Mechanistic studies in mouse models of CS, in which CS variants in ABCC9 and KCNJ8 were engineered into the equivalent mouse loci using CRISPR/Cas9, indicate that cardiac enlargement and enhanced CO are responses to decreased vascular resistance arising from the vascular smooth muscle KATP channel gain‐of‐function, because cardiac enlargement can be reversed when vascular KATP channels specifically are inhibited or genetically knocked down26, 27 (Figure 6). This evidence concerns the gene ABCC9 and Cowden syndrome 1.