Molecular basis of electrocardiographic ST-segment elevation.
ST elevation is a classical hallmark of acute transmural myocardial ischemia. Indeed, ST elevation is the major clinical criterion for committing patients with chest pain to emergent coronary revascularization. Despite its clinical importance, the mechanism of ST elevation remains unclear. Various studies have suggested that activation of sarcolemmal ATP-sensitive potassium (K(ATP)) channels by ischemic ATP depletion may play a role, but little direct evidence is available. We studied mice with homozygous knockout (KO) of the Kir6.2 gene, which encodes the pore-forming subunit of cardiac surface K(ATP) channels. Patch-clamp studies in cardiomyocytes confirmed that surface K(ATP) current was indeed absent in KO, but robust in cells from wild-type mice (WT). We then measured continuous electrocardiograms in anesthetized adult mice before and after open-chest ligation of the left anterior descending artery (LAD). Whereas ST elevation was readily evident in WT after LAD 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 elevation, the surface K(ATP)channel blocker HMR1098 (5 mg/kg IP) suppressed early ST elevation in WT. Thus, the opening of sarcolemmal K(ATP)channels underlies ST elevation during ischemia. These data are the first to link a specific gene product with a common electrocardiographic phenomenon.
Li
R A
RA
Institute of Molecular Cardiobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Leppo
M
M
Miki
T
T
Seino
S
S
Marbán
E
E
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004195:Disease Models, Animal; D004562:Electrocardiography; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D012508:Sarcolemma / Q000378:metabolism
D001549:Benzamides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000255:Adenosine Triphosphate; C410297:HMR 1098; D011188:Potassium