Ventricular Repolarization Components on the Electrocardiogram Cellular Basis and Clinical Signiﬁcance Gan-Xin Yan, MD, PHD, Ramarao S

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View metadata, citation and similar papers at core.ac.uk brought to you by CORE Journal of the American College of Cardiology providedVol. by Elsevier 42, No. - 3,Publisher 2003 Connector © 2003 by the American College of Cardiology Foundation ISSN 0735-1097/03/$30.00 Published by Elsevier Inc. doi:10.1016/S0735-1097(03)00713-7 STATE-OF-THE-ART PAPER Ventricular Repolarization Components on the Electrocardiogram Cellular Basis and Clinical Signiﬁcance Gan-Xin Yan, MD, PHD, Ramarao S. Lankipalli, MD, James F. Burke, MD, FACC, Simone Musco, MD, Peter R. Kowey, MD, FACC Wynnewood, Pennsylvania

Ventricular repolarization components on the surface electrocardiogram (ECG) include J (Osborn) waves, ST-segments, and T- and U-waves, which dynamically change in morphology under various pathophysiologic conditions and play an important role in the development of ventricular arrhythmias. Our primary objective in this review is to identify the ionic and cellular basis for ventricular repolarization components on the body surface ECG under normal and pathologic conditions, including a discussion of their clinical significance. A specific attempt to combine typical clinical ECG tracings with transmembrane electrical recordings is made to illustrate their logical linkage. A transmural voltage gradient during initial ventricular repolarization, which results from the presence of a prominent transient ϩ outward K current (Ito)-mediated action potential (AP) notch in the epicardium, but not endocardium, manifests as a J-wave on the ECG. The J-wave is associated with the early repolarization syndrome and Brugada syndrome. ST-segment elevation, as seen in Brugada syndrome and acute myocardial ischemia, cannot be fully explained by using the classic concept of an “injury current” that flows from injured to uninjured myocardium. Rather, ST-segment elevation may be largely secondary to a loss of the AP dome in the epicardium, but not endocardium. The T-wave is a symbol of transmural dispersion of repolarization. The R-on-T phenomenon (an extrasystole originating on the T-wave of a preceding ventricular beat) is probably due to transmural propagation of phase 2 re-entry or phase 2 early afterdepolarization that could potentially initiate polymorphic ventricular tachycardia or fibrillation. (J Am Coll Cardiol 2003;42:401–9) © 2003 by the American College of Cardiology Foundation

The electrocardiogram (ECG) is widely used in clinical the J-wave, ST-segment, and T- and U-waves. Recent practice to detect cardiac arrhythmias, conduction distur- progress in the basic and clinical research of electrical bances, myocardial ischemia, electrolyte or metabolic dis- heterogeneity across the ventricular wall has provided excit- turbances, structural changes of the myocardium, and drug ing insights into the ionic and cellular basis for ventricular effects. However, the correlation between cellular events and repolarization components. This review attempts to sum- the various components on the surface ECG is not well marize our state of knowledge of ventricular repolarization established, despite the fact that ECG recording has been components and their clinical significance. used in clinical practice for over a century (1). The ECG J (Osborn) wave. The J-wave is a deflection following the waveforms are known to depend on the properties of QRS complex (2). Also referred to as the Osborn wave transmembrane action potentials (APs) of atrial and ven- because of Osborn’s landmark description in the early 1950s tricular myocytes, the spread of excitation, and the charac- (3), a prominent J-wave is often associated with hypother- teristics of the volume conductor. Among them, transmem- mia and hypercalcemia (2,4). However, a distinct J-wave on brane AP as an electromotive generator clearly plays a the ECG is also commonly observed in people with the central role. Therefore, the ECG recording of a normal early repolarization syndrome and those with idiopathic cardiac cycle is composed of two basic processes: depolar- ventricular tachycardia and Brugada syndrome (5–8). ization and repolarization. Ventricular depolarization (acti- In the early 1990s, Antzelevitch et al. (9) proposed a vation) is depicted by the QRS complex, whereas ventricular potential difference between the epicardium and endocar- repolarization is defined by the interval from the beginning dium during ventricular repolarization phases 1 and 2 as the of the QRS complex to the end of the T- or U-wave. On the cellular basis for the J-wave. The ventricular epicardium surface ECG, ventricular repolarization components include commonly displays APs with a prominent transient outward ϩ K current (Ito)-mediated notch (spike and dome). The From the Main Line Health Heart Center, Wynnewood, Pennsylvania. This study absence of a prominent AP notch in the endocardium is the was supported by the American Heart Association, the W. W. Smith Charitable consequence of a much smaller Ito.AnIto-mediated AP Trust, the Fourjay Foundation, the Adolph and Rose Levis Foundation, and the Sharpe Foundation. notch in the epicardium, but not endocardium, may produce Manuscript received December 18, 2002; accepted April 30, 2003. a transmural voltage gradient during early ventricular repo- 402 Yan et al. JACC Vol. 42, No. 3, 2003 Ventricular Repolarization Components on ECG August 6, 2003:401–9

