Stem Cells in Cardiac Repair

Robert J Henning

Disclosures

Future Cardiol. 2011;7(1):99-117. 

In This Article

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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