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Assessing the pattern of ST-segment depression during subendocardial ischemia using a computer simulation of the ventricular electrogram
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Journal of Electrocardiology 42 (2009) 12 – 18 www.jecgonline.com
Assessing the pattern of ST-segment depression during subendocardial ischemia using a computer simulation of the ventricular electrogram Mauro Bertella, MD, a Michele Nanna, MD, FACC, b Emilio Vanoli, MD, c,d Filippo Scalise, MD, FACC, FESC, FSCAI e,⁎ a
Cardiology Department, Vimercate Hospital, Vimercate, Italy b Albert Einstein College of Medicine, Bronx, NY, USA c Cardiology Department, Policlinico di Monza, Monza, Italy d University of Pavia, Pavia, Italy e Cardiac Catheterization Laboratory, Cardiovascular Department, Policlinico di Monza, Monza, Italy Received 12 May 2008
Abstract
The primary aim of the study was to write a simple educational personal computer (PC)–based program able to simulate normal and pathological electrogram (EG) to analyze the ST-segment and T-wave patterns during subendocardial ischemia. Background: The EG waveforms are know to depend on the properties of transmembrane action potentials (APs) of atrial and ventricular myocytes, the spread of excitation, and the characteristics of the volume conductor. Transmembrane AP is an electromotive generator that plays a central role, and it is the principal responsible for the potential differences that are recorded as an EG. The EG can be considered as the algebric sum of 2 transmembrane APs, that is, the AP of the underlying endocardial region minus the AP of the underlying epicardial region. Methods: Using an educational PC software (Microsoft Excel), a normal EG was simulated reproducing planimetrically, point-by-point, normal transmembrane APs recorded from the epicardial and endocardial regions in normal animals. The shape and the voltage of the APs were then modified to closely mimic human APs. To simulate typical subendocardial ischemia, we changed the subendocardial AP according to experimental and clinical observations. Results: The reconstruction of EG by the algebric subtraction (endocardial minus epicardial) APs was possible. The EG, mirroring typical subendocardial ischemia, was simulated without changing the epicardial AP. The EG simulating typical subendocardial ischemia showed a horizontal pattern of ST segment depression. In our model modification of the subendocardial AP combined with “unnatural” changes of the phase 3 of the subendocardial AP produced a downsloping pattern of STsegment depression. Conclusion: The derivated EG waveform obtained with our PC program properly describe the algebric sum of endocardial and epicardial APs. In our opinion, this method represents a useful tool for the study of the AP changes. The simulated ST-depression morphology during subendocardial ischemia appears to be essentially “horizontal” and not downsloping. On the basis of our simplified theoretical model, we propose that ischemia-induced downsloping ST depression should be considered a reciprocal EG change and a manifestation of transmural ischemia in the wall opposite the exploring electrode. © 2009 Elsevier Inc. All rights reserved.
Keywords:
ST-segment depression; Subendocardial ischemia; Action potential
Background Electrocardiographic ST-segment depression has long been recognized as a sign of ischemia,1 but the explanations ⁎ Corresponding author. E-mail address: [email protected] 0022-0736/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jelectrocard.2008.09.003
of the responsible mechanisms have been controversial.2 Most of the current opinion regarding the genesis of ST-segment depression is derived from interpretations based on certain theoretical considerations3 and indirect evidence from animal experiments. 1 Ischemic muscle generates intracellular currents, which effectively cause TQ depression and ST elevation over the ischemic area that are
M. Bertella et al. / Journal of Electrocardiology 42 (2009) 12–18
then described by conventional electrocardiography with alternating current (AC)-coupled amplifiers as ST-segment elevation. On the other hand, ST-segment depression recorded at the epicardium has been considered secondary to an injury current in the underlying subendocardium.4 In conventional stress testing, ST-segment depression is considered incapable of localizing the site of ischemia.5 The standard criterion for this abnormal response is horizontal or downsloping ST-segment depression of 0.10 mV (1 mm) or more for J + 60 milliseconds, in at least three consecutive complexes, where “downsloping” is considered to reflect “more ischemia” than “horizontal” STsegment depression.5 Subendocardial ischemia has been also subdivided into “regional” and “circumferential” for therapeutic and prognostic purposes.6 These concepts are commonly accepted by most cardiologists. However, we wondered why it is not possible to localize the site of ischemia by conventional electrocardiography in patients with ischemia-induced ST-segment depression. It is very curious indeed that the same stress-induced ischemia could be regional, when detected by echocardiography or other imaging techniques (myocardial scintigraphy or magnetic resonance imaging ),7 and “global,” “diffuse” when detected by electrocardiography. The aim of this study was to write an educational personal computer (PC) program, able to simulate normal and pathological electrograms (EGs), to analyze the ST-T patterns of subendocardial ischemia. The EG waveforms are known to depend on the properties of transmembrane action potentials (APs) of atrial and ventricular myocytes, the spread of excitation, and the characteristics of the volume conductor. Among them, transmembrane AP as an electromotive generator clearly plays a central role, and it is ultimately responsible for the potential differences that are registered as an EG. The EG is produced fundamentally by depolarization and repolarization of the left ventricle, which consists of 2 parts, subendocardium located far from the explorer electrode and subepicardium closer to same. The transmembrane AP of the left ventricle can be considered as the subtraction, endocardial minus epicardial, AP curves (Fig. 1). Then, QRS-T waves (systole) and isoelectric lines of EG (diastole) correspond to the sum of systolic and diastolic transmembrane APs. Ashman,8 in 1941, suggested that the unipolar EG can be considered as the algebraic sum of 2 transmembrane APs, that is, the APs of the underlying endocardial region minus the AP of the underlying epicardial region. Using this simplified model, it is possible to reproduce an EG-like waveform.9
13
Fig. 1. The transmembrane AP of the left ventricle considered as the subtraction, endocardial (AP1) minus epicardial (AP2), AP curves. D indicates diastole (resting membrane potential); P, AP plateau region (from Taggart9).