tors that influence Ito or its counter (inward) currents in Abbreviations and Acronyms phases 1 and 2 (e.g., hypothermia and heart rate [4,6]) could AP ϭ action potential modify the size and morphology of the J-wave. ϭ APD action potential duration Although a higher incidence of ventricular tachycardia EAD ϭ early afterdepolarization ϭ (VT) and ventricular fibrillation (VF) has long been ob- ICa L-type calcium current ϭ IKr rapidly activating delayed rectifier potassium served in hypothermic patients with prominent J-waves (2), current the importance of a prominent J-wave in arrhythmogenesis ϭ IKs slowly activating delayed rectifier potassium was not recognized until recently, when Brugada syndrome, current ϭ a clinically malignant entity, was identified (7,8,10,11). As INa inward sodium current ϭ ϩ Ito transient outward K current Brugada syndrome is also associated with ST-segment LQTS ϭ long QT syndrome elevation, it will be discussed in detail in the following TDR ϭ transmural dispersion of repolarization section. VF ϭ ventricular fibrillation VT ϭ ventricular tachycardia The ST-segment. The ST-segment is the portion of the ECG that lies between the end of the QRS complex and the beginning of the T-wave. Normally, the ST-segment stays larization that could manifest as a J-wave or J-point eleva- at the same level as the T-P segment. Two changes in the tion on the ECG. Direct evidence in support of this ST-segment are considered clinically important: ST- hypothesis was recently obtained in an arterially perfused segment displacement and a change in ST-segment mor- canine ventricular wedge preparation (4). As shown in phology. ST-segment displacement, either upward (eleva- Figure 1, the size of the J-wave is closely correlated to the tion) or downward (depression) of more than 1 mm from

Ito-mediated AP notch in the epicardium. Therefore, fac- baseline, is abnormal.

Figure 1. Cellular basis for the J-wave. (A) A prominent J-wave in lead II was recorded from a healthy, young Asian male. (B) Simultaneous recording of transmembrane action potentials (APs) from epicardial (Epi) and endocardial (Endo) regions and a transmural electrocardiogram (ECG) in an arterially perfused canine ventricular wedge preparation. An Ito-mediated AP notch in the epicardium, but not endocardium, was associated with a J-wave. A Ϫ ϭ premature stimulus (S1 S2 300 ms) caused a parallel decrease in the amplitude of the epicardial AP notch and J-wave. Modiﬁed from Yan and Antzelevitch (4), with permission. JACC Vol. 42, No. 3, 2003 Yan et al. 403 August 6, 2003:401–9 Ventricular Repolarization Components on ECG

Figure 2. Possible mechanisms responsible for ST-segment elevation. (A) The concept of “injury current.” The “injury zone” in the epicardium, with a reduction in resting membrane potential, produces an injury current during the resting phase that should result in TQ depression instead of ST-segment elevation. (B) The concept of “loss of action potential (AP) dome or plateau amplitude.” A difference in the AP plateau amplitude generates a transmural voltage gradient that could manifest as ST-segment displacement.

