The Heart, Cardiac Action Potentials, And Arrhythmias .
The heart, cardiac action potentials,and arrhythmias and how wemodel themTrine Krogh-Madsen(Christini lab)
Cardiac action potentials vary by region
Cardiac action potentials Upstroke of ventricularAP is Na mediated. At the peak, Ca2 channels open, causingan inward current thatprolongs AP (plateau). Ca2 influx triggersadditional Ca2 releasefrom the sarcoplasmicreticulum. Cytoplasmic Ca2 produces musclecontraction. Cardiac cells havemany different types ofK channels.
What is “computational modeling”?INaCa INa ICa ICa,b INa INaK3 Na dV Ii/CmdtIi gi·(V - Ei)gi f(V,t)K Ca2 JleakJreleaseNa Jp(Ca)PumpExchangerVoltage-gated ion channelNon-voltage-gated ion channelItoIK1 IKr IKs IKp ICa,K Ip(Ca)CVM model of the canine ventricular myocyte 13 state variables and 60 parameterscourtesy of R. Gilmour
What is “computational modeling”?INaCa INa ICa ICa,b INa INaK3 Na dV f( Ii)dtIi gi·(V - Ei)gi f(V,t)K Ca2 JleakJreleaseNa I Na GNam3hj(V ENa )JV 47.13p(Ca) 1 e .1(V 47.13)αm .32Vdm αm (1 m) βmβm .08e 11dt(V 80)Pumpdhαh .135e 6.8 αh(1 h) βhExchangerdt7.5βh dj1 e .1(V 11)Voltage-gated ion channel αj (1 j) βjV 100dt IKr IKs IKp ICa,K Ip(Ca).175e 23Non-voltage-gated ion channelIto IK1αj RT [ Na ]o1 e.15(V 79)CVM modelENaof the caninemyocyteln( ventricular).3[ Na parameters]i 13 state variablesFand 60βj 1 e .1(V 32)courtesy of R. Gilmour
Cardiac ionic models Surge in development of models of cardiac myocyteEP over the last 5-10 years. 37 models included onCell ML website through2004 1/3 in most recent3 years. Multiple models forsame species/region.Number of Cardiac EP 7200119982000199937 TotalCell ML Site
Why use computational modeling forcardiac electrophysiology? Rodent cardiac myocytes havefundamentally different channelexpression levels (especially repolarizingcurrents). Therefore, transgenic modelsare not always appropriate. Modeling allows one to monitor eachcomponent simultaneously – notpossible in experiments. Dynamics can be observed at resolutions that areunattainable experimentally or clinically. It is often cheaper and easier to do so
Cardiac electrical activity: from one cell to many
Gap junctions behave according to Ohm’s lawI V/RCELL 1CELL 2
Normal and pathologicalelectrocardiograms (ECG)
The cause of ventricular arrhythmias The majority of ventricular arrhythmias are a direct result of thedeterioration of heart tissue resulting from a myocardial infarction(commonly known as a heart attack). Arrhythmias are electrical events. Infarctions are mechanical/fluidevents.F. Netter, 1978
How can scar tissue cause arrhythmias?Ventricular tachycardia is usually characterized by reentrant waves of excitation.Wave propagating in presenceof dense scarWave propagating in presenceof scar with viable, butdamaged, tissue within scar
How can scar tissue cause arrhythmias?Wave propagates around, butnot into, scarWave propagates around, andinto, scar
How can scar tissue cause arrhythmias?Wave propagates through scarslowly because the tissue ispoorly coupled
How can scar tissue cause arrhythmias?
How can scar tissue cause arrhythmias?Waves from either side of thescar merge and propagatebeyond scarWaves from either side of thescar merge and propagate backinto scar (excitable wavespropagate into any tissue that isviable and non-refractory)
How can scar tissue cause arrhythmias?The two intra-scar waves,flowing in opposite directions,annihilate one another. Noreentrant rhythm occurs.
How can scar tissue cause arrhythmias?Now let’s examine what canhappen when an ectopic beatoccurs at the “wrong place andwrong time”.
How can scar tissue cause arrhythmias?Because the slow conductionzone can also lengthenrefractory period, the ectopicwave can block by running intothe tail of the preceding wave
How can scar tissue cause arrhythmias?
How can scar tissue cause arrhythmias?
How can scar tissue cause arrhythmias?By the time the ectopic wavereaches the top of the scar, theslow pathway has recovered, andthe wave can reenter the scar. Areentrant rhythm ensues.
How can scar tissue cause arrhythmias?
How can scar tissue cause arrhythmias?
How can scar tissue cause arrhythmias?
How can scar tissue cause arrhythmias?
