molecule regulation. We identified MV interstitial cell deformation as a key player in leaflet tissue homeostatic regulation and, as such, used it as the metric that makes the critical link between in vitro responses to simulated equivalent in vivo behaviour. Results indicated that cell responses have a delimited range of in vivo deformations that maintain a homeostatic response, suggesting that deviations from this range may lead to deleterious tissue remodelling and failure.