Abstract 3130: Inhibition of p38 Mitogen-Activated Protein Kinase Improves Long-Term Results of Left Ventricular Volume Reduction Surgery for Dilated Cardiomyopathy
Background: A long-term result of left ventricular (LV) volume reduction surgery (LVR) alone for dilated cardiomyopathy (DCM) is insufficient to prevent progressive remodeling. We previously reported that inhibition of p38 MAPK suppressed inflammatory cytokines expression in LV and it prevented progression of DCM and congesive heart filure (CHF). In the present study, we evaluated the effects of a specific p38 MAPK inhibitor (FR167653) on DCM aftrer performed LVR in Dahl salt-sensitive (DS) rats with hypertension-induced LV dilatation at risk of progression to CHF, with the goal of defining better therapeutic options for DCM.
Methods and Results: DS rats, initiated a high-salt diet from 6 weeks of age, daily received FR167653 (2 mg/kg/day) or vehicle intramuscularly after VRS at 18 weeks of age, and were subjected echocardiography and cardiac catheterization. At 4 weeks after LVR, MAPK activation was determined by Western blotting, NF-κB activity was measured by EMSA, and inflammatory cytokine expression was measured by RPA. The degree of apoptosis was determined by measuring the level of TUNEL. Posttreatment of rats with FR167653 after LVR resulted in a reduction in p38 MAPK phosphorylation (P = .022), less nuclear of NF-κB (P = .048), and a decrease in the expression of inflammatory cytokines (P < .05) in the heart and the development of a significantly better LV function (P <.05), when compared to hearts from rats treated with vehicle alone. FR167653 also suppressed the apoptosis factors. Activation of JNK and ERK were observed after LVS, while not inhibited by FR167653. The survival rate at 4 weeks aftre LVS was 90% in FR167653 treated, and 65% in vehicle treated groups. Kaplan-Meier survival analysis demonstrated a significant improvement in FR167653 (P = .0025) compared with vehicle. All rats with sham operation has died of pulmonary congestion due to CHF until 21 weeks of age.
Conclusions: We conclude that inhibition of p38 MAPK with FR167653 attenuates NF-κB activation, inflammatory cytokine expression and apoptosis in LV and substantially preserves LV function after LVR. Thus, FR167653 may have a role in the postoperative treatment to improve a long-term results of LVR for DCM.