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Clinical Application of a Simulated Cell Model of the Cardiac ClinicalClinical ApplicationApplication ofof aa SimulatedSimulated CellCell ModelModel ofof thethe CardiacCardiac VentricularVentricular MyocyteMyocyte RueyRuey J.J. Sung,Sung, MD,MD, FAHA,FAHA, FHRSFHRS Emeritus Professor of Medicine Stanford University School of Medicine Stanford, CA, USA Dean, College of Medicine National Cheng Kung University Tainan, Taiwan 5/24/07 Hodgkin AL and Huxley AF, A Quantitative Description of Membrane Current and its Application to Conduction and Excitation in Nerv e, 1952, J. Physiol , 117:500 -544. FitzHugh (1966) (1)The effect of temperature on action potential of squid a xon. (2)Modified the original Hodgkin -Huxley equations by a temperature factor. Guttman and Barnhill (1970) Found repetitive firing by increasing temperature. HodgkinHodgkin --HuxleyHuxley ModelModel HodgkinHodgkin --HuxleyHuxley FormulationFormulation Rudy Y & Silva JR. Q Rev Biophys. 2006; 39: 57-116 Luo-Rudy Model Luo-Rudy Model Rudy Y & Silva JR. Q Rev Biophys. 2006; 39: 57-116 Rudy Y & Silva JR. Q Rev Biophys. 2006; 39: 57-116 ComputationalComputational CellCell BiologyBiology AndersenAndersen --TawilTawil SyndromeSyndrome (LQT7)(LQT7) TimothyTimothy SyndromeSyndrome (LQT8)(LQT8) Sung et al., Am J Physiol 2006; 291:H2597-H2605 LongLong QTQT SyndromeSyndrome Long QT syndrome is a heart condition that causes the heart (cardiac) muscle to take longer than usual to recharge between beats. Lifebeat Spring online issue (2005) CardiacCardiac ionion currentscurrents andand clonedcloned subunitssubunits AndersenAndersen --TawilTawil syndromesyndrome Anderson -Tawil syndrome is an autosomal dominant disorder that causes: 1. Episodes of muscle weakness (periodic paralysis) 2. Changes in heart rhythm (arrhythmia) 3. Developmental abnormalities. Ann Neurol 35 : 326-330 (1994) Mutations in the KCNJ2 gene on the chromosome 17q could cause type1 ATS. Cell 105 : 511-519 (2001) Andersen-Tawil Syndrome Tawil R. et al. Ann Neurol 1994; 35: 326-330 Tristani-Firouzi M. et al. J. Clin. Invest. 2002; 110:381-388 TimothyTimothy SyndromeSyndrome Splawski et al., 2005; 102:8089- 8096 MechanismsMechanisms ofof DifferentialDifferential PatternsPatterns ofof SurvivalSurvival BetweenBetween AndersenAndersen --TawilTawil (LQT7)(LQT7) andand TimothyTimothy (LQT8)(LQT8) Syndromes.Syndromes. Han -Dong Chang, Sheng -Nan Wu, Ruey J. Sung Stanford University School of Medicine, Stanford California, USA National Cheng Kung University College of Medicine Tainan, Taiwan. Background (I) AndersenAndersen --TawilTawil syndromesyndrome (ATS)(ATS) isis causedcaused byby geneticgenetic mutationsmutations leadingleading toto "loss"loss ofof functionfunction ”” ofof thethe Kir2.1Kir2.1 (I(I K1 )) channelchannel andand TimothyTimothy syndromesyndrome (TS)(TS) toto "gain"gain ofof functionfunction ”” ofof thethe CaCa v1.21.2 (( IICa , L )) channel.channel. BothBoth ATSATS andand TSTS clinicallyclinically manifestmanifest polymorphicpolymorphic ventricularventricular tachycardiatachycardia (( torsadetorsade dede pointes)pointes) withwith QTQT prolongation.prolongation. BackgroundBackground (II)(II) ClinicallyClinically bothboth