Background-A drug delivery system that constitutively and effectively retains cardioprotective reagents in the targeted myocardium has long been sought to treat acute myocardial infarction. We hypothesized that a scaffold-free induced adipocyte cell-sheet (iACS), transplanted on the surface of the heart, might intramyocardially secrete multiple cardioprotective factors including adiponectin (APN), consequently attenuating functional deterioration after acute myocardial infarction. Methods and Results-Induced ACS were generated from adipose tissue-derived cells of wild-type (WT) mice (C57BL/6J), which secreted abundant APN, hepatocyte growth factor, and vascular endothelial growth factor in vitro.Transplanted iACS secreted APN into the myocardium of APN-knockout (KO) mice at 4 weeks. APN was also detected in the plasma of iACS-transplanted APN-KO mice at 3 months (245Ϯ113 pg/mL). After left anterior descending artery ligation, iACS, generated from either WT (nϭ40) or APN-KO (nϭ40) mice, were grafted onto the surface of the anterior left ventricular wall of WT mice, or only left anterior descending artery ligation was performed (nϭ43). Two days later, inflammation and infarct size were significantly diminished only in the WT-iACS treated mice. One month later, cardiomyocyte diameter and percent fibrosis were smaller, whereas ejection fraction and survival were greater in the WT-iACS treated mice compared with the KO-iACS-treated or nontreated mice. Conclusions-Cardioprotective factors including APN, hepatocyte growth factor, and vascular endothelial growth factor were secreted from iACS. Transplantation of iACS onto the acute myocardial infarction heart attenuated infarct size, inflammation, and left ventricular remodeling, mediated by intramyocardially secreted APN in a constitutive manner. This method might be a novel drug delivery system to treat heart disease. (Circulation. 2011;124[suppl 1]:S10 -S17.)Key Words: acute myocardial infarction Ⅲ adiponectin Ⅲ cell therapy Ⅲ drug delivery system Ⅲ tissue engineering D espite recent progress in medical and surgical treatments for heart failure, acute myocardial infarction (AMI) and the subsequent deterioration of cardiac performance is still a major cause of death, worldwide. An array of cardioprotective reagents have been identified to be effective in ameliorating AMI by administrating into the infarcted myocardium in experimental models. 1 However, these reagents have failed to show consistent therapeutic efficacy in several clinical trials, probably due to poor retention or rapid inactivation of reagents in the injured myocardial tissues. 1 Therefore, a drug delivery system (DDS) that retains cardioprotective reagents in the targeted myocardial area has long been sought.Intramyocardially transplanted autologous stem cells secrete various cardioprotective cytokines and growth factors, enhance angiogenesis, reduce fibrosis, attenuate apoptosis, and suppress myocyte hypertrophy, consequently ameliorating AMI in a paracrine manner. 2,3 However, cell transplantation f...