Abstract
Using a murine model of chronic ischemic cardiomyopathy caused by an old myocardial infarction (MI), we have previously found that three doses of 1 × 106 c-kit positive cardiac cells (CPCs) are more effective than a single dose of 1 × 106 cells. The goal of this study was to determine whether the beneficial effects of three doses of CPCs (1 × 106 cells each) can be fully replicated by a single combined dose of 3 × 106 CPCs. Mice underwent a 60-min coronary occlusion; after 90 days of reperfusion, they received three echo-guided intraventricular infusions at 5-week intervals: (1) vehicle × 3; (2) one combined dose of CPCs (3 × 106) and vehicle × 2; or (3) three doses of CPCs (1 × 106 each). In the combined-dose group, left ventricular ejection fraction (LVEF) improved after the 1st CPC infusion, but not after the 2nd and 3rd (vehicle) infusions. In contrast, in the multiple-dose group, LVEF increased after each CPC infusion; at the final echo, LVEF averaged 35.2 ± 0.6% (p < 0.001 vs. the vehicle group, 27.3 ± 0.2%). At the end of the study, the total cumulative change in EF from pretreatment values was numerically greater in the multiple-dose group (6.6 ± 0.6%) than in the combined-dose group (4.8 ± 0.8%), although the difference was not statistically significant (p = 0.08). Hemodynamic studies showed that several parameters of LV function in the multiple-dose group were numerically greater than in the combined-dose group (p = 0.08 for the difference in LVEF). Compared with vehicle, cardiomyocyte cross-sectional area was reduced only in the multiple-dose group (−32.7%, 182.6 ± 15.1 µm2 vs. 271.5 ± 27.2 µm2, p < 0.05, in the risk region and −28.5%, 148.5 ± 12.1 µm2 vs. 207.6 ± 20.5 µm2, p < 0.05, in the noninfarcted region). LV weight/body weight ratio and LV weight/tibia length ratios were significantly reduced in both cell treated groups vs. the vehicle group, indicating the attenuation of LV hypertrophy; however, the lung weight/body weight ratio was significantly reduced only in the multiple-dose group, suggesting decreased pulmonary congestion. Taken together, these results indicate that in mice with chronic ischemic cardiomyopathy, the beneficial effects of three doses of CPCs on LV function and hypertrophy cannot be fully replicated with a single dose, notwithstanding the fact that the total number of cells delivered with one or three doses is the same. Thus, it is the multiplicity of doses, and not the total number of cells, that accounts for the superiority of the repeated-dose paradigm. This study supports the idea that the efficacy of cell therapy in heart failure can be augmented by repeated administrations.
Highlights
Cell therapy is a promising approach to heart failure, both in experimental animals and in humans [1]
Using models of chronic ischemic cardiomyopathy, we found that three repeated doses of c-kit-positive cardiac cells (CPCs) in mice [7] and rats [8,9] and cardiac mesenchymal cells (CMCs) in mice [5] improve left ventricular (LV) function to a greater extent than a single dose; the fact that similar outcomes were observed with two different cell types and in two different species suggests that the greater efficacy of multiple doses is not dependent on species or cell type
This study is a follow-up to our previous investigation, in which we found that administration of three doses of CPCs (1 × 106 cells/dose) at 5-week intervals had significantly greater beneficial effects than a single injection of 1 × 106 CPCs [7]
Summary
Cell therapy is a promising approach to heart failure, both in experimental animals and in humans [1]. Using models of chronic ischemic cardiomyopathy (old myocardial infarction [MI]), we found that three repeated doses of c-kit-positive cardiac cells (CPCs) in mice [7] and rats [8,9] and cardiac mesenchymal cells (CMCs) in mice [5] improve left ventricular (LV) function to a greater extent than a single dose; the fact that similar outcomes were observed with two different cell types and in two different species suggests that the greater efficacy of multiple doses is not dependent on species or cell type Based on these observations and other studies, the concept is emerging that the efficacy of cell therapy in heart failure can be enhanced by the use of multiple doses [2,3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
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 call
