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David S Rosenbaum

Publications and source records attributed to David S Rosenbaum.

At least 19 recordsLinked to original sources
PubMed2006

Importance of spatiotemporal heterogeneity of cellular restitution in mechanism of arrhythmogenic discordant alternans.

BACKGROUND: Spatially discordant cellular alternans form a substrate for development of unidirectional block and ventricular fibrillation. However, the mechanisms responsible for discordant alternans remain poorly understood. Previous work suggests electrical restitution is critical to the development of alternans in single cells. OBJECTIVES: The purpose of this study was to investigate the hypothesis that spatial and temporal heterogeneities of restitution underlie the mechanism eliciting discordant alternans. METHODS: Steady-state pacing was used to elicit concordant cellular alternans in nine Langendorff-perfused guinea pig hearts. A single extrastimulus (S2) was applied every 51st beat following either the even or the odd beat of alternans. The cellular response to S2 was determined using optical mapping to generate action potential duration (APD) restitution curves from 256 ventricular sites for both the even and the odd beats. RESULTS: Restitution kinetics were temporally heterogeneous during alternans, as restitution curves between the even and the odd beats differed significantly. Temporal heterogeneity was quantified by the average separation of restitution between the two curves, or Delta-restitution. Delta-Restitution was spatially heterogeneous and proportional to the amount of alternans at a given ventricular site. A computer simulation based on the experimental results showed the mechanism of discordant alternans was dependent on both spatial and temporal heterogeneities of restitution. CONCLUSION: Both temporal and spatial heterogeneities of restitution exist during cellular alternans in the intact heart. Temporal heterogeneities of restitution, quantified by Delta-restitution, are proportional to the magnitude of cellular alternans. The combination of spatial and temporal heterogeneities of restitution may underlie the genesis of discordant alternans.

Action Potentials↗
PubMed2006

Cellular alternans: a mechanism linking calcium cycling proteins to cardiac arrhythmogenesis.

Essentially all previous research on alternans has been restricted to normal myocardium, whereas sudden cardiac death (SCD) occurs most commonly in patients with ventricular dysfunction (i.e., heart failure), which is associated with marked disruption of proteins responsible for normal calcium cycling in myocytes. Several lines of evidence from studies in normal hearts suggest a link between impaired calcium cycling which characterizes ventricular mechanical dysfunction and impaired calcium cycling that is responsible for alternans. In normal myocardium, cells which exhibit the slowest calcium cycling, and not the slowest repolarization, are most susceptible to alternans. Decreased expression of key calcium cycling proteins is observed in alternans-prone cells. Sarcoplasmic reticulum ATPase (SERCA2a) expression is decreased, suggesting a mechanism for the slower sarcoplasmic reticulum (SR) calcium reuptake observed in alternans-prone cells. In addition, diminished ryanodine receptor (RyR) function leading to abnormal calcium release from the SR is also linked to cellular alternans. Although impaired contractile function clearly predisposes to SCD, the mechanisms linking mechanical to electrophysiological dysfunction in the heart are unclear. We propose that cellular calcium alternans may be an important mechanism linking mechanical dysfunction to cardiac arrhythmogenesis.

Animals↗
PubMed2005

Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy.

OBJECTIVE: We studied a transgenic mouse model of human desmin-related cardiomyopathy with cardiac-specific expression of a 7-amino acid deletion mutation in desmin (D7-des) to test the hypothesis that impaired linkage between desmin and desmosomes alters expression and function of the electrical coupling protein, connexin43 (Cx43). METHODS: Expression of Cx43 and selected mechanical junctions proteins was characterized in left ventrices of D7-des and control mice by quantitative confocal microscopy and immunoblotting. Remodeling of gap junctions was also analyzed by electron microscopic morphometry. The electrophysiological phentoype of D7-des mice was characterized by electrocardiography and optical mapping of transmembrane voltage. RESULTS: Cx43 signal at intercalated disks was decreased by approximately 3-fold in D7-des ventricular tissue due to reductions in both gap junction number and size. Immunoreactive signal at cell-cell junctions was also reduced significantly for adhesion molecules and linker proteins of desmosomes and fascia adherens junctions. Electron microscopy showed decreased gap junction remodeling. However, immunoblotting showed that the total tissue content of Cx43 and mechanical junction proteins was not reduced, suggesting that diminished signal at cell-cell junctions was not due to insufficient protein expression, but to failure of these proteins to assemble properly within electrical and mechanical junctions. Remodeling of gap junctions in D7-des mice led to slowing of ventricular conduction as demonstrated by optical electrophysiological mapping. CONCLUSIONS: These results illustrate how a defect in a protein conventionally thought to fulfill a mechanical function in the heart can also lead to electrophysiological alterations that may contribute to arrhythmogenesis.

