This document addresses transplantation of various autologous cells collectively known as autologous cell therapy (ACT), as a treatment of damaged myocardium. Sources for autologous cells include but are not limited to skeletal myoblasts, endothelial progenitor cells (EPCs), bone marrow mononuclear cells (BMMC), mesenchymal or hematopoietic stem cells. Another method of ACT involves the use of granulocyte colony stimulating factor (GCSF) to increase the volume of circulating hematopoietic stem cells to treat damaged myocardial tissue.  

Investigational and Not Medically Necessary:

Autologous cell therapy, including, but not limited to, skeletal myoblasts, mesenchymal stem cells or hematopoietic stem cells, is considered investigational and not medically necessary as a treatment of damaged myocardium.

Infusion of growth factors (i.e., granulocyte colony stimulating factor [GCSF]) is considered investigational and not medically necessary as a technique to increase the numbers of circulating hematopoietic stem cells as treatment of damaged myocardium.

The use of hematopoietic stem cells, BMMC, skeletal myoblasts, mesenchymal stem cells and circulating or bone marrow-derived endothelial progenitor cells (EPCs) continues to be studied in clinical trials utilizing various techniques attempting revascularization or remodeling of injured myocardial tissue. Hematopoietic stem cells and skeletal myoblasts have been the focus of research. There are continuing issues of determining the optimal cell type, the timing of the transplantation post-infarct, and the delivery mode (directly into myocardium, intracoronary artery or sinus, or intravenously). In addition, there are concerns of harvesting the autologous cells safely and efficiently in the immediate post-infarct period. One of the advantages of using skeletal myoblasts is their easy accessibility through a muscle biopsy. However, the harvested tissue must undergo culture to expand the numbers of skeletal myoblasts. In the some trials, skeletal biopsy must occur 3 to 4 weeks before the anticipated implantation.

At this time there have not been any U.S. Food and Drug Administration (FDA) approvals for any technologies associated with any ACT procedure for the treatment of damaged myocardium. While FDA approval is not required in those situations in which autologous cells are processed on site with existing laboratory procedures and injected with existing catheter devices, specialized technologies do require approval. At this time, there are currently two products under investigation for the treatment of damaged myocardium with ACT. MyoCell™ (Bioheart, Inc., Ft. Lauderdale, FL) consists of autologous skeletal myoblasts that are expanded in a laboratory and supplied as a cell suspension for injection into the damaged myocardial area. In addition, implantation of skeletal myoblasts may require the use of a unique catheter delivery system (MyoCath™, Bioheart, Inc., Fr. Lauderdale, FL) that is also under investigation for FDA approval. The manufacturer is currently conducting clinical trials as part of the FDA approval process. The trials are focusing on individuals with a previous myocardial infarction who undergo epicardial implantation of the cultured myoblasts at the time of coronary artery bypass grafting, or individuals with a prior myocardial infarction and subsequent congestive heart failure who undergo subendocardial implantation using the MyoCath™ device during a catheterization procedure. Also, all participants must receive implantation of a cardiac defibrillator, based on preliminary data suggesting that the implanted myoblasts may be arrhythmogenic (cause irregular heartbeats).

The human studies reported to date are small, and most are non-randomized preliminary case series that have not evaluated the long-term efficacy of autologous cell transplant. Assmus and colleagues (2002) reported on the results of the TOPCARE-AMI study. This study included 20 individuals who had already undergone revascularization after an acute myocardial infarction (MI) and received either bone marrow-derived cells or circulating blood-derived progenitor cells infused into the infarct artery during a second catheterization procedure. Cardiac function was evaluated before and after the transplantation procedure. After four months, the authors reported an improvement in ejection fraction, regional wall motion, and left ventricular end diastolic volume. Stamm and colleagues (2003) injected bone marrow-derived stem cells into the peri-infarct zone in six participants following acute myocardial infarction planned for coronary artery bypass graft (CABG). All participants reported an improvement in cardiac exercise capacity and ejection fraction. Herreros (2003) used an intramyocardial injection of cultured myoblasts in twelve participants undergoing CABG. The procedure was considered safe and feasible, and the authors reported increased global and regional left ventricular function 3 months after surgery. Strauer and colleagues (2002) reported on a clinical trial of ten participants who received intracoronary autologous bone marrow cells 5 to 9 days after acute infarct. This delay in treatment reflects the time needed to harvest and process the bone marrow cells. Cardiac function in these 10 individuals was compared to 10 contemporary control individuals who refused the treatment. At 3 months, the treated participants had a reduction in infarct size compared to no change in the non-randomized control group.

