Abstract Tu067: ROCK2 Specific Inhibition Prevents Isoproterenol Induced Takotsubo Cardiomyopathy in Mice

Abstract

Takotsubo Cardiomyopathy (TCM) is an acute, life-threatening condition characterized by a drop in ejection fraction (EF) and apical ballooning of the left ventricle (LV). TCM is most frequently observed in women and is associated with an emotional or physical stressor. Recent work has demonstrated that the Rho kinase ROCK2 contributes to heart failure phenotypes in mice in other models of heart failure. The role of ROCK2 in TCM is unknown. We tested the hypothesis that ROCK2 inhibition attenuates isoproterenol (ISO)-induced TCM in mice. To induce TCM, male and female mice were given a single dose of 200mg/kg ISO, i.p. and cardiac function was assessed by conscious echocardiography. The effect of ISO overdose on acute heart failure over a 7-day time course was determined followed by an intervention study in which mice were treated with the ROCK2 specific inhibitor KD025/belumosudil (50mg/kg, i.p.) concurrent with heart failure induction. Though ISO induced a drop in EF in both sexes after 24 hours, females exhibited lower EF (46.64±3.11%) than males (68.36±2.62, p<0.0001) mirroring the increased prevalence of clinically defined TCM in females in humans. Female mice were used for the remaining experiments. Invasive hemodynamics revealed reduced contraction and relaxation (dp/dt max and dp/dt min) as well as an increased relaxation time constant Tau 24 hours after ISO injection. A time course study demonstrated that EF begins to normalize by Day 3 and is restored to baseline levels by Day 7. Importantly, ROCK2-specific inhibition prevented ISO-induced drop in EF, thinning of the LV wall, and LV volume expansion. Here, we demonstrate that female mice are more susceptible to ISO-induced cardiac dysfunction. Furthermore, we show that ROCK2 activation is necessary for the development of TCM in mice. These results suggest that FDA-approved KD025/belumosudil could potentially be repurposed for treatment in TCM.