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INVITED REVIEW

Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes

Masonic Medical Research Laboratory, Utica, New York

	ABSTRACT

TOP ABSTRACT ELECTRICAL HETEROGENEITY WITHIN... LONG QT SYNDROME BRUGADA SYNDROME SHORT QT SYNDROME TDR AS THE COMMON... CATECHOLAMINERGIC POLYMORPHIC... CONCLUSION GRANTS REFERENCES

 
This review examines the role of spatial electrical heterogeneity within the ventricular myocardium on the function of the heart in health and disease. The cellular basis for transmural dispersion of repolarization (TDR) is reviewed, and the hypothesis that amplification of spatial dispersion of repolarization underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies is evaluated. The role of TDR in long QT, short QT, and Brugada syndromes, as well as catecholaminergic polymorphic ventricular tachycardia (VT), is critically examined. In long QT syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells; in Brugada syndrome, however, it is thought to be due to selective abbreviation of the APD of the right ventricular epicardium. Preferential abbreviation of APD of the endocardium or epicardium appears to be responsible for the amplification of TDR in short QT syndrome. In catecholaminergic polymorphic VT, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, long QT, short QT, Brugada, and catecholaminergic polymorphic VT syndromes are pathologies with very different phenotypes and etiologies, but they share a common final pathway in causing sudden cardiac death.

long QT syndrome; short QT syndrome; Brugada syndrome; polymorphic ventricular tachycardia; electrophysiology

Among Wiggers’ many seminal contributions to physiology and medicine was his elucidation of the mechanisms responsible for ventricular fibrillation (VF). He described approaches to the prevention and treatment of conditions associated with VF (149). I am pleased to have the opportunity to present some of the work we have done to further his important contributions to our field.

My principal focus will be on the heterogeneity within the ventricular myocardium with respect to electrical activity: how this heterogeneity contributes to spatial dispersion of repolarization and the degree to which amplification of this spatial dispersion contributes to the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies (Table 1), such as long QT, short QT, and Brugada syndromes, as well as catecholaminergic polymorphic ventricular tachycardia (CPVT). Preferential prolongation of the action potential duration (APD) of M cells is responsible for amplification of transmural dispersion of repolarization (TDR) in most cases of long QT syndrome, whereas preferential abbreviation of the APD of the right ventricular (RV) epicardium is believed to responsible for amplification of spatial dispersion of repolarization in Brugada syndrome. Recent reports suggest that preferential abbreviation of APD of the endocardium or epicardium is responsible for amplification of TDR in different forms of short QT syndrome. Although triggered activity has long been invoked to explain arrhythmogenesis in CPVT, recent reports suggest that reversal of the direction of activation of the ventricular wall by triggered beats arising in the epicardium can amplify TDR and, thus, contribute to precipitation of rapid polymorphic ventricular tachycardia (VT), which may underlie sudden death in CPVT.

	ELECTRICAL HETEROGENEITY WITHIN THE VENTRICULAR MYOCARDIUM

TOP ABSTRACT ELECTRICAL HETEROGENEITY WITHIN... LONG QT SYNDROME BRUGADA SYNDROME SHORT QT SYNDROME TDR AS THE COMMON... CATECHOLAMINERGIC POLYMORPHIC... CONCLUSION GRANTS REFERENCES

View larger version (20K): [in this window] [in a new window]   Fig. 1. Ionic distinctions among epicardial (Epi), M, and endocardial (Endo) cells. A: action potentials recorded from myocytes isolated from epicardial, endocardial, and M regions of canine left ventricle (LV). B: current-voltage (I-V) relationships for inward rectifier current (IK1) in myocytes from epicardial, endocardial, and M regions. Values are means ± SD. C: transient outward current (Ito) recorded from epicardial, endocardial, and M cells. D: average peak I-V relationship for Ito of epicardial, endocardial, and M cells. Values are means ± SD. E: voltage-dependent activation of the slowly activating component of delayed rectifier K+ current (IKs). Currents were elicited by voltage-pulse protocol (inset) in Na+-, K+-, and Ca2+-free solution. F: voltage dependence of IKs (current remaining after exposure to E-4031) and IKr (E-4031-sensitive current). Values are means ± SE. *P < 0.05 vs. Epi or Endo. [From Liu et al. (72, 73) and Zygmunt et al. (163)]. G: reverse-mode Na+/Ca2+ exchange currents (INa-Ca) recorded in K+- and Cl–-free solutions at –80 mV. INa-Ca was maximally activated by switch to Na+-free external solution (arrow). H: midmyocardial Na+/Ca2+ exchanger density is 30% greater than endocardial density, calculated as peak outward INa-Ca normalized by cell capacitance. Endocardial and epicardial densities were not significantly different. I: TTX-sensitive late Na+ current (INa). Cells were held at –80 mV and briefly pulsed to –45 mV to inactivate fast INa before step-wise voltage increases to –10 mV. J: normalized late INa measured 300 ms into the test pulse plotted as a function of test pulse potential. [Modified from Zygmunt et al. (163).]

