• Tomonori Shirasaka, Shigeru Miyagawa, Satsuki Fukushima, Atsuhiro Saito, Motoko Shiozaki, Naomasa Kawaguchi, Nariaki Matsuura, Satoshi Nakatani, Yoshiki Sakai, Takashi Daimon, Yutaka Okita, and Yoshiki Sawa.
• Division of Cardiovascular Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
• J. Thorac. Cardiovasc. Surg.. 2013 Aug 1;146(2):413-21.

ObjectivesCardiac functional deterioration in dilated cardiomyopathy (DCM) is known to be reversed by intramyocardial up-regulation of multiple cardioprotective factors, whereas a prostacyclin analog, ONO1301, has been shown to paracrinally activate interstitial cells to release a variety of protective factors. We here hypothesized that intramyocardial delivery of a slow-releasing form of ONO1301 (ONO1301SR) might activate regional myocardium to up-regulate cardiotherapeutic factors, leading to regional and global functional recovery in DCM.Methods And ResultsONO1301 elevated messenger RNA and protein level of hepatocyte growth factor, vascular endothelial growth factor, and stromal-derived factor-1 of normal human dermal fibroblasts in a dose-dependent manner in vitro. Intramyocardial delivery of ONO1301SR, which is ONO1301 mixed with polylactic and glycolic acid polymer (PLGA), but not that of PLGA only, yielded significant global functional recovery in a canine rapid pacing-induced DCM model, assessed by echocardiography and cardiac catheterization (n = 5 each). Importantly, speckle-tracking echocardiography unveiled significant regional functional recovery in the ONO1301-delivered territory, consistent to significantly increased vascular density, reduced interstitial collagen accumulation, attenuated myocyte hypertrophy, and reversed mitochondrial structure in the corresponding area.ConclusionsIntramyocardial delivery of ONO1301SR, which is a PLGA-coated slow-releasing form of ONO1301, up-regulated multiple cardiotherapeutic factors in the injected territory, leading to region-specific reverse left ventricular remodeling and consequently a global functional recovery in a rapid-pacing-induced canine DCM model, warranting a further preclinical study to optimize this novel drug-delivery system to treat DCM.Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

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