A novel murine model of stress-induced cardiomyopathy achieved by chemogenetic stimulation of the locus coeruleus-norepinephrine system

Abstract Background Takotsubo syndrome (TTS) is a stress-induced acute cardiomyopathy characterized by transient left ventricular (LV) dysfunction without obstructive coronary artery disease. TTS is often underdiagnosed and undertreated and typically occurs in middle-aged women who recover from initial symptoms within a few weeks. Despite the apparent recovery, TTS patients have a worse cardiovascular prognosis compared to healthy individuals. To date, the pathophysiology underlying TTS remains unclear. So far, preclinical models barely reflect the complete clinical picture of TTS observed in humans. Moreover, these models display several limitations, e.g., high mortality or disregarding the involvement of the central nervous system. Consequently, much of the current obscurity concerning the pathophysiology of TTS is due to the lack of appropriate preclinical models. Purpose The present study aimed to assess whether chemogenetic activation of the locus coeruleus-(LC)-norepinephrine-(NE) system in vivo can induce LV dysfunction similar to that observed in patients with TTS. For this purpose, we used the designer excitatory receptor activated exclusively by designer drug (DREADD) system. Methods 11-13 weeks-old female Cre-dependent DREADD mice were genetically modified to express a codon-improved Cre recombinase under the dopamine-beta-hydroxylase-(DBH) promoter. For this purpose, a designed excitatory receptor exclusively activated by designer drugs or a control vector was stereotactically delivered to the LC using adenoviral transfection. Restricted expression of DBH-positive noradrenergic neurons to the LC was validated using pupillometry. LC-NE was activated by administering low-dose clozapine 0.03 mg/kg/day intraperitoneally. Serial anatomical and functional assessments of the cardiac phenotype in these mice were performed at baseline, the end of stress induction, and after ten days and three months of the recovery phase using echocardiography and cardiac magnetic resonance imaging. Results Targeted stimulation of the LC-NE system resulted in apical LV wall motion abnormality in 70–83% of mice. A complete recovery of LV wall motion abnormality was observed after the recovery phase. Conclusions Chemogenetic stimulation of the LC-NE system in mice mimics LV wall abnormalities similar to those observed in patients with TTS and may, therefore, be a novel preclinical model to investigate the pathophysiology of TTS.