Myocytes isolated from the epicardial region of the LV wall of the rabbit show a higher density of cAMP-activated Cl^– current than do endocardial myocytes (124). I_to2, initially ascribed to a K⁺ current, is now thought to be primarily due to the Ca²⁺-activated Cl^– current and is also thought to contribute to the action potential notch, but it is not known whether this current differs among the three ventricular myocardial cell types (161). Wang and Cohen (141) reported a larger L-type Ca²⁺ channel current (I_Ca) in canine endocardial than epicardial ventricular myocytes, although other studies failed to detect any difference in I_Ca among cells isolated from epicardial, M, and endocardial regions of the canine LV wall (24, 42). Wang and Cohen also described a low-threshold, rapidly activating and inactivating I_Ca, consisting of an Ni²⁺-sensitive T-type I_Ca and a tetrodotoxin-sensitive I_Ca, in all endocardial myocytes that was small or absent in epicardial myocytes (141).

Between the surface epicardial and endocardial layers are M cells and transitional cells. The M cell, Masonic midmyocardial Moe cell, discovered in the early 1990s, was named in memory of Gordon K. Moe (18, 21, 112). The hallmark of the M cell is the ability of its APD to exceed epicardial or endocardial APD in response to a slowing of rate or in response to agents that prolong APD (Fig. 2) (20, 22, 112).

View larger version (24K): [in this window] [in a new window]   Fig. 2. Transmembrane activity recorded from cells isolated from epicardial, M, and endocardial regions of canine LV at basic cycle lengths (BCL) of 300–5,000 ms (steady-state conditions). M and transitional cells were enzymatically dissociated from the midmyocardial region. Deceleration-induced prolongation of action potential duration (APD) is much greater in M cells than in epicardial and endocardial cells. Spike-and-dome morphology is also more accentuated in epicardial cells. [From Liu et al. (73).]

Distribution of M cells within the ventricular wall has been investigated in greatest detail in the LV of the canine heart. Although transitional cells are found throughout the wall in the canine LV, M cells displaying the longest action potentials [at basic cycle length (BCL) 2,000 ms] are often localized in the deep subendocardium to midmyocardium in the anterior wall (158), deep subepicardium to midmyocardium in the lateral wall (112), and throughout the wall in the region of the RV outflow tracts (18). M cells are also present in the deep cell layers of endocardial structures, including papillary muscles, trabeculae, and the interventricular septum (114). In contrast to Purkinje fibers, M cells are not found in discrete bundles or islets (114, 115), although there is evidence that they may be localized in discrete muscle layers. Cells with the characteristics of M cells have been described in canine, guinea pig, rabbit, pig, and human ventricles (19, 22, 23, 35, 49, 50, 70, 72, 73, 78, 96, 103, 106, 107, 111–115, 117, 121, 145, 147, 155, 158).

Myocytes enzymatically dissociated from the different layers of the LV wall typically display APD values that differ by >200 ms at slow rates of stimulation (BCL 2,000 ms). In the intact ventricular wall, this dispersion of APD is less pronounced (25–55 ms) because of electrotonic interaction among the different cell types. The transmural increase in APD from the epicardium to the endocardium is relatively gradual, except between the epicardium and subepicardium, where there is often a sharp increase in APD (Fig. 3). This has been shown to be due to an increase in tissue resistivity in this region (158), which may be related to the sharp transition of cell orientation in this region, as well as reduced expression of connexin 43 (90, 153), which is principally responsible for intracellular communication in the ventricular myocardium. Other studies have reported opposite results, showing higher expression of connexin 43 protein in the epicardium and endocardium than in the midmyocardium. Also pertinent to this issue is the demonstration by LeGrice et al. (69) that the density of collagen is heterogeneously distributed across the ventricular wall. A greater density of collagen in the deep subepicardium may also contribute to the resistive barrier in this region of the wall, limiting the degree of electrotonic interaction between myocardial layers. The degree of electrotonic coupling, together with the intrinsic differences in APD, determines the extent to which TDR is expressed in the ventricular myocardium (136).

View larger version (74K): [in this window] [in a new window]   Fig. 3. Transmural distribution of APD and tissue resistivity (Rt) across the ventricular wall. A: schematic diagram of coronary-perfused canine LV wedge preparation. Three floating microelectrodes were used to record transmembrane action potentials simultaneously from epicardial, M, and endocardial sites. A transmural ECG was recorded along the same transmural axis across the bath, registering the entire field of the wedge. B: histology of a transmural slice of the LV wall near the epicardial border. Region of sharp transition of cell orientation coincides with region of high Rt in D and region of sharp transition of APD in C. C: distribution of conduction time (CT), APD at 90% repolarization (APD90), and repolarization time (RT = APD90 + CT) in a canine LV wall wedge preparation paced at BCL of 2,000 ms. A sharp transition of APD90 is present between epicardium and subepicardium. D: distribution of total Rt across the canine LV wall. Transmural distances at 0% and 100% represent epicardium and endocardium, respectively. *P < 0.01 vs. Rt at midwall. Rt increases most dramatically between deep subepicardium and epicardium. Error bars represent SE (n = 5). [From Antzelevitch and Dumaine (14) and Yan et al. (158).]

Interventricular differences of APD associated with differences of K⁺ current were reported by Volders and co-workers (137): I_Ks density was nearly twice as large in the RV than in the LV, whereas I_Kr density was comparable in the RV and LV.

