NOS2 and heart failure: In heart failure with reduced ejection fraction (HFrEF), secondary to ischemic or non-ischemic cardiac injury, not only does IL-1 signaling determine iNOS-related damage but it also directly induces inhibition of L-type calcium channel, beta-adrenergic receptor desensitization, downregulation of phospholamban and SERCA, and reduction in mitochondrial production of energy through downregulation of pyruvate dehydrogenase (PDH) activity [41].