Left ventricular hypertrophy (LVH) is a significant cause of morbidity and mortality, but whether its prevention or regression is feasible and/or beneficial is unclear. We generated an αMHC403/+-tTA mouse model in which expression of the familial hypertrophic cardiomyopathy (FHC)-causing Arg403Gln α-myosin heavy chain (αMHC403) mutation is regulatable by oral doxycycline. Serial echocardiography and histology showed that mice expressing αMHC403 throughout life developed progressively increased left ventricular mass (LVM), LV diastolic diameter (LVDD), left atrial diameter (LAD), and reduced fractional shortening (LVFS) (Table 1), and myofibrillar disarray and fibrosis. Transgene inhibition from 6 or 20 weeks did not ameliorate the changes in LVM, LVFS or histology seen at 40 weeks (Table 1). To determine the importance of early transgene expression, additional mice underwent transgenic inhibition from conception to 6 weeks, and were then allowed to express αMHC403 from 6 to 40 weeks (W0–6), which improved LVDD, LAD and LVFS compared with untreated αMHC403/+-tTA mice. Thus, early developmental defects associated with αMHC403 expression provide a structural template for the manifestations of hypertrophy in adult life.
Table 1Echocardiography at 40 Weeks.
| Parameter | WT | αMHC403/+-tTA | W0–6 | W6–40 | W20–40 |
|---|---|---|---|---|---|
| LVM (mg) | 83.4 ± 9.4 | 128.8 ± 23.3 | 105.4 ± 21.7 | 122.3 ± 28.2 | 114.9 ± 17.7 |
| LVDD (mm) | 3.4 ± 0.1 | 3.9 ± 0.2 | 3.4 ± 0.2 | 3.60 ± 0.12 | 3.8 ± 0.3 |
| LVFS (%) | 55 ± 2 | 41 ± 7 | 52 ± 8, | 45 ± 4 | 43 ± 2 |
| LAD (mm) | 1.7 ± 0.1 | 2.3 ± 0.2 | 2.0 ± 0.2, | 2.4 ± 0.2 | 2.4 ± 0.2 |
n = 5–9; W0–6, W6–40, W20–40 = transgenic inhibition until 6 weeks, from 6 to 40 weeks, or from 20 to 40 weeks, respectively. Statistical analysis by ANOVA and t test.
* P < 0.05 vs WT.
# P < 0.05 vs untreated αMHC403/+-tTA.
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© 2011 Published by Elsevier Inc.
