Stem Cells in Cardiac Repair

Robert J Henning

Future Cardiol. 2011;7(1):99-117.

Conclusion & Future Perspective

Although different stem cells are available for cardiac repair, the optimal stem cell for the treatment of all patients with infarcted myocardium remains to be determined. The optimal stem cell should permit transplantation into different patients without requirements for immunosuppression therapy.

Each type of stem cell discussed in this article has benefits, but also disadvantages and limitations, which restrict their application to all patients with heart disease. hESCs are pluripotent, but techniques must be developed to isolate and propagate hESCs without destroying or harming the human embryos in order to ensure adequate supply and availability of these cells for patient care. Autologous skeletal myoblasts must be bioengineered prior to transplantation into the heart in order to express β-myosin, which is characteristic of cardiac myocytes, and gap-junction proteins, to facilitate communication between skeletal myocytes and cardiomyocytes. The optimal bone marrow stem cell for transplantation must be identified that will protect and possibly regenerate myocytes and induce neovascularization. In addition, new techniques must be developed to enhance the survival and propagation of bone marrow cells from older patients with ischemic heart disease and other chronic diseases prior to transplantation into hearts. Moreover, these cells must be propagated without inducing neoplastic differentiation. Since cardiac progenitor cells in hearts significantly diminish with patient aging, techniques must be developed for the efficient propagation and maintenance of cardiospheres from patients, while avoiding the development of teratomas. In vitro priming of stem cells with growth factor cocktails prior to transplantation in the myocardium should be investigated thoroughly in order to enhance stem cell survival, engraftment and transdifferentiation to functional cardiomyocytes that connect with host cardiomyocytes without producing adverse effects.^[100]

Once an optimal stem cell is identified, cell banks should be established that provide readily available, undifferentiated, but accurately characterized, allogeneic stem cells that have significant capacity for in vitro and in vivo propagation for the treatment of patients with heart disease. The optimal timing of stem cell transplantation into patients' hearts after myocardial infarction must be investigated systematically to determine the best time for cell transplantation, in order to maximize chemoattraction of stem cells to ischemic and infarcted myocardium, and facilitate myocardial healing. In this regard, the repeated administration of stem cells to patients will probably be necessary via intracoronary or intravenous injections and should be investigated.

Enhancement of cell engraftment in the heart is mandatory for optimizing the therapeutic benefits of stem cells. Currently, only approximately 1–10% of the stem cells remain in the heart 1–2 h after injection into the beating heart.^[101,102] More than 90% of injected cells migrate to other organs, and substantially less than 10% of the transplanted cells are identified in the heart 4 weeks after transplantation.^[101] Potential treatment strategies to ensure that stem cells remain in the myocardium include preconditioning stem cells with heat shock, coadministering anti-inflammatory drugs and free-radical scavengers with stem cells, insertion or overexpression of antiapoptotic proteins in stem cells, and codelivery of stem cells with extracellular matrix molecules, nanofibers or fibrin glues.^[24]

Investigations must determine the optimal number of stem cells for transplantation and the optimal technique (intramyocardial, intracoronary or intravenous) for injecting stem cells for cardiac repair. With intracoronary injections, large numbers of MSCs can cause cell clumping and microinfarctions. Multiple intramyocardial injections can be associated with high rates of stem cell leakage from the myocardium, disruption of the extracellular matrix and scar formation, thereby potentiating the formation of arrhythmogenic foci. Although some stem cells injected intravenously do reach the heart, many stem cells become lodged in the lungs. Consequently, with intravenous injections, the number of stem cells required for cardiac repair can be fourfold greater than the numbers required for intramyocardial or intracoronary injection for cardiac repair.^[92] Therefore, strategies must be developed to facilitate the homing to the heart of stem cells that are injected intravenously.

Significant discrepancies between the paucity of stem cells engrafted in the heart and the improvement in heart function that occurs with cell therapy suggest that the beneficial effects of stem cells may not be due to replacement of ischemic and infarcted cardiomyocytes but, rather, to the release of biologically active growth factors and anti-inflammatory cytokines, which protect cardiomyocytes and vascular endothelial cells in the injured myocardium. Stem cell paracrine mechanisms may limit myocyte apoptosis/necrosis and extracellular matrix remodeling, stimulate angiogenesis and recruit native stem cells to the damaged myocardium. Consequently, growth factors and anti-inflammatory cytokines secreted by stem cells must be identified, expanded and investigated as new pharmacologic therapies for cardiac repair.

