Targeted overexpression of leukemia inhibitory factor to preserve myocardium in a rat model of postinfarction heart failure

Abstract

Objective: Myocardial infarction leads to cardiomyocyte loss. The cytokine leukemia inhibitory factor regulates the differentiation and growth of embryonic and adult heart tissue. This study examined the effects of gene transfer of leukemia inhibitory factor in infarcted rat hearts. Methods: Lewis rats underwent ligation of the left anterior descending coronary artery and direct injection of adenovirus encoding leukemia inhibitory factor (n = 10) or null transgene as control (n = 10) into the myocardium bordering the ischemic area. A sham operation group (n = 10) underwent thoracotomy without ligation. After 6 weeks, the following parameters were evaluated: cardiac function with a pressure-volume conductance catheter, left ventricular geometry and architecture by histologic methods; myocardial fibrosis by Masson trichrome staining, apoptosis by terminal deoxynucleotidal transferase–mediated deoxyuridine triphosphate nick-end labeling assay, and cardiomyocyte size by immunofluorescence. Results: Rats with overexpression of leukemia inhibitory factor had more preserved myocardium and less fibrosis in both the infarct and its border zone. The border zone in leukemia inhibitory factor–treated animals contained fewer apoptotic nuclei (1.6% ± 0.1% vs 3.3% ± 0.2%, P < .05) than that in control animals and demonstrated cardiomyocytes with larger cross-sectional areas (910 ± 60 μm^2 vs 480 ± 30 μm^2, P < .05). Leukemia inhibitory factor–treated animals had increased left ventricular wall thickness (2.1 ± 0.1 mm vs 1.8 ± 0.1 mm, P < .05) and less dilation of the left ventricular cavity (237 ± 22 μL vs 301 ± 16 μL, P < .05). They also had improved cardiac function, as measured by maximum change in pressure over time (3950 ± 360 mm Hg/s vs 2750 ± 230 mm Hg/s, P < .05) and the slopes of the maximum change in pressure over time–end-diastolic volume relationship (68 ± 5 mm Hg/[s · μL] vs 46 ± 6 mm Hg/[s·μL], P < .05) and the preload recruitable stroke work relationship (89 ± 10 mm Hg vs 44 ± 4 mm Hg, P < .05). Conclusions: Myocardial gene transfer of leukemia inhibitory factor preserved cardiac tissue, geometry, and function after myocardial infarction in rats.

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