Abstract 958: Reversibility of Calcineurin-Dependent Ventricular Remodeling
Introduction: Ventricular hypertrophy will sometimes reverse when the inciting stimulus (e.g. hypertension) is removed; at a certain point, however, pathological remodeling becomes irreversible. Little is known regarding mechanisms of hypertrophy resolution, markers of irreversibility, or the extent to which reverse remodeling can occur. Recent studies have highlighted differences in disease pathogenesis triggered by signaling pathways activated in the postnatal period (e.g. conventional αMHC transgenic technologies) versus activation during adulthood.
Methods and Results: We engineered mice that express in cardiomyocytes a constitutively active calcineurin mutant driven by a tet-off-αMHC promoter (tetCnA mice). During gestation and up to weaning, tetCnA pups were exposed to doxycycline (dox) through their mothers. At 4 wks of age, tetCnA mice were randomized to dox (OFF) or dH2O (ON). In the dH20 group, half received dH20 for 8 wks followed by dox for 8 wks (ON-OFF). Serial transthoracic echocardiography was performed biweekly. Systolic function declined significantly in both ON and ON-OFF mice by 6 wks as compared with OFF mice (%FS 31.5% ± 7.6, n=8 vs 53.4% ± 3.0, n=3). Subsequently, systolic performance continued to deteriorate in ON mice. By contrast, in ON-OFF mice, systolic function was improved 4 wks after resumption of dox (37.6% ± 5.84). By 6 wks, both ON and ON-OFF mice manifested significant increases in LV mass index (LVMI) as compared with OFF mice (5.44 mg/g ± 0.41, n=7 vs 3.7 ± 0.67). Whereas LVMI continued to increase in ON mice (7.09 ± 1.18), LVMI was lower in ON/OFF mice by 4wks after resumption of dox (4.31 ± 0.56). Necropsy at 16 wks revealed evidence of heart failure in ON mice (lung weight / tibia = 13 ± 1.1 mg/mm, n=3), which was significantly higher (p<0.05) than ON/OFF mice (10.8 ± 1.6). Consistent with the echo data, heart mass (HW/BW) was increased in ON mice at 16 wks (7.34 mg/g ± 0.78) as compared with OFF mice (4.94 ± 0.13, p<0.05). In ON/OFF mice, HW/BW at 16 wks was intermediate (6.08 ± 0.31).
Conclusions: Calcineurin activation after the postnatal period is sufficient to trigger pathological ventricular remodeling. After 2 months, declines in ventricular function and pathological increases in cardiac mass remain partially reversible.