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Neovasculogenic therapy to augment perfusion and preserve viability in ischemic cardiomyopathy.
Ann Thorac Surg. 2006 May; 81(5):1728-36.AT

Abstract

BACKGROUND

Ischemic cardiomyopathy is a global health concern with limited therapy. We recently described endogenous revascularization utilizing granulocyte-macrophage colony stimulating factor (GMCSF) to induce endothelial progenitor cell (EPC) production and intramyocardial stromal cell-derived factor-1alpha (SDF) as a specific EPC chemokine. The EPC-mediated neovascularization and enhancement of myocardial function was observed. In this study we examined the regional biologic mechanisms underlying this therapy.

METHODS

Lewis rats underwent left anterior descending coronary artery (LAD) ligation and developed ischemic cardiomyopathy over 6 weeks. Three weeks after ligation, the animals received either subcutaneous GMCSF and intramyocardial SDF injections or saline injections as control. Six weeks after LAD ligation circulating EPC density was studied by flow cytometry. Quadruple immunofluorescent vessel staining for mature, proliferating vasculature was performed. Confocal angiography was utilized to identify fluorescein lectin-lined vessels to assess perfusion. Ischemia reversal was studied by measuring myocardial adenosine triphosphate (ATP) levels. Myocardial viability was assayed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling detection of apoptosis and quantitation of myofilament density.

RESULTS

The GMCSF/SDF therapy enhanced circulating leukocyte (13.1 +/- 4.5 x 10(6) vs 3.1 +/- 0.5 x 10(6)/cc, p = 0.001, n = 6) and EPC (14.2 +/- 6.6 vs 2.2 +/- 2.1/cc, p = 0.001, n = 6) concentrations. Tetraimmunofluorescent labeling demonstrated enhanced stable vasculature with this therapy (39.2 +/- 8.1 vs 25.4 +/- 5.1%, p = 0.006, n = 7). Enhanced perfusion was shown by confocal microangiography of borderzone lectin-labeled vessels (28.2 +/- 5.4 vs 11.5 +/- 3.0 vessels/high power field [hpf], p = 0.00001, n = 10). Ischemia reversal was demonstrated by enhanced cellular ATP levels in the GMCSF/SDF borderzone myocardium (102.5 +/- 31.0 vs 26.9 +/- 4.1 nmol/g, p = 0.008, n = 5). Borderzone cardiomyocyte viability was noted by decreased apoptosis (3.2 +/- 1.4% vs 5.4 +/- 1.0%, p = 0.004, n = 10) and enhanced cardiomyocyte density (40.0 +/- 5.6 vs 27.0 +/- 6 myofilaments/hpf, p = 0.01, n=10).

CONCLUSIONS

Endogenous revascularization for ischemic cardiomyopathy utilizing GMCSF EPC upregulation and SDF EPC chemokinesis upregulates circulating EPCs, enhances vascular stability, and augments myocardial function by enhancing perfusion, reversing cellular ischemia, and increasing cardiomyocyte viability.

Authors+Show Affiliations

Division of Cardiothoracic Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16631663

