Published online before print November 4, 2004, doi: 10.1161/01.RES.0000150055.06226.4e
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Integrative Physiology |
Proarrhythmic Consequences of a KCNQ1 AKAP-Binding Domain Mutation
Computational Models of Whole Cells and Heterogeneous Tissue
From the Department of Bioengineering (J.J.S., S.N.H., M.E.B., A.D.M), Whitaker Institute of Biomedical Engineering, University of California San Diego, La Jolla; and the Department of Physiology (J.L.P.), Loyola University Chicago, Maywood, Ill.
Correspondence to Andrew D. McCulloch, Department of Bioengineering, University of California, San Diego, La Jolla, CA 92037-0412. E-mail amcculloch{at}ucsd.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The KCNQ1-G589D gene mutation, associated with a long-QT syndrome, has been shown to disrupt yotiao-mediated targeting of protein kinase A and protein phosphatase-1 to the IKs channel. To investigate how this defect may lead to ventricular arrhythmia during sympathetic stimulation, we use integrative computational models of ß-adrenergic signaling, myocyte excitation-contraction coupling, and action potential propagation in a rabbit ventricular wedge. Paradoxically, we find that the KCNQ1-G589D mutation alone does not prolong the QT interval. But when coupled with ß-adrenergic stimulation in a whole-cell model, the KCNQ1-G589D mutation induced QT prolongation and transient afterdepolarizations, known cellular mechanisms for arrhythmogenesis. These cellular mechanisms amplified tissue heterogeneities in a three-dimensional rabbit ventricular wedge model, elevating transmural dispersion of repolarization and creating other T-wave abnormalities on simulated electrocardiograms. Increasing heart rate protected both single myocyte and the coupled myocardium models from arrhythmic consequences. These findings suggest that the KCNQ1-G589D mutation disrupts a critical link between ß-adrenergic signaling and myocyte electrophysiology, creating both triggers of cardiac arrhythmia and a myocardial substrate vulnerable to such electrical disturbances.
Key Words: ß-adrenergic signaling • arrhythmia • long-QT syndrome • computational model
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Long QT syndrome (LQTS) is a cardiac disorder in which the QT interval on the electrocardiogram (ECG) is prolonged. Patients with mutations in KCNQ1, which encodes the
subunit of IKs, develop an LQTS (LQT1) particularly susceptible to sudden cardiac death during sympathetic stimulation.1 Whereas healthy individuals have shortened or unchanged QT intervals with exercise or stress, QT intervals in LQT1 patients prolong further,2 suggesting a problem at the interface of the sympathetic nervous system and electrophysiology. Motivated to examine the molecular mechanisms at this interface, Kass and colleagues discovered a signaling complex of KCNQ1, protein kinase A (PKA), and protein phosphatase-1 (PP1) mediated by the A-kinase anchoring protein (AKAP) yotiao.3 LQT1-associated mutation KCNQ1-G589D disrupted the signaling complex, preventing ß-adrenergic regulation of IKs.3 This suggests the possibility that the KCNQ1-G589D mutation, present in 508 of 939 established Finnish LQTS patients4 and associated with exercise-induced arrhythmias,5 may cause an unusual LQTS in which the primary defect occurs in autonomic regulation rather than channel gating per se.
These findings raise a number of integrative questions for which whole-cell and multicellular models are not yet available. What are the cellular mechanisms by which the G589D mutation alters sympathetic response of the myocyte action potential6? Does the mutation prolong the baseline action potential duration (APD) or prevent appropriate rate-dependent APD shortening7? Could this mutation induce trigger events for arrhythmia (eg, afterdepolarizations), and if so, by what mechanisms are these triggers generated6,8? How do these proarrhythmic cellular mechanisms interact with fiber architecture9 and cellular heterogeneity10 to affect action potential propagation and repolarization in the myocardium?
Recent examples have shown a promise of computational models for investigating the impact of gene mutations,11 tissue heterogeneities,12 and dynamical instabilities13 on arrhythmic mechanisms. Here, we use an integrative computational model of ß-adrenergic signaling, excitation-contraction coupling, and action potential propagation to investigate the whole-cell and myocardial consequences of KCNQ1/KCNE1 signaling complex disruption. Model analysis indicates that although the KCNQ1-G589D mutation did not necessarily prolong the QT interval at rest, sympathetic-stimulated increases in ICa, left uncompensated by increased IKs, resulted in QT prolongation. This impaired response to sympathetic stimulation precipitated calcium-mediated afterdepolarizations and transmural dispersion of repolarization in ventricular tissue, significant factors related to arrhythmic risk. However, moderate increases in heart rate protected against these proarrhythmic mechanisms.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Signal Transduction Model
A mechanistic mathematical model of ß-adrenergic signaling in rat14,15 was adapted for the rabbit ventricular myocyte by making the following changes motivated by experimental data: adjusting protein expression levels for ß-adrenergic receptors,16 PDE4,17 PKA,18 and phospholamban19; inclusion of the PDE3 isoform20; and the addition of a KCNQ1/KCNE1 signaling complex containing KCNQ1, KCNE1, yotiao, PKA, and PP1.3 Methods for modeling these signaling networks have been described in detail previously.15 The new signaling model included a total of five PKA phosphorylation targets: the L-type calcium channel (ICaL), phospholamban (PLB), ryanodine receptor (RyR), troponin I (TnI), inhibitor-1, and KCNQ1.