chart. We have planimetrically reconstructed the AP curves using 30 consecutive points (Fig. 2). As these tracings were recorded in dogs, the shape of the APs was modified to make it similar to human potentials (Fig. 3A, B). Indeed, human subepicardial APs are characterized by a clear notch in phase 1, whereas subendocardial APs are characterized by the absence of this notch.11 The left ventricular transmembrane AP wave was obtained by point-by-point subtraction, endocardial minus epicardial, of AP curves. The graphic representation of this EG-like waveform was simply obtained using the MS-Excel graphic tool. To simulate typical subendocardial ischemia, the subendocardial AP was changed according to experimental and clinical observations.12,13 Subendocardial ischemia was simulated without changing the epicardial AP and by increasing the resting transmembrane potential and the duration of phase 3 of the endocardial AP. The AP amplitude and rate of rise of phase 0 of endocardial AP were also reduced. Multiple sequential variations of the endocardial AP were made modifying point-by-point the graphic data source (Fig. 4). Results
Methods Using an educational PC software (Microsoft MS-Excel), a normal EG was simulated reproducing planimetrically, point-by-point, normal transmembrane APs recorded from the epicardial and endocardial regions. We used normal tracings of endocardial and epicardial APs, recorded simultaneously with transmural EG reproduced by Yan and Antzelevitch.10 The EG charts were created by MS-Excel worksheet that included the information needed to build the
The reconstruction of surface EG by the algebraic sum of endocardial and epicardial APs is reproduced in Fig. 5. An EG-like waveform was reproduced, then QRS-T waves (systole) and isoelectric lines of EG (diastole) correspond to the sum of systolic and diastolic transmembrane APs. The EG simulating subendocardial ischemia is reproduced in Fig. 6. The pattern of ST-segment depression appears to be essentially horizontal. Altering only the subendocardial AP, it was possible to obtain a downsloping
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Fig. 2. Planimetric reconstruction of the AP curves with Microsoft MS-Excel. endo indicates endocardial AP; epi, epicardial AP.
pattern of ST-segment depression by introducing “unnatural” changes of the phase 3 of the subendocardial AP (Fig. 7).
Discussion This method represents in our opinion a useful tool to study the cardiac AP changes. In our study, a computer simulation of subendocardial ischemia suggests that the morphology of ST-segment depression should be essentially horizontal and not downsloping. ST-segment depression morphology during isolated subendocardial ischemia: theoretical and experimental data The earliest and most consistent effect of subendocardial ischemia is the loss of myocardial diastolic resting membrane potential resulting in a diastolic current flow toward the epicardium and horizontal elevation of the TQ baseline.13 The diastolic current is interrupted at the onset of the QRS when all myocardial cells are depolarized. As zero current flows during the ST interval, 9 the resulting morphology of the apparent ST-segment shift during unambiguous subendocardial ischemia should be of a variable horizontal to upsloping configuration, depending on the shape of the AP plateau.9 Using a unipolar electrode connected to a direct current–coupled amplifier and placed on normal epicardial tissue, overlying a zone of subendo-
cardial ischemia, it is possible to record early after the onset of subendocardial ischemia the elevated TQ baseline reset above the original baseline.14 The absence of injury flow from depolarized ischemic myocytes causes a transient return to the original baseline and the appearance of STsegment depression.14 The electrophysiological characteristics of ischemic cells are well known: They include increased transmembrane resting potentials, reduced AP amplitude and rate of rise of phase 0, shortened AP, and a conduction delay.14 In our computer simulation of subendocardial ischemia, the phase 3 of the normal endocardial AP was prolonged. This appears to conflict with experimental data, which demonstrated AP duration (APD) shortening during acute ischemia.14 The APD shortening begins within minutes after the onset of acute ischemia and is mediated largely by an increase in the outward repolarizing potassium current and by a decrease in calcium ion influx.14 It was demonstrated that the molecular basis of QTc interval shortening is the activation of K-ATP channels,15 but it was also demonstrated that K-ATP channels are activated by a smaller reduction in intracellular ATP in epicardial cells, than in endocardial cells. The differential sensitivity of ATPregulated channels in endocardial and epicardial cells may be responsible for the differential shortening in APD during ischemia at the 2 sites. These findings were confirmed by Miyoshi et al.12 These authors suggested that the different responses of epicardium and endocardium to K-ATP modulators during regional ischemia could be explained by a lower threshold for activation and/or a denser distribution of K-ATP channels at the epicardial layer.12 Moreover, clinical observations documented that in subendocardial ischemia, slow repolarization in the subendocardial region— which even under physiologic circumstances is the region with the longest refractory period—results in prolongation of QTc interval. Ischemia in this region does not alter the epicardium to endocardium direction of repolarization, but the slow recovery in the subendocardial region augments the magnitude of T wave because repolarization persists in this zone as repolarization subsides in the epicardial layer. As in our computer simulation, the subendocardial AP does not represent a single cell but the sum of the APs of ischemic subendocardial myocytes, so a delayed AP was used. In a model of subendocardial ischemia, Guyton et al16
Fig. 3. Human (A) and canine (B) AP curves.
