Moreover, experiments on transgenic mice lacking ERα nonnuclear signaling, i.e., KRRKI/KI (KRR knock-in mutant ERα) mice, showed that the missing signaling played a pivotal role in cardioprotection against pressure-overload-induced cardiac remodeling and was essential to the therapeutic efficacy of cGMP-PDE5is (cGMP-phosphodiesterase 5 inhibitors) in the treatment of heart failure [144]. Here, ESR1 is linked to heart failure.