Heart failure is a growing epidemic, with systemic hypertension a major risk factor for development of disease. However, the molecular determinants that prevent the transition from a state of hypertensive load to that of overt cardiac failure remain largely unknown. Here in experimental hypertension, knockout of the KCNJ11 gene, encoding the Kir6.2 pore-forming subunit of the sarcolemmal ATP-sensitive potassium (KATP) channel, predisposed to heart failure and death. Defective decoding of hypertension-induced metabolic distress signals in the KATP channel knockout set in motion pathological calcium overload and aggravated cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway. Rescue of the failing KATP knockout phenotype was achieved by alternative control of myocardial calcium influx, bypassing uncoupled metabolic-electrical integration. The intact KCNJ11-encoded KATP channel is thus a required safety element preventing hypertension-induced heart failure, with channel dysfunction a molecular substrate for stress-associated channelopathy in cardiovascular disease.