Abstract 845: Immunomodulation by Cyclophosphamide Improves Left Ventricular Dysfunction in a Murine Post-infarction Chronic Heart Failure Model by Downregulating IL-6 and TNF-alpha
Background: We recently reported that certain anticancer drugs improve left ventricular (LV) dysfunction following myocardial infarction (MI) at the acute phase. Their effects in the chronic phase post-MI, however, remain unknown. Here, we examined the beneficial effects of these drugs in the chronic phase of MI using a mouse model both in vitro and in vivo.
In vitro: Primary cultured ventricular cardiomyocytes and cardiac fibroblasts were incubated in the presence or absence of cyclophosphamide (Cy) and evaluated for cell damage and growth.
In vivo: MI model was created by permanent coronary occlusion.
The MI-bearing mice were randomly assigned to two groups four weeks after the operation. At four and six weeks post-MI, Cy (50 mg/kg) or saline (control, C) were injected intraperitoneally. At eight weeks post-MI, we evaluated cardiac function, histological changes, chemokine expression, and cell survival signaling in the heart. To assess inflammatory markers, protein analysis was performed after Cy treatment.
Cy inhibited cardiac fibroblast proliferation in a dose-dependent manner, but had no remarkable toxicity on cardiomyocytes in vitro.
Cy improved cardiac function (LV ejection fraction; Cy, 42.7 ± 2.6% vs. C, 33.5 ± 4.5%; p<0.01) at eight weeks post-MI, inhibited LV dilatation (LV end-diastolic dimension; Cy, 4.5 ± 0.4 mm vs. C, 5.9 ± 0.9 mm; p<0.01), and decreased heart weight (HW) (HW/body weight; Cy, 5.85 ± 1.51 vs. C, 7.67 ± 1.03; p<0.05) at the chronic phase post-MI without major complications.
The histological findings revealed the LV wall thickening of an infarct scar (Cy, 86.8 ± 32.2 μm vs. C, 47.6 ± 23.0 μm; p<0.01), a decreased fibrosis area (Cy, 19.8 ± 2.1% vs. C, 22.6 ± 2.5%; p<0.05), and decreased inflammatory cells (CD45+ cells) in the MI area. Finally, protein analysis revealed downregulated IL-6 and TNF-alpha, upregulated ANP, and phosphorylated STAT3 in the Cy-treated hearts.
Conclusion: The downregulation of inflammatory cytokines, the upregulation of protective chemokines, and the activation of cell survival signaling may play important roles in the beneficial effects of Cy during post-MI chronic heart failure. These findings suggest a novel, immunomodulatory role for Cy as an indication for heart failure.