Some animal species also display prominent apicobasal electrical heterogeneity (25, 64). Surface electrograms recorded from the isolated Langendorff-perfused rabbit heart display significantly longer QT intervals in the apex than in the base, and this regional difference is augmented in the presence of methanesulfonalinide class III antiarrhythmic drugs (64). In the intact canine heart in vivo, the effective refractory period is longer in the apex than in the base, and exposure to dofetilide enhances the gradient through a longer effective refractory period in the apex than in the base (25). In rabbit ventricular myocytes, Cheng et al. demonstrated a higher density of total K⁺ current in the base than in the apex; I_Ks density was higher in the base than in the apex, whereas I_Kr density was lower in the base than in the apex (134). Consistent with this observation, Brahmajothi et al. (31) reported that expression of ERG transcript (mRNA) and protein in ferret ventricles was more abundant in the apex than in the base.

In addition to electrical heterogeneities, recent studies have demonstrated heterogeneities in mechanical function across the ventricular wall. A number of studies have highlighted the regional differences in mechanical shortening and intracellular Ca²⁺ concentration cycling across the wall of the LV (42, 63, 67, 159). The Ca²⁺ transient that regulates cell shortening during excitation-contraction coupling is a dynamic process that is controlled by Ca²⁺ influx and release, as well as Ca²⁺ reuptake and extrusion. A prominent I_to-mediated phase 1 often present in epicardial and M cells contributes to the manifestation of a larger peak I_Ca (30, 97–99) and a more rapid rise of the Ca²⁺ transient and mechanical contraction. Endocardial cells exhibit slower contraction and relaxation kinetics than epicardial cells because of intrinsic differences in the contractile proteins between the epicardial and endocardial layers, as well as slower kinetics of the Ca²⁺ transient (42, 67, 140, 152). Xiong et al. (152) reported a greater Na⁺/Ca²⁺ exchange current and Na⁺/Ca²⁺ exchange mRNA and protein levels in epicardial than in midmyocardial and endocardial cells. Laurita and co-workers (67) reported significantly less sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a) expression in the subendocardial and midmyocardial layers than in the subepicardial layer, but they uncovered no significant difference in the transmural expression of Na⁺/Ca²⁺ exchange. These intrinsic transmural distinctions are thought to synchronize and improve contractile efficiency of the ventricular myocardium.

The ionic features that distinguish the M cell also sensitize it to a variety of pharmacological agents. Agents that block I_Kr or I_Ks or increase I_Ca or late I_Na generally produce a much greater prolongation of the APD of the M cell than of epicardial or endocardial cells, leading to amplification of TDR.

Amplification of transmural heterogeneities normally present in the early and late phases of the action potential can lead to the development of a variety of arrhythmias, including long QT, Brugada, and short QT syndromes, as well as catecholaminergic VT.

Significant progress has been made in defining the functional role of the various ion channels involved in these syndromes and in identifying the -subunits that encode these channels and the accessory subunits and other regulatory proteins that modulate their expression and function. An excellent review of this area as it relates to the molecular determinants of cardiac repolarization was recently published by Nerbonne and Kass (87).

	LONG QT SYNDROME

TOP ABSTRACT ELECTRICAL HETEROGENEITY WITHIN... LONG QT SYNDROME BRUGADA SYNDROME SHORT QT SYNDROME TDR AS THE COMMON... CATECHOLAMINERGIC POLYMORPHIC... CONCLUSION GRANTS REFERENCES

 
As its name implies, long QT syndrome is characterized by prolongation of the interval between the start of the QRS interval and the end of the T wave in the ECG. Long QT syndromes are phenotypically and genotypically diverse but have in common the appearance of a long QT interval in the ECG, an atypical polymorphic VT, known as torsade de pointes (TdP), and, in many, but not all, cases, a relatively high risk for sudden cardiac death (83, 100, 160). Ten genotypes of congenital long QT syndrome have been identified. They are distinguished by mutations in at least eight different ion channel genes, a structural anchoring protein, and a caveolin protein located on chromosomes 3, 4, 6, 7, 11, 17, and 21 (Table 1) (44, 80, 89, 120, 142, 143).

Two recently genotyped forms of long QT syndrome are associated with multiorgan disease. Andersen-Tawil syndrome (89), also referred to as LQT7, is characterized by skeletal muscle periodic paralysis and frequent ectopy but relatively rare episodes of TdP, secondary to loss-of-function mutations in KCNJ2, which encodes Kir2.1, the channel conducting I_K1. Timothy syndrome, also referred to as LQT8, is a rare congenital disorder characterized by multiorgan dysfunction, including prolongation of the QT interval, lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. Timothy syndrome has been linked to loss of voltage-dependent inactivation due to mutations in CACNA1C, the gene that encodes Ca_v1.2, the -subunit of the Ca²⁺ channel (119). The most recent genes associated with long QT syndrome are CAV3, which encodes caveolin-3, and SCN4B, which encodes Na_VB4, an auxiliary subunit of the cardiac Na⁺ channel. Caveolin-3 spans the plasma membrane twice, forming a hairpin structure on the surface, and is the main constituent of caveolae, small invaginations in the plasma membrane. Mutations in CAV3 and SCNB4 produce a gain of function in late I_Na, causing an LQT3-like phenotype (48, 135).