syndromessyndromes havehave multisystemmultisystem involvementinvolvement (e.g.,(e.g., ATSATS withwith periodicperiodic paralysisparalysis && dysmorphicdysmorphic features,features, TSTS withwith autism,autism, hypoglycemiahypoglycemia && syndactylysyndactyly ).). However,However, despitedespite bothboth havinghaving aa highhigh prevalenceprevalence ofof ventricularventricular arrhythmiasarrhythmias (ATS(ATS 64%64% && TSTS 7171 %% ),), TSTS patientspatients seldomseldom livelive beyondbeyond 33 yearsyears ofof age.age. ObjectiveObjective WeWe soughtsought toto determinedetermine electrophysiologicalelectrophysiological mechanismsmechanisms responsibleresponsible forfor disparatedisparate clinicalclinical outcomesoutcomes betweenbetween ATSATS andand TS.TS. MethodsMethods WeWe adoptedadopted aa modifiedmodified dynamicdynamic LuoLuo --RudyRudy simulationsimulation modelmodel toto studystudy actionaction potentialpotential (AP)(AP) + ofof thethe cardiaccardiac ventricularventricular myocytemyocyte .. [K[K ]]o waswas setset atat 4.54.5 mMmM andand thethe pacingpacing frequencyfrequency atat 1.01.0 Hz.Hz. ToTo simulatesimulate ATS,ATS, wewe progressivelyprogressively reducedreduced Kir2.1Kir2.1 channelchannel conductanceconductance stepwisestepwise byby 10%10% andand toto simulatesimulate TS,TS, wewe increasedincreased thethe timetime constantconstant ofof voltagevoltage --dependentdependent inactivationinactivation (( ττf)) inin thethe CaCa v1.21.2 channel.channel. WeWe obtainedobtained pseudopseudo --ECGECG fromfrom equationsequations describeddescribed byby GimaGima andand Rudy.Rudy. InwardInward rectifierrectifier potassiumpotassium channelchannel CardiacCardiac excitability:excitability: – Tuning of the resting membrane potential – Repolarization at the final phase of cardiac action potential Nature 362: 127-133 (19932005) IK1 (inward rectifier) AP Andersen -Tawil Syndrome mV ms Timothy Syndrome mV ms ResultsResults AndersenAndersen --TawilTawil SyndromeSyndrome Reduction of Kir 2.1 RMP APD QT Tp – Te TDR Channel Conductance, 90 (mV) (ms) (ms) ( ms) (ms) % control -89.0 236.1 240.2 32.2 24.0 50 -81.5 246.0 259.0 58.0 26.9 60 -78.5 250.0 259.0 59.0 30.0 70 -74.2 253.0 259.0 60.0 33.0 80 -69.4 252.0 259.0 61.0 35.0 90 -65.0 247.0 259.0 62.0 37.0 ResultsResults TimothyTimothy SyndromeSyndrome RMP APD QT Tp – Te TDR Multiplication of τ 90 f (mV) (ms) (ms) (ms) (ms) control -89.0 236.1 240.2 32.2 24.0 2X -88.7 291.2 292.3 43.6 42.0 4X -88.2 366.8 369.1 59.2 57.0 6X -87.8 424.7 428.2 75.6 74.0 8X -87.6 471.6 477.8 93.3 84.0 10X -87.3 508.7 513.3 101.1 94.9 EAD AutomaticityAutomaticity EADEAD AutomaticityAutomaticity TimothyTimothy SyndromeSyndrome M cell τf =12X ms Andersen -Tawil Syndrome Timothy Syndrome APDAPD restitutionrestitution curvescurves Andersen -Tawil Syndrome Timothy Syndrome ConclusionConclusion (1)(1) DespiteDespite EADEAD andand spontaneousspontaneous AP,AP, relativelyrelatively stablestable TDRTDR andand flatflat APDAPD restitutionrestitution maymay accountaccount forfor difficultydifficulty inin triggeringtriggering seriousserious arrhythmiasarrhythmias inin ATSATS andand (2)(2) DADDAD --mediatedmediated triggeredtriggered activityactivity inin thethe presencepresence ofof markedmarked