November 15th, 2011
Hype Aside, Hope for Stem Cell Therapy May Be Emerging from Hibernation
Larry Husten, PHD
Two small studies of cardiac stem cells for the treatment of heart failure have shown promise, but ABC News, CBS News, and other media outlets are throwing around words like “medical breakthrough” and “heart failure cure.” ABC News correspondent Richard Besser was so enthusiastic that anchor Diane Sawyer commented that she had never seen him “so excited.” The first author of one of the studies, Roberto Bolli, said the work could represent “the biggest advance in cardiology in my lifetime.”
The reality may be somewhat more prosaic. In the first paper, published in the Lancet, Roberto Bolli and colleagues, including senior author Piero Anversa, report on a phase 1 study still in progress in which 16 patients with post-infarction left ventricular (LV) dysfunction received cardiac stem cells (CSCs) harvested during bypass surgery and subsequently expanded. Seven patients served as controls.
In the treatment group, LV ejection fraction (EF) increased from 30.3% to 38.5% some 4 months after infusion. There was no change in LVEF in the control group. At 1 year follow-up among eight patients in the CSC group, the LVEF had increased by 12.3 EF units.
“Although the primary purpose of our phase 1 trial was to assess the safety and feasibility of using this distinct and unique population of cells, the treatment effects are very encouraging and compare favourably with previous trials of bone marrow cells. The present results provide a strong rationale for further studies of CSC treatment in patients with severe heart failure secondary to ischemic cardiomyopathy, who have a poor prognosis,” the authors wrote.
The results “raise new optimism because the study is based on rigorous quality standards and the reported benefits are of an unexpected magnitude,” wrote Gerd Heusch in an accompanying comment. “Of course, we will have to see whether further data will meet the promises of the present study…”
In a second study, presented by Eduardo Marbán at the AHA, 31 patients were randomized on a 2:1 basis to intracoronary infusion of cardiosphere-derived cells (CDCs) or a control arm. CDC therapy was safe, and the investigators found evidence that it reduced scar and increased healthy heart muscle. The results suggested that regeneration of cardiac tissue had taken place. Positive trends suggesting improved EF and end systolic and diastolic volumes were also observed. The results, the authors concluded, suggest that this could be the “first therapeutic modality to shrink scar while regrowing viable, functional tissue.”
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Two studies presented at the American Heart Association meeting showing only the safety and feasibility, not efficacy, of stem cell therapy in ischemia-induced heart failure evoked loud acclaim by the national media. This is somewhat disingenuous as cardiac cellular therapy has over a decade track record for basic and clinical research that has provided more hope for future promise than documented benefit. The theory of repopulating weakened and scarred myocardium with precursors that will differentiate into new, functioning heart muscle is intuitively exhilarating. However, in fact, just as Jatene ventriculoplasty, skeletal muscle wrap and ventricular restraint devices, this therapeutic option may be more suitably and euphemistically categorized as of potential value only for very highly selected patients. My skepticism is prompted by the following mechanistic deconstruction of what stem cell therapy entails.
Candidates are patients suffering heart failure either from acute myocardial infarction or chronic ischemic cardiomyopathy. Stem cells were used in these studies, but pleuropotentiality is not requisite as adult and immature myocytes as well as skeletal muscle each have their proponents. Cells are delivered to specific ventricular locations by intracoronary infusion during percutaneous intervention or direct implantation with surgical revascularization. Infused cells must diapedese the coronary endothelium assuming too there is adequate perfusion to the ischemic muscle. Then after traversing an intact tissue barrier, they must “engraft” in the hostile milieu of an acute infarction, i.e. susceptible to proteolytic enzymes, scavenging monocytes and activated leukocytes, highly acidic, hyperkalemic and hypoxic environment. Quite simply, the pathological response to infarction is resorption of necrotic muscle with replacement by scar tissue. Why would infused, free cells survive? Then, whether infused by catheter or directly injected, cells will only survive if they can stimulate angiogenesis, similar really to a key step in carcinogenesis. Diffusion alone seems inadequate to nurture cellular growth and development at a macroscopically relevant level compatible with pumping potential.
Now, let us assume that “engraftment” can occur. What are the local triggers that govern differentiation and maturation into adult myocytes? Why not blood conduits and scar tissue? But even if proximity per se directs tissue specific development, how can the new muscle cells beat effectively? Cardiac pump function is predicated upon coordinated contraction of a functional syncytium. Histological staining of islands of myocytes is not documentation of that phenomenon. Moreover, at least 50% of patients with ischemic cardiomyopathy die from malignant ventricular arrhythmia, the substrate for which is disparate electrophysiological properties of the ischemic heart. Isolated clumps of new cells structurally and physically distinct from the native macro and micro cardiac architecture will create or exacerbate this exact substrate for lethality. In fact, previous clinical studies of cellular therapy have noted such increased incidence of ventricular dysrhythmia.
If stem cell therapy does finally prove of incremental benefit to concomitant revascularization for ischemic heart failure, I posit an alternative mechanism to fabricating more contracting muscle mass. Envision these engrafted cells as a living biopolymer that alters the viscoelastic properties of the beating, ventricular chamber. In the acute infarct situation, this will ameliorate ventricular remodeling so as to effect less wall thinning and chamber dilatation, thus modifying infarct size. With chronic dilated cardiomyopathy, the injectate will increase wall thickness thus normalizing wall tension without increasing oxygen utilization. Thus the heart will pump blood more efficiently at a decreased afterload, or impedance to ejection. If I am correct, you do not even need any stem cells to accomplish these goals. Non biodegradable, biopolymers are inexpensive and available alternatives that warrant further investigation.