Long QT syndrome shows autosomal recessive and autosomal dominant patterns of inheritance: 1) a rare autosomal recessive disease associated with deafness (Jervell and Lange-Nielsen) caused by 2 genes that encode for the slowly activating delayed rectifier K⁺ channel (KCNQ1 and KCNE1) and 2) a much more common autosomal dominant form, known as Romano Ward syndrome, caused by mutations in 10 different genes (Table 1). Eight of the 10 genes encode cardiac ion channels.

Acquired long QT syndrome refers to a QT prolongation caused by exposure to drugs that prolong the ventricular action potential (26) or QT prolongation secondary to cardiomyopathies, including dilated or hypertrophic cardiomyopathy, as well as to abnormal QT prolongation associated with bradycardia or electrolyte imbalance (77, 118, 127, 131, 138). The acquired form of the disease is far more prevalent than the congenital form and, in some cases, may have a genetic predisposition (95).

Accentuation of spatial dispersion of repolarization within the ventricular myocardium has been identified as the principal arrhythmogenic substrate in acquired and congenital long QT syndrome. The amplification of spatial dispersion of refractoriness can take the form of an increase of transmural, transseptal, or apicobasal dispersion of repolarization. This exaggerated intrinsic heterogeneity, together with EAD- and DAD-induced triggered activity, both caused by reduction in net repolarizing current, underlie the substrate and trigger for the development of TdP arrhythmias observed under long QT syndrome conditions (17, 27). Models of LQT1, LQT2, and LQT3 have been developed using the canine arterially perfused LV wedge preparation (Fig. 4) (109). These models suggest that, in these three forms of long QT syndrome, preferential prolongation of the M cell APD leads to an increase in the QT interval, as well as an increase in TDR, which contributes to the development of spontaneous, as well as stimulation-induced, TdP (Fig. 5) (103, 106, 108, 129, 130). The spatial dispersion of repolarization is further exaggerated by sympathetic influences in LQT1 and LQT2, accounting for the great sensitivity of patients with these genotypes to adrenergic stimuli (Figs. 4 and 5).

View larger version (25K): [in this window] [in a new window]   Fig. 4. LQT1, LQT2, and LQT3 models of long QT syndrome (LQTS). A–C: action potentials simultaneously recorded from endocardial, M, and epicardial sites of arterially perfused canine LV wedge preparations together with a transmural ECG. BCL = 2,000 ms. Transmural dispersion of repolarization (TDR) across the ventricular wall, defined as the difference in repolarization time between M and epicardial cells, is denoted below ECG traces. LQT1 model was mimicked using isoproterenol (Iso) + chromanol 293B (an IKs blocker). LQT2 was created using the IKr blocker d-sotalol + low extracellular K+ concentration ([K+]o). LQT3 was mimicked using the sea anemone toxin ATX-II to augment late INa. D–F: effect of isoproterenol (Iso) on LQT1, LQT2, and LQT3 models. In LQT1, isoproterenol produces a persistent prolongation of APD90 of the M cell and the QT interval (at 2 and 10 min), whereas APD90 of the epicardial cell is always abbreviated, resulting in a persistent increase in TDR (D). In LQT2, isoproterenol initially prolongs (2 min) and then abbreviates the QT interval and APD90 of the M cell to the control level (10 min), whereas APD90 of the epicardial cell is always abbreviated, resulting in a transient increase in TDR (E). In LQT3, isoproterenol produced a persistent abbreviation of the QT interval and APD90 of M and epicardial cells (at 2 and 10 min), resulting in a persistent decrease in TDR (F). *P < 0.0005 vs. control. P < 0.0005; P < 0.005; P < 0.05 vs. 293B, d-sotalol (d-Sot), or ATX-II. [Modified from Shimizu and Antzelevitch (108104, 105).]

View larger version (35K): [in this window] [in a new window]   Fig. 5. Proposed cellular mechanism for development of torsade de pointes in long QT syndrome. EAD and DAD, early and delayed afterdepolarizations.

On the basis of these early studies, the T_peak-T_end interval in precordial ECG leads was suggested to provide an index of TDR (18). Recent studies have also provided guidelines for the estimation of TDR in the case of more complex T waves, including negative, biphasic, and triphasic T waves (51). In such cases, the interval from the nadir of the first component of the T wave to the end of the T wave was shown to provide an ECG approximation of TDR.

