Our models propose ibrutinib-specific mechanisms mediated by ibrutinib-specific off-targets involved in AF (structural remodeling and atrial fibrosis mediated by HCK, FGR, LYN, FYN, YES1 and FLT3; and electrophysiology regulation mediated by LYN and SRC) and in hypertension (inflammation mediated by LCK, JAK3 and FLT3; and oxidative stress and endothelial dysfunction mediated by ERBB2, BLK, SRC and CSK). Here, JAK3 is linked to endothelial dysfunction.