Imaging and hemodynamic measurement end points must be selected and uniformly employed to demonstrate benefit, permit comparisons of different stem cell investigations and provide insights into stem cell mechanisms of action. Ideally, MRI should be uniformly employed to measure changes in cardiac regional wall motion, ejection fraction, and ventricular end-systolic and end-diastolic volumes.

Although the increases in cardiac LV ejection fraction with stem cell therapy are modest, they are comparable to what has been reported with pharmacology therapy and with angioplasty in patients with myocardial infarctions and ischemic cardiomyopathies.^[103] In the Valsartan in Acute Myocardial Infarction (VALIANT) study, treatment with valsartan increased the LV ejection fraction 1.3 ± 6.7%, while treatment with captopril increased the LV ejection fraction by 2.7 ± 7.2% and combined valsartan and captopril treatment increased the LV ejection fraction by 1.9 ± 7.3%.^[104] In the Intravenous Streptokinase in Acute myocardial Infarction (ISAM) trial, the LV ejection fractions in patients treated initially with thrombolytic therapy averaged 56.8 ± 0.7% in the streptokinase group versus 53.9 ± 0.7% in control patients.^[105] In a comparison of streptokinase with acute coronary angioplasty in the treatment of acute myocardial infarction, LV ejection fraction was 45 ± 12% in patients treated with streptokinase and 51 ± 11% in patients with acute angioplasty.^[106] Moreover, the LV ejection fraction increased only 2.8% in the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complication Trial (CADILLAC) and 4.1% in the Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term follow-up Trial (ADMIRAL).^[107,108] Consequently, the increases in cardiac function with stem cell therapy are comparable to pharmacologic therapy and angioplasty for treatment of acute myocardial infarction.

Although increases in LV ejection fraction with cell therapy reported to date are modest, the clinical end points based on 5-year follow-up studies of patients treated with intracoronary autologous bone marrow cells after myocardial infarction are not. In patients treated with bone marrow cells, a modest but significant increase in LV ejection fraction, and a decrease in infarct size in patients at 3 months and 1 year, resulted in greater exercise capacity and lower mortality at 5 years in comparison with patients not treated with bone marrow cells.^[109] In a study of patients with chronic heart failure due to ischemic heart disease, who were followed for 5 years, bone marrow cell therapy increased ventricular performance, quality of life and survival.^[110]

Additional basic science, preclinical and clinical studies are required in order to address and answer unresolved issues regarding stem cells in cardiac repair. This will require close cooperation and interaction of basic scientists and clinicians. Cell-based cardiac repair in the 21st century will offer new hope for millions of patients worldwide with heart disease who would otherwise suffer from the inexorable progression of heart disease to heart failure and death.

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Acknowledgements
The author thanks Mary Geesey for her assistance with this manuscript.
Due to space limitations the author could not include all the relevant papers that have been published on stem cells and heart disease.

Financial & competing interests disclosure
This work was supported in part by resources of the James A. Haley VA Hospital, the Muscular Dystrophy Association and by the Bugher Foundation. RJ Henning is a cardiology consultant at Veterans Affair Medical Center (Tampa, FL, USA). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Cite this: Stem Cells in Cardiac Repair - Medscape - Jan 01, 2011.

Table 1. Skeletal myoblast studies in patients with heart disease.
Study	Patients (n)	Randomized double-blind	Cell dose	CABG	Findings	Ref.
Menasche et al.	10	No	871 × 10⁶ CD56⁺: 86%	Yes	LV segment contraction increased 63%; EF increased 8%; 4 patients with VTach	[25]
Herreros et al.	12	No	221 × 10⁶ CD56⁺: 65.6%	Yes	Increased LV segment contraction; EF increased 18%; increased ¹⁸F-FDG PET metabolism	[26]
Siminiak et al.	10	No	4 × 10⁵–10⁷ Desmin⁺: 65%	Yes	Increased LV segment contraction; EF increased 7%; 4 patients with VTach	[27]
Menasche et al.	97	Yes	400–800 × 10⁶ CD56⁺: ≥50%	Yes + AICD	Treated = controls; 4 patients with VTach	[28]
Dib et al.	24	No	10⁷–10⁸	Yes	EF increased 7–8% at 12–24 months; 3 patients with VTach	[31,32]

AICD: Automatic implantable cardioverter defibrillators; CABG: Coronary artery bypass surgery; EF: Ejection fraction; FDG: Fluoro-D-glucose; LV: Left ventricle; VTach: Ventricular tachycardia.

