Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial

Abstract

Background: c-kit-positive, lineage-negative cardiac stem cells (CSCs) improve post-infarction left ventricular (LV) dysfunction when administered to animals. We undertook a phase 1 trial (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy [SCIPIO]) of autologous CSCs for the treatment of heart failure resulting from ischaemic heart disease.

Methods: In stage A of the SCIPIO trial, patients with post-infarction LV dysfunction (ejection fraction [EF] ≤40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups. In stage B, patients were randomly assigned to the treatment or control group in a 2:3 ratio by use of a computer-generated block randomisation scheme. 1 million autologous CSCs were administered by intracoronary infusion at a mean of 113 days (SE 4) after surgery; controls were not given any treatment. Although the study was open label, the echocardiographic analyses were masked to group assignment. The primary endpoint was short-term safety of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. This study is registered with ClinicalTrials.gov, number NCT00474461.

Findings: This study is still in progress. 16 patients were assigned to the treatment group and seven to the control group; no CSC-related adverse effects were reported. In 14 CSC-treated patients who were analysed, LVEF increased from 30·3% (SE 1·9) before CSC infusion to 38·5% (2·8) at 4 months after infusion (p=0·001). By contrast, in seven control patients, during the corresponding time interval, LVEF did not change (30·1% [2·4] at 4 months after CABG vs 30·2% [2·5] at 8 months after CABG). Importantly, the salubrious effects of CSCs were even more pronounced at 1 year in eight patients (eg, LVEF increased by 12·3 ejection fraction units [2·1] vs baseline, p=0·0007). In the seven treated patients in whom cardiac MRI could be done, infarct size decreased from 32·6 g (6·3) by 7·8 g (1·7; 24%) at 4 months (p=0·004) and 9·8 g (3·5; 30%) at 1 year (p=0·04).

Interpretation: These initial results in patients are very encouraging. They suggest that intracoronary infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure after myocardial infarction, and warrant further, larger, phase 2 studies.

Funding: University of Louisville Research Foundation and National Institutes of Health.

Conflict of interest statement

Conflicts of Interest. PA is a member of Autologous, LLC. The other authors declare that they have no conflicts of interest.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Trial profile showing a summary of screening, exclusions, and enrollment. Patients were screened at two time points: during the 2 weeks preceding CABG surgery (initial eligibility screening and enrollment), and at 4 ± 1 months after CABG surgery (final enrollment). The trial consisted of two sequential Stages, A (non-randomized) and B (randomized). To assess feasibility and short-term safety of CSC therapy, in Stage A nine consecutive patients were assigned to the treatment arm followed by assignment of four consecutive patients to the control arm. Then, in Stage B, patients were randomized to the treated and control arms in a 2:3 ratio using a block randomization scheme and a block size of five. The Figure summarizes enrollment as of April 1, 2011.

Figure 2

Phenotype of CSCs prior to intracoronary delivery. A, confocal image illustrating the localization of c-kit (green) in CSCs and the FACS analysis of c-kit expression and lineage markers of CSCs for Subject 019. Numerical values are indicated. B, percentage of cells expressing c-kit, lineage markers of cardiac commitment, and the senescence-associated protein p16INK4a. The percentage of viable cells in the final preparation is also illustrated. Yellow bars indicate individual values, red bars indicate means ± SEM.

Figure 3

Growth properties of CSCs prior to intracoronary delivery. A, telomeres in CSC nuclei (red dots) are identified by Q-FISH (left panel, Subject 019) and flow-FISH (central and right panels, Subjects 055 and 056). R cells with long telomeres (48 kbp) and S cells with short telomeres (7 kbp) were used to compute absolute values. In each panel, telomere length is indicated. By flow-FISH, the histograms represent the intensity of PNA probe binding in gated CSCs (red) and control cells (green). B, telomerase activity in CSC lysates from each patient was detected by quantitative PCR. C, population doubling time in CSCs. Yellow bars indicate individual values, red bars indicate means ± SEM.

Figure 4

Echocardiographic analysis at 4 and 12 months after baseline (baseline was 4 ± 1 month after surgical revascularization). A, left ventricular ejection fraction (EF) (measured by 3D echocardiography) at 4 months after baseline in control and treated patients. B, EF at 4 and 12 months after baseline in the eight treated patients that have 1 year of follow-up. C, change in EF from baseline at 4 and 12 months in treated patients (absolute EF units). D, wall motion score index (WMSI) at 4 months after baseline in control and treated patients. E, WMSI at 4 and 12 months after baseline in the eight treated patients that have 1 year of follow-up. Data are means ± SEM.

Figure 5

Cardiac magnetic resonance (cMR) analysis at 4 and 12 months after baseline in treated patients (baseline was 4 ± 1 month after surgical revascularization). A, infarct size. B, change in infarct size from baseline. Data are means ± SEM.

Figure 6

Functional status/quality of life. New York Heart Association (NYHA) functional class (A and B) and quality of life (evaluated by the Minnesota Living with Heart Failure Questionnaire [MLHFQ] score) (C and D) at 4 and 12 months after baseline (baseline was 4 ± 1 month after surgical revascularization). A, NYHA functional class and C, MLHFQ score at 4 months after baseline in control and treated patients. B, NYHA functional class and D, MLHFQ score at 4 and 12 months after baseline in the 10 treated patients that have 1 year of follow-up. Data are means ± SEM.