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Electrical Heterogeneity in the Heart: Physiological, Pharmacological and Clinical Implications

Charles Antzelevitch, Robert Dumaine

10.1002/cphy.cp020117

Source: Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart

Originally published: 2002

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Action Potential and Ionic Distinctions
1.1 Methodological Considerations in the Assessment of Electrical Heterogeneity
2 Pharmacological Distinctions
2.1 Epicardium versus Endocardium
2.2 M‐cells versus Epicardium and Endocardium
2.3 M‐Cells versus Purkinje Cells
3 Molecular Distinctions
3.1 Potassium Channels
3.2 Sodium Channels
3.3 Gap Junctions
3.4 Chloride Conductances
3.5 Calcium Channels
3.6 Pumps and Exchangers
4 Simulation of Action Potential Heterogeneity
5 Developmental Aspects
6 Physiological and Clinical Implications
6.1 Transmural Distribution of Ito and the J Wave
6.2 Phase 2 Re‐entry as a Mechanism of Extrasystolic Activity
6.3 Phase 2 Re‐entry as a Trigger for VT/VF: The Brugada Syndrome
6.4 Early Repolarization Syndrome
6.5 Ischemia
6.6 Role of Transmural Heterogeneity in Inscription of the Electrocardiographic T Wave
6.7 Role of Transmural Heterogeneity in Inscription of the U Wave
6.8 Role of Transmural Heterogeneity in the Long QT Syndrome
6.9 Torsade de Pointes
6.10 Pharmacological Therapy for LQTS: Reducing Transmural Dispersion of Repolarization
7 Summary
Figure 1. Figure 1.

A: Action potentials recorded from myocytes isolated from the epicardial (Epi), endocardial (Endo), and M regions of the canine left ventricle. B:I‐V relations for IK1 in epicardial, endocardial, and M region myocytes. Values are mean ± S.D. C: Transient outward current (Ito) recorded from the three cell types (current traces recorded during depolarizing steps from a holding potential of −80 mV to test potentials ranging between −20 and +70 mV D: The average peak current–voltage relationship for Ito for each of the three cell types. Values are mean ± S.D. E: Voltage‐dependent activation of the slowly activating component of the delayed rectifier K+ current (IKs) (currents were elicited by the voltage pulse protocol shown in the inset; 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 mean ± S.E. * p <0.05 compared with Epi or Endo. G: Reverse‐mode sodium–calcium exchange currents recorded in potassium‐ and chloride‐free solutions at a voltage of −80 mV. INa‐Ca was maximally activated by switching to sodium‐free external solution at the time indicated by the arrow. H: Midmyocardial sodium–calcium exchanger density is 30% greater than endocardial density, calculated as the peak outward INa‐Ca normalized by cell capacitance. Endocardial and epicardial densities were not significantly different. I: TTX‐sensitive late sodium current. Cells were held at −80 mV and briefly pulsed to −45 mV to inactivate fast sodium current before stepping to −10 mV. J: Normalized late sodium current measured 300 msec into the test pulse was plotted as a function of test pulse potential.

From references 133,132,257, with permission. Modified from reference 257 with permission
Figure 2. Figure 2.

Transmembrane activity recorded from cells isolated from the epicardial, M, and endocardial regions of the canine left ventricle at basic cycle lengths (BCL) of 300 to 5000 msec (steady‐state conditions). The M‐cells and transitional cells were enzymatically dissociated from the midmyocardial region. Deceleration‐induced prolongation of APD in M‐cells is much greater than in epicardial and endocardial cells. The spike‐and‐dome morphology is also more accentuated in the epicardial cell.
Figure 3. Figure 3.

Transmural distribution of action potential duration and tissue resistivity in the intact ventricular wall. A: Schematic diagram of the arterially perfused canine LV wedge preparation. The wedge is perfused with Tyrode's solution via a small native branch of the left descending coronary artery and stimulated from the endocardial surface. Transmembrane action potentials are recorded simultaneously from epicardial (Epi), M region (M), and endocardial (Endo) sites using three floating microelectrodes. A transmural ECG is recorded along the same transmural axis across the bath, registering the entire field of the wedge. B: Histology of a transmural slice of the left ventricular wall near the epicardial border. The region of sharp transition of cell orientation coincides with the region of high tissue resistivity depicted in D and the region of sharp transition of action potential duration illustrated in C. C: Distribution of conduction time (CT), APD90, and repolarization time (RT = APD90 + CT) in a canine left ventricular wall wedge preparation paced at BCL of 2000 msec. A sharp transition of APD90 is present between epicardium and subepicardium. Epi: epicardium; M: M‐cell; Endo: endocardium; RT: repolarization time; CT: conduction time. D: Distribution of total tissue resistivity (Rt) across the canine left ventricular wall. Transmural distances at 0% and 100% represent epicardium and endocardium, respectively. * p <0.01 compared with Rt at midwall. Tissue resistivity increases most dramatically between deep subepicardium and epicardium. Error bars represent SEM (n = 5).

From Yan et al. 246, with permission
Figure 4. Figure 4.

Effect of d‐sotalol, a specific IKr blocker, on transmembrane activity recorded from epicardial (Epi), endocardial (Endo), and deep subepicardial (M‐cell) sites in a transmural strip of canine left ventricle. A: Each panel shows superimposed action potentials recorded at basic cycle lengths (BCL) of 300–5000 msec, before and after d‐sotalol (100 μM). B: APD‐rate relations.

