Mitral Valve Biology in Ischemic Mitral Regurgitation

Valvular heart disease (VHD) is a common and growing public health concern, with age-increasing prevalence and important mortality and morbidity. In patients with coronary heart disease and myocardial infarction (MI) or left ventricular (LV) dysfunction, mitral regurgitation (MR) is frequent and doubles mortality. Despite this, little is known about mitral valve (MV) leaflet tissue biology and its potential adaptation to altered ventricular size and function. Such understanding could lead to new therapies that stimulate endogenous repair pathways, including cellular activation, valve matrix production, and potential recruitment of autologous progenitor cells. The MV leaflets are normally prevented from prolapsing by chordae anchored to the LV walls by papillary muscles (PM). In ischemic MR (IMR), expansion of the LV chamber disturbs this finely balanced system: Systolic closure motion of the tethered MV leaflets is restricted, causing MR. A three-dimensional echocardiographic (3D Echo) technique developed by the sponsoring laboratory showed that MV leaflet area increases in patients with IMR, but often not enough to ensure tight closure. It is unknown whether this MV leaflet area increase is the result of active adaptation with increased cell activation and matrix production, or only passive MV leaflet stretch. It is also unknown whether ischemic environment, the prerequisite for IMR, and local inflammatory cytokines released in LV dysfunction support or limit valve adaptation and repair attempts in a way that could provide a potential target for pharmacologic intervention. We will therefore address the following hypotheses in an experimental model that allows independent and controlled variation of leaflet tethering, ischemic environment, and MR flow: 1) MV tissue and biology adapt actively in IMR in a way that promotes adequate MV closure, including proliferation of activated mesenchymal cells capable of augmenting valve size and secreting matrix components; and 2) Ischemic environment and local inflammatory factors in LV dysfunction influence repair adaptation processes, largely in a limiting manner. These studies will provide experience bridging 3D Echo quantification of MV size and MR with cellular, histologic, and immunohistochemical exploration of mechanism, with leading mentors in all disciplines. The anticipated findings will lead to a deeper understanding of MV tissue biology that can promote the development of new therapeutic strategies for MV disease