Abstract 1502: Gender-Specific Reversibility of Calcineurin-Induced Ventricular Remodeling
Background: Ventricular hypertrophy will sometimes reverse when the inciting stimulus (e.g. hypertension) is removed; at a certain point, however, pathological remodeling becomes irreversible. Further, recent studies have highlighted differences in disease pathogenesis triggered by signaling pathways activated in males (M) versus females (F). However, little is known regarding mechanisms of hypertrophy resolution, markers of irreversibility, or the effects of gender-specific mechanisms thereon.
Methods: We engineered mice that express a constitutively active calcineurin mutant driven by a tet-off-αMHC promoter (tetCnA). During gestation, through weaning, and up to 5 wks of age, tetCnA mice were exposed to doxycycline (dox). Then, mice were randomized to dox (OFF) or dH2O (ON) for 16 wks. In the ON group, half received dH20 for 8 wks followed by dox for 8 wks (ON-OFF). Serial echocardiography was performed every 2 wks.
Results: Systolic function declined significantly (p<0.05) and similarly by 8 wks in all ON mice (%FS = 37% ± 2, F-ON n=6; 35% ± 8, M-ON n=6; 38% ± 7, F-ON-OFF n=5; and 35% ± 2, M-ON-OFF n=5) as compared with OFF mice (%FS = 63% ± 5, F-OFF n=6; and 68% ± 7, M-OFF n=4). After 8 wks, resumption of dox to shut off calcineurin expression led to continued declines in systolic function in male mice (%FS at 16 wks 35% ± 3, M-ON-OFF n=5), similar to M-ON (30% ± 1, M-ON n=6), suggesting that pathological remodeling was irreversible. Conversely, systolic performance recovered completely in female ON-OFF mice (%FS at 16 wks = 62% ± 4, n=5) as compared with F-ON (36% ± 5, n=6, p<0.05). Necropsy at 16 wks revealed increased heart mass (p<0.05) in all ON mice and male ON-OFF mice (heart weight / tibia, HW/T = 12.4 ± 1.4 mg/mm, F-ON; 12.7 ± 2.1, M-ON; 12.0 ± 0.7, M-ON-OFF) as compared with all OFF mice (7.1 ± 0.4, F-OFF; 8.1 ± 0.5, M-OFF). Remarkably, heart mass at 16 wks was similar (p=NS) in F-ON-OFF (7.9 ± 0.4, n=5) and F-OFF mice, and accumulation of interstitial fibrosis was less as compared with all other groups.
Conclusions: Calcineurin activation in adolescent male mice triggers pathological remodeling that is severe and irreversible after 2 months. In contrast, similar degrees of calcineurin-induced ventricular remodeling in adolescent female mice remain reversible at 2 months.