Dr. Hani N. Sabbah
Nearly a decade after the first in-man trial to test the efficacy and safety of using stem cells to treat acute myocardial infarction, and after numerous other small phase II clinical trials, we still don’t know which stem cell type to use, what patient population to target, or the most appropriate delivery approach.
Three recent studies characterize the rocky path this area of research has traveled.
First, the pooled results of a meta-analysis of 33 randomized clinical trials conducted to evaluate the safety and efficacy of bone marrow–derived intracardiac stem cell therapy for AMI involving 1,765 subjects showed that stem cell therapy significantly reduced infarct size, modestly improved left ventricular function, and reduced LV volume (Cochrane Database Syst. Rev. 2012 [doi: 10.1002/14651858.CD006536.pub3]). There was also a small reduction in mortality and morbidity in favor of stem cell therapy that did not reach statistical significance.
Second, the results of the CADUCEUS trial showed that intracoronary infusion of autologous cardiosphere-derived stem cells (resident myocardial stem cells derived from right ventricular biopsies) soon after an AMI was safe and feasible, and led to reduced scar size and to an increase in viable muscle mass. Clinically, patients in the stem cell group showed an increase in 6-minute walk distance, but had no improvements in MLHFQ (Minnesota Living With Heart Failure Questionnaire) compared with placebo and no improvement in LV ejection fraction at 6 months (Lancet 2012;379:895-904 [doi:10.1016/S0140-6736(12)60195-0]).
Third, the results of the FOCUS-CCTRN trial, which examined the effects of autologous bone marrow mononuclear cells on functional capacity, LV function, and perfusion in patients with chronic ischemic heart failure, failed to achieve its primary and secondary end points. Compared with placebo, delivery of bone marrow stem cells did not improve LV end-systolic volume, regional wall motion, maximal oxygen consumption, reversibility on SPECT, fixed defect size, or clinical status (JAMA 2012;307:1717-26 [doi: 10.1001/jama.2012.418]).
These reports paint differing scenarios, ranging from encouraging positive outcomes to outright failure. Nonetheless, the weight of evidence suggests that there is merit in pursuing stem cell therapy for the treatment of AMI and possibly its downstream consequences, namely heart failure. The scientific evidence gathered to date appears to support the "safety" side of this form of therapeutic intervention, but to a much lesser extent, the "efficacy" side. Modest improvements in LV function and remodeling are frequently uncovered with many forms of stem cell therapy, but these benefits fall short of positively influencing clinical outcome viewed in terms of mortality and morbidity.
In the case of stem cell therapy, the scientific medical community has deviated somewhat from its usual course of pursuing knowledge, filling in gaps, and only then bringing forward an appropriate "knowledge-based" therapeutic approach, and has instead pursued the path of least resistance.
After many years of trial-by-error experimentation, we can ask ourselves the following: Do we really know if adult cardiospheres are better stem cells than skeletal muscle myoblasts, or for that matter, bone marrow–derived stem cells or even embryonics? Can we confirm that stem cells delivered to the myocardium survive and are integrated into physiologic structures? Are we certain that cell regeneration takes place, and if so, how? Is the integration of exogenous stem cells into the cardiac structure the mediator of benefit or is it what the stem cells elaborate? If the latter, should we not spend more time understanding this "response process"? Is it time to redirect our efforts and treasure to fill in the knowledge gaps in this field if we expect to benefit from this discovery?
We are already paying the price of frequent failures with stem cell therapy just as we did in the recent past with gene therapy. Clinical trial failures have tempered the enthusiasm and suppressed the appetite of the investment community and the pharmaceutical industry for this line of research and its potential therapeutic value. It is time to go back to the basics, gain needed knowledge, and reemerge with better tools that capitalize on the enormous therapeutic potential of stem cell therapy.
Dr. Sabbah is director of cardiovascular research at Henry Ford Health System in Detroit. He disclosed that he is a named inventor on U.S. patents dealing with use of stem cell hypoxia-conditioned media for the treatment of heart failure licensed by Henry Ford Health System to LoneStar Heart.