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Myocardial regeneration therapy for ischemic cardiomyopathy with cyclin A2.
J Thorac Cardiovasc Surg. 2007 Apr; 133(4):927-33.JT

Abstract

OBJECTIVE

Heart failure therapies ranging from revascularization to remodeling to replacement are variably effective. Theoretically, endogenous repair via myocardial regeneration would be an ideal therapy. This study examined the ability to initiate regeneration by adenoviral-mediated expression of the cell cycle regulator cyclin A2. Our prior studies have demonstrated robust cyclin A2 transgene expression and marked antiphosphorylated histone H3 activity with this strategy, indicating the induction of cardiomyocyte mitosis.

METHODS

Adult male, Lewis rats underwent left anterior descending coronary artery ligation followed by intramyocardial delivery of either cyclin A2 adenoviral vector (n = 8) or empty adeno-null vector as a control (n = 8) into the peri-infarct border zone. In vivo myocardial function was analyzed by echocardiography and invasive left ventricular pressure catheter at 6 weeks, when the animals are traditionally in heart failure. Hearts were explanted for immunoblotting and left ventricular geometric analysis. Cellular proliferation was assessed by proliferating cellular nuclear antigen expression.

RESULTS

Cyclin A2 hearts exhibited improved left ventricular function as compared with controls including enhanced cardiac output (32 +/- 3.3 vs 26 +/- 5.0 mL/min, P < .05), stroke volume (0.16 +/- 0.04 vs 0.11 +/- 0.04 mL, P < .05), ejection fraction (72% +/- 7.4% vs 46.% +/- 8.5%, P < .05), fractional shortening (35% +/- 5.4% vs 19% +/- 4.3%, P < .002), maximum pressure (72 +/- 9.3 vs 61 +/- 2.9 mm Hg, P < .05), and end-systolic pressure (67 +/- 7.0 vs 55 +/- 7.0 mm Hg, P < .05). Enhanced myocardial preservation was demonstrated by enhanced left ventricular border zone wall thickness. Increased myocardial proliferation was evidenced by increased expression of proliferating cell nuclear antigen expression in cyclin A2-treated hearts.

CONCLUSIONS

In failing hearts, targeted delivery of cyclin A2 improves hemodynamic function, as measured by echocardiography and pressure catheter analysis, preserves ventricular wall thickness, and may serve as an ideal myocardial regenerative therapy.

Authors+Show Affiliations

Division of Cardiothoracic Surgery, Division of Cardiology, Department of Medicine, Columbia University School of Medicine, New York, New York, USA. wooy@uphs.upenn.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

17382628

Citation

Woo, Y Joseph, et al. "Myocardial Regeneration Therapy for Ischemic Cardiomyopathy With Cyclin A2." The Journal of Thoracic and Cardiovascular Surgery, vol. 133, no. 4, 2007, pp. 927-33.
Woo YJ, Panlilio CM, Cheng RK, et al. Myocardial regeneration therapy for ischemic cardiomyopathy with cyclin A2. J Thorac Cardiovasc Surg. 2007;133(4):927-33.
Woo, Y. J., Panlilio, C. M., Cheng, R. K., Liao, G. P., Suarez, E. E., Atluri, P., & Chaudhry, H. W. (2007). Myocardial regeneration therapy for ischemic cardiomyopathy with cyclin A2. The Journal of Thoracic and Cardiovascular Surgery, 133(4), 927-33.
Woo YJ, et al. Myocardial Regeneration Therapy for Ischemic Cardiomyopathy With Cyclin A2. J Thorac Cardiovasc Surg. 2007;133(4):927-33. PubMed PMID: 17382628.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Myocardial regeneration therapy for ischemic cardiomyopathy with cyclin A2. AU - Woo,Y Joseph, AU - Panlilio,Corinna M, AU - Cheng,Richard K, AU - Liao,George P, AU - Suarez,Erik E, AU - Atluri,Pavan, AU - Chaudhry,Hina W, Y1 - 2007/02/22/ PY - 2006/04/28/received PY - 2006/06/20/revised PY - 2006/07/07/accepted PY - 2007/3/27/pubmed PY - 2007/4/18/medline PY - 2007/3/27/entrez SP - 927 EP - 33 JF - The Journal of thoracic and cardiovascular surgery JO - J Thorac Cardiovasc Surg VL - 133 IS - 4 N2 - OBJECTIVE: Heart failure therapies ranging from revascularization to remodeling to replacement are variably effective. Theoretically, endogenous repair via myocardial regeneration would be an ideal therapy. This study examined the ability to initiate regeneration by adenoviral-mediated expression of the cell cycle regulator cyclin A2. Our prior studies have demonstrated robust cyclin A2 transgene expression and marked antiphosphorylated histone H3 activity with this strategy, indicating the induction of cardiomyocyte mitosis. METHODS: Adult male, Lewis rats underwent left anterior descending coronary artery ligation followed by intramyocardial delivery of either cyclin A2 adenoviral vector (n = 8) or empty adeno-null vector as a control (n = 8) into the peri-infarct border zone. In vivo myocardial function was analyzed by echocardiography and invasive left ventricular pressure catheter at 6 weeks, when the animals are traditionally in heart failure. Hearts were explanted for immunoblotting and left ventricular geometric analysis. Cellular proliferation was assessed by proliferating cellular nuclear antigen expression. RESULTS: Cyclin A2 hearts exhibited improved left ventricular function as compared with controls including enhanced cardiac output (32 +/- 3.3 vs 26 +/- 5.0 mL/min, P < .05), stroke volume (0.16 +/- 0.04 vs 0.11 +/- 0.04 mL, P < .05), ejection fraction (72% +/- 7.4% vs 46.% +/- 8.5%, P < .05), fractional shortening (35% +/- 5.4% vs 19% +/- 4.3%, P < .002), maximum pressure (72 +/- 9.3 vs 61 +/- 2.9 mm Hg, P < .05), and end-systolic pressure (67 +/- 7.0 vs 55 +/- 7.0 mm Hg, P < .05). Enhanced myocardial preservation was demonstrated by enhanced left ventricular border zone wall thickness. Increased myocardial proliferation was evidenced by increased expression of proliferating cell nuclear antigen expression in cyclin A2-treated hearts. CONCLUSIONS: In failing hearts, targeted delivery of cyclin A2 improves hemodynamic function, as measured by echocardiography and pressure catheter analysis, preserves ventricular wall thickness, and may serve as an ideal myocardial regenerative therapy. SN - 1097-685X UR - https://www.unboundmedicine.com/medline/citation/17382628/Myocardial_regeneration_therapy_for_ischemic_cardiomyopathy_with_cyclin_A2_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-5223(06)02345-2 DB - PRIME DP - Unbound Medicine ER -