Summary of Relevant Research
Given the interest in the role of cell therapy in the recovery of damaged myocardium, a significant amount of pre-clinical and clinical evaluation has been conducted over the past decade.
Is there an optimal cell type? What is the effective cell dose? Should one use an autologous versus allogeneic approach? What is the best method of delivery and timing of injections after injury? All of the above are important considerations which remain today without definitive answers.
To address these issues, investigators have carefully studied a number of different approaches, including but not limited to intravascular and inter-myocardial delivery of cells derived from bone marrow, peripheral blood, adipose tissue, and cord blood. Below is a brief summary of completed studies.
In a recent article by Drs. Hoover-Plow and Gong, the authors nicely summarize recent reviews of cardiac cell therapy related studies. The authors report that reviews of completed studies evaluating cardiac recovery document improvements of 10% or less in half of the studies evaluated1. In one highlighted review article, Mozid and colleagues highlighted eight clinical studies targeting chronic ischemic disease and reported that improvement was noted in 75% of studies using bone marrow and 50% of investigations using skeletal myoblasts2.
In another recently published meta-analysis looking at the use of bone marrow for ischemic cardiac disease, Dr. Jeevanantham and colleagues evaluated a total of 50 studies through January 2012, representing over 2,500 patients. When compared with controls, patients receiving bone marrow derived cells exhibited greater LVEF and a smaller infarct size3.
In another referenced article, Wen and co-workers conducted a meta-analysis of eight randomized controlled studies using bone marrow and reported a 6-10% improvement in left ventricular ejection fraction4. Other meta-analyses have reported safety and a 3-6% increase in global left ventricular performance after intracoronary stem cell therapy in patients with acute myocardial infarction5.
In an effort to elucidate potential mechanisms of action from existing clinical trial data, Dr. Suncion and co-workers reviewed lessons learned from completed studies6. The authors report that The Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI), REPAIR-AMI, and Prochymal studies evaluated the efficacy and safety of cell therapy in the acute MI setting, demonstrating a therapeutic effect on attenuation of remodeling7, 8, 9. Separately, early data from Transendocardial Autologous Cells in Ischemic Heart Failure (TAC-HFT) trial support the role of mesenchymal stem cells to achieve reverse remodeling in the chronic MI setting10. While bone marrow has served as the primary source of cells for most studies, others have reported encouraging outcomes with cells such as adipose derived stem cells after myocardial infarction11.
In short, investigative activity in this space has been robust over the past 10 years. While questions remain and it is fair to say that outcomes have been mixed, encouraging results driving larger, future investigation.
There are currently over 450 studies referenced in clinicaltrials.gov under a keyword search of stem cell AND cardiac disease. Over 200 are either actively recruiting or have an unknown recruitment status12. A total of 9 phase 3 studies are listed including RENEW (a study evaluating the role of CD34+ cells with intramyocardial delivery for refractory angina) as well as BAMI (intracorornary infusion of bone marrow aspirate following acute myocardial infarction).
In addition to phase 3 studies, a number of very interesting phase I/II investigations are currently underway. For example, the ATHENA study is evaluating the safety and feasibility of adipose-derived regenerative cells in the treatment of chronic myocardial ischemia. In addition, the National Heart, Lung, and Blood Institute (NHLBI) of the NIH is sponsoring the role of bone marrow derived stem cells delivered directly to damaged myocardium during open heart surgery.
Table 1 below lists selected completed and ongoing clinical trials according to clinicaltrials.gov.
|Condition||Cell Type||Phase||Acronym||Video Link|
|CAD, AMI||Bone Marrow||I/II||REPAIR-ACS||No direct link|
|AMI||Bone Marrow||III||REGEN-AMI||No direct link|
|Chronic ischemic heart failure||Bone Marrow||II/III||REGEN-IHD||No direct link|
|Dilated cardiomyopathy||Bone Marrow||II||NOGA-DCM||No direct link|
|Dilated cardiomyopathy||Bone Marrow||I||POSEIDON||No direct link|
|AMI||Bone Marrow||I||BOOST||No direct link|
|AMI||Bone Marrow||II||ASTAMI||No direct link|
|AMI||Bone Marrow/CPC||I||TOPCARE-AMI||No direct link|
|Ischemic heart failure||Bone Marrow/PBC||III||ESCAPE||No direct link|
|MI, Heart failure||CD133+||II||IMPACT-CABG||http://www.youtube.com/watch?v=ncF-JTBRK8c|
|MI, CAD||CD133+||I/II||PERFECT||No direct link|
|Chronic ischemic heart failure||Adipose||I/II||ATHENA||No direct link|
|AMI||Adipose||II/III||ADVANCE||No direct link|
|Chronic ischemic heart disease||Adipose||I||PRECISE||http://www.youtube.com/watch?v=REfc1BmBB-8|
|Chronic ischemic heart disease||MSC||II||MyStromalCell||No direct link|
|Congestive heart failure||Skeletal myoblasts||II/III||MARVEL||No direct link|
|Ischemic heart disease||Skeletal myoblasts||I/II||MAGIC||No direct link|
|Congestive heart failure||Cardiac||I||ALCADIA||http://www.youtube.com/watch?v=SC09phAnPZA|
|Heart failure||Cardiac progenitor||I||TICAP||No direct link|
In addition to ongoing clinical studies, the role of a patient registry to capture long-term data is paramount to continued progress.
There are a number of publicly available videos that offer a summary of the state of cardiac cell therapies. In 2011, Dr. Udelson and colleagues discuss the findings of novel stem cell therapies reported during session 1 at Scientific Sessions 2011. The video can be found at the following link: http://www.youtube.com/watch?v=kg_7fPrOYco&feature=relmfu. During the 2012 meeting of the American College of Cardiology, Dr. Hare was interviewed on the role of stem cell therapies in the treatment of patients with heart failure. The interview can be viewed at: http://www.youtube.com/watch?v=iTKMkMysuRY.
In addition to annual Society and Association meetings, there a number of scientific programs dedicated to the discussion of cardiac cell therapy. In the United States, the Conference on Cell Therapy for Cardiac Disease (celltherapy.crf.org) has been held annually in New York for the past seven years. In Europe, the International Symposium on Stem Cell Therapy and Cardiovascular Innovations (cardiovascuarcelltherapy.com) has been held for the past nine years. While there are additional quality regional meetings, the above two dedicated meetings bring together international leaders in the field of cardiac cell therapy to discuss latest results, review emerging trends, and discuss the future direction of this promising therapeutic approach.