To the Editor:

In a recent review published in Nature Biotechnology, Naumova et al.1 repeat previously articulated concerns2 about the validity of contrast-enhanced magnetic resonance imaging (MRI) in characterizing myocardial regeneration after cell therapy. The authors raise theoretical concerns that cell administration may promote changes in myocardial vasculature (i.e., a decrease in vascular permeability resulting in reduced gadolinium (Gd)-contrast extravasation or an increase in lymphatic drainage leading to accelerated Gd-contrast washout), which would compromise the ability of contrast-enhanced MRI to accurately measure changes in scarred and viable myocardium after cell therapy. In addition, Naumova et al.1 point out (correctly) that MRI cannot distinguish between myocardial hypertrophy and hyperplasia; thus, the increase in viable myocardial mass observed in patients treated with cardiosphere-derived cells (CDCs) could result from hypertrophy of pre-existing cardiomyocytes rather than generation of new myocardium. The concerns are not inconsequential, as they tend to undermine the conclusion that therapeutic regeneration occurred in patients treated with CDCs in the randomized Cardiosphere-derived Autologous Stem Cells to Reverse Ventricular Dysfunction (CADUCEUS) trial3,4.

We have addressed these concerns experimentally5 in work not cited in Naumova et al.1. Using a porcine model of ischemic cardiomyopathy that was designed to mimic the protocol in the CADUCEUS trial, we provided direct histological confirmation of the validity of MRI measurements of scar size, scar mass and viable mass. Areas classified as either scarred or viable by MRI agreed precisely with the quantification derived from corresponding tissue sections. In addition, we demonstrated that CDC administration does not alter Gd-contrast kinetics (thus excluding the theoretical possibility of reduced contrast extravasation or accelerated contrast washout), and these findings are consistent with the observed lack of changes in vascular density or architecture. Finally, histological measurement of myocyte size excluded myocyte hypertrophy as a contributor to the increase in viable myocardium observed after CDC therapy.

In conclusion, we have validated the fidelity of contrast-enhanced MRI to distinguish and accurately quantify scarred and viable myocardium after cell therapy, supporting its utility for assessing dynamic changes in the infarct and monitoring regenerative efficacy of cell-based therapeutic interventions.