POSSIBLE MECHANISMS RESPONSIBLE FOR ST-SEGMENT condition, the TP depression is transformed to apparent ELEVATION. The classic concept for ST-segment elevation “ST-segment elevation” (Fig. 2A). The low-frequency cut- is the so-called “injury current” theory, explained as current off in the clinical ECG machines may reduce the amplitude flow from the injured myocardium, where the cells are of ST-segment elevation resulting from the injury current. partially depolarized, to the uninjured myocardium (12). In More importantly, the ST-segment elevation caused by the animal experiments, however, the injury current measured injury current alone would theoretically not be associated by using a direct-current coupled amplifier, causes TP-(or with any change in the ST-segment morphology (Fig. 2A). TQ) segment depression rather than ST-segment elevation All of these indicate that the injury current is not a sole (13,14). In clinical practice, however, the ECG signals are contributor to clinically observed ST-segment elevation. input to an ECG recorder with a high-pass (low-cutoff) It is more problematic to use the concept of injury current filter in order to avoid direct current drift. Under this to explain ST-segment displacement in nonischemic or 404 Yan et al. JACC Vol. 42, No. 3, 2003 Ventricular Repolarization Components on ECG August 6, 2003:401–9 structurally normal hearts, as in the early repolarization outward shift of currents may only cause dome depression, syndrome and Brugada syndrome, conditions in which no with a minimal change in AP duration (APD). ST-segment “injured zone” is identified. Because the ST-segment cor- elevation due to complete loss of the epicardial AP dome is responds temporally to the AP plateau phase, the difference coved on the ECG, as seen in Brugada syndrome (11,22). in plateau potentials within the ventricles could produce true ST-segment elevation due to AP dome depression in the ST-segment elevation. As illustrated in Figure 2B, the epicardium, but not endocardium, is usually upward concave depression or loss of the AP dome in the epicardium, but or saddleback-like, as observed in the early repolarization not endocardium, would result in a transmural voltage syndrome. A defect in the sodium channel due to a gene gradient during repolarization that could manifest as ST- mutation in SCN5A is linked with Brugada syndrome (23). segment elevation. This mechanism likely underlies ST- This provides the rationale for the use of sodium channel segment elevation in Brugada syndrome and early repolar- blockers, which increase an outward shift of currents at ization syndrome and perhaps also contributes importantly phases 1 and 2 by inhibition of INa, to unmask the concealed to that observed in acute myocardial ischemia (11,15,16). form of Brugada syndrome (24). Complete loss of the epicardial AP dome may not be THE EARLY REPOLARIZATION SYNDROME. The early repo- uniform—that is, a loss of the dome may occur at some sites larization syndrome is characterized by a distinct J-wave and but not others, due to an intrinsic difference in I and/or a ST-segment elevation predominantly in the left precordial to regional difference in pathophysiologic alterations. Propa- leads. The early repolarization syndrome is a benign ECG gation of the AP dome from sites at which it is maintained phenomenon (6). ST-segment elevation in this syndrome is to sites at which it is lost causes local re-excitation via phase thought to be due to depression (partial loss) of the 2 re-entry, leading to the development of a closely coupled I -mediated AP dome in the left ventricular epicardium to extrasystole (Fig. 3). An increase in transmural dispersion of (15). This is supported by clinical observations that heart repolarization (TDR), also present under this condition, rate and autonomic tone, which influence I , L-type cal- to facilitates transmural propagation of the extrasystole and cium current (I ), and perhaps inward sodium current Ca provides a substrate for the development of polymorphic VT (I ), modify ST-segment elevation in the early repolariza- Na and VF (Fig. 3) (11). tion syndrome (6). However, the exact ionic basis for this T-wave and QT interval. The concordance of QRS po- clinical entity remains unknown. larity with the T-wave suggests that normal ventricular BRUGADA SYNDROME. Brugada syndrome is associated electrical recovery, in contrast to ventricular activation, is with polymorphic VT and VF, which result in recurrent from the epicardium to endocardium (25), a process repre- syncope and sudden cardiac death (10,17). Despite its senting heterogeneous ventricular repolarization. It is now malignant features, Brugada syndrome shares many ECG generally accepted that the ventricular myocardium is not manifestations with the early repolarization syndrome. The uniform, but rather composed of at least three electrophysi- ECG of the patient with Brugada syndrome is characterized ologically distinct cell types: epicardial, endocardial, and M by a normal QT interval and ST-segment elevation in the cells residing at the deep subendocardium (26,27). Epicar- right precordial leads (V1 through V3) or inferior leads (II, dial, endocardial, and M cells differ primarily from each III, and aVF) in the absence of myocardial ischemia or other by their repolarization properties. The hallmark of M defined structural heart disease (7,10,17). Although ob- cells is their tendency to have their APs prolonged dispro- served worldwide, it is more common in Asian males. portionately to the epicardium or endocardium during Similar to what is seen in the early repolarization syndrome, bradycardia or in the presence of APD-prolonging drugs. ST-segment elevation in Brugada patients is significantly Hence, these cells are thought to play an important role in influenced by heart rate and autonomic tone, as well (7,18). delayed ventricular repolarization, as in long QT syndrome A net outward shift of currents at phases 1 and 2 of the (LQTS). right ventricular epicardial AP, which results in depression The ionic basis for the features of M cells that dis- or loss of the AP dome, is responsible for ST-segment tinguish them from the epicardium and endocardium in- elevation in Brugada syndrome (11). The fate of the cludes the presence of a smaller slowly activating delayed epicardial AP dome, under conditions of a net outward shift rectifier potassium current (IKs) but a larger late INa (28,29). of currents, partial loss (depression), or complete loss, is On the other hand, rapidly activating delayed rectifier largely dependent on the intrinsic Ito size (15). When Ito is potassium current (IKr), the ionic target by most APD- prominent, as in the right ventricular epicardium (19–21), prolonging agents, is similar in density across the ven- the outward shift of currents accentuates the Ito-mediated tricular wall. Therefore, the difference in the IKs:IKr ratio AP notch in the epicardium to a more negative potential, so among three transmural cell types plays an important role that ICa fails to activate and the AP dome fails to develop, in TDR (28,30). Any factors that alter the IKs:IKr ratio leading to all-or-none repolarization. All-or-none repolar- could result in abnormal ventricular repolarization. It has ization can result in marked AP abbreviation by 40% to 70% been demonstrated that the mutations of genes that