In a Cochrane Review (Martin-Rendon, 2008) 13 studies involving less than 1000 subjects treated with stem cell treatment for acute myocardial infarction were analyzed. In all trials, the stem cells were an adjunct to successful revascularization of the infarct-related artery. Three studies had follow-up more than 12 months, but the other trial reported follow-up data between 3 to 6 months. The trials appeared to indicate short term improvement in left ventricular ejection fraction (LVEF). However, there was limited data reported on the effects to improving the health outcome. There was heterogeneity among the trials and there was no improvement of the size of the infarct. The authors noted the review was limited by small studies, the lack of standardized stem cell dose and timing of infusions and the need for large randomized trials. Therefore, the authors summarized there was "insufficient evidence on clinical outcomes to draw clear conclusions."

Zohnlnhöfer and colleagues (2008) reported results of a meta-analysis of 445 participants in 10 trials involving the use of GCSF stem cell mobilization after an acute myocardial infarction (AMI). The authors concluded the use of GCSF was safe, but infarct size was not reduced and LVEF function was not improved.

A meta-analysis (Fan, 2008) of 6 controlled trials with 160 participants randomized to GCSF treatment and 160 participants assigned to the control group found no significant improvement in LVEF in the GCSF treatment group.

Kang (2004) used granulocyte colony stimulating factor (GCSF) to increase the number of circulating hematopoietic stem cells in 27 participants with acute MI. The stem cells were harvested in a pheresis procedure and then injected into the coronary artery via a separate angioplasty and stenting procedure. While the therapy was associated with an improvement in cardiac function, the authors noted a high rate of in-stent restenosis in those receiving the GCSF and the trial was stopped.

Smits and colleagues (2003) reported on five individuals with symptomatic heart failure who were treated with direct intramyocardial injection of cultured skeletal myoblasts harvested from a quadriceps biopsy. Compared with baseline, an improvement was noted in ejection fraction and regional wall motion.

In 2006, Hendrikx reported on a small, randomized trial involving individuals with heart failure who received coronary artery bypass grafts (CABG) alone compared with CABG and intramyocardial autologous bone marrow infusions (BMC group). The primary end points were global left ventricular ejection fraction (LVEF) change and changes in the thickness of the infarcted cardiac walls. There was no significant difference in global LVEF between the groups with control baseline of 39.5 ± 5.5% and BMC baseline of 42.9 + 10.3%; (P=0.38). The LVEF increased at four months in the control group to 43.1 ± 10.9% versus 48.9 ± 9.5% (P=0.38) in the BMC group. Similarly, a study by Lunde and colleagues (2006) did not show a significant improvement of global left ventricular function with intracoronary infusion of autologous bone marrow.