From Sicouri et al. 198, with permission
Figure 5. Figure 5.

Effects of chronic amiodarone on the rate dependence of action potential characteristics in epicardial (Epi), M, and endocardial (Endo) tissues isolated from the hearts of untreated dogs (left) as well as those receiving chronic amiodarone therapy (right). A: Transmembrane activity recorded simultaneously from Epi, M, and Endo preparations at basic cycle lengths (BCL) of 500, 800, 2000, and 5000 msec (steady‐state conditions). B: Composite data from twelve untreated dogs and five amiodarone treated dogs. The graphs plot APD‐rate relations for Epi (open circles), Endo (closed circles), and M (open triangles) of untreated (left) and amiodarone‐treated animals (right). Each point represents mean ± S.D. * p<0.01 amiodarone vs. control. [K+]o = 4 mM. Chronic amiodarone treatment leads to much more uniform APD‐rate relations in the three cell types.
Figure 6. Figure 6.

Heterogeneous distribution of KCNE1 and KCNQ1 in canine ventricular myocardium. A: Transmural distribution of KCNE1 (filled columns) and KCNQ1 (hatched columns) mRNA as measured by competitive multiplex PCR. RNA was reverse transcribed using standard protocols and 2 μg of DNA from the epi‐, mid‐, and endocardium was amplified against known concentrations of an exogenous external standard (MIMIC). Data are from a pool of acutely dissociated cells from eight dogs. The concentration at which the amplitude of the two signals was equal was used to determine the amount of dsDNA presented. B: Same protocol as in A, with RNA isolated from the right (RV) and left (LV) ventricles. C: Western blot analysis of the distribution of KCNQ1 in canine right and left ventricles using polyclonal antibodies. Two bands are typically observed with a more intense signal in RV. 70 μg of protein was loaded in each well. D: Same experiment as in C with a KCNE1 antibody; the protein is more strongly expressed in LV.
Figure 7. Figure 7.

Age‐related spike‐and‐dome morphology and changes in Ito in canine ventricular epicardium. Each panel depicts transmembrane activity recorded from right ventricular epicardial tissues (upper trace) and transient outward current (lower trace) recorded from left ventricular epicardial cells isolated from a neonate (5 days of age; A), a young dog (3 months old; B), and an adult dog (C). BCL = 2000 msec; [K+]o = 4 mM. The spike‐and‐dome configuration of the epicardial action potential and Ito density are absent in the neonate, relatively small in the young dog, and most prominent in the adult.
Figure 8. Figure 8.

Phase 2 re‐entry. Re‐entrant activity induced by exposure of a canine ventricular epicardial preparation (0.7 cm2) to simulated ischemia. Microelectrode recordings were obtained from four sites as shown in the schematic (upper right). After 35 min of ischemia, the action potential dome develops normally at site 4, but not at sites 1, 2, or 3. The dome then propagates in a clockwise direction re‐exciting sites 3, 2, and 1 with progressive delays, thus generating a closely coupled re‐entrant extrasystole (156 msec) at site 1. In this example of phase 2 re‐entry, propagation of the dome occurs in a direction opposite that of phase 0, a mechanism akin to reflection. BCL = 700 msec.

Modified from Lukas and Antzelevitz 138, with permission
Figure 9. Figure 9.

Phase 2 re‐entrant extrasystole triggers circus movement re‐entry. A: Exposure of a relatively large canine right ventricular epicardial sheet (6.3 cm2) to simulated ischemia results in loss of the dome at sites 3 and 4 but not at sites 1 and 2 (BCL = 1100 msec). Conduction of the basic beat proceeds normally from the stimulation site (site 2; see schematic a). Propagation of the action potential dome from the right half of the preparation caused reexcitation of the left half via a phase 2 re‐entry mechanism (see schematic b). The extrasystolic beat generated by phase 2 re‐entry then initiates a run of tachycardia that is sustained for 4 additional cycles via typical circus movement re‐entry. The proposed re‐entrant path is shown in schematic c. Note that phase 2 re‐entry provides an activation front roughly perpendicular to that of the basic beat. This type of crossfield activation has previously been shown to predispose to the development of vortex‐like re‐entry in isolated epicardial sheets. B: Recorded after addition of 1 mM 4‐aminopyridine (4‐AP), an inhibitor of the transient outward current. In the continued presence of ischemia, 4‐AP restored the dome at all epicardial recording sites within 3 min. Thus electrical heterogeneity was restored and all re‐entrant activity abolished.

Modified from Lukas and Antzelevitz 138, with permission
Figure 10. Figure 10.