How can scar tissue cause arrhythmias?
How can scar tissue cause arrhythmias?
How can scar tissue cause arrhythmias?
The electrophysiology study
EP study – an effort in signal processing andpattern recognition Catheters inserted via venous circulation are used topace and record from localized areas. Pacing allows the physician to take control of the heartand probe its function, including: Induction of arrhythmia via timed stimuli to confirm risk; Entrainment mapping and pace mapping – techniques thatemploy pattern matching to determine when an electrode hasbeen properly positioned to within an arrhythmia circuit; CARTO mapping – GPS-like mapping system; Endocardial Solutions – multielectrode basket catheter.
One treatment: ablationRadiofrequency energy destroys tissue by resistive heatingthat creates a non-viable lesion.Tissue that shouldn’t conduct, sometime doesAblation is a cure !!!
Ablation – engineering advances Cryoablation - reversibly test the effectiveness of anablation site with moderately cold temperature; moreextreme temperature makes lesion permanent. Ultrasound and microwave - which have better depthpenetration than radiofrequency ablation. Diode lasers - can deliver controlled low energythrough a variety of fiber configurations (such as loops)to achieve thin, continuous lesions in and arounddefined anatomical structures such as valve orifices.
Implantable cardioverter defibrillator (ICD)
Antitachycardia pacing fibrillation therapy
ICDs don’t always work. ICD shocks can be painful. High-power shocks drain batteries quickly. The more “turbulent” a system becomes, themore difficult it is to alter that system’sdynamics. Can we detect the progression to arrhythmiaonset and disrupt it? Can we improve the efficacy of low-powertherapy (i.e., antitachycardia pacing)?
ICDs – engineering advances Size reduction; longevity increase. Arrhythmia detection improvement – reduction in falseshocks, reducing pain and chronic anxiety. Indication expansion – e.g., biventricular pacing forheart failure. Incorporation of understanding of arrhythmia nonlineardynamics into termination algorithms: The more “turbulent” a system becomes, the more difficult it isto alter that system’s dynamics. Can we detect the progression to arrhythmia onset and disruptit? Can we come up with better pacing algorithms?
How can modeling help us understandcardiac arrhythmias?
0-dimensionalcardiac simulation(i.e., single cell)Can be usedto investigate ratedependence ofrepolarization“restitution”
Restitution hypothesis of alternansAAPDn f(DIn-1)DIBIncompleterecovery of IK, ICaIncomplete cyclingof Ca2 CAPD
Alternans controlBasic concept: control alternans by applying (small)electrical stimuli at well-timed intervalsIonic model:
Small pieces ofventricular tissue:
Purkinje fiber experiments(length 2 cm)Small amplitudealternans: controleverywhereLarger amplitudeconcordant alternans:control at stimulus endplus someDiscordant alternans:control at stimulus end,concordant alternans
One-dimensional virtual cardiac fiber
Dynamical spatial heterogeneityCV restitutionIncompleterecovery of INaPropagation of two closely-timed waves down a cable
Alternans in spaceAPDiii 10x 0aDIx ai 1i0i 1ax
Why alternans is problematic:Discordant APD alternans to conduction blockpropagationalong thefiber time modified from R. Gilmour
Alternans control in spatially extendedsystemsPurkinje fiber model:Control offControl offControl onAlternanssuppressed atstimulus endControl onAlternanssuppressedeverywhere
Two-dimensional virtual cardiac tissue
Reentry and tachyarrhythmias
Conduction block can induce reentry
Ionic heterogeneity and alternans2D sheetfibergto, gKsPastore & Rosenbaum,Circ. Res., 2000AnisotropyIonicheterogeneityKrogh-Madsen & Christini,Biophys. J., 2007
w/o ionic heterogeneity:effect of SB is minimalwith ionic heterogeneity:presence of SB causesqualitative change in thedynamics
Three-dimensional virtual cardiac tissue
Whole organ computationalmodeling – 3D atria3D model is built from 2.5-million sets of single-cell kinetic equations, andrealistic human atrial geometry.In addition to anatomical structures such as valves, the model incorporatesheterogeneity in conduction characteristics (diffusion coefficient).Bachmann’s bundlepectinate musclefossa ovalisisthmus regionGong & Christini
PV ectopic focus initiation of AFDiscordant alternans produces a gradient of refractoriness,which causes conduction block and reentry11inferior view;isthmus region in green
Take-home messageCardiac modeling is fun and worthwhile
cardiac electrophysiology? Dynamics can be observed at resolutions that are . slow pathway has recovered, and the wave can reenter the scar. A . heterogeneity in conduction characteristics (diffusion coefficient). Bachmann’s bundle. pectinate muscle.
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