Cardiac regeneration by intramyocardial stem cell therapy: clinical development
Authors: Steinhoff G. 
Published: September 2010

Cardiac stem cell therapy provides novel therapeutic options for chronic ischemic heart disease, but the potential of autologous human bone marrow progenitor cells remains to be evaluated for chronic ischemic cardiac disease. In a clinical phase I trial, which was started in June 2001, we first assessed the feasibility and safety of intramyocardial CD133+ bone marrow cell injection together with coronary artery bypass surgery (CABG) in chronic ischemic heart disease. In the initial safety study, we treated 15 patients and found that left ventricular ejection fraction (LVEF) increased significantly from 39.0 ± 8.7% pre‐operatively to 50.2 ± 8.5% at 6 months and 47.9 ± 6.0% at 18 months (F = 6.03, P = .012, repeated‐measures ANOVA). No procedure‐related complications were observed for up to 3 years. In a subsequent prospective randomized controlled Phase II efficacy trial, 40 patients received either CABG and cell therapy or CABG alone. Here, we observed that in the CABG & cell therapy group, LVEF increased from 37.4 ± 8.4% to 47.1 ± 8.3% at 6 months (F = 24.16,P < .0001, repeated‐measures ANOVA), whereas from 37.9 ± 10.3% to 41.3 ± 9.1% in CABG‐only group (F = 7.72, P = .012). LVEF was significantly higher at 6 months in the CABG & cell therapy group than CABG only (P = .03). Similarly, perfusion in the infarcted myocardium improved more in CABG & cell‐treated patients than in CABG‐only patients. Follow‐up time currently ranges between 27 and 62 months with mean follow up of 44 ± 12 months and encompasses a total of 572 patient months (as of April 2007). In these patients no relevant ventricular arrhythmia was recorded at any time point. There were no adverse tissue changes (e.g. intramyocardial calcification or tumor formation) in the computed tomography. To date long‐term follow‐up functional tests are proceeding. From 35 patients who were treated with stem cell injection (phase I and phase II), one was excluded from the study and two deaths occurred as mentioned above. Among 32 patients remained in the study 13 patients underwent long‐term safety investigations as of April 2007. For further clinical introduction a phase III study is planned to be started in summer 2008 including the heart center in Berlin (DHZB), Hannover (MHH), and Rostock. This will be a placebo controlled, prospective, randomized, double‐blind multicenter, phase III, clinical trial investigating the effects of intramyocardial injection of 5 ml CD133+ bone marrow cells or placebo in 142 patients with coronary artery disease scheduled for CABG surgery. Patients will be randomized to one of the two treatment groups (CD133+ or placebo) in a 1 : 1 ratio. Intramyocardial highly purified CD133+ bone marrow stem cell delivery in CABG patients is safe and provides beneficial effects, though it remains to be proven whether these effects produce a lasting clinical advantage. This therapeutical experience opens a clinical window for cardiac cell therapy as a standard therapy in chronic ischemic heart disease involving primary isolated stem cells. Improved application techniques of primary, cultured, and modified stem cells may prompt the way to establish new treatment possibilities for congenital and adult cardiac disease in the future.