Abstract 3435: Left Ventricular Hypertrophy is Resistant to Inhibition of Expression of the R403Q Alpha-Myosin Heavy Chain Cardiac Hypertrophy-Inducing Mutant Protein
Left ventricular hypertrophy (LVH) develops as a compensatory response to myocardial dysfunction due to diverse causes, but is nonetheless a major risk factor for premature cardiovascular morbidity and mortality. It is thus unclear if regressing LVH is beneficial or may worsen patient outcome. To evaluate the effects of LVH regression, we developed a transgenic mouse model in which the expression of a familial hypertrophic cardiomyopathy (FHC)-inducing mutation (R403Q alpha-MHC) can be regulated in a temporal and dose-dependent manner. In this model, transgene expression can be shut off by feeding with a tetracycline analogue (doxycycline). Serial echocardiography and histology studies were performed in a cohort of mice expressing the FHC mutant (“gene-on”) and in wildtype (WT) littermates. A second cohort of WT and 403/+ mice was randomised to placebo or doxycycline (“gene off”) from 6 (Dox6) or 20 weeks (Dox20) and evaluated at 40 weeks of age. Compared to WT littermates, “gene on” 403/+ mice showed increased LV mass, LV end-diastolic diameter (LVDD) and left atrial diameter (LAD), and reduced fractional shortening (LVFS), with changes evident from 12 weeks of age. LV sections from 403/+ mice showed typical features of FHC: myofibre disarray and interstitial fibrosis. LV mass, LV function and myocardial histology were unchanged in both male and female placebo- vs Dox6 or Dox20 mice at 40 weeks (Table 1⇓). Thus, consistent with the major LV thickening in FHC humans occurring in adolescence, overexpression of R403Q for only 6 weeks is sufficient to trigger the complete LVH phenotypic response. Moreover, switching off the genetic trigger for LVH in 403/+ mice at 6 weeks (prior to overt disease manifestation) or 20 weeks (established disease) does not induce regression of LVH or exacerbate contractile dysfunction. Interventions to induce LVH regression may, therefore, need to be directed at downstream factors in hypertrophic pathways.