Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction

Konstantinos Malliaras, Rachel R. Smith, Hideaki Kanazawa, Kristine Yee, Jeffrey Seinfeld, Eleni Tseliou, James F. Dawkins, Michelle Kreke, Ke Cheng, Daniel Luthringer, Chak Sum Ho, Agnieszka Blusztajn, Ileana Valle, Supurna Chowdhury, Raj R. Makkar, Rohan Dharmakumar, Debiao Li, Linda Marbán, Eduardo Marbán

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Background-Magnetic resonance imaging (MRI) in the CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial revealed that cardiosphere-derived cells (CDCs) decrease scar size and increase viable myocardium after myocardial infarction (MI), but MRI has not been validated as an index of regeneration after cell therapy. We tested the validity of contrast-enhanced MRI in quantifying scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. Methods and Results-Yucatan minipigs underwent induction of MI and 2-3 weeks later were randomized to receive intracoronary infusion of 12.5×106 mismatched allogeneic CDCs or vehicle. Allogeneic CDCs induced mild local mononuclear infiltration but no systemic immunogenicity. MRI revealed that allogeneic CDCs attenuated remodeling, improved global and regional function, decreased scar size, and increased viable myocardium compared with placebo 2 months post-treatment. Extensive histological analysis validated quantitatively the MRI measurements of scar size, scar mass, and viable mass. CDCs neither altered gadolinium contrast myocardial kinetics nor induced changes in vascular density or architecture in viable and scarred myocardium. Histology demonstrated that CDCs lead to cardiomyocyte hyperplasia in the border zone, consistent with the observed stimulation of endogenous regenerative mechanisms (cardiomyocyte cycling, upregulation of endogenous progenitors, angiogenesis). Conclusions-Contrast-enhanced MRI accurately measures scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. MRI represents a useful tool for assessing dynamic changes in the infarct and monitoring regenerative efficacy.

Original languageEnglish
Pages (from-to)2764-2775
Number of pages12
JournalCirculation
Volume128
Issue number25
DOIs
Publication statusPublished - 2013 Dec 24
Externally publishedYes

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Cell- and Tissue-Based Therapy
Swine
Myocardial Infarction
Magnetic Resonance Imaging
Myocardium
Cicatrix
Cardiac Myocytes
Ventricular Dysfunction
Miniature Swine
Gadolinium
Hyperplasia
Blood Vessels
Regeneration
Histology
Up-Regulation
Stem Cells
Placebos

Keywords

  • Adult stem cells
  • Allogeneic transplantation
  • Cell transplantation
  • Magnetic resonance imaging
  • Myocardial infarction
  • Regeneration

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction. / Malliaras, Konstantinos; Smith, Rachel R.; Kanazawa, Hideaki; Yee, Kristine; Seinfeld, Jeffrey; Tseliou, Eleni; Dawkins, James F.; Kreke, Michelle; Cheng, Ke; Luthringer, Daniel; Ho, Chak Sum; Blusztajn, Agnieszka; Valle, Ileana; Chowdhury, Supurna; Makkar, Raj R.; Dharmakumar, Rohan; Li, Debiao; Marbán, Linda; Marbán, Eduardo.

In: Circulation, Vol. 128, No. 25, 24.12.2013, p. 2764-2775.

Research output: Contribution to journalArticle

Malliaras, K, Smith, RR, Kanazawa, H, Yee, K, Seinfeld, J, Tseliou, E, Dawkins, JF, Kreke, M, Cheng, K, Luthringer, D, Ho, CS, Blusztajn, A, Valle, I, Chowdhury, S, Makkar, RR, Dharmakumar, R, Li, D, Marbán, L & Marbán, E 2013, 'Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction', Circulation, vol. 128, no. 25, pp. 2764-2775. https://doi.org/10.1161/CIRCULATIONAHA.113.002863
Malliaras, Konstantinos ; Smith, Rachel R. ; Kanazawa, Hideaki ; Yee, Kristine ; Seinfeld, Jeffrey ; Tseliou, Eleni ; Dawkins, James F. ; Kreke, Michelle ; Cheng, Ke ; Luthringer, Daniel ; Ho, Chak Sum ; Blusztajn, Agnieszka ; Valle, Ileana ; Chowdhury, Supurna ; Makkar, Raj R. ; Dharmakumar, Rohan ; Li, Debiao ; Marbán, Linda ; Marbán, Eduardo. / Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction. In: Circulation. 2013 ; Vol. 128, No. 25. pp. 2764-2775.
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T1 - Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction

AU - Malliaras, Konstantinos

AU - Smith, Rachel R.

AU - Kanazawa, Hideaki

AU - Yee, Kristine

AU - Seinfeld, Jeffrey

AU - Tseliou, Eleni

AU - Dawkins, James F.

AU - Kreke, Michelle

AU - Cheng, Ke

AU - Luthringer, Daniel

AU - Ho, Chak Sum

AU - Blusztajn, Agnieszka

AU - Valle, Ileana

AU - Chowdhury, Supurna

AU - Makkar, Raj R.

AU - Dharmakumar, Rohan

AU - Li, Debiao

AU - Marbán, Linda

AU - Marbán, Eduardo

PY - 2013/12/24

Y1 - 2013/12/24

N2 - Background-Magnetic resonance imaging (MRI) in the CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial revealed that cardiosphere-derived cells (CDCs) decrease scar size and increase viable myocardium after myocardial infarction (MI), but MRI has not been validated as an index of regeneration after cell therapy. We tested the validity of contrast-enhanced MRI in quantifying scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. Methods and Results-Yucatan minipigs underwent induction of MI and 2-3 weeks later were randomized to receive intracoronary infusion of 12.5×106 mismatched allogeneic CDCs or vehicle. Allogeneic CDCs induced mild local mononuclear infiltration but no systemic immunogenicity. MRI revealed that allogeneic CDCs attenuated remodeling, improved global and regional function, decreased scar size, and increased viable myocardium compared with placebo 2 months post-treatment. Extensive histological analysis validated quantitatively the MRI measurements of scar size, scar mass, and viable mass. CDCs neither altered gadolinium contrast myocardial kinetics nor induced changes in vascular density or architecture in viable and scarred myocardium. Histology demonstrated that CDCs lead to cardiomyocyte hyperplasia in the border zone, consistent with the observed stimulation of endogenous regenerative mechanisms (cardiomyocyte cycling, upregulation of endogenous progenitors, angiogenesis). Conclusions-Contrast-enhanced MRI accurately measures scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. MRI represents a useful tool for assessing dynamic changes in the infarct and monitoring regenerative efficacy.

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KW - Adult stem cells

KW - Allogeneic transplantation

KW - Cell transplantation

KW - Magnetic resonance imaging

KW - Myocardial infarction

KW - Regeneration

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