Laser-supported CD133+ cell therapy in patients with ischemic cardiomyopathy: initial results from a prospective phase I multicenter trial

Abstract

Objectives: This study evaluates the safety, principal feasibility and restoration potential of laser-supported CD133+ intramyocardial cell transplantation in patients with ischemic cardiomyopathy.

Methods: Forty-two patients with severe ischemic cardiomyopathy (left ventricular ejection fraction (LVEF) >15% and <35%) were included in this prospective multicenter phase I trial. They underwent coronary artery bypass grafting (CABG) with subsequent transepicardial low-energy laser treatment and autologous CD133+ cell transplantation, and were followed up for 12 months. To evaluate segmental myocardial contractility as well as perfusion and to identify the areas of scar tissue, cardiac MRI was performed at 6 months and compared to the preoperative baseline. In addition, clinical assessment comprising of CCS scoring, blood and physical examination was performed at 3, 6 and 12 months, respectively.

Results: Intraoperative cell isolation resulted in a mean cell count of 9.7±1.2×106. Laser treatment and subsequent CD133+ cell therapy were successfully and safely carried out in all patients and no procedure-related complications occurred. At 6 months, the LVEF was significantly increased (29.7±1.9% versus 24.6±1.5% with p = 0.004). In addition, freedom from angina was achieved, and quality of life significantly improved after therapy (p<0.0001). Interestingly, an extended area of transmural delayed enhancement (>3 myocardial segments) determined in the preoperative MRI was inversely correlated with a LVEF increase after laser-supported cell therapy (p = 0.024).

Conclusions: This multicenter trial demonstrates that laser-supported CD133+ cell transplantation is safe and feasible in patients with ischemic cardiomyopathy undergoing CABG, and in most cases, it appears to significantly improve the myocardial function. Importantly, our data show that the beneficial effect was significantly related to the extent of transmural delayed enhancement, suggesting that MRI-guided selection of patients is mandatory to ensure the effectiveness of the therapy.

Trial registration: EudraCT 2005-004051-35) Controlled-Trials.com ISRCTN49998633.

Figure 1. CONSORT (Consolidated Standards of Reporting Trials) flow diagram presenting the enrollment, intervention allocation, and data analysis of the study.

Figure 2. Surgical timeline of simultaneous CD133+ cell isolation and CABG with subsequent laser treatment(ELIVE)-supported cell transplantation.

ELIVE, endogenous laser-induced ventricular enhancement.

Figure 3. Quality of life after cell therapy.

At all postoperative time points, the physical limitation score of the Seattle Angina Questionnaire (SAQ) was significantly improved (40.2±1.4 after 3 months, 40.9±1.5 after 6 months, 43.7±1.0 after 12 months, versus 28.4±1.5 preoperatively). Pre, preoperatively. Separated values, outliers included in the statistical analysis. Asterisk, p<0.0001 versus pre.

Figure 4. Preoperative indicators for the improvement of the LVEF.

While the preoperative global LVEF values were not correlated with the postoperative increase of the LVEF (A), we found an inverse correlation of the preoperative amount of transmural delayed enhancement (TDE) with the postoperative increase of the LVEF (B). The association of a preoperatively larger percentaged area of hibernating myocardium with a higher increase of the LVEF was not statistically significant (C).

Figure 5. Transmural delayed enhancement (TDE) and the postoperative increase of the LVEF.

TDE in more than three myocardial segments (at screening MRI) resulted in significantly less increase of the LVEF after 6 months, as compared to patients with three or less affected segments (1.0±1.4 versus 10.0±4.3, p = 0.042).