Based on single-channel recordings of IKs conductance21 and whole-cell IKs conductance in rabbit ventricular myocytes,22 KCNQ1 was assumed to be expressed at 25 nmol/L cytosol, with quasi-equilibrium binding (KD=0.1 nmol/L) to an equivalently expressed yotiao. Yotiao was assumed necessary for interaction between KCNQ1 and PKA or PP1,3 binding one PP1 and one PKA holoenzyme per anchoring protein. The KCNQ1-G589D defect associated with LQT1 syndrome was modeled as a 106-fold increase in the dissociation constant for KCNQ1 and yotiao (Figure 1A).
|
Excitation-Contraction Coupling Model
We used a previously published model of excitation-contraction coupling in the adult rabbit ventricular myocyte,22 modified with a simple model of calcium-induced calcium release23 and a reversible Ca SR-ATPase pump.24 Details of modeling the consequences of ICaL, PLB, RyR, and TnI phosphorylation have been described previously14,15 and are summarized in Table S1 in the online data supplement available at http://circres.ahajournals.org. Phosphorylated IKs channels were modeled as being 3.6-fold more likely to be actively gating, with a 35.6 mV leftward shift in the activation curve for the IKs gating variable, consistent with whole-cell patch clamp recordings with cAMP and isoproterenol.25 An IC50 of 0.43 µmol/L was used for nifedipine block of the L-type calcium channel.26 The signaling and excitation-contraction coupling models were fully connected with one another (Figure 1B) and solved numerically with the ode15s algorithm in MATLAB 6.5 (The MathWorks, Natick, Mass). All simulations were begun at steady-state (without isoproterenol) for the cycle length described. Model equations and parameters are provided in the online data supplement.
Rabbit Ventricular Wedge Model
To simulate ß-adrenergic regulation of electrophysiology at the tissue level, we used a 2-element wedge (dimensions 
0.9x0.8x0.5 cm) taken from the original 36-element anatomic model of the rabbit ventricular geometry and fiber architecture described by Vetter and McCulloch.9 This wedge was refined in each direction to yield a 1024 element wedge, which was sufficient to obtain solutions for conduction velocity and action potential duration that were both converged to within 2% (data not shown). Transmural electrical heterogeneity in the wedge was incorporated using endocardial, midmyocardial, and epicardial layers with relative thicknesses of 3:3:2. Relative current densities in each region (see online data supplement for parameters) were estimated from rabbit (endocardial/epicardial data for IKs,27 IKr,27 and Ito28; endocardial/midmyocardial/epicardial INa estimated from upstroke velocity29) or when necessary canine (IKp,10 midmyocardial IKs, IKr, and Ito10). Simulations of a larger heart were performed by decreasing the diffusion coefficient 50%, which increases transmural activation time by 50% as well. Initial conditions for finite element simulations were calculated with the integrated signaling/excitation-contraction coupling cell model. We approximated phosphorylation levels as constant over the interval of tissue simulation, 2 seconds. Simulations were performed using a collocation-Galerkin finite element method.30
Model Validation
The cellular model was validated with independent experimental data from the literature at a variety of functional levels, obtained from isolated rabbit ventricular myocytes whenever possible. The signaling portion of the model exhibited appropriate concentration response of cAMP and PKA activity to isoproterenol (EC50s of 10 nmol/L and 11 nmol/L versus 12 nmol/L and 9 nmol/L31), basal particulate cAMP (3.2 versus 3.0 pmol/mg32), desensitization magnitude (35% versus 37%33), cAMP rise, and PKA activation time (1.4 versus 1 minute32), cAMP decline and PKA deactivation time (t1/2 of 5 minutes and 5 minutes versus 4 minutes and 7 minutes32), and downstream phosphorylation levels (PLB EC50 20 versus 7.1 nmol/L; TnI EC50 21 versus 3.1 nmol/L34) (see Figure S1 in the online data supplement). The functional consequences of ß-adrenergic signaling in the rabbit ventricular myocyte were validated as well, confirming consistent changes in calcium channel current (1.8- versus 2.2-fold increase35), calcium inotropy (1.9- versus 1.8-fold increase in 
[Cai]35), and decreased action potential duration (14% versus 10%36). ß-Adrenergic regulation of IKs caused an increase in maximum conductance (2.7- versus 2.4-fold25), a leftward shift in the conductance-voltage relation (13 versus 9 mV25), and no change in the activation/inactivation time constant25 (see Figure S2 in the online data supplement).
In the ventricular wedge model, the diffusion coefficient was chosen to yield a transmural conduction velocity of 27 cm/s at 3 Hz, agreeing with results from Sung et al,37 who measured transverse velocities of 23±6 cm/s in an isolated Langendorff-perfused rabbit heart. All measurements of electrophysiological function were consistent with the experimental results performed in arterially perfused rabbit wedge preparations of similar size at 1 Hz38: endocardial APD90 (217 versus 212 ms), epicardial APD90 (166 versus 191 ms), QT interval (245 versus 251 ms), and transmural dispersion of repolarization (TDR) (36 versus 43 ms) (see Figure 6C).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Effect of KCNQ1-G589D Mutation on Sympathetic Regulation of IKs
We incorporated known protein interactions in the KCNQ1/KCNE1 signaling complex into a mathematical model of ß-adrenergic signaling and excitation-contraction coupling in the rabbit ventricular myocyte. We found that in wild-type (WT) myocyte models, this signaling complex allows a large dynamic range of KCNQ1 phosphorylation level on isoproterenol stimulation, which is abolished with disruption of the KCNQ1/yotiao interaction caused by the G589D mutation in KCNQ1 (Figure 2A). Incorporating ß-adrenergic regulation of IKs25 into the model, we predicted dynamic changes in WT but not G589D mutant IKs with isoproterenol (Figure 2B). Thus, our mathematical model predicts the known subcellular consequences of the KCNQ1-G589D gene defect consistent with experimental patch-clamp data from expression systems.3
|
KCNQ1-G589D Mutation Prolongs Cardiac Myocyte APD in Response to Isoproterenol
By incorporating the signaling interactions of the KCNQ1/KCNE1 complex into a whole-cell model of signaling and excitation-contraction coupling, we assessed the cellular-level impact of the KCNQ1-G589D mutation. At 1 Hz, WT myocyte models stimulated with isoproterenol exhibited shortened action potentials (decreased APD90 12%) because of the influence of phosphorylated KCNQ1/KCNE channels (Figure 3A). In contrast, G589D myocyte models treated with isoproterenol exhibited 15% larger APD90 than untreated myocytes (Figure 3A). The rate dependence of APD is important for normal function of the heart as well; so we examined whether the G589D mutation altered this relationship either in untreated or isoproterenol-treated conditions. Untreated WT and G589D myocyte models have extremely similar action potentials. Isoproterenol-stimulated G589D mutants exhibit longer APDs than WT for all cycle lengths (CLs) such that the general rate-dependent APD shortening is preserved (Figure 3B).
|
Sympathetic Stimulation May Induce Calcium-Mediated Afterdepolarizations in G589D Mutant Myocytes
Cardiac myocytes with prolonged action potentials are susceptible to early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs), which may serve as cellular-level triggers for cardiac arrhythmias and sudden cardiac death.8 We found both EADs and DADs in isoproterenol-stimulated G589D myocyte models at long cycle lengths, but not in WT. Figure 4A demonstrates the pattern of observed afterdepolarizations with 1 Hz pacing, exhibiting the first EAD at 8 seconds after isoproterenol exposure as PKA-regulated channels undergo significant transitions. Afterdepolarizations subsequently disappear as the signaling state stabilizes. Figure 4B shows action potentials and corresponding calcium concentrations and calcium channel currents during the first EAD from Figure 4A. The prolonged action potential allows the calcium channel to reactivate, initiating the EAD. Because of the short diastolic interval following the EAD, the subsequent action potential is short and thus does not generate a second EAD. DADs were observed secondary to some EADs, as the large amount of calcium brought into the cell forced spontaneous calcium release from the sarcoplasmic reticulum.
|
To better understand the conditions in which G589D mutants are susceptible to EADs and DADs, we characterized the incidence of afterdepolarizations for a range of isoproterenol concentrations and pacing rates. Not surprisingly, incidence of EADs and DADs increases with isoproterenol concentration for G589D myocyte models at 1 Hz, whereas WT myocyte models have neither EADs nor DADs (Figure 5A). Only high concentrations of isoproterenol elicited afterdepolarizations. On the other hand, EAD and DAD incidence in 1 µmol/L isoproterenol-stimulated G589D myocyte models decreases with increasing pacing rate (Figure 5B), presumably because of the shortened APDs (see Figure 4B). Single EADs were also observed following a 1.5 second pause in isoproterenol-stimulated G589D myocyte models nominally at 2 and 3 Hz.
|
G589D Mutation Prolongs QT and Elevates TDR in a Rabbit Ventricular Wedge Model
To investigate potential consequences of the observed proarrythmic cellular mechanisms, we developed a three-dimensional model of action potential propagation in a rabbit ventricular wedge. APD rate-dependence of WT endocardial, midmyocardial, and epicardial cell models were validated with published experimental data29 (Figure 6A and 6B). With these regional cell types, the ventricular wedge model predicted action potential and ECG properties observed experimentally in WT wedge preparations38 (Figure 6C).
