Targeted overexpression of leukemia inhibitory factor to preserve myocardium in a rat model of postinfarction heart failure Mark F. Berry, MD, Timothy.

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Targeted overexpression of leukemia inhibitory factor to preserve myocardium in a rat model of postinfarction heart failure Mark F. Berry, MD, Timothy J. Pirolli, Vasant Jayasankar, MD, Kevin J. Morine, Mireille A. Moise, MD, Omar Fisher, BS, Timothy J. Gardner, MD, Paul H. Patterson, PhD, Y. Joseph Woo, MD The Journal of Thoracic and Cardiovascular Surgery Volume 128, Issue 6, Pages 866-875 (December 2004) DOI: 10.1016/j.jtcvs.2004.06.046 Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Viral transgene expression after direct intramyocardial injection. a, Rat heart with X-gal staining 1 week after direct injection of Adeno.LacZ. Expression, stained blue, is seen in most cardiomyocytes in LV area of injection. b, Immunoblotting for LIF (43 kd) transgene expression performed 1 week after virus injection shows moderate increase in LIF expression in animals injected with Adeno.LIF (lanes 3, 4, 5, and 6) versus control animals (lanes 1 and 2). Staining of the actin band shows equivalent protein loading in all 6 lanes. c, Merged images of double staining of sections for LIF (green) and nonspecific nuclear stain DAPI (blue) demonstrate scattered areas of LIF expression in myocardium bordering infarct in LIF group (left) 6 weeks after MI and viral delivery, whereas control animals (right) do not contain areas of LIF expression (400× magnification). The Journal of Thoracic and Cardiovascular Surgery 2004 128, 866-875DOI: (10.1016/j.jtcvs.2004.06.046) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 a, Hematoxylin and eosin staining demonstrates more preserved myocardium in both border zone and infarct in LIF group than in control group (100× magnification). Control animals have more connective tissue and fewer cardiomyocytes in border zone than LIF group animals (black arrow). LIF group animals have increased cellularity in infarct relative to control animals (black arrowhead). b, Representative cross-sections with Masson trichrome staining (100× magnification) of single rat heart 6 weeks after initial surgery from control group and from LIF group show qualitatively less fibrosis with LIF. Fibrotic areas are stained blue. The Journal of Thoracic and Cardiovascular Surgery 2004 128, 866-875DOI: (10.1016/j.jtcvs.2004.06.046) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Representative TUNEL-stained cross-sections from single animal in control group (a) and LIF group (b) (400× magnification). Apoptotic nuclei are stained dark brown (arrows), and normal nuclei are stained blue-green. c, LIF group animals had smaller percentage of TUNEL-positive cells in infarct border zone area than control animals. The Journal of Thoracic and Cardiovascular Surgery 2004 128, 866-875DOI: (10.1016/j.jtcvs.2004.06.046) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Merged images of double staining of sections for laminin (red) and nonspecific nuclear stain DAPI (blue) demonstrate significantly smaller cardiomyocytes in border zone of control group (a) than LIF group (b) (400× magnification). c, Border zone cardiomyocytes in LIF group animals had higher average cross-sectional areas than border zone cardiomyocytes in control animals, as well as cardiomyocytes in myocardium remote from the infarct in both LIF and control groups. *P < .001 versus control border zone; †P < .001 versus LIF remote. The Journal of Thoracic and Cardiovascular Surgery 2004 128, 866-875DOI: (10.1016/j.jtcvs.2004.06.046) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 a, Representative pressure-volume loops for sham, control, and LIF groups. Loops for LIF are shifted less than control relative to sham. b, LIF group had improved systolic function, as measured by max dP/dt, relative to control group. c, LIF group had less ventricular dilation, as measured by LV EDV, than control group. d, LIF attenuated amount of LV wall thinning in myocardium remote from infarct relative to control group. *P < .05 versus sham; †P < .05 versus control. The Journal of Thoracic and Cardiovascular Surgery 2004 128, 866-875DOI: (10.1016/j.jtcvs.2004.06.046) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 6 a, LIF group shows increased slope and decreased volume intercept for max dP/dt and EDV relationship relative to control group, indicating improved systolic function. b, Representative max dP/dt–EDV relationships for single animal in each experimental group show LIF group shifted rightward and downward less than control group relative to sham group. Each line on graph represents data points for max dP/dt and EDV measured from individual pressure-volume loops obtained during reduction of preload volume by IVC occlusion for single animal from each experimental group. c, LIF group shows increase in slope of SW-EDV relationship, which is PRSW, as well as decreased volume intercept relative to control group, indicating increased contractility. d, Representative SW-EDV relationships for single animal in each experimental group show LIF group shifted rightward and downward less than control group relative to sham group. Each line on graph represents data points for SW and EDV measured from individual pressure-volume loops obtained during reduction of preload volume by IVC occlusion for single animal from each experimental group. *P < .05 versus sham; †P < .05 versus control. The Journal of Thoracic and Cardiovascular Surgery 2004 128, 866-875DOI: (10.1016/j.jtcvs.2004.06.046) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions