ELECTRICAL HETEROGENEITY IN THE HEART

Charles Antzelevitch
Masonic Medical Research Laboratory
2150 Bleecker Street, Utica, NY 13501-1787

Abstract: Recent studies have identified three distinct cell types in the ventricular myocardium: epicardial, M and endocardial cells.  Epicardial and M cell action potentials possess a prominent transient outward current (I_to)-mediated notch responsible for the ‘spike and dome’ morphology of the action potential.  M cells display a smaller slowly activating delayed rectifier current (I_Ks), but a larger late sodium current (late I_Na  ) and sodium-calcium exchange current (I_Na-Ca), than the other cell types.  These ionic distinctions underlie the longer action potential duration (APD) and steeper APD-rate relationship of the M cell, which is more pronounced in the presence of antiarrhythmic agents with class III actions.  Transmural differences in the time-course of early and late repolarization are responsible for the inscription of the electrocardiographic J wave and T wave, respectively.  Amplification of the electrical heterogeneities intrinsic to the ventricular myocardium contribute the development of arrhythmogenic syndromes, including the Brugada and Long QT syndromes.

INTRINSIC ELECTRICAL HETEROGENEITY OF VENTRICULAR MYOCARDIUM

Until approximately a decade ago, the ventricular myocardium was thought to be largely homogeneous.  Recent studies have delineated three distinct myocardial cell types: epicardial, M and endocardial cells.  Differences in the electrophysiologic characteristics and pharmacologic profiles of these three myocardial cell types have been described in the dog, guinea pig, rabbit, and human ventricles. [1]

The principal feature of the M cell is the ability of its action potential to prolong more than that of epicardium or endocardium with slowing of rate.  In the early 1990’s, the M cells became the focus of intense investigation after their identification and characterization in the deep structures of the canine ventricle. [2,3,4]  

The distribution of M cells in the ventricular wall has been investigated in greatest detail in the canine left ventricle.  M cells with the longest action potential duration are typically found in the deep subepicardium to midmyocardium in the lateral wall, deep subendocardium to midmyocardium in the anterior wall, and throughout the wall in the region of the outflow tracts.  M cells are also present in the deep layers of papillary muscles, trabeculae, and interventricular septum [5] .  Tissue slices isolated from the M region display an APD at 90 percent repolarization (APD₉₀) that is more than 100 msec longer than tissues isolated from the epicardium or endocardium at basic cycle lengths of 2000 msec or greater.  In the intact ventricular wall, this disparity in APD₉₀ is less pronounced due to electrotonic coupling of cells.  The transmural increase in APD is gradual, except between the epicardium and subepicardium where there is often a sharp increase in APD.  This has been shown to be due to an increase in tissue resistivity in this region [6] , which may be related to the sharp transition in cell orientation in this region.  Thus, both the degree of electrotonic coupling and intrinsic action potential durations play a key role in the expression of electrical heterogeneity in the ventricular myocardium.

The ionic basis for the prolonged APD of M cells includes a smaller I_Ks and a larger late I_Na [7,8]  and sodium-calcium exchange current (I_Na-Ca) [9] compared to epicardial and endocardial cells.  Other currents, including the rapidly activating delayed rectifier (I_Kr) and inward rectifier (I_K1) currents are similar in the three cell types in the canine heart [8] .  The net result is a decrease in repolarizing current during phases 2 and 3 of the M cell action potential.  These ionic distinctions sensitize the M cells to a variety of pharmacological agents.  Agents that block I_Kr, I_Ks or increase I_Ca or late I_Na  produce much greater prolongation in M cell APD than on the APD of epicardial or endocardial cells.

In addition to differences in currents active during final repolarization, the three cell types differ with respect to currents that contribute to phase 1.  The action potentials of epicardial and M cells display a prominent transient outward current (I_to)-mediated phase 1 that is absent in endocardial cells [10] .  The early repolarization phase gives the epicardial action potential a notched appearance.  In the canine heart, I_to and the action potential notch are much larger in right vs. left ventricular epicardial [11] and M [12] cells.

