Intracoronary Administration of Cardiac Progenitor Cells Alleviates Left Ventricular Dysfunction in Rats With a 30-Day-Old Infarction

Abstract

Background-Administration of cardiac progenitor cells (CPCs) 4 hours after reperfusion ameliorates left ventricular function in rats with acute myocardial infarction (MI). Clinically, however, this approach is not feasible, because expansion of autologous CPCs after acute MI requires several weeks. Therefore, we sought to determine whether CPCs are beneficial in the more clinically relevant setting of an old MI (scar). Methods and Results-One month after coronary occlusion/reperfusion, rats received an intracoronary infusion of vehicle or enhanced green fluorescent protein-labeled CPCs. Thirty-five days later, CPC-treated rats exhibited more viable myocardium in the risk region, less fibrosis in the noninfarcted region, and improved left ventricular function. Cells that stained positive for enhanced green fluorescent protein that expressed cardiomyocyte, endothelial, and vascular smooth muscle cell markers were observed only in 7 of 17 treated rats and occupied only 2.6% and 1.1% of the risk and noninfarcted regions, respectively. Transplantation of CPCs was associated with increased proliferation and expression of cardiac proteins by endogenous CPCs. Conclusions-Intracoronary administration of CPCs in the setting of an old MI produces beneficial structural and functional effects. Although exogenous CPCs can differentiate into new cardiac cells, this mechanism is not sufficient to explain the benefits, which suggests paracrine effects; among these, the present data identify activation of endogenous CPCs. This is the first report that CPCs are beneficial in the setting of an old MI when given by intracoronary infusion, the most widely applicable therapeutic approach in patients. Furthermore, this is the first evidence that exogenous CPC administration activates endogenous CPCs. These results open the door to new therapeutic applications for the use of autologous CPCs in patients with old MI and chronic ischemic cardiomyopathy. (Circulation. 2010;121:293-305.)Key Words: regeneration Ⅲ progenitor cells Ⅲ myocardial infarction Ⅲ reperfusion Ⅲ stem cells C ell-based therapies have the potential to alleviate left ventricular (LV) dysfunction and remodeling after acute myocardial infarction (MI) in experimental animal models 1 and in humans. 2,3 Among the various cells used, c-kitpositive (c-kit pos ) cardiac progenitor cells (CPCs) are attractive because they normally reside in the heart and presumably are responsible for replenishing the pool of cardiac myocytes and coronary vessels under normal conditions. 4 -6 The practical utility of CPCs is further supported by the fact that these cells can be isolated from small fragments of cardiac tissue and expanded for subsequent autologous administration. 5,6 Clinical Perspective on p 305Transplantation of autologous or syngeneic CPCs has been found to be effective in limiting LV dysfunction and remodeling in rodent models of acute MI, both in the setting of a permanent coronary occlusion 4 -6 and in that of a transient occlusion followed by reperfusion. 7 Clinically, how...

Repeated Administrations of Cardiac Progenitor Cells Are Superior to a Single Administration of an Equivalent Cumulative Dose

“…Myocyte size was assessed by staining myocytes with an anti‐α‐sarcomeric actin antibody and myocyte membranes with FITC‐conjugated wheat germ agglutinin to facilitate identification of individual myocytes 3, 7, 8. A single combined dose significantly reduced myocyte size in both the risk and the noninfarcted region, whereas repeated doses reduced myocyte size only in the risk region (Figure 6).…”

“…The rat model of old MI has been described previously 3, 7. Adult female Fischer 344 rats (age, 4 months; weight 175±2 g) underwent a 2‐hour occlusion of the left anterior descending coronary artery followed by reperfusion.…”

“…Serial echocardiograms were obtained at 5 time points: baseline (3 days before coronary artery occlusion), 30 days after MI (before the first treatment), 35 days after the first treatment (before the second treatment), 35 days after the second treatment (before the third treatment), and 35 days after the third treatment (before euthanasia; Figure 1). The echocardiographic studies were performed as described3, 7, 8, 9, 10 using a Vevo 2100 Imaging System equipped with a 20‐MHz transducer.…”

“…The hemodynamic studies were conducted 35 days after the third treatment, just before euthanasia (Figure 1). The protocol has been described previously 3, 7, 8, 9, 10…”

“…Echocardiographic data were analyzed with 2‐way repeated‐measures ANOVA (time and group) followed by Student t tests with Bonferroni correction for intra‐ and intergroup comparisons, as appropriate. Cardiomyocyte area was analyzed by Kruskal–Wallis 1‐way ANOVA on ranks with the Dunn's test 7. All analyses were conducted with SigmaStat 3.5 (StatCon, Witzenhausen, Germany).…”