M. Bertella et al. / Journal of Electrocardiology 42 (2009) 12–18
15
Fig. 4. Multiple and progressive (A-C) variations of the endocardial AP to simulate subendocardial ischemia.
demonstrated that by reducing subendocardial blood flow (measured with radioactive microsphere techniques), while subepicardial flow remained normal, epicardial ST depression localized the site of subendocardial ST elevation as long as a layer of nonischemic epicardial muscle was present. When ischemia became transmural, epicardial ST-elevation occurred.16 Experimental data of Sodi Pallares et al17 refers to EG changes recorded in the presence of a subendocardial scar, mirroring isolated subendocardial infarction. These authors observed in animals that lesions (burning) in the subendocardial muscle of at least 15 mm in diameter are needed to register a pure monophasic wave in the subendocardial area and a moderate negative RS-T displacement in lead V5, placed near the injured region. The injuryinduced ST depression appears horizontal for at least 160 milliseconds after the J point, despite the presence of negative T waves.17 They concluded that subendocardial lesions of sufficient size to be detectable in the precordial and limb leads induce the following modifications in the EG: (1) positivity of the T wave; (2) prolonged QT interval in the initial phase; (3) negative RS-T displacement; (4) negative displacement of the J point; (4) increase in the voltage of S wave; (6) diminution in the voltage of R wave.17
From the transition of subendocardial ischemia to fullthickness ischemia, it was found that epicardial ST depression increased gradually over the boundary region as ischemia progressed, and ST elevation ensued over the ischemic region as ischemia became transmural.18 A greater ST depression was also observed before the occurrence of ST elevation in a study with a perfused canine heart by Guyton et al16 in 1977. The electrical transition from ST depression to ST elevation was consistent with the contention that the current path is in the myocardium. In the normal EG, the ST segment remains isoelectric because there are no significant potential differences occurring in the myocardium during this period. In transmural ischemia, epicardial ST elevation occurs when injury currents flow at the boundary between the ischemic regions and the normal myocardium because of the potential difference between these 2 regions.19 Because the myocardial cells in subendocardial ischemia undergo changes qualitatively similar to those occurring during transmural ischemia,18 it is likely that the injury currents in subendocardial ischemia also originate from the ischemic boundary. Subendocardial ischemia involves only the inner layer of the ventricular wall. Thus, the boundary between the ischemic region and the normal myocardium is likely to
Fig. 5. Reconstruction of surface EG by the algebraic sum of endocardial (endo) and epicardial (epi) APs using MS-Excel graphic tool.
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Fig. 6. Reconstruction of EG simulating subendocardial ischemia using MS-Excel graphic tool (horizontal pattern).
include the transmural boundary parallel to the endocardium and the lateral boundary perpendicular to the endocardium. However, the flow distribution during subendocardial ischemia demonstrated a gradual flow transition from the endocardium to the epicardium,18 but at the lateral boundary, flow changes abruptly from the ischemic zone to the nonischemic zone, producing a sharp lateral interface between ischemic and normal regions. 18 Studies on transmural ischemia also found a sharp lateral interface between ischemic and normal cells with severely ischemic tissue lying adjacent to normal well-perfused tissue.20 In ischemic pig hearts, transmembrane AP recordings using floating microelectrodes also demonstrated a sharp and distinct transition from electrophysiologically abnormal to normal cells. The injury current is directly associated with the spatial gradient of the transmembrane potentials. A greater potential gradient exists at the lateral boundary, which in turn produces a stronger current. Under such circumstances, the greater epicardial potential change should appear at the lateral boundary regions with less change in the ischemic center, where the transmural boundary is located and less injury current occurs. The transition of subendocardial ischemia to full-thickness ischemia showed that as
ischemia progressed, ST depression increased gradually until ischemia became transmural and ST elevation ensued in the ischemic center.18 The increased ST depression occurred at the lateral border, whereas the ST elevation started at the ischemic center. ST elevation gradually progressed toward the ischemic border. These observations support the postulate that the major source of electrical current in subendocardial ischemia is located at the lateral boundary of the ischemia. These complex mechanisms cannot be obviously estimated from our computer simulation that has been only devised for an educational scope. Significance of an ischemia-induced downsloping ST depression Examining our computer simulation of downsloping ST depression (Fig. 7) and comparing it with the shape of a transmembrane AP recorded in normal subjects during ischemia (Figs. 5 and 6), phase 3 of the monophasic AP is also associated with final rapid repolarization. In this AP phase, repolarization proceeds rapidly and the membrane potential shifts to the resting potential. The net membrane current is always outward, and no new depolarization is possible in this phase. In our computer simulation, modify-
Fig. 7. Reconstruction of EG simulating subendocardial ischemia using MS-Excel graphic tool (downsloping pattern).