(i.e., complete loss of AP dome) (11,19). In contrast, when encode IKs and IKr account for most forms of congenital Ito is weaker, as in the left ventricular epicardium, the LQTS (31). JACC Vol. 42, No. 3, 2003 Yan et al. 405 August 6, 2003:401–9 Ventricular Repolarization Components on ECG

Figure 3. The mechanism responsible for J-wave–related arrhythmogenesis. (A) Polymorphic ventricular tachycardia (VT) in a patient with prominent J-waves. Reprinted from Aizawa et al. (5), with permission. (B) Polymorphic VT initiated by phase 2 re-entry in a canine right ventricular wedge in the presence of 2.5 ␮mol/l pinacidil. The action potentials (APs) were simultaneously recorded from two epicardial sites (Epi 1 and Epi 2) and one endocardial (Endo) site. A loss of the AP dome in Epi 1, but not in Epi 2, led to phase 2 re-entry capable of initiating polymorphic VT.

CELLULAR BASIS FOR THE GENESIS OF AN UPRIGHT that of M cells but fails to generate a wave on the ECG in T-WAVE. The temporal relationship between transmem- the canine heart, probably due to their small mass (32). brane APs simultaneously recorded from the canine epicar- The temporal relationship between cellular electrical dium, M region, and endocardium and the ECG T-wave activities and the T-wave remains constant under wide was ﬁrst demonstrated in an arterially perfused ventricular ranges of conditions, including hypokalemia and hyperka- wedge preparation (Fig. 4). Separation of the epicardial AP lemia (Fig. 4). Hyperkalemia produces a steeper slope of AP from that of M cells during the plateau phase marks the phase 3, leading to an increase in the transmural voltage beginning of the upright T-wave. Under normal conditions, gradient. This gives rise to a tall and upright T-wave. The the separation is so gradual that the beginning of the mechanism underlying a change in the T-wave under T-wave is difﬁcult to determine. As shown in Figure 4, hypokalemia is more complicated. A pathologic U-wave is repolarization of the M cells is temporally aligned with the often observed. In contrast to hyperkalemia, the AP phase 3 end of the T-wave (Tend), whereas repolarization of the slope during hypokalemia is attenuated, giving rise to small, epicardium is coincident with the peak of the T-wave opposing voltage gradients that cross over, producing a

(Tpeak). Repolarization of Purkinje ﬁbers usually outlasts low-amplitude T-wave and the so-called “U” wave (Fig. 4B) 406 Yan et al. JACC Vol. 42, No. 3, 2003 Ventricular Repolarization Components on ECG August 6, 2003:401–9

Figure 4. Cellular basis for the T-wave. (A) The electrocardiogram (ECG) tracings were recorded in patients with various serum potassium concentrations. A pathologic U-wave was seen under hypokalemia, whereas a tall and upright T-wave was associated with hyperkalemia. (B) Simultaneous recording of action potentials (APs) from epicardial (Epi) and M cells or endocardial cells (Endo), together with a transmural ECG under various extracellular potassium concentrations. Extracellular potassium primarily inﬂuenced the AP phase 3 slope (repolarization rate); hyperkalemia accelerated phase 3 repolarization, whereas hypokalemia reduced it. The alteration of AP phase 3 slopes and their interplay among different myocardial layers determined the T-wave morphologies under various extracellular potassium concentrations. A pathologic U-wave was present with hypokalemia. Reprinted from Yan et al. (32), with permission.

(32). Under this condition, full repolarization of the epicar- T-wave is “vulnerable,” so that an electrical impulse inter- dium marks the peak of this pathologic U-wave, whereas rupting it (i.e., the R-on-T phenomenon, as shown in Figs. repolarization of both the endocardial and M cells contrib- 3 and 5) could potentially produce functional transmural utes importantly to the descending limb. The apparent T-U re-entry, leading to the development of polymorphic VT complex is, in fact, a T-wave whose ascending limb is and VF (34–37). The Tpeak-end interval, as an index of interrupted. The forces that give rise to the pathologic TDR, has been proved to be clinically useful in assessing U-wave in hypokalemia are similar to those underlying the arrhythmic risk (36,38–40). T-wave. Therefore, a pathologic U-wave is likely a second component of a bifid or notched T-wave. This clarification LONG QT SYNDROME. Both the congenital and acquired is important in two respects. First, the “QT” interval that forms of LQTS represent pathophysiologic states charac- most clinicians try to measure under hypokalemia en- terized by the appearance of a long QT interval on the compasses the time from the beginning of the QRS to the ECG, notched T-waves, U-waves, and an atypical polymor- end of the first component of the T-wave. This interval phic VT known as torsade de pointes (31,39,41). may be equal to or shorter than the QT interval under normal Genetic analysis has identified at least five forms of conditions (33). The true QT interval should therefore congenital LQTS caused by gene mutations located on include the pathologic U-wave under hypokalemia. Second, chromosomes 3, 7, 11, and 21, which are responsible for the mechanisms responsible for the pathologic U-waves defects in INa (SCN5A/LQT3), IKr (HERG/LQT2 and are likely different from those underlying a physiologic MiRP1/LQT6), and IKs (KVLQT1/LQT1 and MinK/ U-wave. LQT5) (31). The long QT syndrome can be acquired due to

The Tpeak-end interval that encompasses the terminal the use of drugs, serum electrolyte disturbances, ventricular portion of the T-wave closely represents TDR (Fig. 4). This hypertrophy, and myocardial ischemia (42,43). The mech- is probably the reason why the terminal portion of the anisms underlying drug-induced LQTS involve either the ACVl 2 o ,2003 2003:401–9 3, 6, No. August 42, Vol. JACC etiua eoaiainCmoet nECG on Components Repolarization Ventricular Yan tal. et