ELECTRICAL HETEROGENEITY AS THE BASIS FOR THE J WAVE AND T WAVE OF THE ECG

Transmural differences in the time course of repolarization of the three predominant myocardial cell types have been shown to be largely responsible for the inscription of the J wave and T wave of the ECG.  The transmural gradient resulting from the presence of an I_to-mediated notch in epicardium but not endocardium gives rise to the J wave, or Osborne wave [13] (Figure 2B).  Voltage gradients developing as a result of the different time course of repolarization of phases 2 and 3 in the three cell types give rise to opposing voltage gradients on either side of the M region, which are in large part responsible for the inscription of the T wave [14] .

When the T wave is upright, the epicardial action potential is the earliest to repolarize and the M cell action potential is the last.  Full repolarization of the epicardium coincides with the peak of the T wave and repolarization of the M region is coincident with the end of the T wave.  It therefore follows that the duration of the M cell action potential determines the QT interval, whereas the duration of the epicardial action potential determines the QTpeak interval.  The Tpeak–Tend interval thus provide an index of transmural dispersion of repolarization [14,3] .

The available data suggest that T_peak-T_end measurements might best be limited to precordial leads since these may more accurately reflect transmural or transseptal dispersion of repolarization.  Recent studies also provide guidelines for the estimation of transmural dispersion of repolarization in the case of more complex T waves, including negative, biphasic, and triphasic T waves [15] .  In these cases, the interval from the nadir of the first component of the T wave to the end of the T wave provides an accurate electrocardiographic approximation of transmural dispersion of repolarization.  The clinical applicability of these concepts remains to be established.  An important initial step towards validation of the T_peak-T_end interval as an index of transmural dispersion was provided in a report by Lubinski et al. [16] , which showed an increase of this interval in patients with congenital long QT syndrome.  Recent studies suggest that the T_peak-T_end interval may be a useful index of transmural dispersion and thus may be prognostic of arrhythmic risk under a variety of conditions [17,18,19] .

THE ROLE OF ELECTRICAL HETEROGENIETY IN ARRHYTHMOGENESIS

Long QT Syndrome

Amplification of the heterogeneities in final repolarization of the ventricular myocardium have been shown to generate the substrate for the development of the long QT syndrome by increasing transmural dispersion of repolarization (TDR) and permitting the induction of early after depolarization (EAD)-induced triggered activity.  Models of the LQT1, LQT2, and LQT3 form of the long QT syndrome have been developed using the canine arterially perfused left ventricular wedge preparation [20] .  These models have shown that in these three forms of LQTS, preferential prolongation of the M cell APD leads to an increase in the QT interval as well as an increase in TDR, the latter providing the substrate for the development of spontaneous as well as stimulation-induced Torsade de Pointes (TdP).

LQT1 is the most prevalent of the congenital long QT syndromes [21] .  LQT1 can be mimicked using an I_Ks blocker (chromanol 293B) together with a b-adrenergic agonist (isoproterenol).  Chromanol 293B alone leads to uniform prolongation of APD in all three cell types with little change in TDR.  Although the QT interval is prolonged, TdP never occurs under these conditions, nor can it be induced.  Addition of isoproterenol results in abbreviation of epicardial and endocardial APD while the M cell APD either prolongs or remains the same.  The dramatic increase in TDR provides the substrate for the development of spontaneous as well as stimulation-induced TdP [22] .  These results highlight the fact that the problem with the long QT syndrome is not the long QT interval, but rather the increase in TDR that often accompanies the prolongation of the QT interval.  The combination of I_Ks block and b adrenergic stimulation creates a broad based T wave in the perfused wedge, similar to that observed in patients with LQT1.  These findings correlate well with the high sensitivity of congenital LQTS patients, especially LQT1 patients, to sympathetic stimulation [23,24] . 

The second most prevalent form of congenital LQTS is LQT2, involving a defect in I_Kr.  Reduced levels of I_Kr are also responsible for most cases of acquired LQTS.  In the canine ventricular wedge model, d-sotalol is used to mimic this variant of the syndrome.  Although all three cell types exhibit an increase in APD when I_Kr is blocked, the M cell prolongs to a greater degree, resulting in an increased TDR and spontaneous as well as stimulation-induced TdP.  If I_Kr block is accompanied by hypokalemia, a deeply notched or bifurcated T wave is observed in the wedge preparation, similar to that seen in patients with LQT2.  Isoproterenol further exaggerates TDR and increases the incidence of TdP in this model.

