Background: Takotsubo syndrome (TTS) is a mechanistically yet not understood acute heart failure syndrome induced by catecholamine storm upon emotional or physical stress. Despite its partial reversibility a lasting impact on patient outcome with increased mortality has been reported. Previous work has shown that the catecholamine responsive histone deacetylase 4 (HDAC4) is required for the maintenance of cardiac function during physical stress and that its N-terminal proteolytic product is cardioprotective by repressing the MEF2. In experimental TTS, myocardial HDAC4 or CaMKII ablation both cause deleterious effects on cardiac function, myocardial damage, and mortality. Here, we investigate the role of the CaMKII-HDAC4 interaction as part of the underlying pathophysiology.

Methods: 12-week-old male mice from a mouse line harbouring an R598F mutation in the HDAC4 gene (RF), that selectively disrupts the interaction between CaMKII and HDAC4, and the corresponding littermates (WT) were injected with epinephrine (EPI) to induce experimental TTS or NaCl with subsequent functional and molecular characterisation.

Results: Two-, eight-, and twenty-four hours after EPI, RF mice showed significantly improved left ventricular ejection fraction compared to WT littermates (2h: 47.16 vs. 31.97%, p<0.001; 8h 55.98 vs 38.91%, p<0.0001; 24h: 65.93 vs. 50.48%, n=10-12, p<0.001 by two-way ANOVA, Fig. 1) with markedly lower hs-Troponin T (2h: 5112 vs. 9597 pg/ml, p<0.01; 24h: 1895 vs. 6113pg/ml, n=6-12, p<0.05 by one-way ANOVA, Fig. 2). One month after insult we detected significantly lower levels of NT-proBNP (2357 vs. 2704 ng/l, p<0.05, n=5-7 by t-test, Fig. 3) in serum samples and lower nppb/gapdh mRNA in ventricular tissue (p<0.01, n=10-12, by t-test, Fig. 4). Two hours after EPI, we observed a significantly lower increase in RCAN 1-4 protein in RF mice compared to WT littermates (Fig. 5 and 6). In addition, we detected two-fold lower Ccl2 and Ccl3 expression two hours after insult providing further evidence that the CaMKII-HDAC4 interaction modulates the myocardial inflammatory response in experimental TTS.

Conclusion: Preventing CaMKII from interacting with HDAC protects mice from left ventricular ejection fraction impairment, myocardial damage and lowers mortality rate in experimental TTS, possibly by modulation of the inflammatory response in the acute phase of TTS. The role of the CaMKII-HDAC4 interaction is subject of an ongoing investigation.