|
Consistent with whole-cell simulations above, ß-adrenergic stimulation prolongs QT and creates broad T-waves in the G589D mutant but not WT wedge model, clearly visible on the simulated ECG (Figure 7A). Strong ß-adrenergic stimulation at low pacing rates triggered small EAD-like responses in the endocardial and midmyocardial regions, but the large EADs seen in single cell simulations appear blunted because of electrotonic coupling. Sympathetic stimulation increases APD in the G589D mutant ventricular wedge heterogeneously (Figure 7B), elevating transmural dispersion of repolarization (TDR) at large cycle lengths (Figure 7C). TDR is often used as an indicator of arrhythmic risk.39 TDR increased with cycle length in both WT and mutant tissue models, suggesting a protective role for higher heart rates (Figure 7C). Increased TDR (from 19 to 39 ms) was also observed in G89D wedge models following a 1.5-second pause from 500- and 333-ms basic cycle lengths.
|
The likelihood for the G589D proarrhythmic cellular mechanisms to manifest ECG abnormalities appears further increased in simulations of a larger heart. A very large, broad T-wave was observed (Figure 7D, second beat), because of strong EADs elicited by the endocardium. On the subsequent beat, small EADs isolated to a region of midmyocardium cause a bifurcated T-wave with an inverted T2 component. Electrotonic coupling appears lower in the larger heart, allowing more irregular repolarization patterns with G589D mutation.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This study investigated potential cell and tissue-level mechanisms that may bridge the KCNQ1-G589D gene mutation to aspects of the LQT1 clinical phenotype. Incorporating the molecular consequences of the KCNQ1-G589D defect into a mathematical model of the rabbit ventricular myocyte, we found increased APD and a susceptibility to afterdepolarizations only with sympathetic stimulation. Extending spatially to model a rabbit ventricular wedge preparation, we examined the role of interactions between these cellular mechanisms, cell-type heterogeneities, and fiber angle distributions on action potential propagation and simulated ECGs. These analyses suggest a mechanistic link from the KCNQ1-G589D gene defect to TDR and possible T-wave abnormalities in the ventricle, clinical indicators of arrhythmic risk in LQT syndrome.
Enhanced calcium channel currents with isoproterenol tended to increase APD, which was counterbalanced by enhanced IKs current in WT but not G589D mutant models. These findings are consistent with experimental data showing variable APD changes in isoproterenol-stimulated WT myocytes,36 but significantly longer APDs when IKs or IKr channels are blocked pharmacologically.40 Isoproterenol shortened WT APD at low but not high rates, qualitatively matching experimental studies showing that high rates either reduce41 or eliminate42 isoproterenol-dependent shortening of WT APD. Although the rate dependence of APD has been hypothesized to be altered with KCNQ1/KCNE1 signaling complex disruption,7 we found that the slow reactivation of IKs maintained rate-dependent shortening of G589D mutant APDs qualitatively similar to WT. The prolonged APD predicted in isoproterenol-stimulated G589D myocyte models increased susceptibility to afterdepolarizations. EADs and DADs, hypothesized as triggers for arrhythmia, have been studied in both mathematical11 and experimental models of drug-induced LQTS.8 The calcium-mediated mechanisms for EAD and DAD initiation, namely ICa reactivation and spontaneous SR calcium release,43 were confirmed by afterdepolarization suppression with the calcium channel blocker nifedipine. Experimentally, isoproterenol may trigger occasional afterdepolarizations in WT myocytes,44 potentially because of stochastic ICa or RyR gating.45 Our deterministic WT models appeared somewhat more stable, which should have made the model more resistant to the observed EADs and DADs with G589D mutation.
We found that during sympathetic stimulation, the predicted cellular consequences of the G589D mutation may amplify existing tissue heterogeneities as evidenced by changes in the ECG and underlying action potentials from the ventricular model. Isoproterenol increased QT interval and TDR in the G589D ventricular wedge model, consistent with pharmacological models of LQT1 in canine.40 Whereas strong electrotonic coupling38 appeared to blunt EADs in our original rabbit wedge model, a larger G589D mutant wedge allowed pronounced ECG abnormalities including sudden large, broad T-waves and T-wave inversion under otherwise unaltered conditions. Similar EADs, TDR, and ECG abnormalities in acquired LQT models have been reported as precursors to torsade de pointes (TdP), a polymorphic ventricular tachycardia.38,39 These mechanistic simulations support the clinical observation that patients with the KCNQ1-G589D mutation are particularly vulnerable to exercise-induced arrhythmias.4,5
Consistent with previous cellular simulations46 and wedge experiments,38,40 QT prolongation, EAD susceptibility, and TDR decreased in models of G589D myocytes and myocardium at increased rates. Whereas sympathetic stimulation increases rate in the intact heart, a vulnerable window to arrhythmia may develop during transitions in sympathetic stimulation39 or following an excitation pause. Pauses may trigger EADs in LQTS47 and have been seen preceding 74% of TdP in congenital LQTS patients.48 We found that pauses allowed EADs in G589D cell models and increased TDR in G589D wedge models at higher pacing rates. This may explain why, as in previous experimental studies,38,40 some proarrhythmic mechanisms were seen at rates lower than expected of the normal rabbit heart. Taken together, our models of myocytes and heterogeneous tissue support the hypothesis that sympathetic stimulation of the ventricle may allow whole-cell and tissue-level arrhythmic mechanisms in G589D mutants, whereas increased heart rate may be protective.
