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Circulation Research. 2002;90:939-950
doi: 10.1161/01.RES.0000018627.89528.6F
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(Circulation Research. 2002;90:939.)
© 2002 American Heart Association, Inc.

Review

Differential Distribution of Cardiac Ion Channel Expression as a Basis for Regional Specialization in Electrical Function

Gernot Schram, Marc Pourrier, Peter Melnyk, Stanley Nattel

From the Departments of Medicine (G.S., M.P., S.N.), Biomedical-Sciences (G.S.), and Pharmacology (M.P.), University of Montreal, Research Center, Montreal Heart Institute, and the Department of Pathology (P.M.), McGill University, Montreal, Quebec, Canada.

Correspondence to Dr Stanley Nattel, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8. E-mail nattel{at}icm.umontreal.ca


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowOverview of Regional Functional...
 down arrowIonic and Molecular Basis...
 down arrowConclusions
 down arrowReferences
 
The cardiac electrical system is designed to ensure the appropriate rate and timing of contraction in all regions of the heart, which are essential for effective cardiac function. Well-controlled cardiac electrical activity depends on specialized properties of various components of the system, including the sinoatrial node, atria, atrioventricular node, His-Purkinje system, and ventricles. Cardiac electrical specialization was first recognized in the mid 1800s, but over the past 15 years, an enormous amount has been learned about how specialization is achieved by differential expression of cardiac ion channels. More recently, many aspects of the molecular basis have been revealed. Although the field is potentially vast, an appreciation of key elements is essential for any clinician or researcher wishing to understand modern cardiac electrophysiology. This article reviews the major regionally determined features of cardiac electrical function, discusses underlying ionic bases, and summarizes present knowledge of ion channel subunit distribution in relation to functional specialization.


Key Words: ion channels • molecular biology • conduction • cardiac arrhythmias • antiarrhythmic drugs


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowOverview of Regional Functional...
 down arrowIonic and Molecular Basis...
 down arrowConclusions
 down arrowReferences
 
Cardiac function depends on the appropriate timing of contraction in various regions, as well as on appropriate heart rate. To subserve these functions, electrical activity in each region is adapted to its specialized function. Regionally specialized cardiac electrical function was recognized in the mid 1800s, when Stannius1 demonstrated that ligatures in the superior vena caval sinus region of the frog caused cardiac asystole, with the sinus continuing to beat. With the widespread application to cardiac ion channel study of patch-clamp methodologies in the 1980s and molecular biology in the 1990s, many underlying mechanisms have been unraveled. The present article reviews the major regionally determined features of cardiac electrical function and the present knowledge regarding ionic and molecular bases.


*    Overview of Regional Functional Specificity
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Overview of Regional Functional...
down arrowIonic and Molecular Basis...
 down arrowConclusions
 down arrowReferences
 
Figure 1 illustrates typical regional action potential (AP) properties in the heart. The normal cardiac impulse originates in the sinoatrial node (SAN) and propagates through the atria to reach the atrioventricular node (AVN). From the AVN, electrical activity passes rapidly through the cable-like His-Purkinje system to reach the ventricles, triggering cardiac pumping action. Figure 2 shows the ionic currents involved in a schematic cardiac AP, provides standard abbreviations for currents and their corresponding subunits, and summarizes principal localization data discussed elsewhere in the present review.



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  		Figure 1. Schematic diagram of AP properties in different regions of the heart.



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  		Figure 2. Principal cardiac ion channel subunits, corresponding currents, and localization. Inset shows schematic diagram of cardiac AP and currents involved in different phases. Outward currents correspond to upward arrows; inward currents correspond to downward arrows.


