Three New Clinical Trials Examine Bone Marrow-Based Stem Cells To Treat Heart Failure


In April of 2013, the results of three clinical trials that examined the effects of bone marrow-derived stem cell treatments in patients with acute myocardial infarction (translation – a recent heart attack) or chronic heart failure. These trials were the SWISS-AMI trial, the CELLWAVE trial, and the C-CURE trial.

The SWISS-AMI trial (Circulation. 2013;127:1968-1979), which stands for the Swiss Multicenter Intracoronary Stem Cells Study in Acute Myocardial Infarction trial, was designed to examine the optimal time of stem cell administration at 2 different time points: early or 5 to 7 days versus late or 3 to 4 weeks after a heart attack. This trial is an extension of the large REPAIR-AMI, which showed that patients who tended to receive bone marrow stem cell treatments later rather than earlier had more pronounced therapeutic effects from the stem cell treatments.

SWISS-AMI examined 60 patients who received standard cardiological care after a heart attack, 58 who received bone marrow stem cells 5-7 days after a heart attack, and 49 patients who received bone marrow stem cells 3-4 weeks after their heart attacks. All stem cells were delivered through the coronary arteries by means of the same technology used to deliver a stent.

When the heart function of all three groups were analyzed, no significant differences between the three groups were observed. Those who received stem cell 5-7 days after a heart attack showed a 1.8% increase in their ejection fractions (the percentage of blood that is ejected from the ventricle with each beat) versus an average decrease of 0.4% in those who received standard care, and a 0.8% increase in those who received their stem cells 3-4 weeks after a heart attack. If these results sound underwhelming it is because they are. The standard deviations of each group so massive that these three groups essentially overlap each other. The differences are not significant from a statistical perspective. Thus the results of this study were definitely negative.

The second study, CELLWAVE (JAMA, April 17, 2013—Vol 309, No. 15, 1622-1631), was a double-blinded, placebo-controlled study conducted among heart attack patients between 2005 and 2011 at Goethe University Frankfurt, Germany. In this study, the damaged area of heart was pretreated with low-energy ultrasound shock waves, after which patients in each group were treated with either low dose stem cells, high-dose stem cells, or placebo. Patients also received either shock wave treatment or placebo shock wave treatment. Thus this was a very well-controlled study. Stem cells were administered through the coronary arteries, just as in the case of the SWISS-AMI study.

The results were clearly positive in this study. The stem cell + shock wave treatment groups showed definite increases in heart function above the placebo groups, and showed fewer adverse effects. The shock wave treatments seem to prime the heart tissue to receive the stem cells. The shock waves induce the release of cardiac stromal-derived factor-1, which is a potent chemoattractor of stem cells.  This is an intriguing procedure that deserves more study.

The third study, C-CURE, is definitely the most interesting of the three (Bartunek et al. JACC Vol. 61, No. 23, June 11, 2013:2329–38). In this trial, mesenchymal stromal cells (MSCs) were isolated from bone marrow and primed with a cocktail of chemicals that pushed the stem cells towards a heart muscle fate. Then the cells were transplanted into the heart by direct injection into the heart muscle as guided by NOGA three-dimensional imaging of the heart.

After initially screening 320 patients with chronic heart failure, 15 were treated with standard care and the other 32 received the stem cell treatment. After a two-year follow-up, the results were remarkable: those who received the stem cell treatment showed an average 7% increase in ejection fraction versus 0.2% for receiving standard care, an almost 25 milliliter reduction in end systolic volume (measures degree of dilation of ventricle – not a good thing and the fact that it decreased is a very good thing) versus a 9 milliliter decrease for those receiving standard care, and were able to walk 62 meters further in 6 minutes as opposed to standard care group who walked 18 meters less in 6 minutes.

While these studies do not provide definitive answers to the bone marrow/heart treatment debate, they do extend the debate. Clearly bone marrow stem cells help some patients and do not help others. The difference between these two groups of patients continues to elude researchers. Also, how the bone marrow is processed is definitely important. When the cells are administered also seems to be important, but the exact time slot is not clear in human patients. It is also possible that some patients have poor quality bone marrow in the first place, and might be better served by allogeneic (someone else’s stem cells) treatments rather than autologous (the patient’s own stem cells) stem cell treatments.

Also, stem cell treatments for heart patients will probably need to be more sophisticated if they are to provide greater levels of healing. Heart muscle cells are required, but so are blood vessels to feed the new heart muscle. If mesenchymal stem cells work by activating resident heart stem cells, then maybe mesenchymal transplants should be accompanied by endothelial progenitor cell transplants (CD117+, CD45+ CD31+ cells from bone marrow) to provide the blood vessels necessary to replace the clogged blood vessels and the new heart muscle that is grown.

Treating Heart Patients with “Smart” Stem Cells


By aggressively treating heart attack patients soon after their episodes, clinicians have been able to reduce early mortality from heart attacks. However, the survival of these patients tends to create a whole new set of issues for them and their hearts. Chronic heart failure is a common aftermath of a heart attack for heart attack survivors. (see Kovacic JC and Fuster V., Clin Pharmacol Ther 2011;90:509-18).