M. Bertella et al. / Journal of Electrocardiology 42 (2009) 12–18
ing APs according to patterns recorded during induced acute ischemia, it was not possible to reproduce a frankly downsloping ST-segment depression. A possible explanation of this apparent contradiction is that ischemia-induced downsloping ST depression should be considered a reciprocal EG change due to transmural ischemia in the cardiac wall opposite the exploring electrode. During transmural ischemia development, it is possible to measure an increase in the resting membrane potential of myocytes. Loss of resting membrane potential generates a diastolic injury current directed from the injured to the normal tissue and therefore a horizontal depression of the baseline TQ segment in EG.14 In the standard EG using capacitor AC amplifiers, TQ segment displacement appears as horizontal ST-segment elevation.14 Very early during the development of ischemia, the APD of epicardial cells transiently lengthens owing to a drop in temperature in the ischemic myocardium, followed by shortening, largely caused by the rise in extracellular potassium. Shortened APD generates an intracellular systolic injury current directed from normal to injured tissue.14 The APD shortening and ST-segment elevation of epicardial cells is associated with the activation of ATP-sensitive potassium channels.12,15 Kondo et al21 observed in animals that early after the onset of transmural ischemia, only the terminal part of the elevated ST segment is inhibited by glibenclamide, a selective blocker of K-ATP channels. Therefore, this systolic current could be responsible during typical transmural ischemia for both the upsloping shift of the terminal part of elevated ST segments and of the downsloping ST depression secondary to reciprocal ST segment shifts. Li et al22 demonstrated in mice that shortly after the onset of ischemia, only sarcolemmal K-ATP channel activation is the molecular basis of ST elevation. The origin of ischemic ST-segment depression In transmural ischemia, epicardial ST elevation occurs when injury currents flow between the ischemic regions and the normal myocardium.19 The region of ST elevation is closely related to the region of ischemia. Two major mechanisms are considered to underlie ST-segment displacement: (1) a localized shortening of APD and diminishing of the amplitude of the AP and (2) a localized decrease in resting membrane potential. The former generates current only during the ST segment. The latter generates an injury current that is interrupted during the ST segment when all the cells are depolarized. The injury current produces a TQsegment shift that cannot be directly detected on the EG; however, the interruption of the injury current during the ST segment produces an apparent ST shift, which is equal and opposite the TQ-segment shift on the AC-coupled EG. With ST depression, there is no satisfactory explanation of the cardiac electrophysiological changes. Previous work23,24 in isolated hearts suggested that the ST-segment response to myocardial injury was elevation and that the STsegment depression recorded at the epicardium was the reciprocal of ST elevation in the underlying subendocardium. The dipole model24 considered the active myocardial event as a single dipole source that contained both the maximum and the minimum potentials. Accordingly, an
17
injured region of the myocardium acts in systole as the positive pole of a layer of dipoles situated on its boundary with normal myocardium, whereas the latter acts as the negative pole. In the event of subendocardial ischemia, the ventricular surface and the precordium over the ischemic region face the negative pole of the dipole; the cavity faces the positive pole.18 Thus, the electrodes over the ischemia should record depressed ST segments, and the cavity should yield elevated ST segments.25 Study limitation Until now, EG, in general, and ST segment shift (depression or elevation), in particular, have been viewed as integrative phenomena not readily amenable to reductionist analysis.22 Our computer simulation is an extremely simplified educational model to teach and learn electrocardiography, starting from the basic principles. Downsloping ST-segment depression could be recorded also in the presence of normal angiography, that is, syndrome X and left ventricular hypertrophy and strain or in coronary artery disease patients in which the limited severity of coronary obstructions in vessels supplying the opposite wall does not justify the appearance of stress-induced reciprocal transmural ischemia. In these patients, pathogenetic mechanisms different from reciprocal transmural ischemia must be sought. The degree of influence of the ischemic modification on endocardial AP is much more complex, and our extremely simplified simulation of subendocardial ischemia represents a potential source of error. The APs represent only 1 single point of transmembrane AP, and in reality, the picture is much more complex with different degrees of severity of ischemia and boundaries between normal and ischemic myocardium in a 3-dimensional fashion. Conclusions The derivated EG-like waveform obtained with this simple educational PC program properly describes the algebraic sum of endocardial and epicardial APs. In our opinion, this program represents a useful tool for the study of the AP changes. The simulated ST-depression morphology during subendocardial ischemia appears to be essentially horizontal and not downsloping. Based on our simplified theoretical model, we propose that ischemia-induced downsloping ST depression should be considered a reciprocal EG change and a manifestation of transmural ischemia in the cardiac wall opposite the exploring electrode. References 1. Gussak I, Bjerregaard P, Egan TM, Chaitman BR. ECG phenomenon called the J-wave: history, pathophysiology, and clinical significance. J Electrocardiol 1995;28:49. 2. Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J-wave. Circulation 1996;93:372. 3. Antzelevitch C, Yan GX. Cellular and ionic mechanisms responsible for the Brugada syndrome. J Electrocardiol 2000;33(Suppl):33.
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4. Kleber AG, Janse MJ, Van Capelle FJL, Durrer D. Mechanism and time course of S-T and T-Q segment changes during acute regional myocardial ischemia in the pig heart determined by extracellular and intracellular recordings. Circ Res 1978;42:603. 5. Fletcher GF, Balady G, Froelicher VF, Hartley LH, Haskell WL, Pollock ML. Exercise standards: a statement for health professionals from the American Heart Association. Circulation 1995;51:580. 6. Sclarovsky S. Electrocardiography of acute myocardial ischaemic syndromes. London: Martin Dunitz Ltd; 1999. p. 13. 7. Picano E. Stress echocardiography. 3rd ed. Berlin: Springer-Verlag; 1997. p. 21. 8. Ashman R, Hull E. Essential of electrocardiography. New York: The MacMillan Co; 1941. 9. Taggart P. The resting and exercise electrocardiogram. In: Sutton P, editor. Measurements in cardiology. New York: The Parthenon Publishing Group; 1999. p. 60. 10. Yan GX, Antzelevitch C. Origin of the J wave. Circulation 1996;93:372. 11. Nabauer M, Beuckelmann DJ, Uberfuhr P, Steinbeck G. Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle. Circulation 1996;93:168. 12. Miyoshi S, Miyazaki T, Moritani K, Ogawa S. Different responses of epicardium and endocardium to K-ATP channel modulators during regional ischemia. Am J Physiol 1996 (Heart Circ Physiol 40):H140. 13. Becker RC, Alpert JS. Electrocardiographic ST segment depression in coronary artery disease. Am Heart J 1988:862. 14. Mirvis DM. Electrocardiology: a physiologic approach. Mosby: St Louis-Year Book, Inc; 1993. 15. Kubota I, Yamaky M, Shibata T, Ikeno E, Hosoya Y, Tomoike H. Role of ATP sensitive K+ channel on ECG ST segment elevation during a
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18. 19. 20.
