Stem Cell Therapy for Patients with Ischemic Cardiomyopathy


A medical research group from Miami Miller School of Medicine has examined the safety of transendocardial stem cell injections with a patient’s own bone marrow stem cells in patients with ischemic cardiomyopathy.

Ischemic cardiomyopathy is the most common type of “dilated cardiomyopathy,” which is a fancy way of saying that the heart enlarges in its failing struggle to supply the body with blood. The enlarged heart has more heart muscle to feed with oxygen, but because the heart enlarges faster than the blood vessels remodel, large portions of the enlarged heart are left without adequate blood supply, and the result is and oxygen deficit, also known as “ischemia.” In patients with ischemic cardiomyopathy, the heart’s ability to pump blood is decreased because the heart’s main pumping chamber, the left ventricle, is enlarged, dilated and weak. Usually, heart ischemia also results from coronary artery disease and heart attacks.

The symptoms of ischemic CM include shortness of breath, swelling of the legs and feet (edema), Fatigue (feeling overly tired), inability to exercise, or carry out activities as usual, angina (chest pain or pressure that occurs with exercise or physical activity and can also occur with rest or after meals), weight gain, cough and congestion related to fluid retention, palpitations or fluttering in the chest due to abnormal heart rhythms (arrhythmia), dizziness or light-headedness, and fainting (caused by irregular heart rhythms, abnormal responses of the blood vessels during exercise, without apparent cause).

Clearly an effective regenerative treatment of ischemic cardiomyopathy (ICM) would address of the needs of some of these patients. Bone marrow transplants into the heart have been tested as treatments and the stem cells were directly injected into the heart muscle (see Williams AR, et al., Circ Res. 2011;108(7):792-796; and Losordo DW, et al., Circ Res. 2011;109(4):428-436). Both of these studies, however used mononuclear cells from bone marrow. Mononuclear cells refer to white blood cells from bone marrow and it includes a wide variety of stem cells, progenitor cells, and other mature white blood cells, but excludes red blood cells or platelets, which have no nuclei.

In order to determine if mesenchymal stem cells were also safe for this type of treatment, Alan W. Haldman and his colleagues from the laboratory of Joshua M. Hare tested 65 patients who suffered from ICM and compared injection of mesenchymal stem cells (n = 19) with placebo (n = 11) and bone marrow mononuclear cells (n = 19). Patients were followed up to one year after their procedures.

To measure serious adverse effects of the procedure, all patients were evaluated at 30 days post-procedure. Severe adverse effects includes death, heart attack, stroke, hospitalization for worsening heart failure, perforation of rupture of the heart, tamponade (compression of the heart due to a collection of fluid around it), or sustained ventricular arrhythmias.

None of the patients in this study showed any severe adverse events up to day 30, and up to 1 year after the procedure, 31.6% of the bone marrow mononuclear and mesenchymal stem cell groups had some sort of serious adverse event, and 38.1% of the placebo group had serious adverse events.

Over one year, the Minnesota Living with Heart Failure score, which is a measure of the quality of life of a heart patient, improved with the mesenchymal stem cell and bone marrow cells but not with the placebo. Also, the 6-minute walk distance increased in the mesenchymal stem cell group, but none of the other groups when the baseline time was compared with the six-month and 12-month trials.

Patients in the mesenchymal stem cell group exhibited a significant increase in 6-minute walk distance when 6-month and 12-month time points were compared to baseline in a repeated measures model (P = .03). No significant difference was observed for patients in the bone marrow cell group (P = .73) or in the placebo group (P = .25). Data markers represent means; error bars, 95% CIs. Analysis of variance (ANOVA) was conducted with repeated measures.aWithin group, P<.05.bWithin group, P<.01.
Patients in the mesenchymal stem cell group exhibited a significant increase in 6-minute walk distance when 6-month and 12-month time points were compared to baseline in a repeated measures model (P = .03). No significant difference was observed for patients in the bone marrow cell group (P = .73) or in the placebo group (P = .25). Data markers represent means; error bars, 95% CIs. Analysis of variance (ANOVA) was conducted with repeated measures.aWithin group, P

Also, the size of the heart scar showed greater shrinkage in the mesenchymal stem cell group than in the other groups.

Significant reduction in scar size as the percentage of left ventricular mass for patients treated with mesenchymal stem cells (MSCs) and those in the placebo group who underwent serial magnetic resonance imaging. Repeated measures of analysis of variance model P values: treatment group, P=.99; time, P=.007; treatment group × time, P=.22. Data markers represent means; error bars, 95% CIs. Analysis of variance (ANOVA) was conducted with repeated measures.aWithin group, P<.05 vs baseline.bWithin group, P<.01 vs baseline.
Significant reduction in scar size as the percentage of left ventricular mass for patients treated with mesenchymal stem cells (MSCs) and those in the placebo group who underwent serial magnetic resonance imaging. Repeated measures of analysis of variance model P values: treatment group, P=.99; time, P=.007; treatment group × time, P=.22. Data markers represent means; error bars, 95% CIs. Analysis of variance (ANOVA) was conducted with repeated measures.aWithin group, P

And if a more visual way to view this would help, here is the heart of one particular patient.  Notice the shrinkage in the red area, which represents the scarred area, after one year.

