Targeting ischemic mitral valve adaptation

Ischemic mitral regurgitation (IMR) is a frequent complication of myocardial infarction (MI) that doubles mortality and heart failure. In the absence of MI for example, in volume overload due to aortic regurgitation the normal mitral valve (MV) is able to match the dilating left ventricle (LV) by increasing leaflet size, thereby maintaining proper leaflet closure. Post MI, in contrast, MV enlargement is frequently inadequate to match LV remodeling, and the valve is also thick and stiff in a way that limits its ability to close. Current therapeutic strategies based on revascularization and heart failure management typically fail to relieve the restricted leaflet closure imposed by displaced leaflet attachments to the infarcted LV walls. Standard surgical annular ring reduction conveys high operative and late mortality. Recurrent MR is frequent because the fundamental leaflet-ventricular mismatch is not addressed. Recent studies identified molecular pathways that can be targeted introducing the intriguing possibility of valve-specific medical therapy. We will test the central hypothesis that valve- specific medical treatment can modulate MV tissue adaptation toward increased leaflet growth with less fibrosis and therefore less MR. The leaflet stretch imposed by the remodeling LV induces the valve endothelial cells (VECs) to undergo endothelial-to-mesenchymal transformation (EMT), becoming valve interstitial cells (VICs) that migrate into the interstitium to enlarge the leaflets. The VECs therefore serve as an adaptive reservoir for valve growth. Transforming growth factor beta (TGF-ß) augments EMT; VIC migration is promoted by nitric oxide (NO). In the ischemic setting, however, excessive TGF-ß signaling stimulates exuberant EMT and activates the cells to become myofibroblasts that express a-smooth muscle actin; those cells secrete and compact collagen matrix, driving fibrosis. Fibrosis may be augmented by valve infiltration of CD45+ myofibroblasts that appear to derive from circulating fibrocytes. Fibrocytes are beneficial in wound healing but contribute to counterproductive fibrosis in multiple organs. Testing our hypothesis requires examining factors that promote valve growth versus fibrosis in a controlled manner. Model systems of EMT and gel contraction by activated VICs will isolate modulating factors without confounders such as CD45+ cell traffic. While the in vitro environment is sufficient to isolate certain components in the valve adaptation process, the complex clinical scenario with factors influencing MV tissue is better addressed in a large- animal model with a clinical-type inferior MI. It also allows us to study possible drug effects on the migration of blood-borne CD45+ cells. This study can be accomplished due to a unique collaborative group which combines strengths in physiologic modeling, cardiac imaging and the basic science of valve and endothelial signaling. This proposal aims to fill a gap in treatment strategies for IMR and has the potential to generate solutions that can be rapidly translated to clinical practice.