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Regenerative Therapy for Advanced Heart Failure:
Where Are We and Where Are We Going?

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ISHLT BSTR Council Communications Liaison
Chief, Division of Cardiology
Drexel University College of Medicine and
Hahnemann University Hospital
Philadelphia, Pennsylvania, USA

If you are like me, your lectures about heart failure, mechanical circulatory support or heart transplant inevitably trigger questions about the status of stem cell therapy for advanced heart failure. This seems to be independent of the audience and can occur when one is speaking to senior physicians, Cardiology fellows, medical students or a lay audience. Stem cells or the very compelling term, regenerative therapy, have clearly captured the imagination of the medical community and the general public. Regenerative therapy offers the advantages of "off-the-shelf", noninvasive therapy which can be provided at any time and without the need for immunosuppressive therapy or other toxic medications. Before regenerative therapy becomes a reality, however, there are a few simple questions that need to be addressed:

  1. Which stem cells should be used?
  2. How many cells should be given?
  3. Which cardiovascular diseases are amenable to regenerative therapy?
  4. At which stage in the disease should stem cells be administered?
  5. Via what route (intravenous or intracoronary) should the stem cells be administered?
  6. How do we measure success with regenerative therapy for advanced heart failure?

I am occasionally presented by patients with studies from the literature (such as the National Enquirer) detailing dramatic results from stem cell therapy for heart disease, usually involving non-randomized, non-placebo controlled anecdotal experiences of regenerative therapy from outside the United States; one such case report from the above mentioned journal involved dramatic clinical benefits from stem cells given to a venerable Hawaiian singer.1 My response in turn involves an explanation of the importance of randomized trials, the need for controls, the benefits of conventional therapy for heart failure (as well as therapies for advanced heart failure such as ventricular assist devices or cardiac transplantation) and the fact that we have limited experience in such clinical trials to validate regenerative therapy. While I am not sure that my discussions are convincing, they are often sleep-inducing as judged by the glazed look on some of my patients faces (one even told me that when he wants to fall asleep, he thinks about my discussion on regenerative therapy and thanked me for the best night's sleep he has had in a long while).

But I digress. What are the data from clinical trials? Most are studies of patients post-MI. The randomized, placebo-controlled BOOST trial of autologous bone marrow stem cells (BMSCs)2 administered via coronary infusion after MI showed that patients who received intracoronary BMSCs had a significant improvement in their left ventricular (LV) ejection fraction (6.7 vs. 0.7%) at six months but by 18 months, this improvement (5.9 vs. 3.1%) was no longer significant.2 The strengths of this study are that it was randomized and placebo controlled but the results were of limited clinical benefit. Other studies have either shown no benefits of autologous BMSCs3 or at best a modest improvement in the recovery of LV contractile function.4-5 No long term clinical outcomes were reported for these studies. These modest findings are reminiscent of the American comedian Groucho Marx's comment that "he worked himself up from nothing to a state of extreme poverty".6

Two intriguing studies reported within the past year used cardiac derived stem cells (CSCs) called cardiospheres.7,8 These studies were conducted in patients with left ventricular dysfunction after myocardial infarction. In the SCIPIO study, CSCs were obtained from atrial appendages removed at the time of CABG.7 In the CADUCEUS study, CSCs were obtained from endomyocardial biopsies from the patients. In both studies, CSCs were purified and expanded ex vivo. In SCIPIO, ventricular function improved and infarct size was reduced in those receiving CSCs. In CADUCEUS, reduction in infarct size was elegantly demonstrated with cardiac magnetic resonance imaging.8 Regional contractility but not LV ejection fraction or dimensions improved. These studies suggest that larger clinical trials of CSCs in patients after myocardial infarction and perhaps patients with other forms of cardiomyopathy should be pursued.

What other studies are underway? Phase I and II clinical trials have been completed using intravenous administration of mesenchymal stem cells in patients post-MI with mild to moderate LV dysfunction: the results of the larger, Phase II study are pending. A clinical trial of patients with significant LV dysfunction post-MI using intravenous autologous BMSCs from the patients is underway. Rigorous clinical trials involving patients with clinical heart failure and ischemic or non-ischemic cardiomyopathies have not been conducted but the small studies mentioned above may serve as pilot studies for future clinical trials.

In summary, the above questions have not been answered and regenerative therapy for advanced heart failure remains a work in progress. So the next time you are asked about the utility of stem cells for advanced heart failure, refer them to this article. Their questions may be answered and at least, they might get a good night's sleep.

Disclosure Statement: The author has no conflicts of interest to disclose. Neither he nor any member of his family is employed by or has received funding from the National Enquirer.


  1. Personal communication from a patient.
  2. GP Meyer, KC Wollert, J Lotz et al.Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months' follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation, 113:2006;1287-1294
  3. K Lunde, S Solheim, S Aakhus et al.Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med, 355:2006; 1199-1209
  4. S Janssens, C Dubois, J Bogaert et al.Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet, 367:2006;113-121
  5. V Schächinger, S Erbs, A Elsässer, the REPAIR-AMI Investigators et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med, 355:2006;1210-1221
  6. From the movie "Monkey Business", Paramount Pictures, 1931
  7. Roberto Bolli, MD, Atul R Chugh, MD, Domenico D'Amario et. Al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 378: 2011; 1847-1857
  8. Raj R Makkar, MD, Rachel R Smith, PhD, Ke Cheng, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 378:2012; 895-904