21. 22. 23.
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bout of epicardial ischemia. A study on epicardial mapping in dogs. Circulation 1993;88:845. Guyton RA, McClenathan JH, Newman GE, Michaelis LL. Significance of subendocardial S-T segment elevation caused by coronary stenosis in the dog. Epicardial S-T segment depression, local ischemia and subsequent necrosis. Am J Cardiol 1977;40:373. Sodi Pallares D, Ponce De Leon J, Bisteni A, Medrano G. Polyparametric electrocardiography concerning new information obtained from clinical electrocardiogram. Prog Cardiovasc Dis 1970;13:97. Li D, Li CY, Yong AC, Kilpatrick D. Source of electrocardiographic ST changes in subendocardial ischemia. Circ Res 1998;82:957. Samson WE, Scher AM. Mechanism of S-T segment alteration during acute myocardial injury. Circ Res 1960;8:780. Reimer KA, Jennings RB. Myocardial ischemia, hypoxia, and infarction. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE, editors. The heart and cardiovascular System. New York (NY): Raven Press Publishers; 1991. p. 1875. Kondo T, Kubota I, Tachibana H, et al. Glibenclamide atenuates peaked Twave in early phase of myocardial ischemia. Cardiovasc Res 1996;31:683. Li RA, Leppo M, Miki T, et al. Molecular basis of electrocardiographic ST-segment elevation. Circ Res 2000;87:837. Wolferth CC, Bellet S, Livezey MM, Murphy F. Negative displacement of the RS-T segment in the electrocardiogram and its relationships to positive displacement: an experimental study. Am Heart J 1945;29:220. Pruitt RD, Valencia F. The immediate electrocardiographic effects of circumscribed myocardial injuries: an experimental study. Am Heart J 1948;35:161. Yu PNG, Stewart JM. Subendocardial myocardial myocardial infarction with special reference to the electrocardiographic changes. Am Heart J 1950;39:862.
Journal of Electrocardiology 42 (2009) 12 – 18 www.jecgonline.com
Assessing the pattern of ST-segment depression during subendocardial ischemia using a computer simulation of the ventricular electrogram Mauro Bertella, MD, a Michele Nanna, MD, FACC, b Emilio Vanoli, MD, c,d Filippo Scalise, MD, FACC, FESC, FSCAI e,⁎ a
Cardiology Department, Vimercate Hospital, Vimercate, Italy b Albert Einstein College of Medicine, Bronx, NY, USA c Cardiology Department, Policlinico di Monza, Monza, Italy d University of Pavia, Pavia, Italy e Cardiac Catheterization Laboratory, Cardiovascular Department, Policlinico di Monza, Monza, Italy Received 12 May 2008
Abstract
The primary aim of the study was to write a simple educational personal computer (PC)–based program able to simulate normal and pathological electrogram (EG) to analyze the ST-segment and T-wave patterns during subendocardial ischemia. Background: The EG waveforms are know to depend on the properties of transmembrane action potentials (APs) of atrial and ventricular myocytes, the spread of excitation, and the characteristics of the volume conductor. Transmembrane AP is an electromotive generator that plays a central role, and it is the principal responsible for the potential differences that are recorded as an EG. The EG can be considered as the algebric sum of 2 transmembrane APs, that is, the AP of the underlying endocardial region minus the AP of the underlying epicardial region. Methods: Using an educational PC software (Microsoft Excel), a normal EG was simulated reproducing planimetrically, point-by-point, normal transmembrane APs recorded from the epicardial and endocardial regions in normal animals. The shape and the voltage of the APs were then modified to closely mimic human APs. To simulate typical subendocardial ischemia, we changed the subendocardial AP according to experimental and clinical observations. Results: The reconstruction of EG by the algebric subtraction (endocardial minus epicardial) APs was possible. The EG, mirroring typical subendocardial ischemia, was simulated without changing the epicardial AP. The EG simulating typical subendocardial ischemia showed a horizontal pattern of ST segment depression. In our model modification of the subendocardial AP combined with “unnatural” changes of the phase 3 of the subendocardial AP produced a downsloping pattern of STsegment depression. Conclusion: The derivated EG waveform obtained with our PC program properly describe the algebric sum of endocardial and epicardial APs. In our opinion, this method represents a useful tool for the study of the AP changes. The simulated ST-depression morphology during subendocardial ischemia appears to be essentially “horizontal” and not downsloping. On the basis of our simplified theoretical model, we propose that ischemia-induced downsloping ST depression should be considered a reciprocal EG change and a manifestation of transmural ischemia in the wall opposite the exploring electrode. © 2009 Elsevier Inc. All rights reserved.
