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

Abstract

Summary 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.

Migration of Resident Cardiac Stem Cells in Myocardial Infarction

“…These cells highly expressed CXCR4 under hypoxic preconditioning (HPC), and were able to migrate to injured myocardium after intravenous injection (Tang et al, 2009). A phase 1 clinical trial of CDCs treatment has been recently carried out in patients 2-4 weeks after acute myocardial infarction (Makkar et al, 2012). Treatment with CDCs was reported to significantly reduce infarct size and increase viable heart mass at 6 months, but without significant improvement in LVEF.…”

Extracellular Vesicle Injection Improves Myocardial Function and Increases Angiogenesis in a Swine Model of Chronic Ischemia

“…Mesenchymal stem cells are currently under clinical investigation as a treatment to improve myocardial function and perfusion in patients with advanced heart failure after myocardial infarction 2, 3. The main benefit of mesenchymal stem cells may be derived from the bioactive encapsulated molecules they secrete in the form of EVs 7.…”

“…Phase 1 clinical trials demonstrate that intracoronary infusion of cardiosphere‐derived cells is efficacious in patients with advanced heart failure after myocardial infarction 2, 3. However, larger‐cohort studies have failed to show a lasting clinical benefit 4, 5.…”

Stem Cell Therapy for Heart Disease

“…43,53,54,62 Heart Failure Additionally, there have been multiple HF trials (Table 2). Many demonstrated benefits in ventricular function noted by increased EF, [68][69][70][71][72][73]75,79,82,83 improved functional class, 75,78,80,82,83,86 reduced infarct size, 70,72,80,[82][83][84] decreased mortality, 79 and acceptable safety outcomes. [66][67][68][69]75,78,80,[82][83][84]86 SCIPIO was the first trial using autologous CSC in HF and showed improvement in EF, infarct size, viable tissue, and HF scores.…”

“…79 Some trials did not show significant results, 76,85 while others demonstrated benefits, but no effect on EF. 66,67,74,77,80,84,86 A highly anticipated trial, FOCUS-CCTRN, assessed BMC via transendocardial injection in chronic HF. However, results indicated no significant change in endpoints.…”