Table 2. Bone marrow and circulating progenitor cells in coronary artery disease patients.
Study	Patients (n)	Randomized	Time post-PCI and/or MI	Cell dose	Injection route	Baseline LVEF (%)	LVEF change (%)	Duration (months)	Other findings	Ref.
Assmus et al.	92	Yes	2348–2470 days	22 ± 10⁶CPC 205 ± 110 × 10⁶ BMC	IC	CPC 39 ± 10; BMC 41 ± 11	CPC: −0.4 BMC: +2.9	3	Patients with previous MI; increased LVEF in BMC but not CPC	[41]
Bartunek et al.	35	Cohort	10 days	12.6 ± 2.2 × 10⁶	IC	45 ± 2.5	+7	4	Increased LV regional function, perfusion and restenosis	[42]
Chen et al.	69	Yes	18.4 ± 0.5 days	8–10 × 10⁹	IC	49 ± 9	+18	6	Increased LVEF by ventriculogram; increased perfusion; decreased ESV	[43]
Erbs et al.	26	Yes	225 ± 87 days	69 ± 14 × 10⁶	IC	51.7 ± 3.7	+7.2	3	Patients with chronic CAD occlusion Rx with CPC; EF by MRI; infarct size decreased 16%	[44]
Ge et al.	20	Yes	1 day	39 ± 22 × 10⁶	IC	53.8 ± 9.2	+4.8	6	Increased perfusion by SPECT	[45]
Hendrikx et al.	20	Yes	217 ± 162 days	60 ± 31 × 10⁶	IM	42.9 ± 10.3	+5	4	CABG in patients with previous CAD; increased regional but not global LV function; 6/9 with induced VTach	[46]
Janssen et al.	67	Yes	1 day	172 × 10⁶	IC	48.5 ± 7.2	+3.3	4	Decreased infarct size	[47]
Kang et al.	96	Yes	<14 days AMI; >14 days OMI	1–2 × 10⁹	IC	52.0 ± 9.9	+5.1 AMI	6	G-CSF for 3 days; decreased ESV and infarct size in AMI; = EF, ESV and infarct size in OMI	[48]
Katritsis et al.	22	Cohort	224 ± 464 days	2–4 × 10⁶	IC	39.7 ± 9.3	+1.6	4	Increased regional but not global LV function	[49]
Lunde et al.	100	Yes	6 ± 1.3 days	68 × 10⁶ (median) 54–130 × 10⁶	IC	41.3 ± 11.0	=	6–12	Increased LVEF in treated and controls; = EDV and infarct size	[50,51]
Meyer et al.	60	Yes	4.8 ± 1.3 days	24.6 ± 9.4 × 10⁸	IC	50 ± 10	+5.9	18 ± 6	Increased LVEF by MRI significantly at 6 but not at 18 months	[52]
Mocini et al.	36	Cohort	AMI <6 months	292 ± 232 × 10⁶	IM	46 ± 6	+5	3–12	CABG in all; troponin increased	[53]
Perin et al.	20	Cohort	ICM	25.5 ± 6.3 × 10⁶	IM trans-endocardial	30 ± 6	+5.1	12	LVEF = controls; increased LV perfusion and exercise	[54]
Ruan et al.	20	Yes	~1 day	NR	IC	53.5 ± 5.8	+5.8	6	Increased LV segmental contraction	[55]
Schachinger et al.	204	Yes	3–8 days	2.4 × 10⁸	IC	48.3 ± 9.2	+6–7	4–12	Increased EF when Rx >4 days post-MI and when EF ≤49%; increased LV perfusion	[56,57]
Strauer et al.	20	Cohort	5–9 days	2.8 ± 2.2 × 10⁷	IC	57 ± 8	+5	3	Increased regional but not global LVEF; decreased ESV and infarct size	[58]
Strauer et al.	36	Cohort	823 ± 945 days	9.0 × 10⁷	IC	52 ± 9	+8	3	Decreased infarct size 30%; increased VO₂ max	[59]
Li et al.	70	Yes	7 ± 5 days	7.3 ± 7.3 × 10⁷	IC	50 ± 8.2	+7	6	G-CSF for 5 days; decreased LV ESV; decreased LV wall motion score	[60]

=: No change; AMI: Acute myocardial infarction; BMC: Bone marrow cell; CABG: Coronary artery bypass surgery; CPC: Circulating progenitor cell; EF: Ejection fraction; ESV: End-systolic volume; G-CSF: Granulocyte colony-stimulating factor; IC: Intracoronary injection; ICM: Ischemic cardiomyopathy; IM: Intramyocardial injection; LVEF: left ventricular ejection fraction; NR: Not recorded; OMI: Old myocardial infarction; PCI: Percutaneous coronary intervention; Rx: Treatment; SPECT: Single photon emission computer tomography; VTach: Ventricular tachycardia.
Adapted, in part, with permission from the American Medical Association Copyright.

