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In this review, we integrate clinical observations with theory and experiment to paint a holistic portrait of cardiac alternans: the underlying mechanisms, arrhythmic manifestations and electrocardiographic signatures. We first summarize the cellular and tissue mechanisms of alternans that have been demonstrated both theoretically and experimentally, including 3 voltage-driven and 2 calcium-driven alternans mechanisms. Based on experimental and simulation results, we describe their relevance to mechanisms of arrhythmogenesis under different disease conditions, and their link to electrocardiographic characteristics of alternans observed in patients. Our major conclusion is that alternans is not only a predictor, but also a causal mechanism of potentially lethal ventricular and atrial arrhythmias across the full spectrum of arrhythmia mechanisms that culminate in functional reentry, although less important for anatomic reentry and focal arrhythmias.<\/jats:p>","DOI":"10.1161\/circresaha.122.321668","type":"journal-article","created":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T19:00:41Z","timestamp":1672945241000},"page":"127-149","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":61,"title":["Cardiac Alternans: From Bedside to Bench and Back"],"prefix":"10.1161","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5217-6022","authenticated-orcid":true,"given":"Zhilin","family":"Qu","sequence":"first","affiliation":[{"name":"Departments of Medicine (Cardiology), Physiology, and Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8622-6427","authenticated-orcid":true,"given":"James N.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Departments of Medicine (Cardiology), Physiology, and Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","first-page":"185","article-title":"Ein Fall von Pulsus bigeminus nebst Bemerkungen uber die Leberschwellungen bei Klappenfehlern und acute Leberatrophie.","volume":"9","author":"Traube L","year":"1872","unstructured":"Traube, L. 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