Citation

Atluri, Pavan, et al. "Neovasculogenic Therapy to Augment Perfusion and Preserve Viability in Ischemic Cardiomyopathy." The Annals of Thoracic Surgery, vol. 81, no. 5, 2006, pp. 1728-36.
Atluri P, Liao GP, Panlilio CM, et al. Neovasculogenic therapy to augment perfusion and preserve viability in ischemic cardiomyopathy. Ann Thorac Surg. 2006;81(5):1728-36.
Atluri, P., Liao, G. P., Panlilio, C. M., Hsu, V. M., Leskowitz, M. J., Morine, K. J., Cohen, J. E., Berry, M. F., Suarez, E. E., Murphy, D. A., Lee, W. M., Gardner, T. J., Sweeney, H. L., & Woo, Y. J. (2006). Neovasculogenic therapy to augment perfusion and preserve viability in ischemic cardiomyopathy. The Annals of Thoracic Surgery, 81(5), 1728-36.
Atluri P, et al. Neovasculogenic Therapy to Augment Perfusion and Preserve Viability in Ischemic Cardiomyopathy. Ann Thorac Surg. 2006;81(5):1728-36. PubMed PMID: 16631663.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neovasculogenic therapy to augment perfusion and preserve viability in ischemic cardiomyopathy. AU - Atluri,Pavan, AU - Liao,George P, AU - Panlilio,Corinna M, AU - Hsu,Vivian M, AU - Leskowitz,Matthew J, AU - Morine,Kevin J, AU - Cohen,Jeffrey E, AU - Berry,Mark F, AU - Suarez,Erik E, AU - Murphy,Danielle A, AU - Lee,William M F, AU - Gardner,Timothy J, AU - Sweeney,H Lee, AU - Woo,Y Joseph, PY - 2005/09/05/received PY - 2005/11/28/revised PY - 2005/12/01/accepted PY - 2006/4/25/pubmed PY - 2006/5/26/medline PY - 2006/4/25/entrez SP - 1728 EP - 36 JF - The Annals of thoracic surgery JO - Ann Thorac Surg VL - 81 IS - 5 N2 - BACKGROUND: Ischemic cardiomyopathy is a global health concern with limited therapy. We recently described endogenous revascularization utilizing granulocyte-macrophage colony stimulating factor (GMCSF) to induce endothelial progenitor cell (EPC) production and intramyocardial stromal cell-derived factor-1alpha (SDF) as a specific EPC chemokine. The EPC-mediated neovascularization and enhancement of myocardial function was observed. In this study we examined the regional biologic mechanisms underlying this therapy. METHODS: Lewis rats underwent left anterior descending coronary artery (LAD) ligation and developed ischemic cardiomyopathy over 6 weeks. Three weeks after ligation, the animals received either subcutaneous GMCSF and intramyocardial SDF injections or saline injections as control. Six weeks after LAD ligation circulating EPC density was studied by flow cytometry. Quadruple immunofluorescent vessel staining for mature, proliferating vasculature was performed. Confocal angiography was utilized to identify fluorescein lectin-lined vessels to assess perfusion. Ischemia reversal was studied by measuring myocardial adenosine triphosphate (ATP) levels. Myocardial viability was assayed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling detection of apoptosis and quantitation of myofilament density. RESULTS: The GMCSF/SDF therapy enhanced circulating leukocyte (13.1 +/- 4.5 x 10(6) vs 3.1 +/- 0.5 x 10(6)/cc, p = 0.001, n = 6) and EPC (14.2 +/- 6.6 vs 2.2 +/- 2.1/cc, p = 0.001, n = 6) concentrations. Tetraimmunofluorescent labeling demonstrated enhanced stable vasculature with this therapy (39.2 +/- 8.1 vs 25.4 +/- 5.1%, p = 0.006, n = 7). Enhanced perfusion was shown by confocal microangiography of borderzone lectin-labeled vessels (28.2 +/- 5.4 vs 11.5 +/- 3.0 vessels/high power field [hpf], p = 0.00001, n = 10). Ischemia reversal was demonstrated by enhanced cellular ATP levels in the GMCSF/SDF borderzone myocardium (102.5 +/- 31.0 vs 26.9 +/- 4.1 nmol/g, p = 0.008, n = 5). Borderzone cardiomyocyte viability was noted by decreased apoptosis (3.2 +/- 1.4% vs 5.4 +/- 1.0%, p = 0.004, n = 10) and enhanced cardiomyocyte density (40.0 +/- 5.6 vs 27.0 +/- 6 myofilaments/hpf, p = 0.01, n=10). CONCLUSIONS: Endogenous revascularization for ischemic cardiomyopathy utilizing GMCSF EPC upregulation and SDF EPC chemokinesis upregulates circulating EPCs, enhances vascular stability, and augments myocardial function by enhancing perfusion, reversing cellular ischemia, and increasing cardiomyocyte viability. SN - 1552-6259 UR - https://www.unboundmedicine.com/medline/citation/16631663/Neovasculogenic_therapy_to_augment_perfusion_and_preserve_viability_in_ischemic_cardiomyopathy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0003-4975(05)02176-4 DB - PRIME DP - Unbound Medicine ER -