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Unfortunately, several clinical trials inhibiting key cytokines like tumor necrosis factor alpha (TNF-\u03b1) and interleukin 1 beta (Il-1\u03b2) turned out negative or even revealed adverse clinical effects. Providing a potential mechanistic explanation for the ineffectiveness of TNF-\u03b1 blockade in heart failure, novel findings demonstrate that the membrane-bound precursor form of TNF-\u03b1, transmembrane TNF-\u03b1 (tmTNF-\u03b1), mediates cardioprotective effects during pressure overload-induced cardiac remodeling. 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