Because we investigated the direct consequences of the G589D mutation, we did not include secondary changes in protein expression. KCNQ1 mutants in cell expression systems suggest a potential for IKs downregulation,3,5 although clinical data are not yet available. Conceivably, the KCNQ1-G589D mutation could work together with IKs downregulation to manifest arrhythmic risk.3 In preliminary simulation studies, we found that a 50% decrease in IKs3 in conjunction with G589D mutation would produce a resting long QT phenotype not seen with G589D mutation alone, without qualitatively affecting the cellular and tissue-level responses to sympathetic stimulation shown above. Perhaps prolonged resting QT, the traditional clinical indicator of LQT1,1 may be a secondary consequence in patients with the G589D mutation. This hypothesis is consistent with experimental models of acquired LQTS that suggest TDR, rather than QT prolongation itself, may allow cellular triggers to propagate into TdP.39 This hypothesis is also consistent with a clinical study that showed LQT1 genotype to correlate better with epinephrine-stimulated QT prolongation than resting QT.2
A mechanistic ß-adrenergic signaling model has allowed us to characterize the graded, dynamic regulation of E-C coupling and mechanistically model the G589D mutation. Thus, we predicted rather than imposed the regulatory consequences of G589D mutation and demonstrated robustness to isoproterenol concentration in the predicted phenotypes. With large changes in phosphorylation levels during simulations, the detailed model was vital for describing a transient vulnerable period for EADs and calculating appropriate initial conditions for ventricular wedge simulations. Finally, the detailed model creates a framework for investigating potential therapeutics such as ß-blockers, PDE inhibitors, and PLB inhibitors in the context of this congenital LQTS.
A number of limitations in this study must be considered when interpreting the results. At the level of signaling networks, many pathway and cross-talk interactions were not modeled. Sympathetic stimulation also activates the ß2-AR and 1-AR pathways, although they are not as prominent as ß1-AR signaling in the overall inotropic and electrophysiological response under normal conditions.49 Calmodulin and CaMKII pathways affect the frequency dependence of several aspects of excitation-contraction coupling50; incorporating these regulatory interactions may increase APD and afterdepolarization incidence at higher pacing rates. The controversial ß-adrenergic actions on IKr have not been included, as they are thought to act indirectly via unknown mechanisms including PKC rather than direct PKA-mediated phosphorylation.51 Although we have included the functional roles of some A-kinase anchoring proteins, many mechanisms for signaling compartmentation are still unclear.49 Our model of calcium handling uses a simplified representation of calcium-induced calcium release,23 which is unable to predict stochastic behavior such as calcium sparks or the role of calcium in the junctional subspace. However, our model is sufficient to predict graded calcium release,23 cytosolic calcium transients,22 and generation of EADs and DADs.11
Although heterogeneities in the myocardium can greatly affect action potential propagation, we have only accounted for the most prominent differences. We have modeled endocardial, midmyocardial, and epicardial myocytes arranged in transmural layers,10 although these cells may not be arranged in distinct layers in the real heart.52 We have modeled fiber angle distributions9 but not the discontinuous architecture of laminar sheets.53 Although we did not model Purkinje fibers, our endocardial pacing as in experimental wedge preparations40 is unlikely to be greatly affected. The experimental perfused-wedge preparation has been used in numerous studies of ventricular heterogeneity and acquired LQTS.8 However, the ventricular wedge used here and in previous experimental work lacks many anatomic and physiologic features of the intact heart. We did not observe TdP, perhaps because of the size of our ventricular wedge.38 Although we have modeled sympathetic stimulation as uniform within the ventricular wedge (as in experimental wedge preparations40), heterogeneity of cardiac innervation and expression of signaling proteins may contribute to arrhythmia.39 Despite these limitations, our computational models successfully predicted many known aspects of cardiac excitation-contraction coupling and its regulation by ß-adrenergic signaling in rabbit.
In conclusion, the KCNQ1-G589D gene defect appears sufficient to prolong the QT interval and generate cellular triggers for arrhythmia during sympathetic stimulation. These cellular arrhythmic mechanisms combine with ventricular heterogeneities to increase transmural dispersion of repolarization and may promote T-wave abnormalities, establishing a vulnerable proarrhythmic environment.
|
Acknowledgments |
|---|
This work was supported by a Whitaker Foundation Graduate Fellowship (to J.J.S), the National Space Biomedical Research Institute (CA00261) (to A.D.M.), the National Biomedical Computation Resource (P41 RR08605) (to A.D.M.), and the National Science Foundation (BES-0096492 (to A.D.M). We acknowledge Donald M. Bers for generously providing computer code of LabHeart.22
|
Footnotes |
|---|
Original received August 18, 2004; revision received October 13, 2004; accepted October 27, 2004.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink P, Wilde AA, Toivonen L, Zareba W, Robinson JL, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, Bloise R. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001; 103: 89–95.
2. Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen WK, Porter CB. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc. 2002; 77: 413–421.
3. Marx SO, Kurokawa J, Reiken S, Motoike H, D’Armiento J, Marks AR, Kass RS. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science. 2002; 295: 496–499.
4. Fodstad H, Swan H, Laitinen P, Piippo K, Paavonen K, Viitasalo M, Toivonen L, Kontula K. Four potassium channel mutations account for 73% of the genetic spectrum underlying long-QT syndrome (LQTS) and provide evidence for a strong founder effect in Finland. Ann Med. 2004; 36 (suppl 1): 53–63.[CrossRef][Medline] [Order article via Infotrieve]
5. Piippo K, Swan H, Pasternack M, Chapman H, Paavonen K, Viitasalo M, Toivonen L, Kontula K. A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics. J Am Coll Cardiol. 2001; 37: 562–568.
6. Kass RS, Moss AJ. Long QT syndrome: novel insights into the mechanisms of cardiac arrhythmias. J Clin Invest. 2003; 112: 810–815.[CrossRef][Medline] [Order article via Infotrieve]
7. Clancy CE, Kurokawa J, Tateyama M, Wehrens XH, Kass RS. K+ channel structure-activity relationships and mechanisms of drug-induced QT prolongation. Annu Rev Pharmacol Toxicol. 2003; 43: 441–461.[CrossRef][Medline] [Order article via Infotrieve]
8. Antzelevitch C, Shimizu W. Cellular mechanisms underlying the long QT syndrome. Curr Opin Cardiol. 2002; 17: 43–51.[CrossRef][Medline] [Order article via Infotrieve]
9. Vetter FJ, McCulloch AD. Three-dimensional analysis of regional cardiac function: a model of rabbit ventricular anatomy. Prog Biophys Mol Biol. 1998; 69: 157–183.[CrossRef][Medline] [Order article via Infotrieve]
10. Antzelevitch C, Dumaine R. Electrical heterogeneity in the heart: physiological, pharmacological and clinical implications. In: Handbook of Physiology, Section 2: The Cardiovascular System. Vol. 1, The Heart. Bethesda, Md: American Physiological Society; 2001: 654–692.
11. Clancy CE, Rudy Y. Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia. Nature. 1999; 400: 566–569.[CrossRef][Medline] [Order article via Infotrieve]
12. Mazhari R, Nuss HB, Armoundas AA, Winslow RL, Marban E. Ectopic expression of KCNE3 accelerates cardiac repolarization and abbreviates the QT interval. J Clin Invest. 2002; 109: 1083–1090.[CrossRef][Medline] [Order article via Infotrieve]
13. Xie F, Qu Z, Yang J, Baher A, Weiss JN, Garfinkel A. A simulation study of the effects of cardiac anatomy in ventricular fibrillation. J Clin Invest. 2004; 113: 686–693.[CrossRef][Medline] [Order article via Infotrieve]
14. Saucerman JJ, Brunton LL, Michailova AP, McCulloch AD. Modeling beta-adrenergic control of cardiac myocyte contractility in silico. J Biol Chem. 2003; 278: 47997–48003.
15. Saucerman JJ, McCulloch AD. Mechanistic systems models of cell signaling networks: a case study of myocyte adrenergic regulation. Prog Biophys Mol Biol. 2004; 85: 261–278.[CrossRef][Medline] [Order article via Infotrieve]
16. Endoh M, Hiramoto T, Ishihata A, Takanashi M, Inui J. Myocardial alpha 1-adrenoceptors mediate positive inotropic effect and changes in phosphatidylinositol metabolism. Species differences in receptor distribution and the intracellular coupling process in mammalian ventricular myocardium. Circ Res. 1991; 68: 1179–1190.
17. Shakur Y, Fong M, Hensley J, Cone J, Movsesian MA, Kambayashi J, Yoshitake M, Liu Y. Comparison of the effects of cilostazol and milrinone on cAMP-PDE activity, intracellular cAMP and calcium in the heart. Cardiovasc Drugs Ther. 2002; 16: 417–427.[CrossRef][Medline] [Order article via Infotrieve]
18. Corbin JD, Sugden PH, Lincoln TM, Keely SL. Compartmentalization of adenosine 3':5'-monophosphate and adenosine 3':5'-monophosphate-dependent protein kinase in heart tissue. J Biol Chem. 1977; 252: 3854–3861.
19. Colyer J, Wang JH. Dependence of cardiac sarcoplasmic reticulum calcium pump activity on the phosphorylation status of phospholamban. J Biol Chem. 1991; 266: 17486–17493.