ECG and arrhythmias with typical features of the Brugada syndrome recorded from canine right ventricular wedge preparations A: Schematic of arterially perfused right ventricular wedge preparation. B: Pressure—induced phase 2 re‐entry and VT. Shown are transmembrane action potentials simultaneously recorded from two epicardial sites (Epi 1 and Epi 2) and one M region (M) site, together with a transmural ECG. Local application of pressure near Epi 2 results in loss of the action potential dome at that site but not at the Epi 1 or M sites. The dome at Epi 1 then re‐excites Epi 2, giving rise to a phase 2 re‐entrant extrasystole that triggers a short run of ventricular tachycardia. Note the ST segment elevation due to loss of the action potential dome in a segment of epicardium. C: Polymorphic VT/VF induced by local application of the potassium channel opener pinacidil (10 μM) to the epicardial surface of the wedge. Action potentials from two epicardial sites (Epi 1 and Epi 2) and a transmural ECG were simultaneously recorded. Loss of the dome at Epi 1 but not Epi 2 creates a marked dispersion of repolarization, giving rise to a phase 2 re‐entrant extrasystole. The extrasystolic beat then triggers a long episode of ventricular fibrillation (22 sec). Right panel: Addition of 4‐aminopyridine (4‐AP. 2 mM), a specific Ito blocker, to the perfusate restored the action potential dome at Epi 1, thus reducing dispersion of repolarization and suppressing all arrhythmic activity. BCL = 2000 msec. D: Phase 2 re‐entry gives rise to VT following addition of pinacidil (2.5 μM) to the coronary perfusate. Transmembrane action potentials form two epicardial sites (Epi 1 and Epi 2) and one endocardial site (Endo), as well as a transmural ECG were simultaneously recorded. Right panel: 4‐AP (1 mM) markedly reduces the magnitude of the action potential notch in epicardium, thus restoring the action potential dome throughout the preparation and abolishing all arrhythmic activity.

D is from Yan and Antzelevitch 245, with permission
Figure 11. Figure 11.

Proposed mechanism for the Brugada syndrome. A shift in the balance of currents serves to amplify existing heterogeneities by causing loss of the action potential dome at some epicardial sites, but not endocardial sites. A vulnerable window develops as a result of the dispersion of repolarization and refractoriness within epicardium as well as across the wall. Epicardial dispersion leads to the development of phase 2 re‐entry, which provides the extrasystole that captures the vulnerable window and initiates VT/VF via a circus movement re‐entry mechanism.
Figure 12. Figure 12.

Whole‐cell current for wild‐type (WT) and Brugada syndrome mutant (T1620M) in transiently transfected TSA201 cells at room temperature (22°C) and 32°C. A: The cartoon depicts the location of the missense mutations R1232W and T1620M previously described by Chen et al. 52. Current recordings obtained at different test potentials from −70 to −25 mV (32°C) and −65 to −20 (22°C) in increments of 5 mV from a holding potential of −120 mV for four representative cells. B: Current decay of T1620M at 32°C. Representative current recordings from WT and T1620M were elicited by a 20 msec depolarizing pulse to a test potential of 10 mV from a holding potential of −140 mV, normalized to the peak inward current and superimposed. C: WT decay time constant (square) is less sensitive to temperature in the physiological range. Cells were maintained at −80 mV and pulsed at 0 mV for 10 msec at temperatures between 22°C and 42°C. Current decay were fitted by a sum of two exponential functions. The fast time constant was plotted against the temperature (log scale) for WT and T1620M (filled circles). Each symbol represents a different cell.

Modified from Dumaine et al. 75, with permission
Figure 13. Figure 13.

Voltage gradients on either side of the M region are responsible for inscription of the electrocardiographic T wave. Top: Action potentials simultaneously recorded from endocardial, epicardial and M region sites of an arterially perfused canine left ventricular wedge preparation. Middle: ECG recorded across the wedge. Bottom: Computed voltage differences between the epicardium and M region action potentials (ΔVM‐Epi) and between the M region and endocardium responses (ΔVEndo‐M). If these traces are representative of the opposing voltage gradients on either side of the M region, responsible for inscription of the T wave, then the weighted sum of the two traces should yield a trace (middle trace in bottom grouping) resembling the ECG, which it does. The voltage gradients are weighted to account for differences in tissue resistivity between M and Epi and Endo and M regions, thus yielding the opposing currents flowing on either side of the M region. A: Under control conditions, the T wave begins when the plateau of epicardial action potential separates from that of the M‐cell. As epicardium repolarizes, the voltage gradient between epicardium and the M region continues to grow, giving rise to the ascending limb of the T wave. The voltage gradient between the M region and the epicardium (ΔVM‐Epi) reaches a peak when the epicardium is fully repolarized; this marks the peak of the T wave. On the other end of the ventricular wall, the endocardial plateau deviates from that of the M‐cell, generating an opposing voltage gradient (ΔVEndo‐M) and corresponding current that limits the amplitude of the T wave and contributes to the initial part of the descending limb of the T wave. The voltage gradient between the endocardium and the M region reaches a peak when the endocardium is fully repolarized. The gradient continues to decline as the M‐cells repolarize. All gradients are extinguished when the longest M cells are fully repolarized. B: d‐sotalol (100 μM) prolongs the action potential of the M‐cell more than those of the epicardial and endocardial cells, thus widening the T wave and prolonging the QT interval. The greater separation of epicardial and endocardial repolarization times also gives rise to a notch in the descending limb of the T wave. Once again, the T wave begins when the plateau of epicardial action potential diverges from that of the M‐cell. The same relationships as described for panel A are observed during the remainder of the T wave. The d‐sotalol–induced increase in dispersion of repolarization across the wall is accompanied by a corresponding increase in the Tpeak‐Tend interval in the pseudo‐ECG.

Modified from Yan and Antzelevitch 244, with permission
Figure 14. Figure 14.

