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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

	Abstract

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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

	Introduction

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Elevation of the ST segment in the electrocardiogram (ECG) is a classical hallmark of acute transmural myocardial ischemia. Indeed, ST elevation is the major clinical criterion for deciding which patients with chest pain require emergent coronary revascularization. Despite its clinical importance, the molecular mechanism underlying ST elevation remains unclear. Various studies have suggested that activation of sarcolemmal ATP-sensitive potassium (K_ATP) channels by ischemic ATP depletion¹ may play a role,^{2 3} but little direct evidence is available. We report that mice with homozygous knockout (KO) of the Kir6.2 gene, which encodes the pore-forming subunit of cardiac surface K_ATP channels,⁴ lack ST-segment elevation in electrocardiographic recordings 5 to 60 minutes after open-chest ligation of the left anterior descending artery. These data directly link K_ATP channels to ischemic ST elevation.

	Materials and Methods

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Generation of Kir6.2 Knockout Transgenic Mice
Transgenic mice with homozygous knockout of the Kir6.2 channel gene were generated as previously described by Miki et al.⁵

Electrophysiology
Cardiomyocytes were isolated from adult mice using conventional enzymatic dissociation. Electrical recordings were performed using the whole-cell patch-clamp technique as previously described⁶ at room temperatures. The internal pipette solution contained (mmol/L) potassium glutamate 120, KCl 25, ATP (magnesium salt) 1, EGTA 10, MgCl₂ 0.5, and HEPES 10 (pH 7.2). The external bath solution contained (mmol/L) NaCl 140, KCl 5, MgCl₂ 1, CaCl₂ 1, and HEPES 10 (pH 7.4).

Ligation of Left Anterior Descending Artery (LAD) and Electrocardiographic Recordings
Animals were anesthetized with Metofane (methoxyflurane; 2 mg/100 g) and ventilated (125 breaths/min, 255 cc/min tidal volume). Via a left thoracotomy, the proximal LAD was occluded by a snare, with myocardial ischemia confirmed by regional cyanosis. Basal body-surface electrocardiographic recording was performed at least 5 minutes after chest opening for acclimatization and immediately after LAD occlusion for continuous monitoring of changes of the ST segment during ischemia. ECGs were simultaneously measured from modified lead I with the arm electrode placed at the base of the sternum, standard lead II, and modified lead III placed on the back of the left shoulder. Needle electrodes were placed under the skin and positioned to obtain maximum recording amplitudes. All electrocardiographic recordings were performed at 36°C to 37°C.

	Results

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To define the role of K_ATP channels in the genesis of electrocardiographic ST elevation, we used mice with homozygous knockout of the Kir6.2 gene.⁵ Such mice have previously been characterized only endocrinologically; they exhibit neonatal hypoglycemia due to loss of functional K_ATP channels in pancreatic ß cells, but go on to exhibit no gross phenotypic abnormalities as adults. Electrophysiological studies in isolated adult cardiomyocytes show that P1075 (100 µmol/L), a potent opener of surface K_ATP channels,⁷ reversibly elicits robust I_K,ATP in cells from wild-type (WT, Figure 1A) but not from KO mice (Figure 1B; pooled data in Figure 1C). The identity of the P1075-induced current in WT as being I_K,ATP was confirmed by its inhibition by the surface I_K,ATP-selective blocker HMR1098⁷ (data not shown). Having verified that K_ATP channels are absent in heart cells from KO mice, we looked for changes of the ST segment during ischemia by measuring continuous ECGs in anesthetized adult mice before and after open-chest ligation of the LAD. Figure 2A shows representative ECG records of WT and KO before (left) and 5 minutes after (right) LAD occlusion. Morphologies of ECGs of WT and KO were similar under control conditions. In contrast, ST elevation was readily evident in WT but virtually absent in KO when recorded 5 minutes after the onset of regional ischemia. These observations suggest that K_ATP channels are critical determinants of ischemic ST elevation. In support of this concept, peritoneal application of HMR1098 (5 mg/kg) also abolished ST elevation in WT at this time point after occlusion (ie, 5 minutes; data not shown). Figure 2B shows the time course of development of ST elevation during the entire 60 minutes of maintained LAD occlusion. In WT, ST segments rose rapidly after occlusion, peaked temporarily at 200 seconds, then exhibited a slow progressive rise over the rest of the 60 minutes of monitoring. This biphasic pattern parallels the biphasic increase in extracellular K⁺ during ischemia⁸ and suggests the presence of at least two mechanisms. In KO, an early rise remained evident over the first 6 to 7 minutes after LAD occlusion, albeit with much smaller peak amplitude than in WT (P<0.01). Afterward, ST elevation was completely absent in KO, in striking contrast to WT. Thus, K_ATP channels are critical for both the initial and the later stages of ischemic ST elevation. Implicit in this interpretation is the premise that the severity of ischemia was comparable in the two groups, in line with the finding that infarct sizes are virtually identical in WT and KO hearts after ischemic protocols similar to these (Nakaya H and Seino S, unpublished data, 2000).