*    Ionic and Molecular Basis of Functional Specificity
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowOverview of Regional Functional...
 *Ionic and Molecular Basis...
down arrowConclusions
 down arrowReferences
 
Sinoatrial Node
Cellular Electrophysiology and Function
The SAN, located in the right atrial (RA) roof between the venae cavae,2 is specialized for physiological pacemaker function. Heart rate control is achieved through autonomic regulation of SAN pacemaking. SAN APs have a relatively positive maximum diastolic potential (MDP) of {approx}-50 mV, a small phase 0 upstroke velocity ({image}max, <2 V/s),3 and prominent phase-4 depolarization maintaining SAN pacemaker dominance. The cell type changes from the typical nodal cell at the center of the SAN to the atrial cell toward the periphery.3 The longest AP durations (APDs) are in the central pacemaking zone, preventing invasion by ectopic impulses and preserving SAN dominance.4 The SAN contains both spider and spindle pacemaker cell types.5 Spider cells have a faster intrinsic rate, a less negative MDP, and a longer APD, suggesting they are primary pacemaking cells of the central node. Cholinergic and ß-adrenergic stimulation slow and accelerate spontaneous SAN activity, respectively. Electrical coupling to the atrium is designed to drive the large atrial muscle mass while insulating the SAN from hyperpolarizing atrial muscle influences.6 SAN dysfunction causes bradyarrhythmias that are associated with syncope but rarely with death.7

Ionic Mechanisms
Ionic properties underlying SAN function are indicated in Figure 3. Many varieties of time-dependent currents contribute to SAN pacemaking.8 A key time-dependent inward current, sometimes called the pacemaker current, is the nonselective cation current (If).9,10 If density is {approx}70% greater in spider than in spindle cells.5 Several other currents flowing between the time of MDP and the phase-0 take off, including L-type Ca2+ current (ICaL), T-type Ca2+ current (ICaT), and the delayed rectifier K+ current (IK), influence pacemaking activity: inward Ca2+ current activation and outward K+ current deactivation contribute to diastolic depolarization.8–10 ICaT is particularly large in the SAN. One study found SAN pacemaker cells to lack the background K+ current predominantly governing MDP (IK1) and the transient outward current (Ito).11 The lack of IK1 explains the positive MDP of SAN cells. A smaller rapid IK component (IKr) in central SAN cells compared with peripheral cells may contribute to their more positive MDP and longer APD.12 A smaller sustained Ito component may also contribute to longer APD in central SAN.13 ICaL underlies AP upstrokes in primary SAN pacemaking tissue.10,11 The Na+ current (INa) may contribute to subsidiary pacemaker activity in peripheral regions, providing a backup mechanism.14 A sustained inward component (Ist) related to ICaL may also contribute to SAN depolarization,11 but this remains controversial.15



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  		Figure 3. Characteristic AP properties of SAN cells. For each ionic property, the molecular basis believed to underlie ionic mechanisms is in italics and parentheses. APs are reproduced from Wu J, Schuessler RB, Rodefeld MD, Saffitz JE, Boineau JP. Morphological and membrane characteristics of spider and spindle cells isolated from rabbit sinus node. Am J Physiol. 2001;280:H1232–H1240, by permission of The American Physiological Society ©2001.

Autonomic regulation of If and ICaL controls heart rate. ß-Adrenergic stimulation positively shifts If activation voltage dependence, accelerating diastolic depolarization.9,16 Adrenergically induced increases in ICaL conductance also enhance SAN phase-4 terminal depolarization.9,10 Acetylcholine slows SAN activity by reducing If, activating the acetylcholine-sensitive K+ current (IKACh) and reducing ICaL.9 The potency of acetylcholine for If inhibition is greater than that for IKACh activation,17 which in turn is greater than that for ICaL inhibition.9 Ist is also autonomically regulated.18

Molecular Basis
Hyperpolarization-activated cation channel (HCN)1-HCN4 cDNAs encode If-like currents.19–22 HCN transcripts are 25 times more abundant in the SAN than in Purkinje cells (PCs) and {approx}140 times more abundant than in ventricular myocardium.20 HCN1 protein and message and HCN4 transcripts are abundant in rabbit SAN, whereas HCN2 protein expression is weak, and HCN3 mRNA is absent.19–21 In the mouse, SAN HCN4 transcripts are abundant, HCN2 levels are moderate, and HCN1 levels are low.22 HCN1 and HCN2 coassemble to form functionally distinct channels.23 The minK-related protein, MiRP1, increases the density and activation rate of If resulting from HCN expression.24 MiRP1 mRNA is highly expressed in rabbit SAN, likely contributing to SAN pacemaker function.24

