Calcineurin signaling promotes Takotsubo cardiomyopathy

Abstract Aims: Takotsubo cardiomyopathy (TTC) presents an acute heart failure (AHF) syndrome that mimics the symptoms of acute myocardial infarction and is often preceded by an episode of emotional and/or physical stress. There is no specific treatment available, and evidence is based mostly on retrospective data. Here, we show that a high-dose of epinephrine (EPI) recapitulates numerous features of human TTC in mice, enabling genetic KO studies. By gene set enrichment network analysis and studies involving myocardial KO of the endogenous calcineurin inhibitor calcium-calmodulin-dependent kinase II (CaMKII), we identify cyclosporine A (CSA) as a novel potential therapy for TTC.Methods and results: high-dose EPI caused reversible AHF with significant ST-segment changes and high-sensitive Troponin T (hs-TnT) elevation. Male mice displayed markedly elevated hs-TnT and mortality when compared to females, mimicking the clinical syndrome. Left ventricular (LV) catecholamines revealed a distinct pattern of blunted norepinephrine as opposed to elevated EPI in male vs. female mice. Gene set enrichment analysis of LV RNA-sequencing after EPI revealed calcineurin-dependent pro-inflammatory gene networks to be significantly enriched, particularly in male hearts. Cardiac-specific deletion of CaMKII caused exacerbated AHF and myocardial damage, that was attenuated by CSA. In human peripheral blood mononuclear cells from TTC patients, expression of the calcineurin reporter regulator of calcineurin 1 isoform 4 (rcan1-4) was significantly increased compared to age- and gender matched controls, indicating human relevance of this pathway.Conclusion: Combining TTC disease modeling and mouse genetics identified calcineurin inhibition as a novel specific therapeutic concept to treat human TTC.