Transient shift of voltage gradients on either side of the M region results in T wave bifurcation. The format is the same as in Figure 13. All traces were simultaneously recorded form an arterially perfused left ventricular wedge preparation. A: Control. B: In the presence of hypokalemia ([K+]o = 1.5 mM), the IKr blocker dl‐sotalol (100 μM) prolongs the QT interval and produces a bifurcation of the T wave, a morphology some authors refer to as T‐U complex. The rate of repolarization of phase 3 of the action potential is slowed, giving rise to smaller opposing transmural currents that cross over, producing a low‐amplitude bifid T wave. Initially the voltage gradient between the epicardium and M regions (M‐Epi) is greater than that between endocardium and M region (Endo‐M). When endocardium pulls away from the M cell, the opposing gradient (Endo‐M) increases, interrupting the ascending limb of the T wave. Predominance of the M‐Epi gradient is restored as the epicardial response continues to repolarize and the Epi‐M gradients increases, thus resuming the ascending limb of the T wave. Full repolarization of epicardium marks the peak of the T wave. Repolarization of both endocardium and the M region contribute importantly to the descending limb. BCL = 1000 msec.

Modified from Yan and Antzelevitch 244, with permission
Figure 15. Figure 15.

Contribution of transmural vs. apicobasal and anterior–posterior gradients to the registration of the T wave. The four ECG traces were simultaneously recorded at 0°, 45°, −45°, and 90° (apicobasal) angles relative to the transmural axis of an arterially perfused left ventricular wedge preparation. Inscription of the T wave is largely the result of voltage gradients along the transmural axis.

Modified from Yan and Antzelevitch 244 with permission
Figure 16. Figure 16.

Correlation of transmembrane and electrocardiographic activity. Transmembrane potentials and a transmural ECG recorded from two different arterially perfused canine left ventricular wedge preparations. A: Action potentials from epicardial (Epi), midmyocardial (M), and endocardial (Endo) sites were simultaneously recorded using floating glass microelectrodes. A transmural ECG was recorded concurrently across the bath. B: Action potentials from epicardium (Epi), midmyocardium (M), and subendocardial Purkinje were recorded simultaneously together with a transmural ECG. In both cases, repolarization of epicardium is coincident with the peak of the T wave of the ECG, whereas repolarization of the M‐cells is coincident with the end of the T wave. The endocardial APD is intermediate (A). Although repolarization of the Purkinje fiber occurs after that of the M‐cell (B), it does not register on the ECG. BCL = 2000 msec.

Modified from yan and Antzelevitch 244, with permission
Figure 17. Figure 17.

Transmembrane action potentials and transmural electrocardiograms (ECG) in control and LQT1 (A and B), LQT2 (C and D), and LQT3 (E and F) models of LQTS (arterially perfused canine left ventricular wedge preparations), and clinical ECG (lead V5) of patients with LQT1 (KvLQT1 defect) (G), LQT2 (HERG defect) (H), and LQT3 (SCN5A defect) (I) syndromes. Isoproterenol + chromanol 293B—an IKs blocker, d‐sotalol + low [K+]o, and ATX‐II—an agent that slows inactivation of late INa are used to mimic the LQT1, LQT2 and LQT3 syndromes, respectively. A–F depict action potentials simultaneously recorded from endocardial (Endo), M, and epicardial (Epi) sites, together with a transmural ECG. BCL = 2000 msec. In all cases, the peak of the T wave in the ECG is coincident with the repolarization of the epicardial action potential, whereas the end of the T wave is coincident with the repolarization of the M‐cell action potential. Repolarization of the endocardial cell is intermediate between that of the M‐cell and epicardial cell. Transmural dispersion of repolarization across the ventricular wall, defined as the difference in the repolarization time between M‐cells and epicardial cells, is denoted below the ECG traces. B: Isoproterenol (100 nM) in the presence of chromanol 293B (30 μM) produced a preferential prolongation of the APD of the M, resulting in an accentuated transmural dispersion of repolarization and broad‐based T waves as commonly seen in LQT1 patients (G). D: d‐Sotalol (100 μM) in the presence of low potassium (2 mM) gives rise to low‐amplitude T waves with a notched or bifurcated appearance due to a very significant slowing of repolarization as commonly seen in LQT2 patients (H). F: ATX‐II (20 nM) markedly prolongs the QT interval, widens the T wave, and causes a sharp rise in the dispersion of repolarization. ATX‐II also produced a marked delay in onset of the T wave due to relatively large effects of the drug on the APD of epicardium and endocardium, consistent with the late‐appearing T wave pattern observed in LQT3 patients (I).

Modified from Shimizu and Antzelevitch 182,183, with permission
Figure 18. Figure 18.

Spontaneous and stimulation‐induced polymorphic ventricular tachycardia with features of torsade de pointes (TdP). A: Stimulation‐induced TdP in a LV wedge preparation pretreated with dl‐sotalol (100 μmol/liter). S1‐S1 = 2000 msec; S1‐S2 = 250 msec. S2 was applied to epicardium. B: Spontaneous TdP in a preparation pretreated with dl‐sotalol (100 μmol/liter). BCL = 2000 msec. A spontaneous premature beat with a coupling interval of 348 msec, likely originating from subendocardial Purkinje system, initiates an episode of torsade de pointes.
Figure 19. Figure 19.