Keywords:
ST-segment depression; Subendocardial ischemia; Action potential
Background Electrocardiographic ST-segment depression has long been recognized as a sign of ischemia,1 but the explanations ⁎ Corresponding author. E-mail address: [email protected] 0022-0736/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jelectrocard.2008.09.003
of the responsible mechanisms have been controversial.2 Most of the current opinion regarding the genesis of ST-segment depression is derived from interpretations based on certain theoretical considerations3 and indirect evidence from animal experiments. 1 Ischemic muscle generates intracellular currents, which effectively cause TQ depression and ST elevation over the ischemic area that are
M. Bertella et al. / Journal of Electrocardiology 42 (2009) 12–18
then described by conventional electrocardiography with alternating current (AC)-coupled amplifiers as ST-segment elevation. On the other hand, ST-segment depression recorded at the epicardium has been considered secondary to an injury current in the underlying subendocardium.4 In conventional stress testing, ST-segment depression is considered incapable of localizing the site of ischemia.5 The standard criterion for this abnormal response is horizontal or downsloping ST-segment depression of 0.10 mV (1 mm) or more for J + 60 milliseconds, in at least three consecutive complexes, where “downsloping” is considered to reflect “more ischemia” than “horizontal” STsegment depression.5 Subendocardial ischemia has been also subdivided into “regional” and “circumferential” for therapeutic and prognostic purposes.6 These concepts are commonly accepted by most cardiologists. However, we wondered why it is not possible to localize the site of ischemia by conventional electrocardiography in patients with ischemia-induced ST-segment depression. It is very curious indeed that the same stress-induced ischemia could be regional, when detected by echocardiography or other imaging techniques (myocardial scintigraphy or magnetic resonance imaging ),7 and “global,” “diffuse” when detected by electrocardiography. The aim of this study was to write an educational personal computer (PC) program, able to simulate normal and pathological electrograms (EGs), to analyze the ST-T patterns of subendocardial ischemia. The EG waveforms are known to depend on the properties of transmembrane action potentials (APs) of atrial and ventricular myocytes, the spread of excitation, and the characteristics of the volume conductor. Among them, transmembrane AP as an electromotive generator clearly plays a central role, and it is ultimately responsible for the potential differences that are registered as an EG. The EG is produced fundamentally by depolarization and repolarization of the left ventricle, which consists of 2 parts, subendocardium located far from the explorer electrode and subepicardium closer to same. The transmembrane AP of the left ventricle can be considered as the subtraction, endocardial minus epicardial, AP curves (Fig. 1). Then, QRS-T waves (systole) and isoelectric lines of EG (diastole) correspond to the sum of systolic and diastolic transmembrane APs. Ashman,8 in 1941, suggested that the unipolar EG can be considered as the algebraic sum of 2 transmembrane APs, that is, the APs of the underlying endocardial region minus the AP of the underlying epicardial region. Using this simplified model, it is possible to reproduce an EG-like waveform.9
13
Fig. 1. The transmembrane AP of the left ventricle considered as the subtraction, endocardial (AP1) minus epicardial (AP2), AP curves. D indicates diastole (resting membrane potential); P, AP plateau region (from Taggart9).
chart. We have planimetrically reconstructed the AP curves using 30 consecutive points (Fig. 2). As these tracings were recorded in dogs, the shape of the APs was modified to make it similar to human potentials (Fig. 3A, B). Indeed, human subepicardial APs are characterized by a clear notch in phase 1, whereas subendocardial APs are characterized by the absence of this notch.11 The left ventricular transmembrane AP wave was obtained by point-by-point subtraction, endocardial minus epicardial, of AP curves. The graphic representation of this EG-like waveform was simply obtained using the MS-Excel graphic tool. To simulate typical subendocardial ischemia, the subendocardial AP was changed according to experimental and clinical observations.12,13 Subendocardial ischemia was simulated without changing the epicardial AP and by increasing the resting transmembrane potential and the duration of phase 3 of the endocardial AP. The AP amplitude and rate of rise of phase 0 of endocardial AP were also reduced. Multiple sequential variations of the endocardial AP were made modifying point-by-point the graphic data source (Fig. 4). Results
Methods Using an educational PC software (Microsoft MS-Excel), a normal EG was simulated reproducing planimetrically, point-by-point, normal transmembrane APs recorded from the epicardial and endocardial regions. We used normal tracings of endocardial and epicardial APs, recorded simultaneously with transmural EG reproduced by Yan and Antzelevitch.10 The EG charts were created by MS-Excel worksheet that included the information needed to build the
The reconstruction of surface EG by the algebraic sum of endocardial and epicardial APs is reproduced in Fig. 5. An EG-like waveform was reproduced, then QRS-T waves (systole) and isoelectric lines of EG (diastole) correspond to the sum of systolic and diastolic transmembrane APs. The EG simulating subendocardial ischemia is reproduced in Fig. 6. The pattern of ST-segment depression appears to be essentially horizontal. Altering only the subendocardial AP, it was possible to obtain a downsloping
14
M. Bertella et al. / Journal of Electrocardiology 42 (2009) 12–18
Fig. 2. Planimetric reconstruction of the AP curves with Microsoft MS-Excel. endo indicates endocardial AP; epi, epicardial AP.
pattern of ST-segment depression by introducing “unnatural” changes of the phase 3 of the subendocardial AP (Fig. 7).
