Ischemic mitral regurgitation is a common complication in the valve following myocardial infarction that increases the rates of heart failure and mortality. Mitral regurgitation is characterized by back-flow through the valve during the cardiac cycle and is caused by a geometric mismatch between the dilated left ventricle and the mitral valve in the post-infarct heart. Effective treatment for ischemic mitral regurgitation remais elusive. Recent reports demonstrate that the valve, previously assumed to be static, can undergo dynamic adaptation to geometric changes in the heart. Excessive endothelial-to-mesenchymal transition (EMT) and transforming growth factor- (TGF-) signaling in the post-infarct heart inhibits this adaptive response during ischemic mitral regurgitation and leads to valve fibrosis. In the proposed research, we will develop a local drug delivery system to target the ischemic mitral valve and release inhibitors of TGF- signaling that have been shown to modulate excess EMT. The local delivery system will be comprised of [a drug-eluting annuloplasty ring that releases therapeutics to the leaflets of the valve (Aim I). Additionally, we will screen for TGF- inhibitors that effectively suppress excessive EMT in valvular endothelial cells (VECs) in vitro (Aim II). The release profile of target candidate therapeutics will be tuned o dampen EMT over the course of 2 months.] Once an appropriate drug delivery formulation is developed, we aim to test the central hypothesis that local TGF- inhibition will mitigate ischemic mitral regurgitation in a large animal model that presents ischemic mitral regurgitation (Aim III). In this manner, a strategy to intervene during ischemic mitral regurgitation is proposed that limits fibrotic remodeling of the valve and coaxes the innate growth capacity of the valve to adapt during mitral regurgitation by modulating excessive EMT and TGF- signaling locally. [The proposed project treats ischemic mitral regurgitation by addressing the underlying biology of the valve and presents broadly enabling technologies that are poised to achieve major improvements in all forms of cardiac valve disease.]

Public Health Relevance

Ischemic mitral regurgitation is a common complication following myocardial infarction that increases rates of heart failure and mortality. This project wll explore a targeted local drug delivery system to treat ischemic mitral regurgitation by inhibiting TGF-? signaling and engaging the natural adaptive ability of the valve. This approach offers promising new avenues for the local treatment of all forms of cardiac valve disease by addressing the underlying biology of disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10A-S (20))
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Meadows, Tawanna
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Massachusetts Institute of Technology
Internal Medicine/Medicine
Schools of Arts and Sciences
United States
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van der Ven, Casper F T; Wu, Pin-Jou; Tibbitt, Mark W et al. (2017) In vitro 3D model and miRNA drug delivery to target calcific aortic valve disease. Clin Sci (Lond) 131:181-195
Tibbitt, Mark W; Dahlman, James E; Langer, Robert (2016) Emerging Frontiers in Drug Delivery. J Am Chem Soc 138:704-17
Tibbitt, Mark W; Rodell, Christopher B; Burdick, Jason A et al. (2015) Progress in material design for biomedical applications. Proc Natl Acad Sci U S A 112:14444-51