Expression of Kir2.1, the predominant cardiac IK1 subunit, is very limited in ferret SAN, which is consistent with the virtual absence of IK1.25 IKACh is formed by complexes containing Kir3.1 and Kir3.4 subunits.26 Kir3.1 protein is present in rat, ferret, and guinea pig SAN.27 Kir3.1 and m2-receptor proteins colocalize.27 Kir3.4 protein is present in rat SAN.27

Four subunits are believed to contribute to IK: the ether-a-go-go–related (ERG) and MiRP1 subunits (thought to be {alpha} and ß subunits of IKr, respectively)28 and KvLQT1 and minK ({alpha} and ß subunits of IKs, respectively),29 although the role of MiRP1 remains controversial.30 MinK transcripts are more abundant in the SAN than in the atrium or ventricle.25 ERG protein and transcript are correlated with the presence of IKr in ferret31 and rabbit32 SAN.

Voltage-activated Ca2+ channel (Cav)3.1 and Cav3.2 encode ICaT {alpha} subunits.33,34 Cav3.1 mRNA expression is 30-fold greater in mouse SAN than in mouse atrium.35 Cav3.2 expression is lower than Cav3.1 expression, but it is also greater in the SAN.35 Cav1.2 and Cav1.3 are ICaL {alpha} subunits. Cav1.3 mRNA expression is low in mouse SAN and atrium, 35 but Cav1.3 knockout creates marked SAN dysfunction.36 Cav1.2 transcripts are more numerous and are more strongly expressed in the SAN than in the atrium.35 Subunits ß and {alpha}2{delta} modulate the density, kinetics, and activation/inactivation of ICaL.37 Little is known about their cardiac localization.

Gap-junctional hemichannel connexin (Cx) proteins are the basis of intercellular electrical coupling.38 The SAN is shielded against hyperpolarizing atrial influences by compartmentalization of Cx expression.6 Many studies report that Cx43, the major cardiac Cx, is absent in the central SAN.6,27,39,40 Cx43 has been detected in the SAN of rabbits,41 hamsters, 42 and dogs.43 Cx45 and Cx40 are expressed in the SAN of rabbit and human hearts.6,44 Cx46 is present in rabbit SAN.40 In canine SAN, 55% of the cells express Cx40 alone; 35% express Cx43, Cx45, and Cx40; and 10% show no Cxs.43 Cells expressing all 3 connexins are located in bundles abutting atrial tissue, whereas Cx40-expressing cells are located in the central SAN.43 Myocytes coexpressing Cx40, Cx43, and Cx45 extend from the SAN into the atrium, transmitting pacemaker impulses that drive the atrium.43,45

Atrium
Cellular Electrophysiology and Function
The MDP in multicellular atrial preparations is {approx}-80 mV.46,47 Isolated atrial-myocyte MDP averages {approx}-70 mV.48,49 Atrial APs have MDPs {approx}5 to 10 mV less negative than ventricular myocytes, exhibit slower phase-3 repolarization, and have little or no spontaneous phase-4 depolarization.

Spatial atrial AP/APD heterogeneity occurs within and between atrial regions50–53 and plays a role in atrial reentrant arrhythmias.53 RA APD decreases progressively from the crista terminalis to the pectinate muscles,51 helping to "stream" the impulses from the SAN toward the AVN.54 Rapid conduction follows fiber orientation in thicker bundles.55 The APD and effective refractory period (ERP) are shorter in the left atrial (LA) free wall than in the RA.49 In guinea pigs, cells from LA sleeves around proximal pulmonary veins have APs similar to those in atrial myocytes, whereas more distally located cells have less negative MDP, shorter APD, and slow pacemaker activity.56

Animal models57–59 and clinical studies60 suggest an important role of the LA in atrial fibrillation. This may partly be due to accelerated LA repolarization, 49 which shortens ERPs, favoring reentry.61 LA pulmonary vein activity also triggers atrial fibrillation.62 In guinea pigs, pulmonary vein cells generate atrial tachycardias that are due to digitalis-induced triggered activity.63 Parasympathetic stimulation shortens atrial APD in a spatially heterogeneous fashion,64 producing important profibrillatory effects.65

Ionic Mechanisms
The ionic mechanisms of atrial cell APs are summarized in Figure 4. If is present in atrial myocytes.66,67 A role for If in atrial ectopy has been suggested,66 but atrial If function has been questioned because of limited activation at atrial MDP.67 Atrial cells have large inward INa,68 providing energy for rapid conduction.