Discussion This method represents in our opinion a useful tool to study the cardiac AP changes. In our study, a computer simulation of subendocardial ischemia suggests that the morphology of ST-segment depression should be essentially horizontal and not downsloping. ST-segment depression morphology during isolated subendocardial ischemia: theoretical and experimental data The earliest and most consistent effect of subendocardial ischemia is the loss of myocardial diastolic resting membrane potential resulting in a diastolic current flow toward the epicardium and horizontal elevation of the TQ baseline.13 The diastolic current is interrupted at the onset of the QRS when all myocardial cells are depolarized. As zero current flows during the ST interval, 9 the resulting morphology of the apparent ST-segment shift during unambiguous subendocardial ischemia should be of a variable horizontal to upsloping configuration, depending on the shape of the AP plateau.9 Using a unipolar electrode connected to a direct current–coupled amplifier and placed on normal epicardial tissue, overlying a zone of subendo-
cardial ischemia, it is possible to record early after the onset of subendocardial ischemia the elevated TQ baseline reset above the original baseline.14 The absence of injury flow from depolarized ischemic myocytes causes a transient return to the original baseline and the appearance of STsegment depression.14 The electrophysiological characteristics of ischemic cells are well known: They include increased transmembrane resting potentials, reduced AP amplitude and rate of rise of phase 0, shortened AP, and a conduction delay.14 In our computer simulation of subendocardial ischemia, the phase 3 of the normal endocardial AP was prolonged. This appears to conflict with experimental data, which demonstrated AP duration (APD) shortening during acute ischemia.14 The APD shortening begins within minutes after the onset of acute ischemia and is mediated largely by an increase in the outward repolarizing potassium current and by a decrease in calcium ion influx.14 It was demonstrated that the molecular basis of QTc interval shortening is the activation of K-ATP channels,15 but it was also demonstrated that K-ATP channels are activated by a smaller reduction in intracellular ATP in epicardial cells, than in endocardial cells. The differential sensitivity of ATPregulated channels in endocardial and epicardial cells may be responsible for the differential shortening in APD during ischemia at the 2 sites. These findings were confirmed by Miyoshi et al.12 These authors suggested that the different responses of epicardium and endocardium to K-ATP modulators during regional ischemia could be explained by a lower threshold for activation and/or a denser distribution of K-ATP channels at the epicardial layer.12 Moreover, clinical observations documented that in subendocardial ischemia, slow repolarization in the subendocardial region— which even under physiologic circumstances is the region with the longest refractory period—results in prolongation of QTc interval. Ischemia in this region does not alter the epicardium to endocardium direction of repolarization, but the slow recovery in the subendocardial region augments the magnitude of T wave because repolarization persists in this zone as repolarization subsides in the epicardial layer. As in our computer simulation, the subendocardial AP does not represent a single cell but the sum of the APs of ischemic subendocardial myocytes, so a delayed AP was used. In a model of subendocardial ischemia, Guyton et al16
Fig. 3. Human (A) and canine (B) AP curves.
M. Bertella et al. / Journal of Electrocardiology 42 (2009) 12–18
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Fig. 4. Multiple and progressive (A-C) variations of the endocardial AP to simulate subendocardial ischemia.
demonstrated that by reducing subendocardial blood flow (measured with radioactive microsphere techniques), while subepicardial flow remained normal, epicardial ST depression localized the site of subendocardial ST elevation as long as a layer of nonischemic epicardial muscle was present. When ischemia became transmural, epicardial ST-elevation occurred.16 Experimental data of Sodi Pallares et al17 refers to EG changes recorded in the presence of a subendocardial scar, mirroring isolated subendocardial infarction. These authors observed in animals that lesions (burning) in the subendocardial muscle of at least 15 mm in diameter are needed to register a pure monophasic wave in the subendocardial area and a moderate negative RS-T displacement in lead V5, placed near the injured region. The injuryinduced ST depression appears horizontal for at least 160 milliseconds after the J point, despite the presence of negative T waves.17 They concluded that subendocardial lesions of sufficient size to be detectable in the precordial and limb leads induce the following modifications in the EG: (1) positivity of the T wave; (2) prolonged QT interval in the initial phase; (3) negative RS-T displacement; (4) negative displacement of the J point; (4) increase in the voltage of S wave; (6) diminution in the voltage of R wave.17
From the transition of subendocardial ischemia to fullthickness ischemia, it was found that epicardial ST depression increased gradually over the boundary region as ischemia progressed, and ST elevation ensued over the ischemic region as ischemia became transmural.18 A greater ST depression was also observed before the occurrence of ST elevation in a study with a perfused canine heart by Guyton et al16 in 1977. The electrical transition from ST depression to ST elevation was consistent with the contention that the current path is in the myocardium. In the normal EG, the ST segment remains isoelectric because there are no significant potential differences occurring in the myocardium during this period. In transmural ischemia, epicardial ST elevation occurs when injury currents flow at the boundary between the ischemic regions and the normal myocardium because of the potential difference between these 2 regions.19 Because the myocardial cells in subendocardial ischemia undergo changes qualitatively similar to those occurring during transmural ischemia,18 it is likely that the injury currents in subendocardial ischemia also originate from the ischemic boundary. Subendocardial ischemia involves only the inner layer of the ventricular wall. Thus, the boundary between the ischemic region and the normal myocardium is likely to
Fig. 5. Reconstruction of surface EG by the algebraic sum of endocardial (endo) and epicardial (epi) APs using MS-Excel graphic tool.
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Fig. 6. Reconstruction of EG simulating subendocardial ischemia using MS-Excel graphic tool (horizontal pattern).
include the transmural boundary parallel to the endocardium and the lateral boundary perpendicular to the endocardium. However, the flow distribution during subendocardial ischemia demonstrated a gradual flow transition from the endocardium to the epicardium,18 but at the lateral boundary, flow changes abruptly from the ischemic zone to the nonischemic zone, producing a sharp lateral interface between ischemic and normal regions. 18 Studies on transmural ischemia also found a sharp lateral interface between ischemic and normal cells with severely ischemic tissue lying adjacent to normal well-perfused tissue.20 In ischemic pig hearts, transmembrane AP recordings using floating microelectrodes also demonstrated a sharp and distinct transition from electrophysiologically abnormal to normal cells. The injury current is directly associated with the spatial gradient of the transmembrane potentials. A greater potential gradient exists at the lateral boundary, which in turn produces a stronger current. Under such circumstances, the greater epicardial potential change should appear at the lateral boundary regions with less change in the ischemic center, where the transmural boundary is located and less injury current occurs. The transition of subendocardial ischemia to full-thickness ischemia showed that as
ischemia progressed, ST depression increased gradually until ischemia became transmural and ST elevation ensued in the ischemic center.18 The increased ST depression occurred at the lateral border, whereas the ST elevation started at the ischemic center. ST elevation gradually progressed toward the ischemic border. These observations support the postulate that the major source of electrical current in subendocardial ischemia is located at the lateral boundary of the ischemia. These complex mechanisms cannot be obviously estimated from our computer simulation that has been only devised for an educational scope. Significance of an ischemia-induced downsloping ST depression Examining our computer simulation of downsloping ST depression (Fig. 7) and comparing it with the shape of a transmembrane AP recorded in normal subjects during ischemia (Figs. 5 and 6), phase 3 of the monophasic AP is also associated with final rapid repolarization. In this AP phase, repolarization proceeds rapidly and the membrane potential shifts to the resting potential. The net membrane current is always outward, and no new depolarization is possible in this phase. In our computer simulation, modify-
Fig. 7. Reconstruction of EG simulating subendocardial ischemia using MS-Excel graphic tool (downsloping pattern).
