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<p>Broken heart syndrome (Takotsubo or stress cardiomyopathy) is a transient form of acute left ventricular dysfunction commonly triggered by emotional or physical stress. Despite its reversible nature, it may lead to severe complications such as pulmonary edema, arrhythmias, or cardiac arrest. Current management remains largely supportive, with no established pharmacological therapy. Metformin, a well-known anti-diabetic drug, has emerged as a potential cardioprotective agent due to its multifaceted actions on cellular metabolism, vascular function, and neuro-hormonal balance. By activating the AMP-activated protein kinase (AMPK) pathway, Metformin improves microvascular perfusion, enhances endothelial nitric oxide bioavailability, and inhibits oxidative stress and NLRP3 inflammasome activation, thereby reducing myocardial inflammation and injury. It also restores the adiponectin/leptin ratio, attenuates macrophage polarization, and modulates the PI3K/AKT/mTOR signaling cascade, thereby preserving mitochondrial function and cardiomyocyte viability. Furthermore, metformin contributes to stabilization of the autonomic and brain–heart axes by mitigating catecholamine-driven sympathetic surges and monoamine oxidase-mediated oxidative damage. Collectively, these mechanisms suggest that Metformin may have significant cardioprotective potential in broken heart syndrome by targeting endothelial dysfunction, neurogenic stress, and inflammatory responses, warranting further preclinical and clinical investigation to validate its therapeutic role.</p> Graphical abstract <p></p> <p>Proposed mechanisms of Metformin in mitigating broken heart syndrome under hyperglycemic conditions. Hyperglycemia contributes to sympathetic overactivity, promoting excessive catecholamine release, coronary vasospasm, and endothelial dysfunction, all of which culminate in broken heart syndrome. Metformin exerts protective effects through multiple mechanisms: it improves coronary microcirculation by enhancing microvascular perfusion, reducing oxidative stress, and alleviating peri-coronary inflammation; restores autonomic regulation by normalizing catecholamine levels and improving brain-heart axis function; and modulates key signaling pathways, including suppression of the PI3K/AKT/mTOR and NLRP3 inflammasome cascades via AMPK-dependent mechanisms. (Created with BioRender.com).</p>

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Metformin as a potential therapeutic agent in broken heart syndrome: Targeting AMPK-dependent cardio-protection and microvascular function

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • Muhannad Almubarak,
  • Hayder M. Al-kuraishy,
  • Nawar R. Hussain,
  • Huda J. Waheed,
  • Mubarak Alruwaili,
  • Ali I. Al-Gareeb,
  • Ali K. Albuhadily,
  • Aya M. Mustafa,
  • Gaber El-Saber Batiha

摘要

Broken heart syndrome (Takotsubo or stress cardiomyopathy) is a transient form of acute left ventricular dysfunction commonly triggered by emotional or physical stress. Despite its reversible nature, it may lead to severe complications such as pulmonary edema, arrhythmias, or cardiac arrest. Current management remains largely supportive, with no established pharmacological therapy. Metformin, a well-known anti-diabetic drug, has emerged as a potential cardioprotective agent due to its multifaceted actions on cellular metabolism, vascular function, and neuro-hormonal balance. By activating the AMP-activated protein kinase (AMPK) pathway, Metformin improves microvascular perfusion, enhances endothelial nitric oxide bioavailability, and inhibits oxidative stress and NLRP3 inflammasome activation, thereby reducing myocardial inflammation and injury. It also restores the adiponectin/leptin ratio, attenuates macrophage polarization, and modulates the PI3K/AKT/mTOR signaling cascade, thereby preserving mitochondrial function and cardiomyocyte viability. Furthermore, metformin contributes to stabilization of the autonomic and brain–heart axes by mitigating catecholamine-driven sympathetic surges and monoamine oxidase-mediated oxidative damage. Collectively, these mechanisms suggest that Metformin may have significant cardioprotective potential in broken heart syndrome by targeting endothelial dysfunction, neurogenic stress, and inflammatory responses, warranting further preclinical and clinical investigation to validate its therapeutic role.

Graphical abstract

Proposed mechanisms of Metformin in mitigating broken heart syndrome under hyperglycemic conditions. Hyperglycemia contributes to sympathetic overactivity, promoting excessive catecholamine release, coronary vasospasm, and endothelial dysfunction, all of which culminate in broken heart syndrome. Metformin exerts protective effects through multiple mechanisms: it improves coronary microcirculation by enhancing microvascular perfusion, reducing oxidative stress, and alleviating peri-coronary inflammation; restores autonomic regulation by normalizing catecholamine levels and improving brain-heart axis function; and modulates key signaling pathways, including suppression of the PI3K/AKT/mTOR and NLRP3 inflammasome cascades via AMPK-dependent mechanisms. (Created with BioRender.com).