Abstract 20312: Rescue of a Mouse Model of Dilated Cardiomyopathy by Myofilament Sensitization to Calcium
Dilated cardiomyopathy (DCM) is a primary disease of the myocardium characterized by decreased contractility and enlargement of cardiac chambers. We have previously shown that E54K mutation in α-tropomyosin (Tm54) reduces myofilament Ca2+ sensitivity and causes DCM in a transgenic mouse model. Thus, we addressed the hypothesis that sensitization of the myofilament to Ca2+ in early phases of DCM would rescue the phenotype of the disease. To sensitize Tm54 myofilament we crossbred Tm54 mice with mice expressing the slow skeletal troponin I isoform (ssTnI mice) in place of cardiac TnI, which has been demonstrated to increase the sarcomere response to Ca2+. Four groups were obtained: non-transgenic (NTG), Tm54, ssTnI and Tm54/ssTnI. Myofilament Ca2+ sensitivity was assessed by pCa50 (pCa necessary to obtain 50% of the maximal force) in skinned fiber preparation. Cardiac functional parameters were obtained by high resolution echocardiography and hemodynamic studies were obtained using pressure-volume catheter. Data were obtained in 5-month old mice and expressed as mean±SE. Significant differences were accepted when p<0.05, using ANOVA followed by Tukey's test. The Tm54/ssTnI Ca2+ sensitivity was higher when compared to Tm54 (pCa50, NTG=5.86±0.004, ssTnI=6.10±0.011, Tm54=5.74±0.005 and Tm54/ssTnI=5.99±0.020, N=8 each group, ANOVA p=0.0006). Contractility was significantly better in Tm54/ssTnI when compared to Tm54, as assessed by ejection fraction (in %, NTG=65.3±2.17, ssTnI=80.1±2.70, Tm54=29.2±1.39 and Tm54/ssTnI=65.1±2.34, N=8 each group, ANOVA p=0.0001) and the load-independent parameter PRSW (in mmHg, NTG(7)=71.7±9.3, ssTnI(6)=60.9±4.0, Tm54(8)=37.6±7.8 and Tm54/ssTnI(4)=59.1±4.9, ANOVA p=0.02). Tm54 mice showed an increased diastolic LV dimension compared to NTG, which was improved in Tm54/ssTnI (in mm, NTG=3.99±0.08, ssTnI=3.85±0.14, Tm54=5.13±0.10 and Tm54/ssTnI=4.28±0.06, N=8 each group, ANOVA p=0.01). Histological analysis using Masson's trichrome demonstrated decreased collagen deposition in Tm54/ssTnI when compared to Tm54. Our data strongly indicate that myofilament sensitization to Ca2+ may be a useful preventive therapeutic strategy in sarcomere-linked DCM associated with decreased Ca2+ sensitivity.
- © 2010 by American Heart Association, Inc.