Details

Autor(en) / Beteiligte

• Eckhouse, Shaina R
• Purcell, Brendan P
• McGarvey, Jeremy R
• Lobb, David
• Logdon, Christina B
• Doviak, Heather
• O'Neill, Jason W
• Shuman, James A
• Novack, Craig P
• Zellars, Kia N
• Pettaway, Sara
• Black, Roy A
• Khakoo, Aarif
• Lee, Taeweon
• Mukherjee, Rupak
• Gorman, Joseph H
• Gorman, Robert C
• Burdick, Jason A
• Spinale, Francis G

Titel

Local hydrogel release of recombinant TIMP-3 attenuates adverse left ventricular remodeling after experimental myocardial infarction

Ist Teil von

• Science translational medicine, 2014-02, Vol.6 (223), p.223ra21

Ort / Verlag

United States

Erscheinungsjahr

2014

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) contributes to the left ventricle (LV) remodeling that occurs after myocardial infarction (MI). However, translation of these observations into a clinically relevant, therapeutic strategy remains to be established. The present study investigated targeted TIMP augmentation through regional injection of a degradable hyaluronic acid hydrogel containing recombinant TIMP-3 (rTIMP-3) in a large animal model. MI was induced in pigs by coronary ligation. Animals were then randomized to receive targeted hydrogel/rTIMP-3, hydrogel alone, or saline injection and followed for 14 days. Instrumented pigs with no MI induction served as referent controls. Multimodal imaging (fluoroscopy/echocardiography/magnetic resonance imaging) revealed that LV ejection fraction was improved, LV dilation was reduced, and MI expansion was attenuated in the animals treated with rTIMP-3 compared to all other controls. A marked reduction in proinflammatory cytokines and increased smooth muscle actin content indicative of myofibroblast proliferation occurred in the MI region with hydrogel/rTIMP-3 injections. These results provide the first proof of concept that regional sustained delivery of an MMP inhibitor can effectively interrupt adverse post-MI remodeling.