Although these relationships are relatively straightforward in the coronary-perfused wedge preparation, extrapolation to the surface ECG recorded in vivo needs to be approached with great caution and will require careful validation. The T_peak-T_end interval is unlikely to provide an absolute measure of transmural dispersion in vivo, as elegantly demonstrated by Xia and co-workers (151). However, changes in this parameter are thought to be capable of reflecting changes in spatial dispersion of repolarization, particularly TDR, and, thus, may be prognostic of arrhythmic risk under a variety of conditions (57, 102, 125, 126, 144, 150). Takenaka et al. (125) recently demonstrated exercise-induced accentuation of the T_peak-T_end interval in LQT1, but not LQT2, patients. These observations, coupled with those of Schwartz et al. (101), demonstrating an association between exercise and risk for TdP in LQT1, but not LQT2, patients, point to the potential value of the T_peak-T_end interval in forecasting risk for the development of TdP. Direct evidence in support of the T_peak-T_end interval as an index to predict TdP in patients with long QT syndrome was provided by Yamaguchi and co-workers (154), who concluded that the T_peak-T_end interval is more valuable than corrected QT (QTc) and QT dispersion as a predictor of TdP in patients with acquired long QT syndrome. Shimizu et al. (102) demonstrated that the T_peak-T_end interval, but not QTc, predicted sudden cardiac death in patients with hypertrophic cardiomyopathy. In a case-controlled study comparing 30 cases of acquired bradyarrhythmias complicated by TdP and 113 cases with uncomplicated bradyarrhythmias, Topilski et al. (128) found that QT, QTc, and T_peak-T_end intervals were strong predictors of TdP, with the best single discriminator being a prolonged T_peak-T_end interval. Watanabe et al. (144) demonstrated that a prolonged T_peak-T_end interval is associated with inducibility, as well as spontaneous development, of VT in high-risk patients with organic heart disease.

An association between increased T_peak-T_end interval and arrhythmic risk is therefore slowly coming into focus, but a direct validation of the T_peak-T_end interval measured at the body surface as an index of TDR is still lacking. Guidelines for such validation have been suggested (5, 51, 155). Because the precordial leads view the electrical field across the ventricular wall, the T_peak-T_end interval would be expected to be most representative of TDR in these leads. The precordial leads are unipolar leads placed on the chest that are referenced to the Wilson central terminal. The direction of these leads is radially toward the "center" of the heart, the center of the Einthoven triangle. In contrast to the precordial leads, the bipolar limb leads, including leads I, II, and III, do not look across the ventricular wall. Although T_peak-T_end intervals measured in these limb leads may provide an index of TDR, they are more likely to reflect global dispersion, including apicobasal and interventricular dispersion of repolarization (88, 151).

A prominent increase in TDR is likely to be arrhythmogenic, because the dispersion of repolarization and refractoriness occurs over a very short distance (the width of the ventricular wall), creating a steep repolarization gradient (1, 4). It is the steepness of the repolarization gradient, rather than the total magnitude of dispersion, that determines its arrhythmogenic potential. Apicobasal or interventricular dispersion of repolarization is less informative, because it may or may not be associated with a steep repolarization gradient and, thus, may or may not be associated with arrhythmic risk.

Another critical factor to consider is that TDR can be highly variable in different regions of the ventricular myocardium, particularly under pathophysiological conditions. Consequently, it is important to measure the T_peak-T_end interval independently in each of the precordial leads, and it is inadvisable to average the T_peak-T_end interval among several leads (151). Because long QT syndrome is principally an LV disorder, TDR is likely to be greatest in the LV wall or septum and, thus, to be best reflected in left precordial leads or lead V₃, respectively. Yamaguchi et al. (154), in their study of acquired long QT syndrome, targeted lead V₅. In contrast, because Brugada syndrome is an RV disorder, TDR is greatest in the RV free wall and, thus, is best reflected in the right precordial leads. For this reason, Castro et al. (38) targeted lead V₂ in their study. The criteria for validation of the T_peak-T_end interval as an index of TDR require that 1) individual precordial leads, and not bipolar limb leads, be evaluated and 2) TDR be present at baseline and significantly augmented as a result of an intervention.

Recently, Opthof and co-workers (88) set out to test the hypothesis that the T_peak-T_end interval reflects transmural dispersion. Plunge electrodes were used to quantitate TDR and global dispersion of repolarization, and the T_peak-T_end interval (Tp-e) was, regrettably, measured using only a single-limb lead, lead II. The use of two anesthetics, propofol and isoflurane, which are known to suppress Na⁺ channel currents in a variety of cells, including M cells, together with a pacing rate of 130 beats/min, resulted in little to no TDR (2.7–14.5 ms). The recording of precordial ECGs was not possible in this open-chest dog model. Thus the two fundamental criteria for validation were not met, leading the authors to conclude that "Tp-e does not correlate with TDR, but is an index of total dispersion of repolarization." Thus the quest for direct validation or invalidation of the T_peak-T_end interval measured at the body surface as an index of TDR continues.

Although most studies concur that the T_peak-T_end interval provides a measure of spatial dispersion of repolarization, the extent to which an augmented T_peak-T_end interval is prognostic of arrhythmic risk will depend on the repolarization gradient (i.e., proximity of the regions displaying disparate repolarization times). It would be helpful to know the extent to which the T_peak-T_end interval provides an index of TDR, in which case the differences in refractoriness are certain to be within close proximity. An ideal model in which to test the hypothesis might be the chronic atrioventricular (AV)-block dog treated with I_Kr blockers, since changes in the T_peak-T_end interval could be accurately correlated with TDR in a model that displays prominent TDR and, additionally, correlated with the risk for development of TdP.