Animals↗
PubMed2005

Optical measurements reveal nature of intercellular coupling across ventricular wall.

Previously, we showed that intercellular uncoupling through gap junctions is an important mechanism for maintaining transmural heterogeneities of repolarization that are responsible for ventricular arrhythmias in disease states such as heart failure. However, rotational anisotropy between transmural muscle layers also may influence coupling. To determine the effect of rotational anisotropy on transmural coupling, we developed a numerical three-dimensional model of passive cardiac tissue in which rotational anisotropy was varied in a controlled fashion. Simulations of optical mapping demonstrated that spatial averaging produced a voltage decay in space best fit by a single decaying exponential compared with the theoretically predicted decay. As fiber orientation varied by 90 degrees with respect to the transmural surface, the effective transmural space constant (lambda(TM)) changed by only 0.31% in simulations. In contrast, reducing intercellular conductivity by 24% decreased lambda(TM) by 7.7%. In the canine wedge preparation (n = 5), lambda measured by optical mapping of the epicardial and subepicardial surface was similar transverse (lambda(TV) = 0.73 +/- 0.10 mm) and transmural (lambda(TM) = 0.70 +/- 0.08 mm) to subepicardial fibers. We confirmed previous findings that lambda(TM) in subepicardial layers was significantly reduced by 14 +/- 2% compared with deeper layers of myocardium, providing evidence for transmural uncoupling in the epicardial-midmyocardial interface. These data establish the theoretical and experimental basis for measuring intercellular coupling between muscle layers spanning the ventricular wall with optical mapping techniques. Furthermore, this study demonstrates that transmural uncoupling at the epicardial-midmyocardial interface may be attributable to heterogeneous expression of cardiac gap junctions and not rotational anisotropy.

Action Potentials↗
PubMed2005

IKs blockade reduces dispersion of repolarization in heart failure.

BACKGROUND: The slow and rapid (I(Kr)) components of I(K) are major determinants of ventricular repolarization. Unlike I(Kr), which is homogeneously expressed across the transmural wall, I(Ks) expression is reduced in midmyocardial cells and presumably contributes significantly to transmural dispersion of repolarization. Increased dispersion of repolarization during pharmacologic blockade of I(Kr) is proarrhythmic, primarily due to relatively selective prolongation of midmyocardial cell action potential duration (APD). The mechanisms underlying proarrhythmia in heart disease associated with impaired repolarization, such as heart failure, are unknown. We hypothesize that, in contrast to I(Kr) blockade, I(Ks) blockade will have little effect on midmyocardial cells and hence decrease dispersion of repolarization in heart failure. OBJECTIVES: The purpose of this study was to determine the effect of blockade of the slow component of the delayed rectifier current (I(Ks)) on arrhythmogenic dispersion of repolarization and proarrhythmia in heart failure. METHODS: Optical action potentials were simultaneously recorded from 256 sites spanning the transmural wall of the arterially perfused canine wedge preparation. Hearts from dogs with heart failure induced by rapid pacing (n = 6) were compared with normals (n = 6). RESULTS: Baseline dispersion of repolarization, as measured from the range of transmural APD during stimulation at a cycle length of 2,000 ms, was significantly higher in heart failure (75 +/- 24 ms) compared with controls (39 +/- 21 ms, P < .04). I(Ks) blockade with 30 microM chromanol decreased dispersion of repolarization by 40% (P < .02) in heart failure, reducing it to values found in normals. Decreased dispersion of repolarization was due to a larger, relatively selective, drug-induced APD prolongation of epicardial (23%) compared with midmyocardial cells (9%, P < .02). VT could not be induced in failing hearts under conditions of I(Ks) blockade, and no proarrhythmia was observed. CONCLUSION: I(Ks) blockade significantly reduced heart failure-induced dispersion of repolarization to values seen in nonfailing hearts. By prolonging repolarization without increasing dispersion of repolarization, I(Ks) blockade may have antiarrhythmic effects without creating proarrhythmia.