TDRTDR andand steepsteep APDAPD restitutionrestitution maymay bebe responsibleresponsible forfor thethe propensitypropensity toto lethallethal ventricularventricular arrhythmiasarrhythmias inin TS.TS. Thus,Thus, clinicallyclinically TSTS connotesconnotes aa worseworse prognosisprognosis thanthan ATS.ATS. Clancy CE & Rudy Y. Cardio Res. 2001; 50: 301-313 Clancy CE & Rudy Y. Cardio Res. 2001; 50: 301-313 TranslationalTranslational DiscoveryDiscovery Basic Science Clinical Medicine Computational Biology 動力與創新動力與創新 DynamismDynamism andand InnovationInnovation ThanksThanks forfor youryour attentionattention TheThe modelmodel ofof IICa,LCa,L AndersenAndersen --TawilTawil SyndromeSyndrome A. B. ms ms Am J Physiol. 2006 Dec;291(6):H2597-605. Table 1. Effect of stepwise reduction of voltage -dependent inactivation of the Cav1.2 channel on RMP, APD90, QT, TP -TE and TDR RMP APD QT T -T TDR τf 90 P E (mV) (ms) (ms) (ms) (ms) 1X (C) -89.0 236.1 240.2 32.2 24.0 2X -88.7 291.2 292.3 43.6 42.0 4X -88.2 366.8 369.1 59.2 57.0 6X -87.8 424.7 428.2 75.6 74.0 8X -87.6 471.6 477.8 93.3 84.0 10X -87.3 508.7 513.3 101.1 94.9 12X -87.2 541.4 546.3 109.7 107.9 14X -85.8 569.9 580.2 123.3 115.9 16X -83.2 595.5 608.7 134.3 125.9 18X -86.4 615.4 634.2 144.2 140.9 20X -86.6 635.3 657.9 151.9 151.9 Table 2. Effect of stepwise reduction of voltage -dependent inactivation of the Cav1.2 channel on RMP, APD90, QT, TP -TE and TDR under the influence of beta -adrenergic stimulation RMP APD QT T -T TDR τf 90 P E (mV) (ms) (ms) (ms) (ms) 1X (C) -87.5 247.1 239.1 33.0 37.0 2X -87.1 294.1 287.1 45.0 48.0 4X -86.3 363.0 356.0 62.4 61.0 6X -85.6 415.0 410.0 79.0 76.0 8X -84.9 455.0 449.0 91.0 88.0 10X -84.3 489.0 483.0 102.0 100.0 12X -83.7 517.0 509.0 113.0 108.0 14X -83.2 540.0 535.0 122.0 118.0 16X -82.7 559.0 556.0 126.0 126.0 18X -82.5 578.0 578.0 132.0 136.0 20X -81.8 595.0 596.0 139.0 144.0 Table 3. Maximal Slope of APD Restitution Curves Endo M Epi τf C β C β C β 1X 0.51 1.0 0.97 1.07 0.4 0.81 2X 2.35 2.75 1.45 2.40 0.51 2.02 4X 2.40 3.15 2.15 3.10 1.57 2.83 b = beta-adrenergic stimulation C = control with beta-adrenergic stimulation Endo = endocardial cell M = mid-myocardial cell Epi = epicardial cell tf = time constant of voltage-dependent inactivation of the Cav1.2 channel ReferencesReferences Sung RJ , Tamer DM, Agha AS, Castellanos A, Myerburg RJ, Telband H. Etiology of the electrocardiographic pattern of “incomplete right bundle branch block ” in atrial septal defect: An electrophysiologic study. Journal of Pediatrics, 87:1182 -1186, 1975. Sung RJ , Tamer DM, Garcia OL, Castellanos A, Myerburg RJ, Gelband H. Analysis of surgically induced right bundle branch block pattern using intracardiac recording techniques. Circulation, 54:442 -446, 1976. Sung RJ , Castellanos A, Gelband H, Myerburg H, Myerburg RJ. Mechanism of reciprocating tachycardia initiated during sinus rhythm in conce aled Wolff -Parkinson - White syndrome. Circulation, 54:338 -345, 1976. Sung RJ , Ferrer P, Gardia OL, Castellanos A, Gelband H. Atrioventricular reciprocal rhythm and chronic reciprocating tachycardia in a newborn infant with concealed Wolff -Parkinson -White syndrome. British Heart Journal,
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