20. Movsesian MA, Komas N, Krall J, Manganiello VC. Expression and activity of low Km, cGMP-inhibited cAMP phosphodiesterase in cardiac and skeletal muscle. Biochem Biophys Res Commun. 1996; 225: 1058–1062.[CrossRef][Medline] [Order article via Infotrieve]
21. Yang Y, Sigworth FJ. Single-channel properties of IKs potassium channels. J Gen Physiol. 1998; 112: 665–678.
22. Puglisi JL, Bers DM. LabHEART: an interactive computer model of rabbit ventricular myocyte ion channels and Ca transport. Am J Physiol Cell Physiol. 2001; 281: C2049–C2060.
23. Faber GM, Rudy Y. Action potential and contractility changes in [Na(+)](i) overloaded cardiac myocytes: a simulation study. Biophys J. 2000; 78: 2392–2404.[Medline] [Order article via Infotrieve]
24. Shannon TR, Ginsburg KS, Bers DM. Reverse mode of the sarcoplasmic reticulum calcium pump and load-dependent cytosolic calcium decline in voltage-clamped cardiac ventricular myocytes. Biophys J. 2000; 78: 322–333.[Medline] [Order article via Infotrieve]
25. Walsh KB, Kass RS. Distinct voltage-dependent regulation of a heart-delayed IK by protein kinases A and C. Am J Physiol. 1991; 261: C1081–C1090.[Medline] [Order article via Infotrieve]
26. Bean BP, Nowycky MC, Tsien RW. Beta-adrenergic modulation of calcium channels in frog ventricular heart cells. Nature. 1984; 307: 371–375.[CrossRef][Medline] [Order article via Infotrieve]
27. Xu X, Rials SJ, Wu Y, Salata JJ, Liu T, Bharucha DB, Marinchak RA, Kowey PR. Left ventricular hypertrophy decreases slowly but not rapidly activating delayed rectifier potassium currents of epicardial and endocardial myocytes in rabbits. Circulation. 2001; 103: 1585–1590.
28. McIntosh MA, Cobbe SM, Kane KA, Rankin AC. Action potential prolongation and potassium currents in left-ventricular myocytes isolated from hypertrophied rabbit hearts. J Mol Cell Cardiol. 1998; 30: 43–53.[CrossRef][Medline] [Order article via Infotrieve]
29. McIntosh MA, Cobbe SM, Smith GL. Heterogeneous changes in action potential and intracellular Ca2+ in left ventricular myocyte sub-types from rabbits with heart failure. Cardiovasc Res. 2000; 45: 397–409.
30. Rogers JM, McCulloch AD. A collocation–Galerkin finite element model of cardiac action potential propagation. IEEE Trans Biomed Eng. 1994; 41: 743–757.[CrossRef][Medline] [Order article via Infotrieve]
31. Hayes JS, Brunton LL, Mayer SE. Selective activation of particulate cAMP-dependent protein kinase by isoproterenol and prostaglandin E1. J Biol Chem. 1980; 255: 5113–5119.
32. Buxton IL, Brunton LL. Compartments of cyclic AMP and protein kinase in mammalian cardiomyocytes. J Biol Chem. 1983; 258: 10233–10239.
33. Drazner MH, Peppel KC, Dyer S, Grant AO, Koch WJ, Lefkowitz RJ. Potentiation of beta-adrenergic signaling by adenoviral-mediated gene transfer in adult rabbit ventricular myocytes. J Clin Invest. 1997; 99: 288–296.[Medline] [Order article via Infotrieve]
34. Stemmer PM, Ledyard TH, Watanabe AM. Protein dephosphorylation rates in myocytes after isoproterenol withdrawal. Biochem Pharmacol. 2000; 59: 1513–1519.[CrossRef][Medline] [Order article via Infotrieve]
35. Ginsburg KS, Bers DM. Modulation of excitation-contraction coupling by isoproterenol in cardiomyocytes with controlled SR Ca2+ load and Ca2+ current trigger. J Physiol. 2004; 556: 463–480.
36. Sanguinetti MC, Jurkiewicz NK, Scott A, Siegl PK. Isoproterenol antagonizes prolongation of refractory period by the class III antiarrhythmic agent E-4031 in guinea pig myocytes. Mechanism of action. Circ Res. 1991; 68: 77–84.
37. Sung D, Mills RW, Schettler J, Narayan SM, Omens JH, McCulloch AD. Ventricular filling slows epicardial conduction and increases action potential duration in an optical mapping study of the isolated rabbit heart. J Cardiovasc Electrophysiol. 2003; 14: 739–749.[Medline] [Order article via Infotrieve]
38. Yan GX, Rials SJ, Wu Y, Liu T, Xu X, Marinchak RA, Kowey PR. Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization. Am J Physiol Heart Circ Physiol. 2001; 281: H1968–H1975.