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  		Figure 4. Basis of atrial cell AP properties. APs are reproduced from Spach MS, Dolber PC, Anderson PA. Multiple regional differences in cellular properties that regulate repolarization and contraction in the right atrium of adult and newborn dogs. Circ Res. 1989;65:1594–1611, by permission of the American Heart Association ©1989.

Atrial IK1 is 6- to 10-fold smaller than ventricular IK1,69,70 explaining the less negative atrial MDP and slower phase-3 repolarization. Ultrarapid delayed rectifier current (IKur), activating two orders of magnitude faster than IKr, has been described in rat,71 mouse,72 human,73 and canine74 atria. In humans and dogs, IKur is present in atria but not in ventricles.75,76 Atrial IK includes both IKr and the slow component, IKs.77–79 Unlike normal ventricular myocytes, in which ICaT is lacking in the absence of cardiac hypertrophy,80 ICaT is readily detectable in atrial myocytes48 and may be important in atrial tachycardia–induced ionic remodeling.81 Atrial tachyarrhythmias and heart failure produce discrete atrial ionic remodeling,48,82,83 which is important in arrhythmogenesis.61 A recent study suggests that atrial tachycardia causes ionic remodeling and afterdepolarizations in pulmonary vein myocytes.84 A number of discrepancies make that study difficult to interpret; these discrepancies include an IK1 reversal potential of -40 mV in cells with a resting potential of -65 mV, the simultaneous measurement of inward and outward currents with similar kinetics at the same test potentials with no attempt to isolate components, and the generation of 25-mV delayed afterdepolarizations by transient inward currents <10 pA.

Myocytes from different RA regions show discrete ionic current distributions that explain their AP properties.52 LA free-wall myocytes have larger IKr compared with RA, accounting for their shorter APDs and ERPs.49 IKACh density is {approx}6 times greater in the atrium than in the ventricle.85

Molecular Basis
HCN2 and HCN4 are expressed in the atrium.86 HCN4 message levels are much lower in the atrium than in the SAN.21

Kir2.1 is the most abundant Kir2-family (IK1) subunit mRNA in the atrium and ventricle and is equally expressed in each.70 Kir2.3 transcripts are more concentrated in human atrium than ventricle, and Kir2.2 transcripts are equal and sparse in both.70 Kir2-subunit mRNA expression does not account for atrioventricular IK1 differences. Kir2.1 protein expression is {approx}80% greater in the ventricle than in the atrium, whereas Kir2.3 protein expression is 228% greater in the atrium.87 Kir2.3 protein localizes to transverse tubules of most atrial but few ventricular cells, whereas the converse is true of Kir2.1.87 The role of these atrioventricular differences in Kir2 protein expression in the much weaker atrial IK1 is uncertain.

Kir3.1 mRNAs are expressed strongly in rat atria but not ventricles, 88,89 and Kir3.1 and Kir3.4 proteins are abundant in the atrium and sparse in the ventricle,27 consistent with predominantly atrial IKACh expression.85 Recent work suggests that homomeric Kir3.4 channels may also contribute to atrial IKACh.90,91

The principal subunits thought to encode Ito include Kv1.4, Kv4.2, and Kv4.3.92 Kv4.2 contributes to rat atrial Ito, 93 localizing to the sarcolemma and T tubules.94 Kv1.4 transcript expression is stronger in rat atrium than ventricle,95 but Kv1.4 protein is almost undetectable in both.96 In rabbit atrium, Kv1.4 is a major contributor to Ito, whereas in human atrium, Ito is encoded entirely by Kv4.3.97

The molecular basis of atrial IKur varies widely among species.98 Kv1.2 and Kv1.5 contribute to rat atrial IKur.93 Human atrial IKur is encoded by Kv1.5, with no corresponding component in the ventricle.99 Kv3.1 is the molecular basis of canine atrial IKur, and like the corresponding current, it is absent in the ventricle.76

