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ORIGINAL ARTICLE |
Division of Cellular & Molecular Cardiology
1 Department of Cardiovascular & Thoracic Surgery
2 The Achutha Menon Centre for Health Science Studies, Sree Chitra Tirunal Institute for Medical Sciences & Technology Trivandrum – 695011, India
Chandrasekharan C Kartha, MD, Tel: +91 471 2524608, Fax: +91 471 2446433, Email: cckartha{at}yahoo.com, Division of Cellular & Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram – 695011, India.
ABSTRACT
Recent animal studies and clinical trials have reported the scope of heart-resident ckit-positive stem cells in regenerating infarcted myocardium. The determinants of successful isolation of such cells are unknown. The objective of this study was to determine the influence of risk factors for coronary artery disease and disease severity on the successful isolation of ckit-positive cells from right atrial tissue of patients with coronary artery disease. The findings suggest that coronary artery disease and cardiac remodeling in chronic ischemia may not affect the yield of ckit-positive cells from atrial tissue, but a significant negative correlation between the age of the patient and the number of migrated ckit-positive cells was observed. This suggests that in older patients, stem cell isolation from cardiac biopsies may not succeed, and such cells may not be available for cell therapy.
Key Words: Adult Stem Cells • Coronary Artery Disease • Risk Factors
INTRODUCTION
Beltrami and colleagues1 demonstrated the presence of ckit-positive cells in postnatal hearts. Subsequently, they provided evidence that this subpopulation of cells can be isolated from mouse heart, grown in vitro in sufficient numbers, and injected into mouse heart to repopulate infarcted regions of the myocardium with cardiocytes and blood vessels.2 Recently, stem cells have been isolated from endomyocardial biopsies obtained from cardiac transplant patients. These cells are cardiogenic in vitro and have been shown to promote cardiac regeneration and improve cardiac function in a nude mouse infarct model. These observations provide hope for adult heart-derived stem cell therapy in patients with ischemia and chronic heart failure. It is not yet clear whether the yield of ckit+ cells from cardiac tissue is influenced by disease severity or risk factors in patients with chronic coronary artery disease.
Therefore, we examined the effects of patient characteristics, including coronary artery disease severity and risk factors, on the yield of ckit+ cells from adult human heart.
PATIENTS AND METHODS
The study group comprised 30 patients aged 38–72 years who had undergone coronary artery bypass grafting at our institute (Table 1
). The study was approved by the institutional ethics committee, and right atrial samples were obtained from patients after obtaining their informed consent. Cardiovascular risk factors were defined as follows. Smoking was a history of smoking for more than 2 years. Hypertension was repeatedly elevated blood pressure with systolic pressure >140 mm Hg and diastolic pressure >90 mm Hg for more than 1 year. Diabetes was the need for oral anti-diabetic drug therapy or insulin use. Dyslipidemia was defined as low density lipoprotein >130 mg·dL–1, high density lipoprotein <40 mg·dL–1, triglycerides >150 mg·dL–1, and total cholesterol >200 mg·dL–1. The total vascular risk score was calculated for each patient by considering hypertension, diabetes, smoking, and dyslipidemia, as reported earlier.3 Patients were grouped depending on the presence or absence of individual risk factors as well as according to the severity of coronary artery occlusion (number of affected coronary arteries assessed during coronary angiography), functional class, mitral regurgitation, wall motion abnormalities, total vessel blockage, involvement of the right coronary artery, and intake of drugs. The clinical profile of the study group is given in Table 1.
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Data are expressed as mean ± standard deviation. Comparisons of means among groups were performed by one-way analysis of variance. Bivariate correlation and single linear regression were undertaken to assess the relationship between cardiac stem cell counts and age. A p value of 0.05 or less was considered statistically significant.
