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


RESULTS
Yucatan minipigs underwent induction of MI and 2-3 weeks later were randomized to receive intracoronary infusion of 12.5×10(6) 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.
From Cedars-Sinai Heart Institute, Los Angeles, CA (K.M., R.R.S, H.K., K.Y., J.S., E.T., J.F.D., K.C., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S, M.K., A.B., I.V., L.M.); Gift of Life Michigan, Ann Arbor (C.-S.H.); and Cedars-Sinai Biomedical Imaging Research Institute, Los Angeles, CA (R.D., D.L.).
Konstantinos
K
Malliaras
Rachel R
RR
Smith
Hideaki
H
Kanazawa
Kristine
K
Yee
Jeffrey
J
Seinfeld
Eleni
E
Tseliou
James F
JF
Dawkins
Michelle
M
Kreke
Ke
K
Cheng
Daniel
D
Luthringer
Chak-Sum
CS
Ho
Agnieszka
A
Blusztajn
Ileana
I
Valle
Supurna
S
Chowdhury
Raj R
RR
Makkar
Rohan
R
Dharmakumar
Debiao
D
Li
Linda
L
Marbán
Eduardo
E
Marbán
D000818:Animals; D064987:Cell- and Tissue-Based Therapy; D002921:Cicatrix / Q000473:pathology; D004195:Disease Models, Animal; D005682:Gadolinium; D006321:Heart / Q000503:physiopathology*; D007107:Immune System / Q000503:physiopathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology*; D012038:Regeneration / Q000502:physiology*; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D016896:Treatment Outcome
D005682:Gadolinium
adult stem cells; allogeneic transplantation; cell transplantation; magnetic resonance imaging; myocardial infarction; regeneration