Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy

Kristine Yee, Konstantinos Malliaras, Hideaki Kanazawa, Eleni Tseliou, Ke Cheng, Daniel J. Luthringer, Chak Sum Ho, Kentaro Takayama, Naoto Minamino, James F. Dawkins, Supurna Chowdhury, Doan Trang Duong, Jeffrey Seinfeld, Ryan C. Middleton, Rohan Dharmakumar, Debiao Li, Linda Marbán, Raj R. Makkar, Eduardo Marbán

Research output: Contribution to journalArticle

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Abstract

Background: Epicardial 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 Results: We 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. Conclusions: Dose-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.

Original languageEnglish
Article numbere113805
JournalPLoS One
Volume9
Issue number12
DOIs
Publication statusPublished - 2014 Dec 2
Externally publishedYes

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cardiomyopathy
myocardium
Cardiomyopathies
Magnetic resonance imaging
Cicatrix
Dilatation
Myocardium
Swine
Miniature Swine
injection
Injections
swine
dosage
placebos
myocardial infarction
Placebos
Antibodies
Myocardial Infarction
heart
cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy. / Yee, Kristine; Malliaras, Konstantinos; Kanazawa, Hideaki; Tseliou, Eleni; Cheng, Ke; Luthringer, Daniel J.; Ho, Chak Sum; Takayama, Kentaro; Minamino, Naoto; Dawkins, James F.; Chowdhury, Supurna; Duong, Doan Trang; Seinfeld, Jeffrey; Middleton, Ryan C.; Dharmakumar, Rohan; Li, Debiao; Marbán, Linda; Makkar, Raj R.; Marbán, Eduardo.

In: PLoS One, Vol. 9, No. 12, e113805, 02.12.2014.

Research output: Contribution to journalArticle

Yee, K, Malliaras, K, Kanazawa, H, Tseliou, E, Cheng, K, Luthringer, DJ, Ho, CS, Takayama, K, Minamino, N, Dawkins, JF, Chowdhury, S, Duong, DT, Seinfeld, J, Middleton, RC, Dharmakumar, R, Li, D, Marbán, L, Makkar, RR & Marbán, E 2014, 'Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy', PLoS One, vol. 9, no. 12, e113805. https://doi.org/10.1371/journal.pone.0113805
Yee, Kristine ; Malliaras, Konstantinos ; Kanazawa, Hideaki ; Tseliou, Eleni ; Cheng, Ke ; Luthringer, Daniel J. ; Ho, Chak Sum ; Takayama, Kentaro ; Minamino, Naoto ; Dawkins, James F. ; Chowdhury, Supurna ; Duong, Doan Trang ; Seinfeld, Jeffrey ; Middleton, Ryan C. ; Dharmakumar, Rohan ; Li, Debiao ; Marbán, Linda ; Makkar, Raj R. ; Marbán, Eduardo. / Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy. In: PLoS One. 2014 ; Vol. 9, No. 12.
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AU - Yee, Kristine

AU - Malliaras, Konstantinos

AU - Kanazawa, Hideaki

AU - Tseliou, Eleni

AU - Cheng, Ke

AU - Luthringer, Daniel J.

AU - Ho, Chak Sum

AU - Takayama, Kentaro

AU - Minamino, Naoto

AU - Dawkins, James F.

AU - Chowdhury, Supurna

AU - Duong, Doan Trang

AU - Seinfeld, Jeffrey

AU - Middleton, Ryan C.

AU - Dharmakumar, Rohan

AU - Li, Debiao

AU - Marbán, Linda

AU - Makkar, Raj R.

AU - Marbán, Eduardo

PY - 2014/12/2

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N2 - Background: Epicardial 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 Results: We 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. Conclusions: Dose-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.

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