ATP-sensitive potassium (KATP) channels are expressed throughout the body and serve to couple cellular metabolism to membrane excitability. The channels are composed of pore-forming Kir6 subunits co-assembled with obligate regulatory SUR subunits and are critically regulated by the intracellular nucleotides ATP and ADP – activating in response to metabolic compromise. Mutations of the KCNJ11 and ABCC8 genes, which encode the predominant Kir6.2 and SUR1 subunits expressed in pancreatic beta-cells, have long been associated with insulin secretion disorders. The effects of mutations of the paralogous KCNJ8 and ABCC9 genes (encoding Kir6.1 and SUR2), remained less clear, until discoveries over the last decade which have now associated congenital gain-of-function with the rare heritable disorder Cantu Syndrome, and loss-of-function with ABCC9-related intellectual disability and myopathy syndrome (AIMS).  Here we report a summary of recent works dissecting the mechanisms of cardiovascular remodeling in Cantu Syndrome using knock-in mouse models of the disease, which reveal that KATP overactivity in vascular smooth muscle (VSM) drives low systemic vascular resistance, and secondary cardiac remodeling to high-output heart failure (HOHF). Inspired by these findings, we will report preliminary data testing the generality of this pathophysiological cascade, derived from the conditional deletion of other ion channels in mice, which tests whether VSM hypo-excitability inevitably drives HOHF. In addition, we will summarize recent advances in understanding of the human consequences of LoF mutations in ABCC9 in AIMS, alongside dissection of skeletal muscle and cardiac pathology, and preliminary data on novel gene-therapy approaches to counter myopathy.