KvLQT1 transcripts are abundant in ferret RA.100 MinK is less abundant in the atrium than in the SAN.100 ERG mRNA is abundantly expressed in the atrium, as is the longer (ERG1a) variant, with larger expression in the ventricle versus atrium in humans and larger expression in the atrium versus ventricle in rats.101

ERG protein levels in dogs are larger in the LA than in the RA, consistent with a larger LA IKr.49 No information is available about the molecular basis of intra-atrial regional differences in Ito and ICaL.52 Cardiomyocytes in pulmonary veins contain Kir2.1 subunits and show IK1-like currents,102 but otherwise, little is known about their molecular electrophysiology.

Cav3.1 and Cav3.2 transcripts are found in mouse atrium,35 consistent with the atrial presence of ICaT.48 Cav1.2 transcripts are abundant in the atria, and their downregulation is believed to be central to atrial electrical remodeling.103,104 The Na+ channel {alpha} subunit, Nav1.5, is abundantly expressed in atrial myocytes, on the atrial surface, and in T-tubular membranes and intercalated disks, consistent with large INa.105

Cx43 protein is present on bovine, guinea pig, and human atrial myocytes,106–108 with a distinct transitional zone containing interdigitating Cx43-expressing atrial and Cx43-lacking nodal cells at the periphery of the SAN.45,106,108 Canine and rabbit RA gap junctions contain mainly Cx40 and Cx43 and less Cx45.39,109 Cx40 expression in the atrium is much stronger than in the ventricle (where it is virtually undetectable) in humans, rabbits, guinea pigs, and mice.107,109–111 Cx40 is more abundant in human RA than LA.107

Atrioventricular Node
Cellular Electrophysiology and Function
The primary function of the AVN is to govern the ventricular response to supraventricular activation. AVN cells have low excitability and postrepolarization refractoriness,112 which limit the maximum number of impulses that can traverse to the ventricles113 and prevent dangerously rapid ventricular rates in response to supraventricular tachyarrhythmias.

The AVN has a complex 3D structure. APs from intact AVN have slow upstrokes and small amplitudes.114 Within the compact AVN, MDPs are {approx}-64 mV, phase-4 depolarization results in takeoff potentials of {approx}-60 mV, and {image}max is <20 V/s.115 Cell types include N cells in the compact node and NH cells at the junction with the His bundle.115 A modern classification divides the AVN into a transitional cell area, compact node, posterior nodal extension, and lower nodal cell bundle.116

Ovoid and rod-shaped cells have been isolated from the compact AVN.117 Ovoid cells have N- or NH-like APs showing postrepolarization refractoriness and no AP abbreviation with increased frequency, less negative MDPs, faster diastolic-depolarization, and smaller {image}max than those in rod-shaped cells. Rod-shaped cells display APs intermediate between typical AVN and atrial cells (AN type).117 AVN cells have pacemaking activity,117,118 particularly in the midnodal and lower nodal regions.119 Spontaneous activity in AN cells is suppressed by atrial electrotonic influences.120

AV node reentrant arrhythmias were classically related to the presence of dissociable AVN pathways,121 which are typically manifested clinically as a faster conducting pathway with a longer refractory period and a slower conducting pathway with more brief refractoriness.122 Although the detailed physiology is not completely clear, there is evidence that the posterior nodal extension may form the slow pathway substrate.116

Ionic Mechanisms
The ionic basis of AVN properties is illustrated in Figure 5. If is present in 95% of ovoid cells versus {approx}10% of rod-shaped cells, and If density is {approx}25-fold larger in ovoid cells, which is consistent with the much greater ovoid cell pacemaker activity.117 INa and Ito are present in few ovoid cells but in almost all rod-shaped cells.117 ICaL underlies the compact AVN AP upstroke.123 4-Aminopyridine inhibits spontaneous AVN APs, which is consistent with a role for Ito in AVN pacemaking.124 Ito elimination in transgenic mice causes atrioventricular block.125



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  		Figure 5. Basis of AVN cell AP properties. AP is reproduced from Munk AA, Adjemian RA, Zhao J, Ogbaghebriel A, Shrier A. Electrophysiological properties of morphologically distinct cells isolated from the rabbit atrioventricular node. J Physiol. 1996;493:801–818, by permission of The Physiological Society ©1996.