Action Potentials↗
PubMed2005

Molecular correlates of repolarization alternans in cardiac myocytes.

Arrhythmogenic action potential alternans (APD-ALT) is thought to arise from beat to beat alteration in cellular Ca(2+) cycling. Previously, we found that spatial heterogeneity in APD-ALT between ventricular myocytes is key to the mechanism linking APD-ALT to cardiac arrhythmogenesis. However, the cellular and molecular basis for APD-ALT is poorly understood. To test the hypothesis that spatial heterogeneities in expression and function of calcium cycling proteins underlies heterogeneities in APD-ALT, endocardial and epicardial myocytes were isolated from left ventricular free wall of 20 guinea pig hearts. APD-ALT and Ca(2+) transient alternans (Ca-ALT) were measured simultaneously as stimulus rate was increased progressively. Endocardial myocytes exhibited greater susceptibility to cellular alternans than epicardial myocytes as evidenced by a significantly lower pacing rate threshold for APD-ALT (113 +/ -9 bpm vs. 151 +/- 8 bpm, respectively, P < 0.05) and for Ca-ALT (110 +/- 8 bpm vs. 149 +/- 8 bpm, respectively, P < 0.05). APD-ALT never occurred without Ca-ALT, whereas Ca-ALT was readily induced in the absence of APD-ALT by repetitive constant action potential waveform, suggesting that Ca-ALT was not secondary to APD-ALT. Importantly, there were significant voltage-independent differences in Ca(2+) cycling between endocardial and epicardial myocytes as evidenced by weaker Ca(2+) release (32% lower Ca(2+) amplitude, and 16% longer rise time), and slower Ca(2+) reuptake (24% larger Ca(2+) decay time constant, and 9% longer Ca(2+) transient duration) in endocardial compared to epicardial myocytes. Taken together these data indicate that myocytes that are most susceptible to APD-ALT exhibit impaired Ca(2+) release and reuptake. Moreover, transmural differences in Ca(2+) cycling function was associated with significantly reduced endocardial expression of ryanodine release channel (by 22%) and SERCA2 (by 40%), suggesting a potential molecular basis for spatially heterogeneous APD-ALT. Moreover, transmural differences in expression and function of key SR Ca(2+) cycling proteins may underlie spatial heterogeneity of APD-ALT that has been closely linked to cardiac arrhythmogenesis.

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PubMed2005

Cellular mechanisms of Torsade de Pointes.

Torsade de Pointes (TdP) is a life-threatening arrhythmia closely linked to abnormal cardiac repolarization. It has been demonstrated that cardiac ion channel alterations underlying cellular repolarization results in the phenotypic expression of long QT syndrome, which is closely associated with TdP. However, the mechanisms by which prolonged repolarization leads to TdP remain controversial. Prolonged repolarization is associated with triggered activity, and multiple foci of triggered activity can underlie a TdP phenotype. Action potential shortening associated with rapid ventricular rhythms, in theory, removes conditions for triggered activity. Therefore, while triggered activity may initiate TdP, another mechanism may be responsible for the maintenance of TdP. Re-entrant arrhythmias can also give rise to a TdP phenotype. In intact myocardium significant inhomogeneities of repolarization are manifest in the presence of IKr blockade. Large repolarization gradients between subepicardial and midmyocardial cells formed zones of conduction block responsible for sustained reentrant TdP. Gap junction proteins responsible for intercellular coupling between subepicardial and midmyocardial cells are reduced in normal myocardium which may maintain arrhythmogenic gradients of repolarization. Therefore, the mechanism of TdP is multi-factorial and related to triggered activity and spatial inhomogeneities of ion channel expression combined with regional expression patterns of gap junctions.

Cation Transport Proteins↗
PubMed2005

[Transmural optical mapping of pause dependent torsade de pointes in canine long QT models].

