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(Circulation Research. 2000;87:837.)
© 2000 American Heart Association, Inc.

Reports

Molecular Basis of Electrocardiographic ST-Segment Elevation

Ronald A. Li, Michelle Leppo, Takashi Miki, Susumu Seino, Eduardo Marbán

From the Institute of Molecular Cardiobiology, The Johns Hopkins University School of Medicine (R.A.L., M.L., E.M.), Baltimore, Md; Department of Molecular Medicine, Chiba University Graduate School of Medicine (T.M., S.S.), Inohana, Chuo-ku, Chiba, Japan.

Correspondence to Dr Eduardo Marbán, Institute of Molecular Cardiobiology, The Johns Hopkins University School of Medicine, 720 Rutland Ave/Ross 844, Baltimore, MD 21205. E-mail marban{at}jhmi.edu

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_ATPchannel blocker HMR1098 (5 mg/kg IP) suppressed early ST elevation in WT. Thus, the opening of sarcolemmal K_ATPchannels underlies ST elevation during ischemia. These data are the first to link a specific gene product with a common electrocardiographic phenomenon.

Key Words: ST elevation • ischemia • ATP-sensitive K⁺ channels • homozygous knockout

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