View larger version (21K): [in this window] [in a new window]   Figure 1. Figure 1. Absence of ATP-sensitive potassium current (IK,ATP) in KO mice. A, Representative current record of whole-cell patch-clamp recording of adult cardiomyocytes isolated from WT mice. Extracellular application of 100 µmol/L P1075 elicited robust IK,ATP in WT, which was reversible after drug washout. Cells were stimulated to 0 mV for 300 ms from a holding potential of -80 mV preceded by a 100-ms prepulse to -10 mV. B, Typical recordings from KO cardiomyocytes under the same conditions as in panel A. In contrast to WT, IK,ATP was absent in KO cells. C, Summary of IK,ATP densities of WT and KO.

View larger version (17K): [in this window] [in a new window]   Figure 2. Figure 2. Electrocardiographic phenotypes of WT and KO mice. A, Typical electrocardiographic recordings of WT (top) and KO (bottom) before (left) and 5 minutes after (right) LAD occlusion. Whereas elevation of the ST segment was evident in WT, it was virtually absent in KO. B, Time course of development of peak ST-segment elevation during 60 minutes of LAD occlusion. In WT (•), ST elevation continued to rise over the entire 60 minutes of ECG recording after a transient rise 2 to 4 minutes after LAD occlusion. In contrast, ST elevation gradually declined to baseline after a similar early rise, with significantly smaller peak elevation, in KO (). Data shown are mean±SEM from 5 animals each for WT and KO.

	Discussion

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Mechanistically, ischemia leads to an increase of extracellular K⁺ with membrane depolarization, depletion of intracellular ATP, and action potential shortening.^{8 9 10 11 12 13 14} The findings that sulfonylureas, blockers of I_K,ATP, partially prevent action potential shortening and extracellular K⁺ accumulation implicate the involvement of K_ATP channels in these biochemical processes.^{3 4 15} Together, these cellular events lead to electrical inhomogeneity within the heart, generating injury currents between ischemic and normal cells and shifting the ST segment in the ECG. ST elevation can also result from transmural differences in voltage during systole.¹⁶ The opening of K_ATP channels is more likely to affect action potential duration rather than the resting membrane potential, although the present measurements do not allow us to make that distinction. The differential ATP sensitivities of epicardial and endocardial K_ATP channels may further accentuate transmural voltage gradients during ischemia when ATP is depleted.¹⁷ Our results do not distinguish the relative importance of these mechanisms in ST elevation, but they do clinch the notion that K_ATP channels are critical in the genesis of these electrocardiographic events.

Pharmacological studies in large-animal models of ischemia hint that the opening of K_ATP channels precipitates ventricular fibrillation, a major cause of sudden cardiac death.¹⁵ In principle, KO mice present an opportunity to test this hypothesis. Unfortunately, mice do not develop ischemic ventricular fibrillation,¹⁸ perhaps because their hearts are too small to sustain reentry.¹⁹ Such tests are performed better in large animals; indeed, the results of Billman et al^{15 20 21} with K_ATP channel blockers lend credence to the hypothesis that these channels are indeed critical for the pathogenesis of fibrillation.

In conclusion, we have shown that the activity of a single gene product underlies the elevation of electrocardiographic ST segments during ischemia. Until now, the ECG in general and ST elevation in particular have been viewed as integrative phenomena not readily amenable to reductionist analysis. Our work provides a counterexample to such skepticism by showing that a complex, clinically relevant electrocardiographic phenomenon can have a straightforward molecular basis.

	Acknowledgments

 

This work was supported by the National Institutes of Health to E.M.. R.A.L. is the recipient of a fellowship award from the Heart and Stroke Foundation of Canada. S.S. is supported by Grants-in-Aid for Creative Basic Research from the Ministry of Education, Science, Sports and Culture, Japan. E.M. holds the Michel Mirowski, MD Professorship of Cardiology of the Johns Hopkins University. The authors would like to thank Drs Gordon Tomaselli, Brian O’Rourke, Harald Kögler, Norihito Sasaki, and Masaharu Akao for helpful discussions.

	Footnotes

 
This manuscript was sent to Michael R. Rosen, Consulting Editor, for review by expert referees, editorial decision, and final disposition.

Received September 11, 2000; accepted October 3, 2000.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, R. A. Articles by Marbán, E. Search for Related Content PubMed PubMed Citation Articles by Li, R. A. Articles by Marbán, E. Related Collections Electrophysiology Genetically altered mice Ion channels/membrane transport Acute myocardial infarction