OBJECTIVE: To investigate the mechanism of pause dependent torsade de pointes (TdP) in long QT (LQT) conditions. METHODS: Optical mapping was used to measure transmural action potentials from the arterially perfused left ventricular canine wedge preparation. D-sotalol and ATX-II were administered to mimic LQT 2 and LQT 3, respectively. RESULTS: In LQT models, the pause significantly enhanced M cell action potential (control group Steady state stimulation S1S1: (291 +/- 27) ms, after pause: (307 +/- 28) ms, P > 0.05; LQT 2 S1S1: (356 +/- 20) ms, after pause: (381 +/- 25) ms, P < 0.05; LQT 3 S1S1: (609 +/- 92) ms, after pause: (675 +/- 98) ms P < 0.05), dispersion of transmural repolarization (control group S1S1: (24 +/- 6) ms, after pause: (27 +/- 6) ms, P > 0.05; LQT 2 S1S1: (35 +/- 9) ms, after pause: (46 +/- 11) ms, P < 0.05; LQT 3 S1S1: (121 +/- 85) ms, after pause: (171 +/- 98) ms, P < 0.05) and the M cell island-like distribution more clearly compared to baseline pacing. Pause dependent early afterdepolarizations (EADs), EAD-induced triggered activity and TdP more likely occurred under LQT 3 condition (82%, P < 0.05). The triggered beat after pause often broke through at the margin of M cells island where the repolarization gradients was maximal. The unidirectional conduction block and slow conduction were observed vividly at this region. CONCLUSION: These data suggest that M cells island plays an important role in origination and maintenance of pause dependent TdP.

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PubMed2004

Altered connexin43 expression produces arrhythmia substrate in heart failure.

Recently, we found that repolarization heterogeneities between subepicardial and midmyocardial cells can form a substrate for reentrant ventricular arrhythmias in failing myocardium. We hypothesized that the mechanism responsible for maintaining transmural action potential duration heterogeneities in heart failure is related to intercellular uncoupling from downregulation of cardiac gap junction protein connexin43 (Cx43). With the use of the canine model of pacing-induced heart failure, left ventricles were sectioned to expose the transmural surface (n = 5). To determine whether heterogeneous Cx43 expression influenced electrophysiological function, high-resolution transmural optical mapping of the arterially perfused canine wedge preparation was used to measure conduction velocity (theta(TM)), effective transmural space constant (lambda(TM)), and transmural gradients of action potential duration (APD). Absolute Cx43 expression in failing myocardium, quantified by confocal immunofluorescence, was uniformly reduced (by 40 +/- 3%, P < 0.01) compared with control. Relative Cx43 expression was heterogeneously distributed and lower (by 32 +/- 18%, P < 0.05) in the subepicardium compared with deeper layers. Reduced Cx43 expression in heart failure was associated with significant reductions in intercellular coupling between transmural muscle layers, as evidenced by reduced theta(TM) (by 18.9 +/- 4.9%) and lambda(TM) (by 17.2 +/- 1.4%; P < 0.01) compared with control. Heterogeneous transmural distribution of Cx43 in failing myocardium was associated with lower subepicardial theta(TM) (by 12 +/- 10%) and lambda(TM) (by 13 +/- 7%), compared with deeper transmural layers (P < 0.05). APD dispersion was greatest in failing myocardium, and the largest transmural APD gradients were consistently found in regions exhibiting lowest relative Cx43 expression. These data demonstrate that reduced Cx43 expression produces uncoupling between transmural muscle layers leading to slowed conduction and marked dispersion of repolarization between epicardial and deeper myocardial layers. Therefore, Cx43 expression patterns can potentially contribute to an arrhythmic substrate in failing myocardium.

Action Potentials↗
PubMed2004

Role of calcium cycling versus restitution in the mechanism of repolarization alternans.

T-wave alternans, a powerful marker of arrhythmic events, results from alternation in action potential duration (APD). The underlying cellular mechanism of APD alternans is unknown but has been attributed to either intracellular calcium (Ca2+) cycling or membrane ionic currents, manifested by a steep slope of cellular APD restitution. To address these mechanisms, high-resolution optical mapping techniques were used to measure action potentials and Ca2+ transients simultaneously from hundreds of epicardial sites in the guinea pig model of pacing-induced T-wave alternans (n=7). The pacing rates (ie, alternans threshold) at which T-wave (369+/-11 bpm), APD (369+/-21 bpm), and Ca2+ (371+/-29 bpm) alternans first appeared were comparable. Importantly, the site of origin of APD alternans and Ca2+ alternans consistently occurred together near the base of the left ventricle, not where APD restitution was steepest. In addition, APD and Ca2+ alternans were remarkably similar both spatially and temporally during discordant alternans. In conclusion, the mechanism underlying T-wave alternans in the intact heart is more closely associated with intracellular Ca2+ cycling rather than APD restitution.

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PubMed2004

Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo.