M. Bertella et al. / Journal of Electrocardiology 42 (2009) 12–18
ing APs according to patterns recorded during induced acute ischemia, it was not possible to reproduce a frankly downsloping ST-segment depression. A possible explanation of this apparent contradiction is that ischemia-induced downsloping ST depression should be considered a reciprocal EG change due to transmural ischemia in the cardiac wall opposite the exploring electrode. During transmural ischemia development, it is possible to measure an increase in the resting membrane potential of myocytes. Loss of resting membrane potential generates a diastolic injury current directed from the injured to the normal tissue and therefore a horizontal depression of the baseline TQ segment in EG.14 In the standard EG using capacitor AC amplifiers, TQ segment displacement appears as horizontal ST-segment elevation.14 Very early during the development of ischemia, the APD of epicardial cells transiently lengthens owing to a drop in temperature in the ischemic myocardium, followed by shortening, largely caused by the rise in extracellular potassium. Shortened APD generates an intracellular systolic injury current directed from normal to injured tissue.14 The APD shortening and ST-segment elevation of epicardial cells is associated with the activation of ATP-sensitive potassium channels.12,15 Kondo et al21 observed in animals that early after the onset of transmural ischemia, only the terminal part of the elevated ST segment is inhibited by glibenclamide, a selective blocker of K-ATP channels. Therefore, this systolic current could be responsible during typical transmural ischemia for both the upsloping shift of the terminal part of elevated ST segments and of the downsloping ST depression secondary to reciprocal ST segment shifts. Li et al22 demonstrated in mice that shortly after the onset of ischemia, only sarcolemmal K-ATP channel activation is the molecular basis of ST elevation. The origin of ischemic ST-segment depression In transmural ischemia, epicardial ST elevation occurs when injury currents flow between the ischemic regions and the normal myocardium.19 The region of ST elevation is closely related to the region of ischemia. Two major mechanisms are considered to underlie ST-segment displacement: (1) a localized shortening of APD and diminishing of the amplitude of the AP and (2) a localized decrease in resting membrane potential. The former generates current only during the ST segment. The latter generates an injury current that is interrupted during the ST segment when all the cells are depolarized. The injury current produces a TQsegment shift that cannot be directly detected on the EG; however, the interruption of the injury current during the ST segment produces an apparent ST shift, which is equal and opposite the TQ-segment shift on the AC-coupled EG. With ST depression, there is no satisfactory explanation of the cardiac electrophysiological changes. Previous work23,24 in isolated hearts suggested that the ST-segment response to myocardial injury was elevation and that the STsegment depression recorded at the epicardium was the reciprocal of ST elevation in the underlying subendocardium. The dipole model24 considered the active myocardial event as a single dipole source that contained both the maximum and the minimum potentials. Accordingly, an
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injured region of the myocardium acts in systole as the positive pole of a layer of dipoles situated on its boundary with normal myocardium, whereas the latter acts as the negative pole. In the event of subendocardial ischemia, the ventricular surface and the precordium over the ischemic region face the negative pole of the dipole; the cavity faces the positive pole.18 Thus, the electrodes over the ischemia should record depressed ST segments, and the cavity should yield elevated ST segments.25 Study limitation Until now, EG, in general, and ST segment shift (depression or elevation), in particular, have been viewed as integrative phenomena not readily amenable to reductionist analysis.22 Our computer simulation is an extremely simplified educational model to teach and learn electrocardiography, starting from the basic principles. Downsloping ST-segment depression could be recorded also in the presence of normal angiography, that is, syndrome X and left ventricular hypertrophy and strain or in coronary artery disease patients in which the limited severity of coronary obstructions in vessels supplying the opposite wall does not justify the appearance of stress-induced reciprocal transmural ischemia. In these patients, pathogenetic mechanisms different from reciprocal transmural ischemia must be sought. The degree of influence of the ischemic modification on endocardial AP is much more complex, and our extremely simplified simulation of subendocardial ischemia represents a potential source of error. The APs represent only 1 single point of transmembrane AP, and in reality, the picture is much more complex with different degrees of severity of ischemia and boundaries between normal and ischemic myocardium in a 3-dimensional fashion. Conclusions The derivated EG-like waveform obtained with this simple educational PC program properly describes the algebraic sum of endocardial and epicardial APs. In our opinion, this program represents a useful tool for the study of the AP changes. The simulated ST-depression morphology during subendocardial ischemia appears to be essentially horizontal and not downsloping. Based on our simplified theoretical model, we propose that ischemia-induced downsloping ST depression should be considered a reciprocal EG change and a manifestation of transmural ischemia in the cardiac wall opposite the exploring electrode. References 1. Gussak I, Bjerregaard P, Egan TM, Chaitman BR. ECG phenomenon called the J-wave: history, pathophysiology, and clinical significance. J Electrocardiol 1995;28:49. 2. Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J-wave. Circulation 1996;93:372. 3. Antzelevitch C, Yan GX. Cellular and ionic mechanisms responsible for the Brugada syndrome. J Electrocardiol 2000;33(Suppl):33.
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