The extent to which TDR exists in the normal heart in vivo has been a matter of considerable debate (18, 21, 43). The controversy derives in large part from the fact that quantitation of TDR in animals in vivo is hampered by 1) the inability to record local repolarization accurately and 2) the unavoidable use of anesthesia, which reduces TDR. These same constraints apply to the measurement of TDR in the human heart (8, 123). Indirect evidence for the presence of a prominent TDR in the human heart in the absence of general anesthesia was provided in a recent study (56). Theoretical studies have been helpful in understanding the role of electrical coupling in the expression of TDR under in vivo conditions (136).

The available data support the hypothesis that TDR, rather than QT prolongation, underlies the principal substrate for the development of TdP (9, 11, 27, 46, 54). Our working hypothesis for the development of long QT syndrome-related TdP presumes the presence of electrical heterogeneity in the form of TDR under baseline conditions and the amplification of TDR by agents that reduce net repolarizing current via a reduction in I_Kr or I_Ks or augmentation of I_Ca or late I_Na (Fig. 5). Conditions leading to a reduction of I_Kr or augmentation of late I_Na produce a preferential prolongation of the M cell action potential. As a consequence, the QT interval is prolonged and is accompanied by a dramatic increase in TDR, thus creating a vulnerable window for the development of reentry. The reduction in net repolarizing current also predisposes to the development of EAD-induced triggered activity in M and Purkinje cells, which provides the extrasystole that triggers TdP when it falls within the vulnerable period. -Adrenergic agonists further amplify transmural heterogeneity (transiently) in the case of I_Kr block but reduce it in the case of I_Na agonists (70, 108).

Although agents that block I_Kr or increase late I_Na clearly augment TDR, not all agents that prolong the QT interval increase TDR. Amiodarone, a potent antiarrhythmic agent used in the management of atrial and ventricular arrhythmias, is rarely associated with TdP. Chronic administration of amiodarone prolongs the APD in the epicardium and endocardium but increases APD less, or even decreases it at slow rates, in the M region, thereby reducing TDR (116). In a dog model of chronic complete AV block and acquired long QT syndrome, 6 wk of treatment with amiodarone produced a major QT prolongation without TdP. In contrast, after 6 wk of treatment with dronedarone, TdP occurred in four of eight dogs, with the highest spatial dispersion of repolarization (105 ± 20 ms) (132).

Pentobarbital sodium is another agent that prolongs the QT interval but reduces TDR. Pentobarbital has been shown to produce a dose-dependent prolongation of the QT interval, accompanied by a reduction in TDR (111). TdP is not observed under these conditions, nor can it be induced with programmed electrical stimulation. Amiodarone and pentobarbital have in common the ability to block I_Ks, I_Kr, and late I_Na. This combination produces a preferential prolongation of the APD of the epicardium and endocardium, so that the QT interval is prolonged but TDR is actually reduced and TdP does not develop. Cisapride is another agent that blocks inward and outward currents. In the canine LV wedge preparation, cisapride produces a biphasic dose-dependent prolongation of the QT interval and TDR. TDR peaks at 0.2 µM, and it is only at this concentration that TdP is observed. Higher concentrations of cisapride lead to an abbreviation of TDR and elimination of TdP, even though the QT interval is further prolonged (46). This finding suggests that the spatial dispersion of repolarization is more important than the prolongation of the QT interval in determining the substrate for TdP.

Block of I_Ks with chromanol 293B also increases the QT interval without augmenting TDR. Chromanol 293B prolongs the APD of the three cell types homogeneously, neither increasing TDR nor widening the T wave. TdP is never observed under these conditions. The addition of -adrenergic agonist, however, abbreviates the APD of epicardial and endocardial cells, but not the M cell, resulting in a marked accentuation of TDR and the development of TdP (108).

	BRUGADA SYNDROME

TOP ABSTRACT ELECTRICAL HETEROGENEITY WITHIN... LONG QT SYNDROME BRUGADA SYNDROME SHORT QT SYNDROME TDR AS THE COMMON... CATECHOLAMINERGIC POLYMORPHIC... CONCLUSION GRANTS REFERENCES

 
Brugada syndrome is another inherited channelopathy in which amplification of TDR leads to the development of polymorphic VT and sudden cardiac death (10). Brugada syndrome is characterized by an elevated ST segment or J wave in the right precordial leads (V₁–V₃), often followed by a negative T wave. First described in 1992, Brugada syndrome is associated with a high incidence of sudden cardiac death secondary to a rapid polymorphic VT or VF (32). The ECG characteristics of Brugada syndrome are dynamic and often concealed but can be unmasked by potent Na⁺ channel blockers such as ajmaline, flecainide, procainamide, disopyramide, propafenone, and pilsicainide (33, 92, 110).