OBJECTIVE: Mutations in the cardiac sodium channel gene SCN5A are responsible for type-3 long QT disease (LQT3). The genesis of cardiac arrhythmias in LQT3 is multifaceted, and the aim of this study was to further explore mechanisms by which SCN5A mutations lead to arrhythmogenesis in vivo. METHODS: We engineered selective cardiac expression of a long QT syndrome (LQTS) mutation (N1325S) in human SCN5A and generated a transgenic mouse model, TGM(NS31). RESULTS: Conscious and unrestrained TGM(NS31)L12 mice demonstrated a significant prolongation of the QT-interval and a high incidence of spontaneous polymorphic ventricular tachycardia (VT) and fibrillation (VF), often resulting in sudden cardiac death (n=52:156). Arrhythmias were suppressed by mexiletine, a sodium channel blocker for the late persistent sodium current. Action potentials (APs) from TGM(NS31)L12 ventricular myocytes exhibited early afterdepolarizations and longer 90% AP durations (APD90=69 +/- 5.9 ms) than control (APD90=46.7 +/- 4.8 ms). Voltage-clamp experiments in transgenic myocytes revealed a peak inward sodium current (INa) followed by a slow recovery from inactivation. After mexiletine application, transgenic ventricular APDs were shortened, and recovery from inactivation of INa was enhanced. These suggest that the N1325S transgene is responsible for the abnormal signals present in transgenic cells as well as the genesis of lethal arrhythmias in mice. Interestingly, transgenic but not wild-type myocytes displayed longer APDs with a shortening of CLs. CONCLUSIONS: Our findings show that a new model for LQTS has been established, and we report on an arrhythmogenic mechanism that, unlike other SCN5A mutations, results in poor restitution of APD with increasing rate as a possible substrate for arrhythmogenesis.

Action Potentials↗
PubMed2004

Targeted activation of c-Jun N-terminal kinase in vivo induces restrictive cardiomyopathy and conduction defects.

The stress-activated protein kinase, c-Jun N-terminal kinase (JNK), has been implicated in the process of cardiac hypertrophy and apoptosis, yet the specific roles of JNK in heart failure are unclear. To determine the effects of JNK activation in intact heart, we established transgenic animals using a Cre/loxP-mediated gene switch approach to achieve targeted expression of an upstream activator, mitogen-activated protein kinase kinase 7 (D) (MKK7D), in ventricular myocytes. MKK7D expression led to significant JNK activation, robust induction of the fetal gene program, and contractile dysfunction. The animals died approximately 7 weeks after birth with signs of congestive heart failure. Doppler mode echocardiography revealed a marked stiffening of JNK-activated hearts that was associated with the remodeling of specific extracellular matrix components. Gene expression analysis of MKK7D hearts revealed up-regulation of transforming growth factor beta signaling, offering a potential molecular mechanism underlying changes in extracellular matrix composition. In addition, we demonstrated that JNK activation led to specific loss of connexin 43 protein and gap junctions without affecting the expression or localization of other key intercalated disc proteins. This specific and localized gap junction remodeling resulted in significant slowing of ventricular electrical conduction in JNK-activated hearts. These results represent the first characterization of JNK-mediated cardiac pathology in vivo and support an important role for JNK signaling in specific aspects of cardiac remodeling in the pathogenesis of cardiac disease.

Animals↗
PubMed2004

Electrotonic load triggers remodeling of repolarizing current Ito in ventricle.

A change in activation sequence electrically remodels ventricular myocardium, causing persistent changes in repolarizing currents (T-wave memory). However, the underlying mechanism for triggering activation sequence-dependent remodeling is unknown. Optical action potentials were mapped with high resolution from the epicardial surface of the arterially perfused canine wedge preparation (n = 23) during 30 min of baseline endocardial stimulation, followed by 40 min of epicardial stimulation, and, finally, restoration of endocardial stimulation. Immediately after the change from endocardial to epicardial stimulation, phase 1 notch amplitude of epicardial cells was attenuated by 74 +/- 8% (P < 0.001) compared with baseline and continued to diminish during the period of epicardial pacing, suggesting progressive remodeling of the transient outward current (Ito). When endocardial pacing was restored, notch amplitude did not immediately recover but remained attenuated by 23 +/- 10% (P < 0.001), also consistent with a remodeling effect. Peak Ito current measured from isolated epicardial myocytes changed by 12 +/- 4% (P < 0.025), providing direct evidence for Ito remodeling occurring on a surprisingly short time scale. The mechanism for triggering remodeling of Ito was a significant reduction (by 14 +/- 4%, P < 0.001) of upstroke amplitude in epicardial cells during epicardial stimulation. Reduction in upstroke amplitude during epicardial pacing was explained by electrotonic load on epicardial cells by fully repolarized downstream endocardial cells. These data suggest a novel mechanism for triggering electrical remodeling in the ventricle. Electrotonic load imposed by a change in activation sequence reduces upstroke amplitude, which, in turn, attenuates Ito according to its known voltage-dependent properties, triggering downregulation of current.

