Targeting Takotsubo Syndrome: Molecular Mechanisms and Treatment Efficacy through cMyBP-C Phosphorylation Modulation

Background: Takotsubo syndrome (TTS) is an acute cardiac dysfunction resembling acute myocardial infarction but not caused by coronary artery disease. It often follows severe emotional or physical stress and temporarily impairs left ventricular function. The exact pathophysiological mechanisms remain partially understood, but sarcomeric dysfunction due to catecholamine surge is implicated. This study aims to elucidate the molecular mechanisms of TTS in vivo to identify potential pharmacological therapies, enhancing treatment specificity and effectiveness for TTS patients.

Methods: A TTS mouse model was established through intraperitoneal injection of epinephrine. Cardiac function was assessed via ultrasound imaging at 2- and 8-hours post-TTS induction. Murine heart tissues were analyzed for phosphorylation changes. Treatments with Levosimendan and Omecamtiv mecarbil were evaluated in the TTS mouse model.

Results: The TTS mouse model exhibited typical apical ballooning. Left ventricular ejection fraction (LV-EF) was significantly reduced in TTS compared to controls (Fig. 1). Western blot analysis of cardiac myosin binding protein C (cMyBP-C) showed hypophosphorylation at all phosphorylation sites (Ser273, Ser282, and Ser302) at 8 hours, with partial changes at 2 hours (Fig. 2). Levosimendan treatment reverses hypophosphorylation and improved LV-EF. Omecamtiv mecarbil also affects cMyBP-C phosphorylation (Fig. 3) and enhances LV-EF (Fig. 1B). Both drug interventions decrease mortality in the TTS mouse model.

Conclusion: This study links decreased cMyBP-C phosphorylation in a TTS mouse model with reduced cardiac function. It suggests that β-AR coupling switch from Gs to Gi leads to hypophosphorylation of cMyBP-C and altered Ca signaling. Therapeutic interventions with Levosimendan and Omecamtiv mecarbil ameliorate hypophosphorylation and positively affect cardiac function.

Perspective:  Comparative analyses of heart biopsies and blood samples from TTS patients regarding cMyBP-C phosphorylation will strengthen the translational approach, potentially leading to targeted myosin activating therapies for TTS.