Multigene adenoviral therapy for the attenuation of ischemia-reperfusion injury after preservation for cardiac transplantation Haitham J. Abunasra, FRCS,

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Presentation transcript:

Multigene adenoviral therapy for the attenuation of ischemia-reperfusion injury after preservation for cardiac transplantation Haitham J. Abunasra, FRCS, Ryszard T. Smolenski, MD, PhD, John Yap, FRCS, Mary Sheppard, MD, FRCPath, Timothy O'Brien, MD, PhD, Magdi H. Yacoub, FRS The Journal of Thoracic and Cardiovascular Surgery Volume 125, Issue 5, Pages 998-1006 (May 2003) DOI: 10.1067/mtc.2003.263 Copyright © 2003 American Association for Thoracic Surgery Terms and Conditions

Fig. 1 Experimental protocol. Four days after gene transfection, hearts were subjected to 6 hours of global ischemia and 1 hour of reperfusion. Hearts were assessed for efficacy of gene transfection with immunohistochemical methods and for function by intraventricular balloon. The Journal of Thoracic and Cardiovascular Surgery 2003 125, 998-1006DOI: (10.1067/mtc.2003.263) Copyright © 2003 American Association for Thoracic Surgery Terms and Conditions

Fig. 2 Group A transgene expression. Demonstration of β-galactosidase transgene expression by histochemical staining with X-gal in heart transfected with AdCMVLacZ. Myocytes stain positively for β-galactosidase (yellow arrows). Original magnification ×600. The Journal of Thoracic and Cardiovascular Surgery 2003 125, 998-1006DOI: (10.1067/mtc.2003.263) Copyright © 2003 American Association for Thoracic Surgery Terms and Conditions

Fig. 3 Immunohistochemical staining for eNOS. A, Immunohistochemical staining of midventricular section in heart transfected with AdeNOS with monoclonal antibody to eNOS (counterstained with mercury-free hematoxylin) showing endothelial (yellow arrows) and cardiomyocyte (red arrows) expressions of eNOS. Some inflammatory cells can be seen (bright green arrow). Original magnification ×400. B, Immunohistochemical staining of midventricular section of heart transfected with AdCMVLacZ with monoclonal antibody to eNOS (counterstained with mercury-free hematoxylin) showing some endothelial expression of native eNOS (yellow arrows). Original magnification ×200. The Journal of Thoracic and Cardiovascular Surgery 2003 125, 998-1006DOI: (10.1067/mtc.2003.263) Copyright © 2003 American Association for Thoracic Surgery Terms and Conditions

Fig. 4 Mn-SOD immunohistochemical staining. A, Immunohistochemical staining of midventricular section of heart transfected with AdMnSOD with monoclonal antibody to Mn-SOD (counterstained with mercury-free hematoxylin). Expression is present in cardiomyocytes (red arrows). Original magnification ×200. B, Immunohistochemical staining of midventricular section in heart transfected with AdCMVLacZ with monoclonal antibody to Mn-SOD (counterstained with mercury-free hematoxylin). Some staining of native Mn-SOD can be seen in cardiac myocytes (red arrows). Original magnification ×300. The Journal of Thoracic and Cardiovascular Surgery 2003 125, 998-1006DOI: (10.1067/mtc.2003.263) Copyright © 2003 American Association for Thoracic Surgery Terms and Conditions

Fig. 5 Immunohistochemical staining for eNOS and Mn-SOD. A, Immunohistochemical staining of midventricular portion in heart transfected with AdeNOS and AdMnSOD with monoclonal antibody to eNOS (counterstained with mercury-free hematoxylin). Most eNOS overexpression can be seen in endothelial cells (yellow arrows) with smaller expression in myocytes (red arrows). Original magnification ×200. B, Immunohistochemical staining of midventricular portion in same heart (transfected with AdeNOS and AdMnSOD) with monoclonal antibody to Mn-SOD (counterstained with mercury-free hematoxylin). Overexpression of Mn-SOD can be seen in cardiomyocytes (red arrows). Original magnification ×200. The Journal of Thoracic and Cardiovascular Surgery 2003 125, 998-1006DOI: (10.1067/mtc.2003.263) Copyright © 2003 American Association for Thoracic Surgery Terms and Conditions

Fig. 6 Recovery of LVDP after ischemia. Isolated hearts in four experimental groups (n = 6 in each group) were subjected to 6 hours of cold (4°C) global ischemia followed by 1 hour of reperfusion. Statistically significantly better recovery of LVDP after ischemia was shown in groups B, C, and D relative to group A. No statistically significant differences were found between groups B, C, or D, although group C hearts showed best recovery. Data are expressed as percentage of LVDP before ischemia. Asterisk indicates P = .009 versus group A; double asterisk indicates P < .001; triple asterisk indicates P = .015. Bar heights represent mean; error bars represent SD. The Journal of Thoracic and Cardiovascular Surgery 2003 125, 998-1006DOI: (10.1067/mtc.2003.263) Copyright © 2003 American Association for Thoracic Surgery Terms and Conditions

Fig. 7 Recovery of minimum (min) dP/dt after ischemia (n = 6 in each group). Improved recoveries of minimum dP/dt after 6 hours of cold global ischemia and 1 hour of reperfusion were shown in groups B, C, and D relative to group A. No statistically significant differences were found between groups B, C, or D, although group C hearts showed best recovery. Data are expressed as percentage of basal minimum dP/dt before ischemia. All asterisks indicate P < .001 versus group A. Bar heights represent mean; error bars represent SD. The Journal of Thoracic and Cardiovascular Surgery 2003 125, 998-1006DOI: (10.1067/mtc.2003.263) Copyright © 2003 American Association for Thoracic Surgery Terms and Conditions

Fig. 8 Recovery of maximum (max) dP/dt after ischemia (n = 6 in each group). Improved recoveries of maximum dP/dt after 6 hours of cold global ischemia and 1 hour of reperfusion were shown in groups B, C, and D relative to group A. Differences between B, C, and D were not statistically significant. Data are expressed as percentage of baseline maximum dP/dt measured before ischemia. All asterisks indicate P < .001 versus group A. Bar heights represent mean; error bars represent SD. The Journal of Thoracic and Cardiovascular Surgery 2003 125, 998-1006DOI: (10.1067/mtc.2003.263) Copyright © 2003 American Association for Thoracic Surgery Terms and Conditions

Fig. 9 Recovery of RPP after ischemia (n = 6 in each group). Statistically significant improvements in recovery of RPP after 6 hours of cold global ischemia and 1 hour of reperfusion were shown in groups B and C relative to groups D and A. Difference between groups D and A was not statistically significant (P = .93). Data are expressed as percentage of RPP measured before ischemia. Asterisk indicates P = .003 versus group A and P = .106 versus group D; double asterisk indicates P = .011 versus group A and P = .307 versus group D. Bar heights represent mean; error bars represent SD. The Journal of Thoracic and Cardiovascular Surgery 2003 125, 998-1006DOI: (10.1067/mtc.2003.263) Copyright © 2003 American Association for Thoracic Surgery Terms and Conditions