SGLT2 inhibition prevents apex-specific cardiac dysfunction and inflammation in an experimental model of Takotsubo Syndrome
S Kerth, A Petry, T Tatarcheh, N Spielmann, M Hrabe De Angelis, O Morel, V Schini-Kerth, A GoerlachAbstract
Background
Takotsubo syndrome (TTS) is characterized by acute, reversible apical left ventricular (LV) dysfunction triggered by catecholamine excess and associated with dysregulated β-adrenergic signaling. Increasing evidence implicates inflammatory activation and oxidative stress in TTS pathophysiology. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exert pleiotropic cardiovascular effects, including modulation of inflammatory and oxidative stress pathways; however, their role in TTS, particularly with respect to regional myocardial vulnerability, remains unknown.
Purpose
To investigate the cardioprotective effects of SGLT2 inhibition in an epinephrine-induced mouse model of TTS.
Methods
Male mice (12 weeks old) received empagliflozin (Empa, 30 mg/kg) in drinking water or no treatment for 7 consecutive days, followed by a single intraperitoneal epinephrine injection (2.5 mg/kg) and sacrifice after 24 h. Transthoracic echocardiography was performed at 1, 5, and 10 min, 1 h, 2 h, and 24 h post-injection. Gene expression was analyzed by RT-qPCR, protein localization by immunofluorescence and ROS formation by dihydroethidium fluorescence.
Results
In control mice, epinephrine induced a transient, regionally restricted apical LV dysfunction, characterized by reduced ejection fraction and fractional shortening, increased LV systolic internal diameter, apical systolic diameter, and end-diastolic volume. Fractional shortening was transiently reduced at the apex but not at the base. No such effects were observed in Empa-treated mice. In control mice, apical dysfunction was associated with increased reactive oxygen species formation and upregulation of NADPH oxidase subunits (p22phox, NOX1, NOX2, NOX4) and SGLT2, effects confined to the apex. Furthermore, epinephrine induced apex-specific markers of endothelial activation (ICAM-1, VCAM-1), senescence (p16, p21), and a pro-inflammatory response (TNF-α and IL-6), and CD68⁺ macrophage infiltration. None of these changes were observed in the myocardium from the base nor in Empa-treated mice.
Conclusion
SGLT2 inhibition prevented epinephrine-induced apical LV dysfunction in a murine model of Takotsubo syndrome and was associated with attenuation of oxidative stress, endothelial activation, and inflammatory responses in the apex. These findings support inflammation-related mechanisms as contributors to apical myocardial vulnerability in TTS.