A, Short-axis views of the basal area of a patient’s heart, with delayed tissue enhancement delineated at the septal wall. Delayed tissue enhancement corresponds to scarred tissue and is depicted brighter than the nonscarred tissue (automatically detected and delineated with red using the full width at half maximum technique). The red, green, and white lines demarcating the endocardial, epicardial contours, and borders of the segments, respectively, were drawn manually. Twelve months after injection of mesenchymal stem cells, scar mass was reduced from 30.85 g at baseline to 21.17 g at 12 months. B, Long-axis 2-chamber views of the same heart with delayed tissue enhancement delineated at the anterior and inferior wall, as well as the entire apex. At baseline and at 12 months after injection of mesenchymal stem cells, the delayed tissue enhancement receded in the midinferior and basal anterior walls (see Interactive of representative cardiac MRI cine sequences).
A, Short-axis views of the basal area of a patient’s heart, with delayed tissue enhancement delineated at the septal wall. Delayed tissue enhancement corresponds to scarred tissue and is depicted brighter than the nonscarred tissue (automatically detected and delineated with red using the full width at half maximum technique). The red, green, and white lines demarcating the endocardial, epicardial contours, and borders of the segments, respectively, were drawn manually. Twelve months after injection of mesenchymal stem cells, scar mass was reduced from 30.85 g at baseline to 21.17 g at 12 months. B, Long-axis 2-chamber views of the same heart with delayed tissue enhancement delineated at the anterior and inferior wall, as well as the entire apex. At baseline and at 12 months after injection of mesenchymal stem cells, the delayed tissue enhancement receded in the midinferior and basal anterior walls (see Interactive of representative cardiac MRI cine sequences).

The authors concluded from this study that these “results provide the basis for larger studies to provide definitive assessment of safety and to assess efficacy of this new therapeutic approach.”  Mesenchymal stem cells might certainly provide a way to treat ICM patients.  Also, if the patient’s bone marrow is of poor quality as a result of their poor health, then mesenchymal stem cells from a donor might provide healing for these patients.  For now, I say, “bring on the larger trials!!”

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.

SCIPIO Clinical Trial Shows Remarkable Promise


Scipio Africanus is the name given to a very competent Roman general who defeated that wily Carthaginian general Hannibal at the Second Punic War. SCIPIO, therefore, is a fitting name for a remarkable clinical trial that goes by the longer title: Cardiac Stem Cell Infusion in Patients with Ischemic Cardiomyopathy.  This clinical trial is the brainchild of researchers at the University of Louisville and Brigham and Women’s Hospital, and is the first clinical trial to test the safety and efficacy of heart-based stem cells as treatments for heart attack patients.

SCIPIO researchers isolated and expanded cardiac stem cells (CSCs) from approximately one gram of atrial tissue.  This tissue was taken from heart attack patients during coronary bypass surgery.  CSCs were initially discovered and cultured by scientists in the laboratory of Piero Anversa at Brigham and Women’s Hospital in Boston (see Frati C, et al., Resident cardiac stem cells. Current Pharmaceutical Design. 2011 17(30):3252-7).  CSCs have the capacity to express several heart-specific genes and, in animal studies, can repair the heart after a heart attack.  Anversa’s lab was quite careful to establish that the isolated cardiac stem cells expressed a gene called “c-kit,” which is a marker for these stem cells, and that these cells had good growth potential and were largely uncommitted.  In this case Anversa was quite sure that the cells given to the patients were able to grow, differentiate, and integrate into the heart.

Between three to four months after coronary artery bypass surgery, around one million CSCs were transplanted into the heart of each heart attack patient.  This feature of the clinical trial is known as an  “autologous” stem cell treatment, since each patient received stem cells taken from their own body.  Autologous stem cells treatments minimize the risk of rejection by the patient’s immune system.

Throughout the following year after the stem cell treatment, participating patient’s left ventricles were viewed and their heart function was assessed with echocardiography and magnetic resonance imaging.   To say that the results were encouraging is an understatement.  Before the stem cell treatment, each patient was experiencing a stable decrease in left ventricular function.  There was no change in left ventricular function and functional status in the seven control patients who underwent coronary bypass surgery but did not undergo CSC transplantations.  However, 14 of the 16 patients who received CSCs transplants showed an 8.2% average increase in ejection fraction and a 24% decrease in infarct size.  In eight patients studied one year after the CSC treatments, these benefits not only were sustained, actually increased.  Even more encouraging is the absence of adverse effects, which confirms the overall safety of the CSC treatment.

SCIPIO study author, Dr. John Loughran, said this about the current status of the SCIPIO study: “We have enrolled 20 CSC-treated patients, all of whom have been treated with CSC infusion. The trial is currently closed to enrollment.  All patients are followed at serial time points for 2 years. We are working diligently on the creation of an IND application to the FDA for a Phase 2 clinical trial. We hope for this next investigation to be underway within 2 years.”

Dr. Loughran also noted that the isolation of CSCs from the heart is safe and feasible.  This will allow physicians to also treat heart patients who do not depend on surgery, which turns out to be the majority of heart patients.  A simple heart biopsy could probably provide enough tissue for CSC isolation and expansion in the laboratory.

Roberto Bolli, M.D., Director, Institute for Molecular Cardiology at the University of Louisville, echoed these sentiments:  “Harvesting, culturing and infusing CSCs are not particularly expensive and could be repeated multiple times in the same patient. We have preliminary data suggesting that CSCs can be isolated and expanded from minuscule fragments of cardiac tissue obtained during endomyocardial biopsy, which would make this procedure widely applicable in patients with heart failure.”

There are also possibilities that CSCs can be tested for use as a treatment for other heart-based diseases.