Since the heart muscle (myocardium) has only a limited capacity to regenerate after a heart attack, multifaceted treatments have emerged that are designed to relieve symptoms and improve the patient’s clinical status. In particular, therapies target impaired contractility of the heart and the ability of the heart to handle the workload without enlarging. However, these treatments do not address the loss of heart muscle that underlies all heart attacks (see McMurray JJ. Systolic heart failure. N Engl J Med 2010;362:228-38). To address the loss of contracting heart tissue, stem cells, traditionally isolated from bone marrow, have been used in several clinical trials. However, the results of these studies have been highly variable, since most bone marrow stem cells placed in a heart after a heart attack, die soon after implantation.

To improve the ability of bone marrow stem cells to repair the heart, Andre Terzic from the Mayo Clinic Center for Regenerative Medicine has designed a special cocktail to induce mesenchymal stem cells from bone marrow to become more heart-friendly. This cocktail consisted of the following growth factors: TGFβ1, BMP-4, Activin-A, retinoic acid, IGF-1, FGF-2, α-thrombin and IL-6. Mesenchymal stem cells were cultured for 10 days in this cocktail and then tested for heart-specific genes.

Terzic calls this procedure “cardiopoiesis,” and when he subjected bone marrow mesenchymal stem cells (BM-MSCs) to this procedure, they expressed a cadre of genes that is normally found in developing heart cells (Nkx2-5, MEF2C, GATA4, TBX5, etc.). In an earlier publication, Terzic and his colleagues transplanted BM-MSCs from heart patients into the hearts of mice that had suffered a heart attack and compared the effects of these cells on the heart, with BM-MSCs that had undergone this guided cardiopoiesis protocol. The results were astounding. Not only did the function of the hearts that had received the guided cardiopoiesis M-MSCs much more normal than those had had received the untreated BM-MSCs, but post-mortem examination of the hearts showed that the hearts that had received guided cardiopoiesis BM-MSCs contained human heart muscle cells integrated into the heart muscle tissue (Atta Behfar, et al., J Am Coll Cardiol. 2010 August 24; 56(9): 721–734). Therefore, this procedure, cried out for a clinical trial, and data from such a trial has already been reported.

A, Human-specific troponin-I (green) in the anterior wall of naive- versus CP-treated hearts, respectively, co-localized with ventricular myosin light chain (MLC2v, red). Bar, 100 μm. B, Human troponin-I staining of naïve versus CP hMSC treated hearts, counterstained with α-Actinin (red), demonstrated engraftment of human cells. Cell cycle activation, documented by Ki-67 expression (yellow, arrows), noted in human troponin positive and endogenous cardiomyocytes. C, Confocal evaluation of collateral vessels from CP hMSC treated hearts demonstrated human-specific CD-31 (PECAM-1) staining. D, Human lamin staining (arrows) co-localized with nuclei of smooth muscle in vessels from CP hMSC treated but not saline or naïve treated hearts. Bar, 20 μm for B-D.
A, Human-specific troponin-I (green) in the anterior wall of naive- versus CP-treated hearts,
respectively, co-localized with ventricular myosin light chain (MLC2v, red). Bar, 100 μm.
B, Human troponin-I staining of naïve versus CP hMSC treated hearts, counterstained with
α-Actinin (red), demonstrated engraftment of human cells. Cell cycle activation,
documented by Ki-67 expression (yellow, arrows), noted in human troponin positive and
endogenous cardiomyocytes. C, Confocal evaluation of collateral vessels from CP hMSC
treated hearts demonstrated human-specific CD-31 (PECAM-1) staining. D, Human lamin
staining (arrows) co-localized with nuclei of smooth muscle in vessels from CP hMSC
treated but not saline or naïve treated hearts. Bar, 20 μm for B-D.

In a paper from February 2013 (Bartunek J, et al., Journal of the American College of Cardiology (2013), doi: 10.1016/j.jacc.2013.02.071), Terzic and his team has reported on the administration of BM-MSCs into the hearts of 34 heart patients. Of these patients, 21 were implanted with their own BM-MSCs that had undergone guided cardiopoiesis and the other 12 received standard therapy for heart patients with no transplanted cells.

The results from this study were striking to say the least. According to Terzic, “The benefit to patients who received cardiopoietic stem cell delivery was significant.” Cardiologist Charles Murry wrote in an editorial, “Six months after treatment, the cell therapy group had a seven percent absolute improvement in EF (ejection fraction) over baseline, versus a non-significant change in the control group. The improvement in EF is dramatic, particularly given the duration between the ischemic injury and cell therapy. It compared favorably with our most potent therapies in heart failure.”

This clinical trial, known as the C-CURE trial, which stands for Cardiopoietic Stem Cell Therapy in Heart Failure. was an international, multi-center trial that treated enrolled patients from hospitals in Belgium, Serbia, and Switzerland. This trial represents the culmination of almost a decade of work by Terzic and others. “Discovery of rare stem cells that could inherently promote heart regeneration provided a critical clue. In following this natural blueprint, we further developed the know-how needed to convert patient-derived stem cells into cells that can reliably repair a failing heart.”

For this trial, Mayo Clinic partnered with Cadio3 Biosciences, which is a bio-science company in Mort-Saint-Guilbert, Belgium. This company provided advance product development, manufacturing scale-up, and clinical trial execution.  Adaptation of this exciting new technology to the clinic could mean a new exciting fix for heart patients.