ArticlesIntracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial
Introduction
Myocardial infarction is common, and many patients develop substantial scarring despite optimum treatment.1 The presence and extent of myocardial scarring predisposes to progressive unfavourable left ventricular remodelling, heart failure, and sudden death.2, 3 Present treatment approaches seek to limit the initial injury and block secondary maladaptive pathways. Conversely, regenerative therapy seeks to shrink scar and regrow healthy heart muscle. Despite more than a decade of clinical trials of cardiac regenerative therapy, this ambitious goal remains elusive. Trials with bone marrow mononuclear cells4, 5, 6, 7 or mesenchymal stem cells in patients after myocardial infarction have shown an excellent safety profile,8 but efficacy is inconsistent5, 7 and sometimes transient.6 Most studies have assessed global functional endpoints such as ejection fraction. However, the actual targets of regeneration—scar mass and viable myocardial mass—can be measured rigorously by contrast-enhanced MRI. In the few controlled studies of stem cells that used MRI to assess outcomes, scar size (ie, scar mass normalised by total left ventricular mass) did not change substantially, if at all, after cell therapy, with little or no relation to ejection fraction.4, 5, 6, 9, 10, 11 Even positive studies have failed to show increases in viable myocardium in addition to shrinkage of scar tissue.4
The notion of endogenous mammalian heart regeneration, which has traditionally been viewed as heretical, has gained support recently.12 Various populations of putative endogenous cardiac progenitor cells have been identified, with widespread preclinical evidence for efficacy in cardiac repair and functional improvement after myocardial infarction.13 The present study uses a straightforward approach for generation of heart-derived cells as therapeutic candidates. Percutaneous endomyocardial biopsies are used to obtain source tissue and the cardiosphere culture method14 to yield tens of millions of cardiosphere-derived cells (CDCs) in a timely manner.15 CDCs are clonogenic, have multilineage potential, can be safely delivered via the intracoronary route, and mediate reductions in scar size in preclinical models of myocardial infarction.16, 17, 18, 19
In the CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) study, we aimed to assess safety of autologous intracoronary CDCs administered to patients 1·5–3 months after myocardial infarction, and test the hypothesis that CDCs convert scar tissue to viable myocardium.
Section snippets
Study design and participants
An investigator-sponsored Investigational New Drug Application (number 13930) was granted by the US Food and Drug Administration (FDA) for the CADUCEUS protocol, which involved two sites: the Cedars-Sinai Heart Institute (CA, USA) and The Johns Hopkins Hospital (MD, USA).
Patients with a recent myocardial infarction (≤4 weeks previously) and left ventricular dysfunction (ejection fraction 25–45% by clinically indicated imaging after infarction) were eligible for inclusion if they were aged 18
Results
Between May 5, 2009, and Dec 16, 2010, we screened 436 patients and randomly allocated 31 eligible patients to treatment groups (figure 2). Two patients allocated to receive CDCs withdrew consent before first biopsy sampling and another became ineligible for infusion because of occlusion of the infarct-related artery detected at the time of intended infusion. Four patients received a low cell dose (12·5 million cells), one received an intermediary cell dose (17·3 million cells), and 12 received
Discussion
Regeneration is defined as regrowth of lost or destroyed parts or organs.26 Although nature provides numerous examples of spontaneous regeneration after injury, we have, as physicians, thus far failed in our efforts to achieve therapeutic regeneration. Our study provides an initial indication that therapeutic regeneration might indeed be possible in cardiac tissue.
We report a phase 1 clinical trial of heart-derived cells that reached its prespecified primary endpoints: the controlled
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