In a randomized controlled study conducted in Russia and reported by Pokushalov (2009), 109 individuals with a prior history of myocardial infarction and end-stage chronic heart failure were randomized to intramyocardial transplantation of autologous bone marrow mononuclear cells (BMMC) or to an untreated control group. Inclusion criteria were a history of myocardial infarction greater than 12 months prior to enrollment, fixed perfusion defect on single photon emission computed tomography (SPECT) imaging, non-revascularizable, symptomatic on optimal medical therapy and left ventricular ejection fraction less than 35%. The 55 participants randomized to the treatment cohort were injected with BMMCs combined with medical therapy. Fifty-four individuals randomized to the control group were treated with optimal medical therapy alone. The primary endpoint measured was the change in the myocardial defects on SPECT imaging at rest and under pharmacological stress between baseline and follow-up at 6 and 12 months. A semi-quantitative 20-segment scoring system was used with a range of scores from 0 to 4 (0-normal activity, 4=no activity). Scores for each of 20 myocardial segments were added to yield summed stress and summed rest scores. The summed rest score in the treatment group improved after 12 months (30.2 ± 5.6 to 27.8 ± 5.1; p = 0.032) and the summed stress score also improved (34.5 ± 5.4 to 28.1 ± 5.2; p = 0.016). The stress and rest scores did not change significantly in the control group. No change in myocardial perfusion was noted in 12 (21.8%) of the participants in the treatment group, and 3 (5%) had deterioration. Secondary measures including New York Heart Association (NYHA) functional class, 6-minute walk, and frequency of daily angina significantly improved in the treatment group but not in the control group. The authors concluded that these promising early findings need to be repeated in randomized, double blind placebo-controlled studies using larger cohorts of participants.

Currently, there are multiple clinical trials in progress, and the majority of the trials are phases I and II. Treatment protocols have not been standardized and various sources of autologous cells are being studied. However, at this time, there is insufficient evidence to support the use of autologous cell transplantation or the infusion of growth factors as treatment of damaged myocardium.

From a basic science viewpoint, it must be shown that autologous cells, when transplanted into the heart, can 1) truly regenerate myocardium by incorporating themselves into the native tissue, surviving, differentiating, and ultimately electromechanically coupling to each other, or 2) serve as a trophic factor leading to survival of injured myocardial tissue and improved cardiac function through tissue preservation and ventricular remodeling. For example, preliminary studies have suggested that transplanted myoblasts are potentially arrhythmogenic. For this reason, two investigational device exemption (IDE) trials currently underway require that all individuals receive a cardiac defibrillator in order to participate. Additionally, selection criteria for this technology are still evolving, and two different groups are the focus of these IDE trials. One investigation involves individuals who are in the immediate post-infarct period, where it is believed autologous cell transplant might function to alter the cardiac remodeling process. The other population under investigation is comprised of individuals with congestive heart failure, where it is hypothesized that ACT may function to stimulate myocardial regenesis.

At this time, the medical evidence supporting the use of ACT in the peri-infarct period is limited to a few randomized controlled studies and a few case series with very small sample populations and very limited follow-up times. The use of ACT in individuals with congestive heart failure is limited to small case series studies with non-randomized controls. While there are some encouraging data, many questions are outstanding regarding the basic science of this technology as well as its clinical applications and the appropriate timing for the treatment. At this time, there is insufficient evidence to support the use of autologous cell transplantation.

Another method of ACT involves the infusion of growth factors, such as granulocyte colony stimulating factor (GCSF), with the intention of increasing the concentration of circulating hematopoietic stem cells as a treatment of damaged myocardium. At this time there is great uncertainty from pre-clinical trials as to the efficacy of this strategy. There have been limited studies addressing this technique in a clinical setting. In a report of one small randomized controlled trial comparing the use of bone marrow transplant to GCSF infusion for the treatment of individuals with acute myocardial infarction who had undergone recent angioplasty and stenting, the researchers ended the trial early. The authors reported that the GCSF group had a significantly higher rate of restenosis than the bone marrow group. The current medical evidence is insufficient to allow any conclusions regarding the use of this treatment method.

Description of Coronary Heart Disease (CHD)
The American Heart Association reports an estimated 17,600,000 people in the US suffer from coronary heart disease (CHD). Of these, 8,500,000 people have had at least one myocardial infarction (MI, or heart attack) and 10,200,000 suffer angina. Coronary vascular disease (CVD) is the most common cause of death in the United States. Coronary artery or CHD occurs when the flow of blood through one or more of the coronary arteries becomes inadequate. This results in oxygen deprivation in the heart muscle, and may eventually result in heart attack or even death (Lloyd-Jones, 2010).

