Abstract 15058: Reduced Efficiency of Contraction in the ACTC E99k Mouse Model of Hypertrophic Cardiomyopathy
We produced a transgenic mouse that expresses the cardiac actin (ACTC) mutation E99K mutation at a level of 50% total actin. This mutation has been reported in 76 patients with hypertrophy cardiomyopathy with a predominately apical phenotype. The model recapitulates symptoms including higher myofibrillar Ca2+-sensitivity, apical hypertrophy, fibrosis, myocyte disarray and sudden cardiac death. Intact papillary muscle from 11 wks old ACTC E99K mouse and NTG littermates was used in the experiments. At 27oC, intact papillary muscle of ACTC E99K mouse, stimulated at 2Hz, generated 2X higher maximum force than the NTG muscle with the same time to peak. ACTC E99K muscle took 50% longer time to relax to 50% peak force. To mimic the cardiac cycle, each stimulus was followed by an isometric period, shortening by 10%L0, an isometric period (isovolumic relaxation), and lengthening by 10% L0. The efficiency during contractions was measured during 40 twitches in 20s (27oC) at 4 different ramp shortening and lengthening speeds. Net work was calculated as the integral of active force and length change. Heat production was deduced from temperature change measured with a thermopile of constantan-chromel thermocouples. Over 20 seconds of ramp shortening and lengthening, muscle of ACTC E99K mouse (n=14) did more work/mg muscle (33 ± 1, mJ/g) than muscles from NTG (19 ± 4, mJ/g, n=12), but with disproportionately higher total energy cost (263 ± 10, mJ/g) than NTG (114 ± 18, mJ/g). ACTC E99K muscle was significantly less efficient (0.126 ± 0.009 vs. 0.162 ± 0.013, p<0.05). Thus ACTC E99K mouse muscle was thus found to have a hyper-contractile phenotype, impaired relaxation and a 22% lower efficiency before hypertrophy is developed. These altered parameters could be accounted for by the 2.5-fold higher myofibrillar Ca2+-sensitivity caused by the ACTC E99K mutation and support the hypothesis that inefficient contraction is a primary trigger for hypertrophy in HCM.
- © 2012 by American Heart Association, Inc.