Hypercholesterolemia was the first cardiovascular risk factor to be associated with the loss of cardioprotection due to deterioration of several signaling mechanisms (Ferdinandy et al., 2007, 2014), including disruption of NO-cGMP-PKG pathway (Giricz et al., 2009), KATP signaling (Csonka et al., 2014), Connexin43 distribution (Gorbe et al., 2011), inhibition of opening of mitochondrial permeability transition pores (Yadav et al., 2010), among several other (Andreadou et al., 2017). The gene discussed is PRKG1; the disease is familial hypercholesterolemia.