In 15% of Brugada syndrome probands, the syndrome is associated with mutations in SCN5A, the gene that encodes the -subunit of the cardiac Na⁺ channel (39). Over 100 mutations in SCN5A have been linked to Brugada syndrome in recent years (see Ref. 12 for references; also see http://www.fsm.it/cardmoc). Only a fraction of these mutations have been studied in expression systems and shown to result in loss of function due to 1) failure of Na⁺ channel expression, 2) a shift in the voltage and time dependence of I_Na activation, inactivation, or reactivation, 3) entry of the Na⁺ channel into an intermediate state of inactivation from which it recovers more slowly, or 4) accelerated inactivation of the Na⁺ channel. Negative SCN5A results generally do not rule out causal gene mutations, since the promoter region, cryptic splicing mutations, or the presence of gross rearrangements is generally not part of routine investigation. Recently, Hong et al. (62) were the first to report a dysfunctional Na⁺ channel created by an intronic mutation giving rise to cryptic splice site activation in SCN5A in a family with Brugada syndrome. The deletion of fragments of segments 2 and 3 of domain IV of SCN5A caused complete loss of function. Bezzina and co-workers (29) recently provided interesting evidence in support of the hypothesis that an SCN5A promoter polymorphism common in Asians modulates variability in cardiac conduction and may contribute to the high prevalence of Brugada syndrome in the Asian population. Sequencing of the SCN5A promoter identified a haplotype variant consisting of six polymorphisms in near-complete linkage disequilibrium that occurred at an allele frequency of 22% in Asian subjects and was absent in whites and blacks.

Weiss et al. (146) described a second locus on chromosome 3, close to but distinct from SCN5A, linked to the syndrome in a large pedigree in which the syndrome is associated with progressive conduction disease, a low sensitivity to procainamide, and a relatively good prognosis. The gene was recently identified in a preliminary report as the glycerol-3-phosphate dehydrogenase 1-like (GPD1L) gene, and the mutation in GPD1L was shown to result in a reduction of I_Na (75).

The third and fourth genes associated with Brugada syndrome were recently identified and shown to encode the ₁-subunit (CACNA1C) and -subunit (CACNB2b) of the L-type cardiac Ca²⁺ channel. Mutations in the - and -subunits of the Ca²⁺ channel also lead to a shorter-than-normal QT interval, in some cases creating a new clinical entity consisting of a combined Brugada/short QT syndrome (16).

The development of extrasystolic activity and polymorphic VT in Brugada syndrome has been shown to be due to amplification of heterogeneities intrinsic to the early phases (phase 1-mediated notch) of the action potential of cells residing in different layers of the RV wall of the heart (Fig. 6). Rebalancing of the currents active at the end of phase 1 can lead to accentuation of the action potential notch in the RV epicardium, which is responsible for the augmented J wave and the elevated ST segment associated with Brugada syndrome (see Refs. 7 and 10 for references). Under physiological conditions, the ST segment is isoelectric because of the absence of major transmural voltage gradients at the level of the action potential plateau. Accentuation of the RV action potential notch under pathophysiological conditions leads to exaggeration of transmural voltage gradients and, thus, accentuation of the J wave or elevation of the J point (Fig. 6). If the action potential of the epicardium continues to repolarize before that of the endocardium, the T wave remains positive, giving rise to a saddleback configuration of the ST segment elevation. Further accentuation of the notch is accompanied by a prolongation of the action potential of the epicardium, causing it to repolarize after that of the endocardium, thus leading to inversion of the T wave (55, 156).

View larger version (53K): [in this window] [in a new window]   Fig. 6. Cellular basis for ECG and arrhythmic manifestation of Brugada syndrome. Transmembrane action potentials from 1 endocardial and 2 epicardial sites are shown, together with a transmural ECG recorded from a canine coronary-perfused right ventricular (RV) wedge preparation. A: control (BCL = 400 ms). B: combined Na+ and Ca2+ channel block with 5 µM terfenadine accentuates epicardial action potential notch, creating a transmural voltage gradient that manifests as an ST segment elevation or exaggerated J wave in the ECG. C: continued exposure to terfenadine results in all-or-none repolarization at the end of phase 1 at some epicardial sites but not others, creating a local epicardial dispersion of repolarization, as well as TDR. D: phase 2 reentry occurs when epicardial action potential dome propagates from a site where it is maintained to regions where it has been lost, giving rise to a closely coupled extrasystole. E: extrastimulus (S1–S2 = 250 ms) applied to epicardium triggers a polymorphic ventricular tachycardia (VT). F: phase 2 reentrant extrasystole triggers a brief episode of polymorphic VT. [Modified from Fish and Antzelevitch (55).]

View larger version (37K): [in this window] [in a new window]   Fig. 7. Proposed mechanism for Brugada syndrome. A shift in balance of currents serves to amplify existing heterogeneities by causing loss of the action potential (AP) dome at some epicardial, but not endocardial, sites. A vulnerable window develops as a result of the dispersion of repolarization and refractoriness within the epicardium, as well as across the wall. Epicardial dispersion leads to development of phase 2 reentry, which provides the extrasystole that captures the vulnerable window and initiates VT/ventricular fibrillation (VF) via a circus movement reentry mechanism. [Modified from Antzelevitch (6).]

	SHORT QT SYNDROME

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The ECG commonly displays tall peaked symmetrical T waves in SQT1, SQT2, and SQT3 because of acceleration of phase 3 repolarization. An augmented T_peak-T_end interval associated with this ECG feature of the syndrome suggests that TDR is significantly increased (Fig. 8). Evidence in support of the hypothesis derives from studies of an LV wedge model of the short QT syndrome demonstrating that an increase in outward repolarizing current can preferentially abbreviate endocardial/M cell action potential, thus increasing TDR and creating the substrate for reentry (52). The K⁺ channel opener pinacidil used in this study caused a heterogeneous abbreviation of APD among the different cell types spanning the ventricular wall, thus creating the substrate for the genesis of VT under conditions associated with short QT intervals. Polymorphic VT could be readily induced with programmed electrical stimulation. The increase in TDR was further accentuated by isoproterenol, leading to easier induction and more persistent VT/VF. An increase of TDR to >55 ms was associated with inducibility of VT/VF. In long QT syndrome models, a >90-ms TDR is required to induce TdP. The easier inducibility in short QT syndrome is due to the reduction in the wavelength (refractory period x conduction velocity) of the reentrant circuit, which reduces the pathlength required for maintenance of reentry (52).

