Influence of Genetic and Epigenetic Factors in Takotsubo Syndrome: Insights and Gaps of an Incompletely Understood Disease

Takotsubo syndrome (TTS) is a temporary and reversible form of cardiomyopathy that clinically mimics acute coronary syndrome, typically triggered by intense physical or emotional stress. It mainly affects postmenopausal women and exhibits significant variation among individuals regarding its onset, progression, and outcomes. Although significant advances have been made since its initial description in 1990, the underlying pathophysiological mechanisms remain incompletely understood, limiting the development of effective prevention and targeted treatment strategies. A potential genetic predisposition has been suggested, supported by reports of familial clustering; however, a systematic and updated characterization of genetic and epigenetic factors associated with TTS is still lacking. This systematic and critical review aims to offer a comprehensive overview of current evidence on genetic susceptibility and epigenetic biomarkers potentially involved in the pathogenesis of TTS. Due to the heterogeneity and inconsistency of available findings, particular attention is also given to the methodological limitations of existing genetic studies. Finally, the review examines emerging multimodal approaches that may offer new perspectives for understanding the complex biological foundations of this syndrome.