Molecular basis of electrocardiographic ST-segment elevation

ST elevation is a classical hallmark of acute transmural myocardial ischemi a, Indeed, ST elevation is the major clinical criterion for committing pati ents with chest pain to emergent coronary revascularization. Despite its cl inical importance, the mechanism of ST elevation remains unclear. Various s tudies have suggested that activation of sarcolemmal ATP-sensitive potassiu m (K-ATP) channels by ischemic ATP depletion may play a role, but little di rect evidence is available. We studied mice with homozygous knockout (KO) o f the Kir6.2 gene, which encodes the pore-forming subunit of cardiac surfac e KATP channels. patch-clamp studies in cardiomyocytes confirmed that surfa ce K-ATP current was indeed absent in KO, but robust in cells from wild-typ e mice (WT). We then measured continuous electrocardiograms in anesthetized adult mice before and after open-chest ligation of the left anterior desce nding artery (LAD). Whereas ST elevation was readily evident ill WT after L AD ligation, it was markedly suppressed in KO, Such qualitative differences persisted for the rest of the 60-minute observation period of ischemia, In support of the concept that K-ATP channels are responsible for ST elevatio n, the surface K-ATP channel blocker HMR1098 (5 mg/kg IF) suppressed early ST elevation in WT. Thus, the opening of sarcolemmal K-ATP channels underli es ST elevation during ischemia, These data are the first to link a specifi c gene product with a common electrocardiographic phenomenon.