The idea that MTHFR-mediated disorders in the folate cycle trigger endothelial dysfunction, and that this condition may in turn influence the IAS phenotype, grounds on several clinic, translational, and basic research studies: An appropriate L-Arg/ADMA ratio, indicative of a physiological NO production, is required for the proper post-natal cardiomyocyte proliferation and differentiation [40], suggesting that a fully performing eNOS is mandatory for postnatal heart development [41]. The gene discussed is MTHFR; the disease is endothelial dysfunction.