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Activation of NCX and sodium/hydrogen exchanger-1 (NHE-1), at cardiac and vascular level, mediate the maladaptive neurohormonal stimulation (sympathetic nervous system, RAAS, and natriuretic peptide system) during the pathophysiological course toward HF (Packer, 2017)

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Subsequent efforts to amplify signaling further led to third-generation CARs harboring two distinct co-stimulatory domains, although their clinical superiority over second-generation designs remains equivocal