The Genetic Puzzle of the Stress-Induced Cardiomyopathy (Takotsubo Syndrome): State of Art and Future Perspectives

Takotsubo syndrome (TS), also known as stress-induced cardiomyopathy, is classically characterized by an acute onset mimicking myocardial infarction and by distinctive transient wall motion abnormalities detectable via echocardiography, often resembling a Japanese octopus trap (the so-called “takotsubo”). The possibility that a genetic background may contribute to TS susceptibility emerged early, supported by several familial case reports. Despite a large number of investigations, no definitive genetic markers associated with TS risk have been conclusively identified. The lack of a clear Mendelian inheritance pattern suggests a multifactorial etiology and pathogenesis, likely involving complex gene–environment interactions and a polygenic background. This review analyzes the genetic variants implicated in the different functional pathways contributing to TS pathogenesis and discusses the current state of knowledge regarding its genetic underpinnings. Finally, we propose future directions for research aimed at identifying a multigene susceptibility panel that could be useful in diagnosis, prevention strategies, and the identification of novel therapeutic targets for individuals at high risk. We conclude that innovative approaches based on data-mining algorithms and nonlinear analytic methods applied to large patient datasets may be instrumental in resolving the genetic complexity of TS.