Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial

Abstract

Background: Cardiosphere-derived cells (CDCs) reduce scarring after myocardial infarction, increase viable myocardium, and boost cardiac function in preclinical models. We aimed to assess safety of such an approach in patients with left ventricular dysfunction after myocardial infarction.

Methods: In the prospective, randomised CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial, we enrolled patients 2-4 weeks after myocardial infarction (with left ventricular ejection fraction of 25-45%) at two medical centres in the USA. An independent data coordinating centre randomly allocated patients in a 2:1 ratio to receive CDCs or standard care. For patients assigned to receive CDCs, autologous cells grown from endomyocardial biopsy specimens were infused into the infarct-related artery 1·5-3 months after myocardial infarction. The primary endpoint was proportion of patients at 6 months who died due to ventricular tachycardia, ventricular fibrillation, or sudden unexpected death, or had myocardial infarction after cell infusion, new cardiac tumour formation on MRI, or a major adverse cardiac event (MACE; composite of death and hospital admission for heart failure or non-fatal recurrent myocardial infarction). We also assessed preliminary efficacy endpoints on MRI by 6 months. Data analysers were masked to group assignment. This study is registered with ClinicalTrials.gov, NCT00893360.

Findings: Between May 5, 2009, and Dec 16, 2010, we randomly allocated 31 eligible participants of whom 25 were included in a per-protocol analysis (17 to CDC group and eight to standard of care). Mean baseline left ventricular ejection fraction (LVEF) was 39% (SD 12) and scar occupied 24% (10) of left ventricular mass. Biopsy samples yielded prescribed cell doses within 36 days (SD 6). No complications were reported within 24 h of CDC infusion. By 6 months, no patients had died, developed cardiac tumours, or MACE in either group. Four patients (24%) in the CDC group had serious adverse events compared with one control (13%; p=1·00). Compared with controls at 6 months, MRI analysis of patients treated with CDCs showed reductions in scar mass (p=0·001), increases in viable heart mass (p=0·01) and regional contractility (p=0·02), and regional systolic wall thickening (p=0·015). However, changes in end-diastolic volume, end-systolic volume, and LVEF did not differ between groups by 6 months.

Interpretation: We show intracoronary infusion of autologous CDCs after myocardial infarction is safe, warranting the expansion of such therapy to phase 2 study. The unprecedented increases we noted in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes.

Funding: US National Heart, Lung and Blood Institute and Cedars-Sinai Board of Governors Heart Stem Cell Center.

Figure 1. Manufacture and characteristics of CDCs

(A–D) Process flow for manufacture of CDCs. Biopsy specimens are minced into about 1 mm explants that spontaneously yield outgrowth cells (seen budding off the explant in B). These explants are harvested and plated in suspension culture to enable the self-assembly of three-dimensional cardiospheres (C). Subsequent replating of cardiospheres on adherent culture flasks yields CDCs (D). Histogram of time to achievement of the prespecified dose (E). As criteria for identity, representative histograms of flow cytometry data (F) and pooled data (G; logarithmic axis) show that more than 98% of cells expressed CD105, whereas fewer than 0·5% expressed CD45. CDC=cardiosphere-derived cell.

Figure 2. Trial profile and study timeline

(A) CADUCEUS trial profile. (B) Study events and timeline. Major efficacy data are based on comparisons of the baseline MRIs and the 6-month and 12-month MRIs. Study procedures below the timeline apply only to those participants who were randomly allocated to receive CDCs, but all participants underwent the MRI studies shown above the timeline. CDC=cardiosphere-derived cell. *Two patients in the low dose group and four in the high dose group. †Delay due to investigation of contamination.

Figure 3. Representative MRI and changes in scar size

Short-axis MRI of heart at baseline (82 days after myocardial infarction; A) and 6 months after CDC infusion (B) in a participant randomly allocated to receive CDCs. Short-axis MRI of heart at baseline (77 days after myocardial infarction; C) and after 6 months (D) in a control. Infarct scar tissue (green arrows) is evident by areas of hyperintensity (white) whereas viable myocardium appears dark. Difference in scar size from baseline to 6 months (E) or 12 months (F). CDC=cardiosphere-derived cell.

Figure 4. Scar mass and viable left ventricular mass on MRI

We noted decreases in scar mass and increases in viable mass on MRI in patients treated with CDCs but not controls. (A) Differences in scar mass between groups from baseline to 6 months or 12 months. (B) Differences in viable left ventricular mass from baseline to 6 months or 12 months. (C) Correlation between the change in scar mass and the change in viable mass in individual patients at 6 and 12 months compared with baseline. CDC=cardiosphere-derived cell.

Figure 5. Myocardial regeneration in rats treated with CDCs

Representative images of Masson trichrome-stained sections of vehicle control (A) and intracoronary CDC-treated (B) rat hearts 3 weeks after treatment (scar tissue stained blue and viable myocardium stained red). Enlarged regions show striking differences in transmurality of scar and extent of viable myocardium in the infarcted region. (C) Quantification of scar size, scar mass, and viable mass in CDC-treated and control hearts. (D) Cardiomyocyte cross-sectional area in the peri-infarct area of CDC-treated and control hearts shown no hypertrophy in the CDC-treated hearts. CDC=cardiosphere-derived cell. DAPI=4’,6-diamidino-2-phenylindole. α-SA=α-sarcomeric actinin.

Figure 6. Global function, chamber volumes, and regional function in participants in the CADUCEUS study

(A) Treatment effects (baseline vs 6 months) for MRI-derived ejection fraction. (B) Treatment effects (baseline vs 6 months) for end-diastolic volume. (C) Treatment effects (baseline vs 6 months) for end-systolic volume. (D) Regional strain in infarct-related segments at 6 months. (E) Systolic thickening in infarct-related segments at 6 months. CDC=cardiosphere-derived cell.