Author + information
- Jaco H. Houtgraaf, MD,
- Wijnand K. den Dekker, MD,
- Bas M. van Dalen, MD, PhD,
- Tirza Springeling, MD,
- Renate de Jong, MD,
- Robert J. van Geuns, MD, PhD,
- Marcel L. Geleijnse, MD, PhD,
- Francisco Fernandez-Aviles, MD, PhD,
- Felix Zijlsta, MD, PhD,
- Patrick W. Serruys, MD, PhD and
- Henricus J. Duckers, MD, PhD⁎ ()
- ↵⁎Thoraxcenter Erasmus Medical Center, Room Ee2389A, PO Box 2040, 3000 CA Rotterdam, the Netherlands
To the Editor:
In preclinical animal models of acute myocardial infarction (AMI), administration of freshly isolated adipose tissue–derived regenerative cells (ADRCs) immediately after the AMI improved left ventricular (LV) function and myocardial perfusion (1,2). The predominant working mechanism of ADRC therapy in AMI is believed to be through paracrine release of antiapoptotic, immunomodulatory, and proangiogenic factors. These factors evoke cardiomyocyte salvage and stimulate neoangiogenesis in the infarct border zone and eventually result in reduced infarct scar formation and adverse cardiac remodeling (1–3). ADRCs comprise, among other cells, immune-competent cells, endothelial progenitor cells, and mesenchymal stem cells. The amount of these mesenchymal stem cells in freshly isolated adipose tissue digestates is ∼2,500-fold greater than that of freshly aspirated bone marrow, which makes cell culture unnecessary to generate therapeutically sufficient cells (4). On average, 20 to 40 million cells can be isolated and prepared within 2 h after liposuction from as little as 200 g of lipoaspirate, enabling the treatment of AMI patients within hours after the primary percutaneous coronary intervention (PPCI).
The APOLLO trial is a randomized, double-blind, placebo-controlled, phase I/IIa study (NCT00442806) designed to assess the safety and feasibility of intracoronary infusion of ADRCs in the treatment of patients in the acute phase of a large ST-segment elevation acute myocardial infarction (STEMI). Patients were eligible for enrollment if interventional treatment for their AMI was successful, they history of heart disease, and the area of LV hypo- or akinesia corresponded to the culprit lesion. The residual LV ejection fraction (LVEF) needed to be between 30% and 50% as measured by transthoracic echocardiography after the PPCI. After informed consent, the patients underwent a liposuction procedure of the periumbilical region, after which ADRCs were isolated using the Cytori Celution device (Cytori Therapeutics Inc., San Diego, California). Within 24 h after the PPCI, the ADRCs were infused intracoronarily, while carefully monitoring for coronary flow–related side effects. The main safety endpoints were defined as the change in coronary flow (pre- vs. post-infusion), the occurrence of an major adverse cardiovascular and cerebrovascular event (MACCE) or severe adverse event (SAE), or hospitalization due to congestive heart failure during the 6-month follow-up. Feasibility endpoints were defined as the change in LVEF, infarct size as determined by delayed enhancement-cardiac magnetic resonance imaging, and perfusion defect as assessed by sestamibi-single-photon emission computed tomography (MIBI-SPECT) (visual rest score).
A total of 14 patients presenting with an anterior wall AMI were enrolled in the trial and randomized 3:1 to receive an intracoronary infusion of either 20 million ADRCs (n = 10) or placebo solution (n = 4) in the culprit artery (see Table 1 for baseline demographics). One patient in the treatment group was omitted from analysis due to the inadvertent use of an inappropriate cell strainer, resulting in 9 analyzable patients. The liposuction procedure was well tolerated in all patients, although in 2 patients, a significant bleeding event occurred. After these 2 bleeding events, a protocol amendment that regulated strict control of heparin use after the PPCI and excluded the use of glycoprotein IIb/IIIa inhibitors resulted in no more serious bleeding events in the remaining 10 patients. Intracoronary infusion of, on average, 17.4 ± 4.1 million ADRCs was successful and well tolerated in all patients and did not result in any coronary flow impediment as measured by coronary angiography and coronary flow reserve. One patient in the cell treatment group experienced a target lesion revascularization as opposed to none in the control group (p = NS). SAEs occurred in 2 of 4 patients (50%) in the placebo group and 3 of 9 patients (33%) in the ADRC group (p = NS). Importantly, no unanticipated adverse effects related to the ADRC therapy were reported.
MIBI-SPECT analysis demonstrated a +4% improvement in global LVEF in ADRC-treated patients from 52.1% to 56.1%, whereas the placebo group deteriorated by −1.7% (52.0% to 50.3%), rendering an absolute difference between the treatment groups of +5.7% (p = 0.114). A similar positive trend of improved cardiac function was found by CMR analysis, which demonstrated a +4.6% improvement of global LVEF in the ADRC-treated group from baseline to 6-month follow-up (p = 0.091). The percentage of the left ventricle infarcted was reduced by −52% (31.6 ± 5.3 % to 15.3 ± 2.6% at 6-month follow-up, p = 0.002; Fig. 1A) in the ADRC-treated patients, as opposed to no change in the placebo-treated AMI patients (24.7 ± 9.2 % vs. 24.7 ± 4.1%; p = 0.48 for difference between groups). In addition, in the placebo group, the perfusion defect deteriorated by +1.8% (15.0 ± 4.9% to 16.8 ± 4.3%) compared with a significant improvement of the perfusion defect in ADRC-treated patients from 16.9 ± 2.1% to 10.9 ± 2.4% at 6-month follow-up (change of −6.0%, p = 0.004; Fig. 1B; p = 0.23 for difference between groups).
The main findings of the APOLLO trial at the 6-month clinical and angiographic follow-up time point are 1) liposuction to harvest ADRCs in the acute phase of an AMI is safe and feasible; 2) intracoronary infusion of freshly isolated ADRCs was safe and did not result in an alteration of coronary flow or any indication of microvascular obstruction; 3) no SAEs were related to the ADRC therapy; and 4) ADRC infusion resulted in a trend toward improved cardiac function, accompanied by a significant improvement of the perfusion defect and a 50% reduction of myocardial scar formation. The latter is consistent with findings in preclinical studies and concordant with the presumed proangiogenic, antiapoptotic, and immunomodulatory working mechanism of ADRC therapy.
The ongoing ADVANCE study is a multicenter, prospective, randomized, placebo-controlled phase IIb/III clinical trial that will assess the safety and efficacy of an intracoronary infusion of 2 doses of ADRC in up to 375 patients with an STEMI. This study was initiated in May 2011.
Please note: The APOLLO trial was supported by Cytori Therapeutics Inc. (San Diego, California).
- American College of Cardiology Foundation
- Valina C.,
- Pinkernell K.,
- Song Y.H.,
- et al.
- Madonna R.,
- Geng Y.J.,
- De Caterina R.