Proposed cellular mechanism for the development of torsade de pointes in the LQT1, 2, and 3 forms of the long QT syndrome.
Figure 20. Figure 20.

Similarities and differences in mechanisms responsible for the development of arrhythmias in the Brugada and long QT syndromes. Amplification of intrinsic heterogeneities underlies arrhythmogenicity in both syndromes. In the case of the Brugada syndrome, an increase in net outward current amplifies the heterogeneity normally present in the early phases of the action potential, leading to accentuation of the epicardial notch and finally loss of the action potential dome, resulting in marked abbreviation of the potential at some epicardial sites. In the case of the long QT syndrome, a decrease in net outward current amplifies the heterogeneity normally present in the late phases of the action potential, by producing a preferential prolongation of the M‐cell action potential.


Figure 1.

A: Action potentials recorded from myocytes isolated from the epicardial (Epi), endocardial (Endo), and M regions of the canine left ventricle. B:I‐V relations for IK1 in epicardial, endocardial, and M region myocytes. Values are mean ± S.D. C: Transient outward current (Ito) recorded from the three cell types (current traces recorded during depolarizing steps from a holding potential of −80 mV to test potentials ranging between −20 and +70 mV D: The average peak current–voltage relationship for Ito for each of the three cell types. Values are mean ± S.D. E: Voltage‐dependent activation of the slowly activating component of the delayed rectifier K+ current (IKs) (currents were elicited by the voltage pulse protocol shown in the inset; 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 mean ± S.E. * p <0.05 compared with Epi or Endo. G: Reverse‐mode sodium–calcium exchange currents recorded in potassium‐ and chloride‐free solutions at a voltage of −80 mV. INa‐Ca was maximally activated by switching to sodium‐free external solution at the time indicated by the arrow. H: Midmyocardial sodium–calcium exchanger density is 30% greater than endocardial density, calculated as the peak outward INa‐Ca normalized by cell capacitance. Endocardial and epicardial densities were not significantly different. I: TTX‐sensitive late sodium current. Cells were held at −80 mV and briefly pulsed to −45 mV to inactivate fast sodium current before stepping to −10 mV. J: Normalized late sodium current measured 300 msec into the test pulse was plotted as a function of test pulse potential.

From references 133,132,257, with permission. Modified from reference 257 with permission


Figure 2.

Transmembrane activity recorded from cells isolated from the epicardial, M, and endocardial regions of the canine left ventricle at basic cycle lengths (BCL) of 300 to 5000 msec (steady‐state conditions). The M‐cells and transitional cells were enzymatically dissociated from the midmyocardial region. Deceleration‐induced prolongation of APD in M‐cells is much greater than in epicardial and endocardial cells. The spike‐and‐dome morphology is also more accentuated in the epicardial cell.



Figure 3.

Transmural distribution of action potential duration and tissue resistivity in the intact ventricular wall. A: Schematic diagram of the arterially perfused canine LV wedge preparation. The wedge is perfused with Tyrode's solution via a small native branch of the left descending coronary artery and stimulated from the endocardial surface. Transmembrane action potentials are recorded simultaneously from epicardial (Epi), M region (M), and endocardial (Endo) sites using three floating microelectrodes. A transmural ECG is recorded along the same transmural axis across the bath, registering the entire field of the wedge. B: Histology of a transmural slice of the left ventricular wall near the epicardial border. The region of sharp transition of cell orientation coincides with the region of high tissue resistivity depicted in D and the region of sharp transition of action potential duration illustrated in C. C: Distribution of conduction time (CT), APD90, and repolarization time (RT = APD90 + CT) in a canine left ventricular wall wedge preparation paced at BCL of 2000 msec. A sharp transition of APD90 is present between epicardium and subepicardium. Epi: epicardium; M: M‐cell; Endo: endocardium; RT: repolarization time; CT: conduction time. D: Distribution of total tissue resistivity (Rt) across the canine left ventricular wall. Transmural distances at 0% and 100% represent epicardium and endocardium, respectively. * p <0.01 compared with Rt at midwall. Tissue resistivity increases most dramatically between deep subepicardium and epicardium. Error bars represent SEM (n = 5).

From Yan et al. 246, with permission


Figure 4.

Effect of d‐sotalol, a specific IKr blocker, on transmembrane activity recorded from epicardial (Epi), endocardial (Endo), and deep subepicardial (M‐cell) sites in a transmural strip of canine left ventricle. A: Each panel shows superimposed action potentials recorded at basic cycle lengths (BCL) of 300–5000 msec, before and after d‐sotalol (100 μM). B: APD‐rate relations.

From Sicouri et al. 198, with permission


Figure 5.

Effects of chronic amiodarone on the rate dependence of action potential characteristics in epicardial (Epi), M, and endocardial (Endo) tissues isolated from the hearts of untreated dogs (left) as well as those receiving chronic amiodarone therapy (right). A: Transmembrane activity recorded simultaneously from Epi, M, and Endo preparations at basic cycle lengths (BCL) of 500, 800, 2000, and 5000 msec (steady‐state conditions). B: Composite data from twelve untreated dogs and five amiodarone treated dogs. The graphs plot APD‐rate relations for Epi (open circles), Endo (closed circles), and M (open triangles) of untreated (left) and amiodarone‐treated animals (right). Each point represents mean ± S.D. * p<0.01 amiodarone vs. control. [K+]o = 4 mM. Chronic amiodarone treatment leads to much more uniform APD‐rate relations in the three cell types.



