Hype Aside, Hope for Stem Cell Therapy May Be Emerging From Hibernation 3

Two small studies of cardiac stem cells for the treatment of heart failure have shown promise, but ABC NewsCBS 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 Pierro 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% 4 months after infusion. There was no change in the EF in the control group. At one year followup in 8 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 favorably 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,”  writes 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 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.”

Here is the press release from the Lancet: the

First-in-man study shows cardiac stems cells show promise for treatment of heart failure caused by ischaemic heart disease (The Lancet)

The first trial in humans to use the heart’s own stem cells to battle heart failure has produced promising results. The initial findings from this ongoing study appear in an Article published Online First in The Lancet, timed to coincide with a presentation at the American Heart Association’s Scientific Sessions meeting, Orlando, FL, USA. The Article is by Professor Roberto Bolli, University of Louisville, KY, USA and Professor Piero Anversa, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA, and colleagues.

Heart failure is a common, lethal, disabling, and expensive disorder.  The most common cause of heart failure in the developed world is ischaemic heart disease—a blocking of the heart blood vessels causing death of heart muscle tissue. This leads to the heart pumping less blood, resulting in a decrease in left ventricular ejection fraction (LVEF). Available treatments do not address the fundamental problem of the loss of cardiac tissue.

The adult heart contains cardiac stem cells (CSCs) that are self-renewing, clonogenic (able to produce identical daughter cells), and multipotent—ie, they differentiate into all three major cardiac lineages (myocytes, vascular smooth muscle cells, and endothelial cells). In animal models, CSCs have helped improve heart failure, but these cells have never been tried in humans. In this study, the authorsdid a phase 1 clinical trial of CSCs in patients with heart failure after a heart attack to assess the safety and feasibility of intracoronary CSC infusion, and to test the hypothesis that this intervention would improve the contractile function of the heart and the general clinical status of the patient.

The authors report the results in 23 patients with severe heart failure (LVEF <40%), each of whom has had coronary artery bypass grafting (CABG). 16 of these received CSCs, while the other seven (control group) received standard care. Patients received an infusion of 1 million CSCs via a balloon catheter, at a mean time of 4 months after their CABG.  In 14 CSC-treated patients who were analysed, LVEF increased from 30·3% before CSC infusion to 38·5% at 4 months after infusion. LVEF did not change in the control group.  Importantly, the positive effects of CSCs were even more pronounced at 1 year in eight of the CSC patients, in whom LVEF increased by 12.3% (from 30.2% before CSCs to 42.5% at 1 year). In the seven treated patients in whom cardiac MRI could be done, the size of the dead tissue (infarct) decreased from 32·6 g by 7·8 g (24%) at 4 months and 9·8 g (30%) at 1 year.

The authors conclude: “Our study is the first report of the administration of CSCs in people. The results are a significant addition to the current data because they introduce a new potential treatment for heart failure… The present results provide a strong rationale for further studies of CSC treatment in patients with severe heart failure secondary to ischaemic cardiomyopathy, who have a poor prognosis.”

In a linked Comment, Professor Gerd Heusch, University School of Medicine, Essen, Germany,  says: “The results from SCIPIO raise new optimism because the study is based on rigorous quality standards and the reported benefits are of an unexpected magnitude…we will have to see whether further data will meet the promises of the present study: more patients will need to be followed up over a longer period.”

He concludes: “It is to be hoped that SCIPIO has the same potential to transform cardiac cell therapy that its namesake Scipio Africanus achieved in Roman military campaigns against Karthago.”

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  1. agree entirely that this is aggrandizing geometrically the significance of these 2 small studies. the operative word is small and one must also realize these are safety and feasibility studies, not powered in any way to show benefit. there was concurrent surgical revasculaization, which can render increased pump function and ameliorate remodeling independent of cell seeding. cellular therapy now has at least a decade or more of basic and clinical investigations and we are still conflicted as to how and why it works, mode of delivery and what cells should be utilized. and a final stern warning, perhaps 50% of deaths attributed to severe heart failure are arrythmic in nature. it is hard enough to intuit how onjected cells can form a functional syncytium to improve contractility, it is impossible to pretend that surviving implants have the same electrophysiological properties as native myocytes. are not disparate electrophysiological properties etiologic in arrythmogenesis? previous clinical experience with cellular therapy has reaffirmed this theoretical limitation.

  2. To amplify what I said the other day, 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.

  3. Pingback: Harvard-Brigham heart researcher under investigation earns Lancet Expression of Concern | Retraction Watch

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