IK deactivates faster in AVN than in ventricular myocytes.126 Contrary to the SAN, where both IKr and IKs are important, IKr predominates in the AVN.127 IKr activation contributes to AVN repolarization and deactivation to diastolic depolarization.123 There is little IK1 in the AVN,123 consistent with its positive MDP.

Molecular Basis
Data regarding ion channel subunit distribution in the AVN are limited. As opposed to transitional or lower nodal cells, midnodal cells of the rabbit AVN display little or no Na+ channel {alpha} subunit or Cx43 protein.128 Cx43 expression is sparse or absent in the AVN.129–132 Low-level Cx43 expression colocalizes with Cx40 in the rat.132 Targeted disruption of Cx40-subunit expression impairs atrioventricular conduction in the mouse,133–135 although much of the delay is attributable to slowing in the ventricular conduction system.136 Cx45 is strongly expressed in the rodent AVN and conducting system.137

His-Purkinje System
Cellular Electrophysiology and Function
PCs forming the bundles of His and the Purkinje system are specialized for rapid conduction. PC MDP is 5 to 10 mV more negative (averaging {approx}-90 mV) than is working ventricular MDP.138,139 {image}max is also greater in PCs ({approx}400 to 800 V/s) than in the ventricle (150 to 300 V/s), and the PC plateau voltage is lower.138,139 APD is more prolonged in PCs than in ventricular muscle at slow rates.140,141 PCs show prominent phase-4 depolarization, providing ventricular escape pacemakers.142 PCs preferentially generate drug-induced early afterdepolarizations that excite adjacent ventricular muscle,141 likely explaining endocardial early afterdepolarizations that trigger torsade de pointes arrhythmias.143,144

Ionic Mechanisms
Multicellular Purkinje fiber preparations were used for classic voltage-clamp studies because of favorable geometry; however, because of the difficulty of isolating PCs, much less work has been done recently. Ionic bases for PC AP properties are illustrated in Figure 6. Both ICaL and ICaT are present in PCs, with ICaT being quite substantial.145,146 PCs have a smaller ICaL than ventricular myocytes, consistent with their less positive plateau.147 ICaT inhibition does not affect Purkinje fiber automaticity, suggesting that ICaT may not be important for PC pacemaking.148



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  		Figure 6. Basis of PC AP properties. AP is adapted from Callewaert G, Carmeliet E, Vereecke J. Single cardiac Purkinje cells: general electrophysiology and voltage-clamp analysis of the pace-maker current. J Physiol. 1984;349:643–661, by permission of The Physiological Society ©1984.

Two studies showed smaller IK1 in PCs than in ventricular muscle,147,149 whereas one study showed no significant differences.150 Ito in human150 and canine151 PCs displays striking differences compared with ventricular myocytes, including sensitivity to 10 mmol/L tetraethylammonium, {approx}9-fold greater sensitivity to 4-aminopyridine, and slower reactivation. PC IK resembles ventricular and atrial IK.152 If is observed in human PCs, consistent with their pacemaker activity.150 Slowly inactivating INa may contribute to maintaining PC APD, especially at slow rates.153 Downregulation of Ito and IK1 in PCs of dogs with congestive heart failure enhances their sensitivity to IKr blocker–induced APD prolongation, possibly explaining the increased risk of drug-induced long-QT syndrome in patients with congestive heart failure.154

Molecular Basis
HCN1 and HCN4 transcripts are expressed in rat and rabbit Purkinje fibers.20 HCN expression in PCs is lower than that in the SAN but higher than that in ventricles.20

Canine Purkinje fibers do not significantly express Kv4.2 or Kv1.4 mRNA, and Kv4.3 mRNA levels in PCs are similar to those in the midmyocardium.155 K+ channel interacting protein (KChIP)2 mRNA is denser in myocardium than in PCs, whereas Kv3.4 is more concentrated in PCs, 155 compatible with their tetraethylammonium-sensitive Ito.152 ERG and KvLQT1 mRNA levels are lower in PCs,155 suggesting that smaller IK may contribute to their longer APD. Cav1.2 mRNA levels are lower in PCs,155 consistent with their smaller ICaL.147 Cav3.1, Cav3.2, and Cav3.3 expression is much greater in PCs than in the ventricle,155 compatible with their large ICaT.145,146

Cx40 mRNA is 3 to 5 times more abundant in PCs than in the ventricle.39,44,156 Cx40 colocalizes with Cx43 in the rat cardiac conducting system.132 Cx45 in mouse and rat hearts is found only in the His-Purkinje system.157 The extensive expression of Cx in Purkinje tissue may be crucial for very rapid conduction.

