Abstract 14075: G-CSF Leads to a Normalization of Diastolic Function in a Mouse Model of Diastolic Heart Failure
Background: The treatment of patients with heart failure with a preserved ejection fraction (HFpEF) represents a daily clinical challenge because contemporary therapeutical approaches failed to improve diastolic function. Fibrosis is a major point in the pathogenesis of HFpEF. As recently shown, granulocyte colony-stimulating factor (G-CSF) modulates inflammatory reactions in a mouse model of pressure overload and subsequent unloading, thereby leading to the regression of cardiac fibrosis and a significant improvement of functional parameters. In the present study, we developed a mouse model for HFePF and treated these mice with G-CSF. Material and
Methods: Healthy C57BL6/J-mice (n=40) received a continuous infusion of low dose Angiotensin II (AngII, 0.5 µg/kg/min) via an osmotic pump. Sham-operated mice served as control. After four weeks, diastolic functional parameters (E’/A’, E/E’) were assessed by high-resolution echocardiography and mice were randomized in an experimental group (G-CSF 300 µg/kg BW/d) and a control group (saline). After 7 days, diastolic function was assessed by echocardiography again.
Results: AngII infusion led to HFpEF compared to sham (E’/A’: 0.72±0.07 vs. 1.78±0.11, p<0.01; E/E’: 53.4±5.6 vs. 2.4±1.2, p<0.01). G-CSF treated mice with HFpEF revealed a normalization of diastolic functional parameters, while saline treated mice had persistent HFpEF (E’/A’: 1.85±0.17 vs. 0.79±0.18, p<0.01; E/E’: 24.9±1.3 vs. 55.6±11.1, p<0.05). Immunohistochemistry showed the development of perivascular fibrosis. After G-CSF treatment, regression of fibrosis and decrease of myocardial collagen content could be observed. Analysis of inflammatory mediators showed an increased expression of cytokines with collagen-degrading and immunomodulatory properties (cathelicidin, lactoferrin, calgranulin-A) in the myocardium of G-CSF treated mice.
Conclusion: Low-dose AngII application leads to the development of HFpEF in mice. Treatment with G-CSF treatment induces regression of fibrosis and normalizes diastolic functional parameters. These effects can be explained by G-CSF-induced immunomodulatory effects. Therefore, G-CSF could be a promising therapeutical approach for the treatment of HFpEF.
- © 2012 by American Heart Association, Inc.