39. Verrier RL, Antzelevitch C. Autonomic aspects of arrhythmogenesis: the enduring and the new. Curr Opin Cardiol. 2004; 19: 2–11.[CrossRef][Medline] [Order article via Infotrieve]
40. Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation. 1998; 98: 2314–2322.
41. Stengl M, Volders PG, Thomsen MB, Spatjens RL, Sipido KR, Vos MA. Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. J Physiol. 2003; 551: 777–786.
42. Sosunov EA, Gainullin RZ, Moise NS, Steinberg SF, Danilo P, Rosen MR. beta(1) and beta(2)-adrenergic receptor subtype effects in German shepherd dogs with inherited lethal ventricular arrhythmias. Cardiovasc Res. 2000; 48: 211–219.
43. January CT, Riddle JM. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ Res. 1989; 64: 977–990.
44. Priori SG, Corr PB. Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines. Am J Physiol. 1990; 258: H1796–H1805.[Medline] [Order article via Infotrieve]
45. Greenstein JL, Tanskanen AJ, Winslow RL. Modeling the actions of beta-adrenergic signaling on excitation-contraction coupling processes. Ann N Y Acad Sci. 2004; 1015: 16–27.[CrossRef][Medline] [Order article via Infotrieve]
46. Clancy CE, Rudy Y. Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death. Cardiovasc Res. 2001; 50: 301–313.
47. Viswanathan PC, Rudy Y. Pause induced early afterdepolarizations in the long QT syndrome: a simulation study. Cardiovasc Res. 1999; 42: 530–542.
48. Viskin S, Fish R, Zeltser D, Belhassen B, Heller K, Brosh D, Laniado S, Barron HV. Arrhythmias in the congenital long QT syndrome: how often is torsade de pointes pause dependent? Heart. 2000; 83: 661–666.
49. Steinberg SF, Brunton LL. Compartmentation of G protein-coupled signaling pathways in cardiac myocytes. Annu Rev Pharmacol Toxicol. 2001; 41: 751–773.[CrossRef][Medline] [Order article via Infotrieve]
50. Maier LS, Bers DM. Calcium, calmodulin, and calcium-calmodulin kinase II: heartbeat to heartbeat and beyond. J Mol Cell Cardiol. 2002; 34: 919–939.[CrossRef][Medline] [Order article via Infotrieve]
51. Heath BM, Terrar DA. Protein kinase C enhances the rapidly activating delayed rectifier potassium current, IKr, through a reduction in C-type inactivation in guinea-pig ventricular myocytes. J Physiol. 2000; 522 (Pt 3): 391–402.
52. Akar FG, Yan GX, Antzelevitch C, Rosenbaum DS. Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long-QT syndrome. Circulation. 2002; 105: 1247–1253.
53. LeGrice IJ, Smaill BH, Chai LZ, Edgar SG, Gavin JB, Hunter PJ. Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog. Am J Physiol. 1995; 269: H571–H582.[Medline] [Order article via Infotrieve]
Related Article:
Circ. Res. 2004 95: 1135-1136.
This article has been cited by other articles:
 |
|
 |
|
  J. R. H. Mauban, M. O'Donnell, S. Warrier, S. Manni, and M. Bond AKAP-Scaffolding Proteins and Regulation of Cardiac Physiology Physiology, April 1, 2009; 24(2): 78 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G Campbell, S. N Flaim, C. H Leem, and A. D McCulloch Mechanisms of transmurally varying myocyte electromechanics in an integrated computational model Phil Trans R Soc A, September 28, 2008; 366(1879): 3361 - 3380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Plank, L. Zhou, J. L Greenstein, S. Cortassa, R. L Winslow, B. O'Rourke, and N. A Trayanova From mitochondrial ion channels to arrhythmias in the heart: computational techniques to bridge the spatio-temporal scales Phil Trans R Soc A, September 28, 2008; 366(1879): 3381 - 3409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Mohler and X. H. T. Wehrens Mechanisms of Human Arrhythmia Syndromes: Abnormal Cardiac Macromolecular Interactions Physiology, October 1, 2007; 22(5): 342 - 350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Michailova, W. Lorentz, and A. McCulloch Modeling transmural heterogeneity of KATP current in rabbit ventricular myocytes Am J Physiol Cell Physiol, August 1, 2007; 293(2): C542 - C557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Dodge-Kafka, L. Langeberg, and J. D. Scott Compartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of A-Kinase Anchoring Proteins Circ. Res., April 28, 2006; 98(8): 993 - 1001. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Hunter and P. Nielsen A Strategy for Integrative Computational Physiology Physiology, October 1, 2005; 20(5): 316 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Healy and A. D. McCulloch An ionic model of stretch-activated and stretch-modulated currents in rabbit ventricular myocytes Europace, January 1, 2005; 7(s2): S128 - S134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Winslow and J. L. Greenstein The Ongoing Journey to Understand Heart Function Through Integrative Modeling Circ. Res., December 10, 2004; 95(12): 1135 - 1136. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||