Ventricular Muscle
Cellular Electrophysiology and Function
MDPs of ventricular myocytes are {approx}-85 mV.138,139,158 The plateau is relatively positive, at {approx}10 to 20 mV, and phase-3 repolarization is rapid. As in working atrial muscle, there is no significant phase-4 depolarization or automaticity.

Regional ventricular AP heterogeneity is well established. Compared with endocardium, epicardial APs show a smaller overshoot, a more prominent phase 1 followed by a notch (spike and dome), and a briefer APD, but MDP and {image}max are not significantly different.159 Epicardial-endocardial AP differences are crucial for the ECG T wave.159 Midmyocardial cells (M cells) are a cell population in the deep subepicardium.160,161 Like PC APDs, M-cell APDs increase substantially at slow rates and have a larger {image}max ({approx}300 V/s) than do endocardial and epicardial cells ({approx}200 V/s).160 M-cell APs in the right ventricle (RV) compared with the left ventricle (LV) have a smaller upstroke, a deeper notch, and a shorter duration.162 In the rat, APD is shortest at the apex and longest in the septum, with intermediate values in the free wall.163 Transmural ERP heterogeneity caused by differential M-cell APD prolongation may contribute to torsade de pointes by promoting transmural reentry,164 particularly in the presence of hypokalemia, slow heart rates, and APD-prolonging drugs.165

Ionic Mechanisms
The information available about the ionic bases of transmural AP heterogeneity in the ventricles is summarized in Figure 7. Ito differences between epicardium and endocardium were originally inferred from phase-1 repolarization properties.159 Ito is larger in epicardium than endocardium for dogs, cats, rabbits, and humans.166–169 In guinea pigs, IKr and IKs are smaller in endocardial cells than in epicardial or M cells.170 In cats and guinea pigs, IK is larger in the epicardium,171,172 with IKr responsible for the difference in guinea pigs.172 The outward component of IK1 is smaller in cat epicardium171 but not guinea pig172 or dog173 epicardium.



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  		Figure 7. AP properties of ventricular epicardium, midmyocardium, and endocardium. APs are reproduced from Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle: the M cell. Circ Res. 1991;68:1729–1741, by permission of the American Heart Association ©1991.

M-cell properties are not attributable to differences in IK1 or Ito.174 Smaller IKs in M cells contributes to their longer APD.173,175 M cells also have a larger late INa than do epicardial or endocardial cells in dogs176 but not in guinea pigs.172 RV M-cell APDs are shorter than LV M-cell APDs, possibly because of larger Ito and/or IKs in the RV.162 A smaller IKs in LV apical versus basal myocytes may underlie longer apical APD, although IKr appears larger at the apex.177 Regional differences in outward IK1178 and in IKr179 may be a significant determinant of VF.

Molecular Basis
HCN2 is the only isoform in rabbit ventricle, and its mRNA expression is minimal.20 HCN4 mRNA has been detected in rat ventricle.20 HCN2 and HCN4 have been detected in human ventricle but have not been quantified.180 HCN1 and HCN3 were not detected in the ventricle.19,21 Low-level HCN expression in the ventricle is consistent with its lack of automaticity.

