Abstract
BackgroundEpicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI), but clinically-translatable transendocardial injection has never been evaluated. We sought to assess the feasibility, safety and efficacy of percutaneous transendocardial injection of heart-derived cells in porcine chronic ischemic cardiomyopathy.Methods and ResultsWe studied a total of 89 minipigs; 63 completed the specified protocols. After NOGA-guided transendocardial injection, we quantified engraftment of escalating doses of allogeneic cardiospheres or cardiosphere-derived cells in minipigs (n = 22) post-MI. Next, a dose-ranging, blinded, randomized, placebo-controlled (“dose optimization”) study of transendocardial injection of the better-engrafting product was performed in infarcted minipigs (n = 16). Finally, the superior product and dose (150 million cardiospheres) were tested in a blinded, randomized, placebo-controlled (“pivotal”) study (n = 22). Contrast-enhanced cardiac MRI revealed that all cardiosphere doses preserved systolic function and attenuated remodeling. The maximum feasible dose (150 million cells) was most effective in reducing scar size, increasing viable myocardium and improving ejection fraction. In the pivotal study, eight weeks post-injection, histopathology demonstrated no excess inflammation, and no myocyte hypertrophy, in treated minipigs versus controls. No alloreactive donor-specific antibodies developed over time. MRI showed reduced scar size, increased viable mass, and attenuation of cardiac dilatation with no effect on ejection fraction in the treated group compared to placebo.ConclusionsDose-optimized injection of allogeneic cardiospheres is safe, decreases scar size, increases viable myocardium, and attenuates cardiac dilatation in porcine chronic ischemic cardiomyopathy. The decreases in scar size, mirrored by increases in viable myocardium, are consistent with therapeutic regeneration.
Highlights
Six million Americans [1] and 23 million people worldwide [2] suffer from chronic heart failure
Cells derived from the heart are attractive; intracoronary infusion of autologous cardiosphere-derived cells (CDCs) [6, 7] or c-kit+ heart-derived cells [8] has shown promising results in patients with post-ischemic ventricular dysfunction [9]
Since increased cellular retention has been associated with greater long-term benefits on cardiac function both in animal models [11, 12, 13] and in humans [14, 15], there is good reason to believe that development of delivery methods with better engraftment might enhance the efficacy of cell therapy, especially in the setting of chronic ischemic cardiomyopathy, where local homing signals are reduced [16]
Summary
Six million Americans [1] and 23 million people worldwide [2] suffer from chronic heart failure. Since increased cellular retention has been associated with greater long-term benefits on cardiac function both in animal models [11, 12, 13] and in humans [14, 15], there is good reason to believe that development of delivery methods with better engraftment might enhance the efficacy of cell therapy, especially in the setting of chronic ischemic cardiomyopathy, where local homing signals are reduced [16]. Intramyocardial injection enables the use of cardiospheres (CSps, three-dimensional spherical clusters of heart-derived cells), which are more efficacious than CDCs when both human products are delivered IM in immunodeficient mice with acute MI [25]. Epicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI), but clinically-translatable transendocardial injection has never been evaluated. The superior product and dose (150 million cardiospheres) were
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