Figure 6.

Heterogeneous distribution of KCNE1 and KCNQ1 in canine ventricular myocardium. A: Transmural distribution of KCNE1 (filled columns) and KCNQ1 (hatched columns) mRNA as measured by competitive multiplex PCR. RNA was reverse transcribed using standard protocols and 2 μg of DNA from the epi‐, mid‐, and endocardium was amplified against known concentrations of an exogenous external standard (MIMIC). Data are from a pool of acutely dissociated cells from eight dogs. The concentration at which the amplitude of the two signals was equal was used to determine the amount of dsDNA presented. B: Same protocol as in A, with RNA isolated from the right (RV) and left (LV) ventricles. C: Western blot analysis of the distribution of KCNQ1 in canine right and left ventricles using polyclonal antibodies. Two bands are typically observed with a more intense signal in RV. 70 μg of protein was loaded in each well. D: Same experiment as in C with a KCNE1 antibody; the protein is more strongly expressed in LV.



Figure 7.

Age‐related spike‐and‐dome morphology and changes in Ito in canine ventricular epicardium. Each panel depicts transmembrane activity recorded from right ventricular epicardial tissues (upper trace) and transient outward current (lower trace) recorded from left ventricular epicardial cells isolated from a neonate (5 days of age; A), a young dog (3 months old; B), and an adult dog (C). BCL = 2000 msec; [K+]o = 4 mM. The spike‐and‐dome configuration of the epicardial action potential and Ito density are absent in the neonate, relatively small in the young dog, and most prominent in the adult.



Figure 8.

Phase 2 re‐entry. Re‐entrant activity induced by exposure of a canine ventricular epicardial preparation (0.7 cm2) to simulated ischemia. Microelectrode recordings were obtained from four sites as shown in the schematic (upper right). After 35 min of ischemia, the action potential dome develops normally at site 4, but not at sites 1, 2, or 3. The dome then propagates in a clockwise direction re‐exciting sites 3, 2, and 1 with progressive delays, thus generating a closely coupled re‐entrant extrasystole (156 msec) at site 1. In this example of phase 2 re‐entry, propagation of the dome occurs in a direction opposite that of phase 0, a mechanism akin to reflection. BCL = 700 msec.

Modified from Lukas and Antzelevitz 138, with permission


Figure 9.

Phase 2 re‐entrant extrasystole triggers circus movement re‐entry. A: Exposure of a relatively large canine right ventricular epicardial sheet (6.3 cm2) to simulated ischemia results in loss of the dome at sites 3 and 4 but not at sites 1 and 2 (BCL = 1100 msec). Conduction of the basic beat proceeds normally from the stimulation site (site 2; see schematic a). Propagation of the action potential dome from the right half of the preparation caused reexcitation of the left half via a phase 2 re‐entry mechanism (see schematic b). The extrasystolic beat generated by phase 2 re‐entry then initiates a run of tachycardia that is sustained for 4 additional cycles via typical circus movement re‐entry. The proposed re‐entrant path is shown in schematic c. Note that phase 2 re‐entry provides an activation front roughly perpendicular to that of the basic beat. This type of crossfield activation has previously been shown to predispose to the development of vortex‐like re‐entry in isolated epicardial sheets. B: Recorded after addition of 1 mM 4‐aminopyridine (4‐AP), an inhibitor of the transient outward current. In the continued presence of ischemia, 4‐AP restored the dome at all epicardial recording sites within 3 min. Thus electrical heterogeneity was restored and all re‐entrant activity abolished.

Modified from Lukas and Antzelevitz 138, with permission


Figure 10.

ECG and arrhythmias with typical features of the Brugada syndrome recorded from canine right ventricular wedge preparations A: Schematic of arterially perfused right ventricular wedge preparation. B: Pressure—induced phase 2 re‐entry and VT. Shown are transmembrane action potentials simultaneously recorded from two epicardial sites (Epi 1 and Epi 2) and one M region (M) site, together with a transmural ECG. Local application of pressure near Epi 2 results in loss of the action potential dome at that site but not at the Epi 1 or M sites. The dome at Epi 1 then re‐excites Epi 2, giving rise to a phase 2 re‐entrant extrasystole that triggers a short run of ventricular tachycardia. Note the ST segment elevation due to loss of the action potential dome in a segment of epicardium. C: Polymorphic VT/VF induced by local application of the potassium channel opener pinacidil (10 μM) to the epicardial surface of the wedge. Action potentials from two epicardial sites (Epi 1 and Epi 2) and a transmural ECG were simultaneously recorded. Loss of the dome at Epi 1 but not Epi 2 creates a marked dispersion of repolarization, giving rise to a phase 2 re‐entrant extrasystole. The extrasystolic beat then triggers a long episode of ventricular fibrillation (22 sec). Right panel: Addition of 4‐aminopyridine (4‐AP. 2 mM), a specific Ito blocker, to the perfusate restored the action potential dome at Epi 1, thus reducing dispersion of repolarization and suppressing all arrhythmic activity. BCL = 2000 msec. D: Phase 2 re‐entry gives rise to VT following addition of pinacidil (2.5 μM) to the coronary perfusate. Transmembrane action potentials form two epicardial sites (Epi 1 and Epi 2) and one endocardial site (Endo), as well as a transmural ECG were simultaneously recorded. Right panel: 4‐AP (1 mM) markedly reduces the magnitude of the action potential notch in epicardium, thus restoring the action potential dome throughout the preparation and abolishing all arrhythmic activity.