Table 3. Human bone marrow studies in patients with acute myocardial infarction.
Study	Patients (n)	Randomized	Time post-MI (days)	Cell dose	Baseline LVEF (%)	LVEF change (%)	Duration (months)	Other findings	Ref.
Strauer et al.	20	Cohort	8	2.8 ± 2.2 × 10⁷	57 ± 8	+5	3	Increased regional but not global LVEF; decreased LV ESV and infarct size	[58]
Bartunek et al.	35	Cohort	10	12.6 ± 2.2 × 10⁶	45 ± 2.5	+7	4	Increased LV regional function, perfusion and restenosis	[42]
Li et al.	70	Cohort	6	7.3 ± 7.3 × 10⁷	50 ± 8.2	+7	6	Decreased LV ESV, LV wall motion score	[60]
Janssen et al.	67	Yes	1	172 × 10⁶	48.5 ± 7.2	+3.3	4	Decreased infarct size	[47]
Wollert et al.	60	Yes	4.8	24.6 × 10⁸	50.0 ± 10.0	=	6–18	Increased LVEF at 6 but not at 18 months	[37,38]
Kang et al.	96	Yes	4	1–2 × 10⁹	52.0 ± 9.9	+5.1 AMI	6	Decreased LV ESV and infarction in acute MI; = ESV and = OMI	[48]
Lunde et al.	100	Yes	6	68 × 10⁶	41.3 ± 11.0	=	6–12	Increased LVEF in treated and controls; = EDV and infarct size	[50,51]
Ge et al.	20	Yes	1	4 × 10⁷	53.8 ± 9.2	+4.8	6	Increased LV regional wall perfusion by SPECT	[45]
Meluzin et al.	66	Yes	5–9	10⁷–10⁸	42 ± 2	+3–5	3–12	LVEF increased 3% with 10⁷; LVEF increased 5–7% with 10⁸ at 3–12 months	[62,63]
Schachinger et al.	204	Yes	3–8	2.4 × 10⁸	48.3 ± 9.2	+6–7	4–12	Increased EF when Rx >4 days post-MI and when EF <49%; increased LV perfusion	[56,57]

=: No change; AMI: Acute myocardial infarction; BMC: Bone marrow cell; CPC: Circulating progenitor cell; EF: Ejection fraction; ESV: End-systolic volume; G-CSF: Granulocyte colony-stimulating factor; IC: Intracoronary injection; ICM: Ischemic cardiomyopathy; IM: Intramyocardial injection; LVEF: left ventricular ejection fraction; OMI: Old myocardial infarction; SPECT: Single photon emission computer tomography.

Sidebar

Executive Summary

Cardiovascular investigators are currently exploring the use of human embryonic stem cell (hESCs), skeletal myoblasts, and adult bone marrow stem cells to limit infarct size and regenerate myocardium in damaged hearts in research animals and in patients.
hESCs are pluripotent cells that can regenerate myocardium in infarcted hearts, attenuate heart remodeling and contribute to left ventricular systolic-force development. However, large quantities of hESCs-cardiac progenitor cells must be generated, immune rejection must be prevented and the grafts must survive over the long term to significantly improve myocardial contraction.
Autologous skeletal myoblasts can survive in infarcted myocardium in small numbers, proliferate, differentiate into skeletal myofibers and increase the left ventricle (LV) ejection fraction. Skeletal myoblasts do not form electromechanical connections with host cardiomyocytes. Consequently, electrical re-entry can occur in skeletal muscle transplanted into hearts and cause cardiac arrhythmias.
Patients with coronary disease who received autologous bone marrow cells, which contain hematopoietic and mesenchymal stem cells, show significant 3.7% (range: 1.9–5.4%) increases in LV ejection fraction, decreases in LV end-systolic volume of −4.8 ml (range: −1.4 to −8.2 ml) and reductions in infarct size of 5.5% (range: −1.9 to −9.1%) without experiencing cardiac arrhythmias.
Transdifferentiation of bone marrow cells into cardiac myocytes occurs infrequently. Rather, bone marrow cells appear to release biologically active factors that limit myocardial damage. The biologically active factors released by stem cells must be identified and investigated as new pharmacologic therapies for cardiac repair.
Although different stem cells are available for cardiac repair, the optimal stem cell for the treatment of all patients with infarcted myocardium remains to be determined. The optimal timing of stem cell transplantation after myocardial infarction must be determined. The optimal number of stem cells for transplantation, and the optimal technique (intramyocardial, intracoronary or intravenous injection) for injecting stem cells for cardiac repair, must be determined.

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