Action Potentials↗
PubMed2004

Heterogeneous connexin43 expression produces electrophysiological heterogeneities across ventricular wall.

Recently we found that electrophysiological (EP) heterogeneities between subepicardial and midmyocardial cells can form a substrate for reentrant ventricular arrhythmias. However, cell-to-cell coupling through gap junctions is expected to attenuate transmural heterogeneities between cell types spanning the ventricular wall. Because connexin43 (Cx43) is the principal ventricular gap junction protein, we hypothesized that transmural EP heterogeneities are in part produced by heterogeneous Cx43 expression across the ventricular wall. The left ventricles of eight dogs were sectioned to expose the transmural surface. To determine whether heterogeneous Cx43 expression influenced EP function, high-resolution transmural optical mapping of the arterially perfused canine wedge preparation was used to measure transmural conduction velocity (thetaTM), dV/dt(max), transmural space constant (lambdaTM), and transmural gradients of action potential duration (APD). Relative Cx43 expression, quantified by confocal immunofluorescence, was significantly lower (by 24 +/- 17%; P < 0.05) in subepicardial compared with deeper layers. Importantly, reduced subepicardial Cx43 was associated with transmural heterogeneities of EP function evidenced by selectively reduced subepicardial thetaTM (by 18 +/- 9%; P < 0.05) compared with deeper layers. In subepicardial regions, dV/dt(max) was fastest (by 19 +/- 15%) and lambdaTM was smallest (by 18.1 +/- 2%), which suggests that conduction slowing was attributable to localized uncoupling rather than reduced excitability. The maximum transmural APD gradients occurred in the same regions where Cx43 expression was lowest; this suggests that Cx43 expression patterns served to maintain APD gradients across the transmural wall. These data demonstrate that heterogeneous Cx43 expression is closely associated with functionally significant EP heterogeneities across the transmural wall. Therefore, Cx43 expression patterns can potentially contribute to arrhythmic substrates that are dependent on transmural electrophysiological heterogeneities.

Action Potentials↗
PubMed2004

Nature, significance, and mechanisms of electrical heterogeneities in ventricle.

Previously, dispersion of repolarization (DOR) has been extensively linked to the development of arrhythmias and sudden cardiac death. The electrical heterogeneities that cause DOR between transmural myocyte layers have been reported in a wide variety of animals and humans. The underlying causes of transmural electrical heterogeneities are in part due to heterogeneous functional expression of proteins responsible for ion handling. Recently, we found that electrophysiologic heterogeneities between subepicardial and midmyocardial cells can form a substrate for reentrant ventricular arrhythmias. However, cell-to-cell coupling through gap junctions is expected to attenuate transmural heterogeneities between cell types spanning the ventricular wall. In this article we review a hypothesis that regional uncoupling resulting from expression patterns of gap junctions across the ventricular wall underlies DOR, and DOR can be amplified under disease conditions which remodel gap junctions. We find the principle gap junction protein, connexin43 (Cx43), is selectively reduced in the subepicardium (by 24%) compared to deeper layers of normal canine left ventricle. Additionally, the greatest DOR occurs within the subepicardial-midmyocardial interface, precisely where Cx43 expression is reduced. The present data suggests that ion channel and gap junction heterogeneities act in conjunction to form and maintain transmural DOR. Importantly, both ion channel and gap junction remodeling occurs during many disease states such as heart failure. Importantly, in the absence of ion channel remodeling, pharmacological uncoupling increases transmural DOR, particularly within the epicardial-midmyocardial interface, to values observed in heart failure. Therefore, these data suggest that heterogeneous Cx43 expression produces functionally significant electrophysiologic heterogeneities across the ventricular wall and may be a mechanism for promoting DOR which underlie arrhythmias in heart failure.

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