Kir2.1 is by far the most abundant Kir transcript in the human heart.70 Antisense experiments and studies in Kir2.1 and Kir2.2 knockout mice indicate that Kir2.1 subunits are the major, but not only, component of IK1.181,182

Ito in rat ventricle is thought to be encoded predominantly by Kv4.2 and Kv4.3.96,183–185 Kv4.2 mRNA expression in the rat LV wall is correlated with the gradient in Ito density.95 In ferret ventricle, the transmural Ito gradient is due to stronger endocardial expression of Kv1.4 versus epicardial predominance of Kv4.2 and Kv4.3.186 Kv4.3 underlies Ito in dog and human hearts.187,188 Kv4.2 mRNA is not detectable in canine187 or human189 ventricle. Kv4.2 is thought to encode the fast component and Kv1.4 is thought to encode the slow component of Ito in rodents.190 Kv4.1 mRNA expression is very low, suggesting little importance for native cardiac Ito.95

KChIP2 substantially increases functional expression and modifies inactivation of Kv4 subunits.191 KChIP2 expression is greater in the epicardium than in the endocardium, consistent with the transmural Ito gradient, whereas Kv4.3 is uniformly expressed across the wall.192 KChIP2 knockout virtually eliminates Ito.193 KChAP may be a chaperone for Kv channels that form Ito.194

Kv1.5 has been observed at the intercalated disk of human ventricular and atrial myocytes, but longitudinal membrane staining is seen only in the atrium,195 perhaps accounting for atrium-specific expression of the corresponding current.75,99 Rat Kv2.1 is more abundant in the ventricle than in the atrium.95 Kv2.1 may encode rat ventricular IKur, but there is poor correlation between Kv2.1 expression and IKur density in rat ventricle.196

Human minK mRNA levels are not significantly different among epicardial, midmyocardial, and endocardial tissues.197 However, a dominant negative KvLQT1 splice variant (isoform 2) is more strongly expressed in the midmyocardium, potentially accounting for lower IKs in M cells.197 In the ferret, ERG protein expression is stronger in the epicardium.31 ERG mRNA is 1.5-fold more abundant than Kv4.3 in canine RV and is the most prevalent K+ channel species in the heart,32 consistent with its prominent role in repolarization. MiRP1 is expressed sparsely in rabbit ventricle.24 Along with recent studies showing limited effects of MiRP1 coexpression on ERG currents,30 this observation raises questions about the role of MiRP1 in ventricular IKr.

Cav1.2 and ICaL ß and {alpha}2/{delta} subunits are present in the human septum and LV.198 Nav1.1 and ß1 and ß2 subunits are expressed along the Z lines in adult rat cardiac myocytes.199 ß1 subunits modulate INa, but ß2-subunit function may be limited to cell adhesion.199 As in the atrium, in the ventricles, Nav1.5 is the principal Na+ channel {alpha} subunit found on membranes and the T-tubular system and at the intercalated disk region.105

Cx43 is the predominant Cx in the ventricles.107,111,156 Heterozygous knockout of Cx43 slowed ventricular conduction in adult mice, with minimal effects on the atrium, as reported in one study,111 but did not affect conduction in mouse embryos in another.200 Homozygote Cx43 knockouts had severe impairment of ventricular conduction, consistent with a critical role in ventricular conduction that can be compensated in the heterozygote.200


*    Conclusions
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowOverview of Regional Functional...
 up arrowIonic and Molecular Basis...
 *Conclusions
down arrowReferences
 
A tremendous amount has been learned over the last 10 to 15 years regarding the ionic and molecular basis of cardiac regional electrical specialization. Nevertheless, many aspects remain unexplained. The molecular biology of ion channel expression in the AVN and Purkinje fibers remains largely unexplored. The basis of intra-atrial and intraventricular regional variations in ion channel function remains poorly understood, and the distribution of ion channel subunits in specific cellular subtypes in complex regions such as the SAN and AVN remains largely unknown. Species differences in ion channel distribution are incompletely understood and complicate extrapolations of experimental findings to humans. The effects of disease states on regional ion channel function are virtually unknown. Targeted modulation of regional ion channel function by genetic engineering approaches may open up entirely new therapeutic vistas, and its feasibility has been demonstrated.201


*    Acknowledgments
 
This work was supported by the Canadian Institutes of Health Research and Quebec Heart and Stroke Foundation. The authors thank Nadine Vespoli for excellent secretarial help.

Received January 7, 2002; revision received April 8, 2002; accepted April 8, 2002.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowOverview of Regional Functional...
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 up arrowConclusions
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