Figure 5. The mechanism responsible for the initiation of torsade de pointes (TdP). (A) An R-on-T extrasystole initiated an episode of torsade de pointes in a patient with a prolonged QT interval who was receiving sotalol. (B) Transmembrane action potentials (APs) from the epicardium (Epi) and endocardium (Endo) were simultaneously recorded together with a transmural electrocardiogram (ECG) in an 407 arterially perfused rabbit left ventricle. dl-sotalol, an IKr blocker, markedly prolonged the QT interval and induced phase 2 early afterdepolarization (EAD) in the endocardium. The phase 2 EADs, in turn, produced R-on-T extrasystoles capable of initiating torsade de pointes. Reprinted from Yan et al. (35), with permission. 408 Yan et al. JACC Vol. 42, No. 3, 2003 Ventricular Repolarization Components on ECG August 6, 2003:401–9

inhibition of outward currents (IKr and/or IKs)orthe role in the genesis of the T-wave and pathologic U-wave. enhancement of the inward current (late INa). However, The hypothesis that the Purkinje network is responsible for most agents that cause clinical torsade de pointes target IKr. the physiologic U-wave seems most plausible, as repolariza- Preferential APD prolongation of M cells is thought to tion of subendocardial Purkinje fibers is temporally aligned underlie QT prolongation, the phenotypic appearance of with the expected appearance of the U-wave on the ECG abnormal T-waves, the pathologic U-wave, and the devel- (50). However, direct experimental evidence supporting this opment of torsade de pointes (32). hypothesis is still lacking. It is generally accepted that a focal activity initiates the Summary. Inscription of the J (Osborn) wave, ST-segment onset of torsade de pointes, whereas functional re-entry is displacement, and the T-wave on the ECG is the conse- responsible for its maintenance (32,35,44). Disproportional quence of electrical heterogeneities among the ventricular AP prolongation of M cells in response to APD-prolonging epicardium, M cells, and endocardium during ventricular agents, low extracellular potassium, and bradycardia can repolarization. The transmural voltage gradient secondary result in a marked increase in TDR that serves as a reentrant to the difference in the Ito-mediated AP notch between the substrate. The focal activity is derived from phase 2 early epicardium and endocardium underlies the genesis of the afterdepolarization (EAD) and its transmural propagation, J-wave. Moreover, exaggeration of this gradient has been as shown in Figure 5 (35,42). linked to the development of polymorphic VT and VF in Brugada syndrome and acute myocardial ischemia. The T-WAVE ALTERNANS. T-wave alternans, defined as a beat- ST-segment can deviate upward (elevation) or downward to-beat change in T-wave morphology, amplitude, and/or (depression) by either of the following two cellular mecha- polarity, usually heralds the onset of ventricular arrhythmias nisms, or both: 1) an injury current due to a difference in or sudden cardiac death in patients who have various resting membrane potentials between injured and uninjured pathophysiologic conditions (45,46). T-wave alternans is myocardium; and 2) a voltage gradient generated by a invariably associated with an alternate change in the QT difference in AP plateau amplitudes. Intrinsically different and Tpeak-end intervals (42,46). repolarization properties among the epicardium, M cells, Recent studies have demonstrated that T-wave alternans and endocardium, as well as their interplay, are responsible is the ECG manifestation of a beat-to-beat change in TDR for various morphologies of the T-wave and pathologic (42,47). In T-wave alternans associated with ventricular U-wave. The T-wave is a symbol of TDR. The Tpeak-end hypertrophy and failure, the endocardium or subendocar- interval as an index of TDR is clinically useful in assessing dium displays a significantly alternate change in APD (42), arrhythmic risk in LQTS. a phenomenon that may be secondary to intracellular calcium alteration in the presence of a robust sarcoplasmic Reprint requests and correspondence: Dr. Gan-Xin Yan, Main reticulum function (48). 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