RESULTS
Small round phase-bright cells were seen migrating from adherent tissue explants grown from right atrial samples collected from all patients in the study. The cells formed cardiospheres when grown in a medium supplemented with growth factors. These cells stained positive for ckit and MDR1 in FACS. However, the number of migrated cells varied significantly among the explant cultures. Cardiosphere-derived cells stained positively for ckit, MDR1, CD34, and the cardiac differentiation markers cTNI and MHC.4 Cardiovascular risk factors and other clinical parameters did not seem to affect the number of ckit+ cells migrating from explanted atrial tissue samples. The number of migrating cells was also unaffected by any of the drugs taken by the patients (Table 2). Among the various clinical parameters analyzed, only the age of the patient had a statistically significant relationship with the stem cell number (p 
0.05, r = –0.419; Figure 1).
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Recent animal studies and clinical trials have reported the scope of heart-resident ckit+ stem cells in regenerating infarcted myocardium. The determinants of successful isolation of such cells are however unknown. The evidence reported here suggests that coronary artery disease and cardiac remodeling in chronic ischemia may not affect the yield of ckit+ cells from atrial tissue. Our findings support current pursuits in developing cardiac regenerative therapy in patients with coronary artery disease, using autologous stem cells isolated and grown from cardiac biopsies.
Embryonic stem cells, bone marrow-derived stem cells, mesenchymal stem cells, skeletal myoblasts, and circulating endothelial progenitor cells have all been assessed for myocardial regeneration, both in animals and humans.6–9 Recently, it has been demonstrated that ckit+ cells isolated from small myocardial samples (so-called cardiac stem cells) are also possibly capable of efficient myocardial repair.10 Compared to other cell types, autologous adult cardiac stem cells are considered more efficient in rebuilding damaged myocardium.11 They have the advantage of being non-immunogenic, and they might not undergo malignant transformation as may happen with cells derived from embryos. Anversa and colleagues12 showed that stem cells isolated from cardiac biopsies are functionally competent and grow in vivo when grafted into a recipient heart, thus indicating the therapeutic possibilities of using cardiac-derived stem cells in myocardial ischemia or end-stage heart disease. Be that as it may, several issues remain to be clarified before the clinical utility of heart-derived stem cells is accepted.13 Among these is the concern that the population of resident stem cells in cardiac tissue may be affected by the factors responsible for coronary artery disease or myocardial disease. Alterations, if any, in the population of stem cells in the heart would influence the success of stem cell isolation from cardiac biopsies, and thus hamper the clinical utility of such treatment. Our findings embolden the efforts to develop a strategy for myocardial regeneration in patients with coronary artery disease, using autologous stem cells isolated from cardiac biopsies.
Our observations are interesting given the contrasting observations on circulating endothelial progenitor cells. There is increasing evidence that patients at risk of coronary artery disease have decreased numbers of circulating progenitor cells, and thus impaired vasculogenesis.14,15 Cardiovascular risk factors and the number of stenosed coronary arteries also seem to relate to the formation of functional circulating progenitor cells in culture.16,17 A decline in endothelial progenitor cell number and function with age has been reported.18 This was attributed to loss of functional telomeres in the absence of telomerase activity, which is a major cause of loss of proliferative capacity in mammalian cells.19,20 Our data illustrate a similar significant inverse correlation between patient age and cardiac stem cell yield from atrial biopsies. This suggests that in older patients, stem cell isolation from cardiac biopsies may not succeed, and such cells may not be available to them for cell therapy.
We have provided evidence for the first time that the yield of stem cells from cardiac biopsies is not influenced by either disease severity or risk factors for coronary artery disease. Except in older patients, isolation of stem cells from adult heart tissue could provide an avenue for developing regenerative cell therapy in patients with coronary artery disease.
ACKNOWLEDGMENTS
The studies were supported by a grant from the Department of Biotechnology, Government of India. We are thankful to the Director, Sree Chitra Tirunal Institute for Medical Sciences and Technology, for providing the necessary facilities to perform the study. We thank the Medical Records Department of the institute for providing the patients’ data.
REFERENCES
Asian Cardiovasc Thorac Ann 2009;
17:139-142
© 2009 by SAGE Publications
DOI: 10.1177/0218492309103292
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