While some studies suggest AC5 overexpression improves cardiac function in transgenic mice during exercise (Esposito et al., 2008), deletion of AC5 protects the heart in most models of cardiac stress including heart failure; in contrast, AC6 overexpression has been correlated with cardioprotective effects (Wu et al., 2017; Ostrom et al., 2022). This evidence concerns the gene ADCY5 and heart failure.