View larger version (23K): [in this window] [in a new window]   Fig. 8. Proposed mechanism for arrhythmogenesis in short QT syndrome. An increase in net outward current due to a reduction in late inward current or augmentation of outward repolarizing current serves to abbreviate APD heterogeneously, leading to amplification of TDR and creation of a vulnerable window for the development of reentry. Reentry is facilitated by increase in TDR and abbreviation of refractoriness.

	TDR AS THE COMMON DENOMINATOR IN CHANNELOPATHY-INDUCED SUDDEN CARDIAC DEATH

TOP ABSTRACT ELECTRICAL HETEROGENEITY WITHIN... LONG QT SYNDROME BRUGADA SYNDROME SHORT QT SYNDROME TDR AS THE COMMON... CATECHOLAMINERGIC POLYMORPHIC... CONCLUSION GRANTS REFERENCES

View larger version (35K): [in this window] [in a new window]   Fig. 9. Role of TDR in channelopathy-induced sudden cardiac death. In long QT syndrome, QT interval increases as a function of disease or drug concentration; in Brugada syndrome, it remains largely unchanged; and in short QT syndrome, it decreases as a function of disease or drug. Long QT, short QT, and Brugada syndromes have in common the ability to amplify TDR, which results in development of torsades des pointes (TdP) when dispersion reaches threshold for reentry. Threshold for reentry decreases as APD and refractoriness are reduced. [Modified from Antzelevitch and Oliva (15).]

	CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA

TOP ABSTRACT ELECTRICAL HETEROGENEITY WITHIN... LONG QT SYNDROME BRUGADA SYNDROME SHORT QT SYNDROME TDR AS THE COMMON... CATECHOLAMINERGIC POLYMORPHIC... CONCLUSION GRANTS REFERENCES

Numerous studies have provided evidence that DAD-induced triggered activity underlies monomorphic or bidirectional VT in patients with CPVT (74, 85). The cellular mechanisms underlying the various ECG phenotypes and the transition of monomorphic VT to polymorphic VT or VF were recently elucidated with the use of low-dose caffeine to mimic the defective Ca²⁺ homeostasis encountered under conditions that predispose to CPVT (86).

The combination of isoproterenol and caffeine was found to lead to the development of DAD-induced triggered activity arising from the epicardium, endocardium, or M region. Alternation of epicardial and endocardial sources of ectopic activity gave rise to a bidirectional VT. The triggered activity-induced monomorphic, bidirectional, and slow polymorphic VT would be expected to be hemodynamically well tolerated because of the relatively slow rate of these rhythms and are unlikely to be the cause of sudden death in these syndromes.

Ectopic activity or VT in the model arose from the epicardium and was associated with an increased T_peak-T_end interval and augmented TDR due to reversal of the normal transmural activation sequence. The increase in TDR created a vulnerable window across the ventricular wall that, when invaded by a premature extrasystole, permitted the precipitation of a very rapid polymorphic VT, which would be expected to lead to hemodynamic compromise (86). Thus, even in a syndrome in which arrhythmogenesis is traditionally ascribed to triggered activity, sudden cardiac death may be due to amplification of TDR, giving rise to reentrant VT/VF.

	CONCLUSION

TOP ABSTRACT ELECTRICAL HETEROGENEITY WITHIN... LONG QT SYNDROME BRUGADA SYNDROME SHORT QT SYNDROME TDR AS THE COMMON... CATECHOLAMINERGIC POLYMORPHIC... CONCLUSION GRANTS REFERENCES

 
Amplification of spatial dispersion of refractoriness in ventricular myocardium, particularly that due to augmentation of TDR, can predispose to the development of potentially lethal reentrant arrhythmias in a variety of ion channelopathies, including long QT, short QT, and Brugada syndromes, as well as CPVT. These same principles apply to arrhythmogenesis associated with hypertrophic and dilated cardiomyopathies (2, 3, 133, 139), as well as some arrhythmias associated with ischemia and reperfusion (45, 157).

	GRANTS

TOP ABSTRACT ELECTRICAL HETEROGENEITY WITHIN... LONG QT SYNDROME BRUGADA SYNDROME SHORT QT SYNDROME TDR AS THE COMMON... CATECHOLAMINERGIC POLYMORPHIC... CONCLUSION GRANTS REFERENCES

 
This work was supported by National Heart, Lung, and Blood Institute Grant HL-47678 and grants from the American Heart Association and New York State and Florida Grand Lodges of Free and Accepted Masons.

	FOOTNOTES

 

Address for reprint requests and other correspondence: C. Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501-1787 (e-mail: ca{at}mmrl.edu)

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