Use of ATX-II to augment late I_Na provides a model of LQT3.   The APD of each of the three cell types in the perfused wedge is prolonged with ATX-II, leading to a delay in the onset of the T wave [25] .  Since the M cell has a higher concentration of late I_Na, the APD prolongation is more pronounced in this region, especially at slower stimulation rates.  As in the other forms of LQTS, exaggerated prolongation of APD in the M region results in an increase in TDR and induction of TdP.  b adrenergic stimulation abbreviates APD of all cell types under these conditions, causing an ameliorative effect in this model of LQTS.  TDR is importantly reduced owing to the fact that the APD of the M cell abbreviates more than that of epicardium or endocardium [26] .

It is noteworthy that the arrhythmogenic effects of sympathetic activation in the wedge models display very a different time-course in the case of LQT1 and LQT2.  In the LQT1 model, isoproterenol produces an increase in TDR that is most prominent during the first two minutes, but which persists although to a lesser extent during steady-state.  TdP incidence is enhanced during the initial period as well as during steady-state.  In the LQT2 model, isoproterenol produces only a transient increase in TDR that persists for less than 2 minutes.  TdP incidence is therefore enhanced only for a brief period of time.  Very similar time-courses have recently been demonstrated in the response of LQT1 and LQT2 patients to epinephrine [18] .  These differences in time-course may explain the important differences in autonomic activity and other gene-specific triggers that contribute to events in patients with different LQTS genotypes [21,24] .

Brugada Syndrome

Amplification of transmural heterogeneities in the early phases of the action potential are thought to be responsible for the Brugada syndrome. [27]   Pedro and Josep Brugada first defined this as a distinct clinical syndrome associated with syncopal episodes and sudden cardiac death in 1992 [28] . Responsible for 20% of sudden deaths in patients with an apparently normal heart, it is an inherited disorder, displaying an autosomal dominant mode of transmission with incomplete penetrance [29] .

Electrocardiographically, the syndrome is characterized by a right bundle branch block pattern and ST segment elevation in right precordial leads V₁ to V₃ in the absence of ischemia, electrolyte abnormalities, or structural heart disease.  Differential diagnosis of patients with this syndrome is confounded by the fact that the electrocardiographic features are often concealed [30] . In these patients, ECG analysis following administration of potent sodium channel blockers such as ajmaline, procainamide, and flecainide can reveal the Brugada phenotype [31] . The only established effective treatment for patients with the Brugada syndrome is the implantation of an intracardiac defibrillator (ICD).

The only gene thus far linked to the syndrome is the a subunit of the cardiac sodium channel gene, SCN5A, (see [27] for references), the same gene implicated in the LQT3 form of the long QT syndrome.  Bezzina and co-workers [32] recently reported a mutation in SCN5A (1795InsD) capable of producing both the Brugada and LQT3 phenotypes.  The mutations uncovered thus far all reduce I_Na via: 1) failure of the sodium channel to express; 2) reduced current due to a shift in the voltage- and time-dependence of I_Na activation, inactivation or reactivation; and 3) reduced contribution of I_Na during the early phases of the action potential due to accelerated inactivation of I_Na.

In addition to SCN5A, gene mutations that alter the intensity or kinetics of I_to, I_Kr, I_Ks, I_K-ATP, I_Ca, or I_Cl(Ca) so as to increase the activity of the outward currents and/or diminish that of the inward currents are candidates for the Brugada syndrome.  Other candidate genes include those encoding for autonomic receptors that directly modulate ion current density and/or alter the expression of channels in the membrane (e.g., sympathetic control of I_to). 

Models of the Brugada syndrome have been developed in the canine right ventricular wedge preparation using potassium channel openers such as pinacidil (2.5 mM) to augment I_K-ATP or a combination of a sodium channel blocker like flecainide (7 mmol/L) and acetylcholine (2-3 mmol/L) [33] .  Transmembrane action potentials recorded under these conditions display all-or-none repolarization at the end of phase 1 of the action potential at some epicardial but not endocardial sites.  The ECG consequently displays an elevation of the ST segment.   Phase 2 reentry is observed due to propagation of the action potential dome from sites at which the dome is maintained to sites at which it is lost, giving rise to closely coupled extrasystoles, which in turn precipitate VT/VF.

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