D is from Yan and Antzelevitch 245, with permission


Figure 11.

Proposed mechanism for the Brugada syndrome. A shift in the balance of currents serves to amplify existing heterogeneities by causing loss of the action potential dome at some epicardial sites, but not endocardial sites. A vulnerable window develops as a result of the dispersion of repolarization and refractoriness within epicardium as well as across the wall. Epicardial dispersion leads to the development of phase 2 re‐entry, which provides the extrasystole that captures the vulnerable window and initiates VT/VF via a circus movement re‐entry mechanism.



Figure 12.

Whole‐cell current for wild‐type (WT) and Brugada syndrome mutant (T1620M) in transiently transfected TSA201 cells at room temperature (22°C) and 32°C. A: The cartoon depicts the location of the missense mutations R1232W and T1620M previously described by Chen et al. 52. Current recordings obtained at different test potentials from −70 to −25 mV (32°C) and −65 to −20 (22°C) in increments of 5 mV from a holding potential of −120 mV for four representative cells. B: Current decay of T1620M at 32°C. Representative current recordings from WT and T1620M were elicited by a 20 msec depolarizing pulse to a test potential of 10 mV from a holding potential of −140 mV, normalized to the peak inward current and superimposed. C: WT decay time constant (square) is less sensitive to temperature in the physiological range. Cells were maintained at −80 mV and pulsed at 0 mV for 10 msec at temperatures between 22°C and 42°C. Current decay were fitted by a sum of two exponential functions. The fast time constant was plotted against the temperature (log scale) for WT and T1620M (filled circles). Each symbol represents a different cell.

Modified from Dumaine et al. 75, with permission


Figure 13.

Voltage gradients on either side of the M region are responsible for inscription of the electrocardiographic T wave. Top: Action potentials simultaneously recorded from endocardial, epicardial and M region sites of an arterially perfused canine left ventricular wedge preparation. Middle: ECG recorded across the wedge. Bottom: Computed voltage differences between the epicardium and M region action potentials (ΔVM‐Epi) and between the M region and endocardium responses (ΔVEndo‐M). If these traces are representative of the opposing voltage gradients on either side of the M region, responsible for inscription of the T wave, then the weighted sum of the two traces should yield a trace (middle trace in bottom grouping) resembling the ECG, which it does. The voltage gradients are weighted to account for differences in tissue resistivity between M and Epi and Endo and M regions, thus yielding the opposing currents flowing on either side of the M region. A: Under control conditions, the T wave begins when the plateau of epicardial action potential separates from that of the M‐cell. As epicardium repolarizes, the voltage gradient between epicardium and the M region continues to grow, giving rise to the ascending limb of the T wave. The voltage gradient between the M region and the epicardium (ΔVM‐Epi) reaches a peak when the epicardium is fully repolarized; this marks the peak of the T wave. On the other end of the ventricular wall, the endocardial plateau deviates from that of the M‐cell, generating an opposing voltage gradient (ΔVEndo‐M) and corresponding current that limits the amplitude of the T wave and contributes to the initial part of the descending limb of the T wave. The voltage gradient between the endocardium and the M region reaches a peak when the endocardium is fully repolarized. The gradient continues to decline as the M‐cells repolarize. All gradients are extinguished when the longest M cells are fully repolarized. B: d‐sotalol (100 μM) prolongs the action potential of the M‐cell more than those of the epicardial and endocardial cells, thus widening the T wave and prolonging the QT interval. The greater separation of epicardial and endocardial repolarization times also gives rise to a notch in the descending limb of the T wave. Once again, the T wave begins when the plateau of epicardial action potential diverges from that of the M‐cell. The same relationships as described for panel A are observed during the remainder of the T wave. The d‐sotalol–induced increase in dispersion of repolarization across the wall is accompanied by a corresponding increase in the Tpeak‐Tend interval in the pseudo‐ECG.

Modified from Yan and Antzelevitch 244, with permission


Figure 14.

Transient shift of voltage gradients on either side of the M region results in T wave bifurcation. The format is the same as in Figure 13. All traces were simultaneously recorded form an arterially perfused left ventricular wedge preparation. A: Control. B: In the presence of hypokalemia ([K+]o = 1.5 mM), the IKr blocker dl‐sotalol (100 μM) prolongs the QT interval and produces a bifurcation of the T wave, a morphology some authors refer to as T‐U complex. The rate of repolarization of phase 3 of the action potential is slowed, giving rise to smaller opposing transmural currents that cross over, producing a low‐amplitude bifid T wave. Initially the voltage gradient between the epicardium and M regions (M‐Epi) is greater than that between endocardium and M region (Endo‐M). When endocardium pulls away from the M cell, the opposing gradient (Endo‐M) increases, interrupting the ascending limb of the T wave. Predominance of the M‐Epi gradient is restored as the epicardial response continues to repolarize and the Epi‐M gradients increases, thus resuming the ascending limb of the T wave. Full repolarization of epicardium marks the peak of the T wave. Repolarization of both endocardium and the M region contribute importantly to the descending limb. BCL = 1000 msec.