Description of Technology(s)
Autologous cell transplantation (ACT) for the treatment of damaged myocardium involves the transplantation of various types of cells into a damaged heart with the goal of replacing damaged heart muscle or to assist in the healing process. Various types of ACT have been researched to either stimulate regeneration of the heart muscle or modify ventricular remodeling post-infarct. For example, it is thought that after an MI an increased number of hematopoietic stem cells are released into the circulation and then engrafted into the heart. While these stem cells do not normally result in effective myocardial regeneration, it is theorized that enhancement of this process through a form of ACT, medical augmentation of stem cell production with granulocyte colony stimulating factor (GCSF) might result in improved cardiac regeneration or remodeling.

In humans, skeletal myoblasts, harvested from a muscle biopsy, or hematopoietic stem cells, harvested from the bone marrow or peripheral blood, or mesenchymal stem cells, harvested from the bone marrow have also been investigated as cell sources for ACT. The harvested cells can be transplanted in a variety of ways, frequently as an adjunct to coronary artery bypass surgery; for example, either by injecting directly into the nonfunctional heart muscle, or injecting into a coronary artery or coronary sinus. It is theorized that through the release of chemokines released by the heart, circulating hematopoietic stem cells may have a natural homing ability to reach damaged myocardium.

The proposed benefits of ACT for the treatment of damaged myocardium are improved heart function, restored myocardial viability and potentially extended lifespan.

At this time the risks of ACT for the treatment of damaged myocardium are unknown. Insufficient and conflicting data have been reported to allow a proper understanding of how this technology may affect individuals either in the short or long term. However, there are known risks related to the various methods utilized to harvest and transplant autologous cells, including pain, hemorrhage, cardiac arrest, and death.

Autologous cell therapy: A medical treatment involving the transplantation of various types of cells harvested from the individual and then returned to them in a unique manner. This treatment may involve one or several types of cells and has been proposed for a wide variety of conditions.

Growth factors: A group of substances produced by the body that stimulate the survival, proliferation, differentiation and function of specific cells or tissues in the body. One example is granulocyte colony stimulating factor (GCSF), which stimulates the production of a certain type of white blood cell.

Hematopoietic stem cells: A type of cell from which blood cells are created.

Mesenchymal stem cells: A type of bone marrow derived cell from which muscles are created.

Myocardium: The medical term for the heart muscle.

Progenitor cells: Primitive cells capable of replication, differentiation and formation into mature cells.

Skeletal myoblasts: A type of cell from which skeletal muscle fibers are created.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

When services are Investigational and Not Medically Necessary:
For the following procedure and diagnosis codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary: 