Modified from Yan and Antzelevitch 244, with permission


Figure 15.

Contribution of transmural vs. apicobasal and anterior–posterior gradients to the registration of the T wave. The four ECG traces were simultaneously recorded at 0°, 45°, −45°, and 90° (apicobasal) angles relative to the transmural axis of an arterially perfused left ventricular wedge preparation. Inscription of the T wave is largely the result of voltage gradients along the transmural axis.

Modified from Yan and Antzelevitch 244 with permission


Figure 16.

Correlation of transmembrane and electrocardiographic activity. Transmembrane potentials and a transmural ECG recorded from two different arterially perfused canine left ventricular wedge preparations. A: Action potentials from epicardial (Epi), midmyocardial (M), and endocardial (Endo) sites were simultaneously recorded using floating glass microelectrodes. A transmural ECG was recorded concurrently across the bath. B: Action potentials from epicardium (Epi), midmyocardium (M), and subendocardial Purkinje were recorded simultaneously together with a transmural ECG. In both cases, repolarization of epicardium is coincident with the peak of the T wave of the ECG, whereas repolarization of the M‐cells is coincident with the end of the T wave. The endocardial APD is intermediate (A). Although repolarization of the Purkinje fiber occurs after that of the M‐cell (B), it does not register on the ECG. BCL = 2000 msec.

Modified from yan and Antzelevitch 244, with permission


Figure 17.

Transmembrane action potentials and transmural electrocardiograms (ECG) in control and LQT1 (A and B), LQT2 (C and D), and LQT3 (E and F) models of LQTS (arterially perfused canine left ventricular wedge preparations), and clinical ECG (lead V5) of patients with LQT1 (KvLQT1 defect) (G), LQT2 (HERG defect) (H), and LQT3 (SCN5A defect) (I) syndromes. Isoproterenol + chromanol 293B—an IKs blocker, d‐sotalol + low [K+]o, and ATX‐II—an agent that slows inactivation of late INa are used to mimic the LQT1, LQT2 and LQT3 syndromes, respectively. A–F depict action potentials simultaneously recorded from endocardial (Endo), M, and epicardial (Epi) sites, together with a transmural ECG. BCL = 2000 msec. In all cases, the peak of the T wave in the ECG is coincident with the repolarization of the epicardial action potential, whereas the end of the T wave is coincident with the repolarization of the M‐cell action potential. Repolarization of the endocardial cell is intermediate between that of the M‐cell and epicardial cell. Transmural dispersion of repolarization across the ventricular wall, defined as the difference in the repolarization time between M‐cells and epicardial cells, is denoted below the ECG traces. B: Isoproterenol (100 nM) in the presence of chromanol 293B (30 μM) produced a preferential prolongation of the APD of the M, resulting in an accentuated transmural dispersion of repolarization and broad‐based T waves as commonly seen in LQT1 patients (G). D: d‐Sotalol (100 μM) in the presence of low potassium (2 mM) gives rise to low‐amplitude T waves with a notched or bifurcated appearance due to a very significant slowing of repolarization as commonly seen in LQT2 patients (H). F: ATX‐II (20 nM) markedly prolongs the QT interval, widens the T wave, and causes a sharp rise in the dispersion of repolarization. ATX‐II also produced a marked delay in onset of the T wave due to relatively large effects of the drug on the APD of epicardium and endocardium, consistent with the late‐appearing T wave pattern observed in LQT3 patients (I).

Modified from Shimizu and Antzelevitch 182,183, with permission


Figure 18.

Spontaneous and stimulation‐induced polymorphic ventricular tachycardia with features of torsade de pointes (TdP). A: Stimulation‐induced TdP in a LV wedge preparation pretreated with dl‐sotalol (100 μmol/liter). S1‐S1 = 2000 msec; S1‐S2 = 250 msec. S2 was applied to epicardium. B: Spontaneous TdP in a preparation pretreated with dl‐sotalol (100 μmol/liter). BCL = 2000 msec. A spontaneous premature beat with a coupling interval of 348 msec, likely originating from subendocardial Purkinje system, initiates an episode of torsade de pointes.



Figure 19.

Proposed cellular mechanism for the development of torsade de pointes in the LQT1, 2, and 3 forms of the long QT syndrome.



Figure 20.

Similarities and differences in mechanisms responsible for the development of arrhythmias in the Brugada and long QT syndromes. Amplification of intrinsic heterogeneities underlies arrhythmogenicity in both syndromes. In the case of the Brugada syndrome, an increase in net outward current amplifies the heterogeneity normally present in the early phases of the action potential, leading to accentuation of the epicardial notch and finally loss of the action potential dome, resulting in marked abbreviation of the potential at some epicardial sites. In the case of the long QT syndrome, a decrease in net outward current amplifies the heterogeneity normally present in the late phases of the action potential, by producing a preferential prolongation of the M‐cell action potential.

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Article Title: Electrical Heterogeneity in the Heart: Physiological, Pharmacological and Clinical Implications
 

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Charles Antzelevitch, Robert Dumaine. Electrical Heterogeneity in the Heart: Physiological, Pharmacological and Clinical Implications. Compr Physiol 2011, Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart: 654-692. First published in print 2002. doi: 10.1002/cphy.cp020117