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Abbott JD, Giodano FJ. Stem cells and cardiovascular disease. J Nucl Cardiol. 2003; 10(4):403-412.
2. Assmus B, Honold J, Schächinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med. 2006; 355(12):1222-1232.
3. Assmus B, Schachinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation. 2002; 106(24):3009-3017.
4. Fan L, Chen L, Chen X, and Fu F. A meta-analysis of stem cell mobilization by granulocyte colony-stimulating factor in the treatment of acute myocardial infarction. Cardiovasc Drugs Ther. 2008; 22:45-54.
5. Forrester JS, Price MJ, Makkar RR. Stem cell repair of infarcted myocardium: an overview for clinicians. Circulation. 2003; 108(9):1139-1145.
6. Hendrikx M, Hensen K, Clijsters C, et al. Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation. 2006; 114(1 Suppl):I101-I107.
7. Herreros J, Prosper F, Perez A, et al. Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. Eur Heart J. 2003; 24(22):2012-2020.
8. Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet. 2006; 367(9505):113-121.
9. Kang HJ, Kim HS, Zhang SY, et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet. 2004; 363(9411):751-756.
10. Kang S, Yang Y, Li CJ, and Gao RG. Effectiveness and tolerability of administration of granulocyte colony-stimulating factor on left ventricular function in patients with myocardial infarction: a meta-analysis of randomized controlled trials. Clin Therapeutics. 2007; 29(11):2406-2418.
11. Kuethe F, Richartz BM, Kasper C, et al. Autologous intracoronary mononuclear bone marrow cell transplantation in chronic ischemic cardiomyopathy in humans. Int J Cardiol. 2005; 100(3):485-491.
12. Lee MS, Makkar RR. Stem cell transplantation in myocardial infarction: a status report. Ann Intern Med. 2004; 140(9):729-737.
13. Lloyd-Jones D, Adams RJ, Brown TM, et al., on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics 2010 update. A report from the American Heart Association. Circulation. 2010; 121(7):e46-e215.
14. Losordo DW, Schatz RA, White CJ, et al. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation. 2007; 115(25):3165-3172.
15. Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2007; 355(12):1199-1209.
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21. Pokushalov E, Romanov A, Chernyavsky A, et al. Efficiency of intramyocardial injections of autologous bone marrow mononuclear cells in patients with ischemic heart failure: a randomized study. J Cardiovasc Transl Res. 2010; 3(2):160-168.
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25. Schächinger V, Erbs S, Elsässer A, et al., REPAIR-AMI Investigators. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J. 2006; 27(23):2775-2783.
26. Siminiak T, Kalawski R, Fiszer D, et al. Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up. Am Heart J. 2004; 148(3):531-537.
27. Smits PC, van Geuns RJ, Poldermans D, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol. 2003; 42(12):2063-2069.
28. Stamm C, Westphal B, Kleine HD. et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet. 2003; 361(9351):45-46.
29. Strauer BE, Brehm M, Zeus T, et al. Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease: the IACT Study. J Am Coll Cardiol. 2005; 46(9):1651-1658.
30. Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002; 106(15):1913-1938.
31. Tendera M, Wojakowski W. Clinical trials using autologous bone marrow and peripheral blood-derived progenitor cells in patients with acute myocardial infarction. Folia Histochem Cytobiol. 2005; 43(4):233-235.
32. Traverse JH, McKenna DH, Harvey K, et al. Results of a phase 1, randomized, double-blind, placebo-controlled trial of bone marrow mononuclear stem cell administration in patients following ST-elevation myocardial infarction. Am Heart J. 2010; 160(3):428-434.
33. Wojakowski W, Tendera M, Michalowsa A, et al. Mobilization of CD34/CXCR4+, CD34/CD117+, c-met+ stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction. Circulation. 2004; 110(20):3213-3220.
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35. Zohlnhöfer D, Dibra A, Koppara T, et al. Stem cell mobilization by granulocyte colony-stimulating factor for myocardial recovery after acute myocardial infarction. J Am Coll Cardiol. 2008; 51(15):1429-1437.
36. Zohlnhöfer D, Ott I, Mehilli J, et al., REVIVAL-2 Investigators. Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA. 2006; 295(9):1003-1010.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Blue Cross Blue Shield Association. Autologous progenitor cell therapy for the treatment of ischemic heart disease. TEC Assessment. 2008; 23(4).
2. Martin-Rendon E, Brusnkill S, Doree C, et al. Stem cell treatment for acute myocardial infarction. Cochrane Database of Systemic Reviews. 2008; 4; CD006536.

1. American Heart Association. Available at: http://www.americanheart.org. Accessed on December 8, 2010.
2. National Heart, Lung, and Blood Institute. What Is Heart Failure? January 2010. Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/Hf/HF_WhatIs.html. Accessed on December 8, 2010.
3. National Heart, Lung, and Blood Institute. What is Coronary Artery Disease? February 2009. Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/Cad/CAD_WhatIs.html. Accessed on December 8, 2010.

Autologous Cell Therapy for the Treatment of Damaged Myocardium
Cellular Cardiomyoplasty
Heart - Autologous Cell Therapy for Damaged Myocardium
Myocardial Damage, Autologous Cell Transplantation for
Myocath™
Myocell™

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.