Abriel, H.

Fromer, M.

Granges, S.

Kappenberger, L.

Muller, O.

Prudat, Y.

Pruvot, E.

Ruchat, P.

Vesin, J.M.

Vogt, P.

Serveur académique lausannois

Propagation Velocity Kinetics and Repolarization Alternansin a Sheep Model of Pacing-Induced Atrial FibrillationY Prudat1, JM Vesin1, S Granges1, P Ruchat2, M Fromer2,O Muller2, H Abriel2, L Kappenberger2, P Vogt2, E Pruvot21Signal Processing Institute, EPFL, Lausanne, Switzerland2Service of cardiology, CHUV, Lausanne, SwitzerlandAbstractRepolarization alternans, a beat-to-beat alternation inaction potential duration, enhances dispersion of repolar-ization when propagation velocity is involved. In this work,repolarization dynamics and propagation velocity kineticsare studied in a chronic sheep model of pacing-inducedatrial fibrillation. Two pacemakers were implanted in foursheep, the first one to deliver pacing protocols and the sec-ond one to record a unipolar electrogram. Measuring invivo in a free-behaving sheep model right atrial CV kinet-ics and repolarization alternans during electrical remod-elling was shown to be feasible. A significant and gradualdecrease of propagation velocity and right atrial effectiverefractory period during the weeks preceding sustainedatrial fibrillation was observed. Repolarization alternansand propagation velocity kinetics are promising parame-ters for in vivo assessment of atrial fibrillation susceptibil-ity.1. IntroductionAtrial fibrillation (AF) is the most common arrhythmiaand is frequently responsible for morbid and fatal com-plications. This study investigates the potential of orig-inal electrophysiological parameters (i.e. repolarizationalternans and propagation velocity kinetics) in predictingAF susceptibility in a pacing-induced sheep model of sus-tained AF.It has been shown experimentally that sustained AF re-quires a critical amount of dispersion of repolarization [1]and a critical slowing down of propagation velocity [2].Repolarization alternans, a beat-to-beat alternation in ac-tion potential duration, enhances dynamically the disper-sion of repolarization when propagation velocity is in-volved [3]. Moreover, atrial cells are especially proneto repolarization alternans because of the absence of T-tubules [4]. However, it is unknown whether repolarizationalternans plays a role in sustaining AF and whether the in-volvement of propagation velocity restitution at slow heartrates decreases atrial repolarization alternans threshold.We hypothesize that the increased susceptibility to AFthat takes place during the time course of pacing-inducedelectro-anatomical remodelling is associated with :1. a gradual reduction in atrial repolarization alternansthreshold;2. a gradual reduction in atrial propagation velocity.In this paper, we report on the feasibility of studyingatrial repolarization alternans and propagation velocity ki-netics in a chronic free-behaving sheep model of pacing-induced AF. First we describe the experimental procedureand the parameter extraction approach we used. Then, wepresent some results on the evolution of propagation ve-locity kinetics with respect to the induction of AF. We alsopresent preliminary observations of repolarization wave al-ternation at high pacing rates.2. MethodsTwo pacemakers (VitatronTM ), each with a single leadscrewed into the right atrium (figure 1 (a)) were implantedin four sheep. The first pacemaker was used to recorda broadband (sampling frequency 800 Hz, 0.4 Hz highpass filter) unipolar atrial electrogram (EGM). Figure 1 (b)shows a typical intracavitar EGM. The pacemaker impulse(I) is followed by right atrial depolarization (Ra) and re-polarization (Ta), and far-field ventricular depolarization(Rv). An EGM and a subcutaneous ECG were recordedwith a Holter device and transmitted to a computer byBluetooth. The second pacemaker was used to deliverlong term intermittent burst pacing and electrophysiologi-cal protocols.2.1. Signal analysisIn order to extract the different parameters (repolariza-tion alternans threshold and propagation velocity), iden-tification of timing of each event must first be extractedfrom EGM signals. These different types of event areISSN 0276−6547 953 Computers in Cardiology 2006;33:953−956.(a)IRaRvTaSpikeRaRVRASVCHeadTailBack(b)BackFigure 1. (a) X-ray view of the pacemaker’s leads screwedin the right atrium. (b) Typical right atrial EGM with pace-maker impulse (I), atrial depolarization (Ra), atrial T wave(Ta) and far-field ventricular depolarization (Rv)pacemaker impulse, atrial depolarization and repolariza-tion waves, and far-field ventricular depolarization wave.The pacemaker impulse constitutes the highest fre-quency component of the EGM. The impulse detection iscarried out as follows :1. application of a highpass filter to the EGM signal. AChebyshev filter was used (cutoff frequency 180 Hz);2. application of a threshold (α = 85% of the maximalamplitude of the filtered signal);3. identification of pacemaker impulses as local maxima.Atrial depolarization waves were then identified as thelocal minima (window length of 50 ms) following thepacemaker impulse. A template matching approach wasused to identify the timing of T waves. In order to reducenoise and artifacts, a fourth order polynomial was fittedon each T wave segment. A threshold (85 % of maximalamplitude) was applied to the subcutaneous ECG to detectthe far-field ventricular depolarizations. They were thenidentified by the local maxima.2.2. Experimental procedureThree different pacing protocols, named S1S1, S1S2and burst pacing, were used in the experimental procedure.The first two are measurement protocols and the last one isused for AF induction.The S1S1 protocol was used to determine of atrial repo-larization alternans threshold. It consists of sequences of400 beats applied to the sheep’s right atrium. From one se-quence to the next, the coupling interval is decremented by10 millisecond (ms) steps, starting at 400 ms. This proto-col stops when some stimulus fails to depolarize the rightatrium.The S1S2 protocol was used to determine restitution ofatrial activation time. This protocol consists of sequencesof 20 beats at 400 ms cycle length (S1) followed by deliv-ery of a premature beat (S2). From one sequence to thenext, the time interval between the last S1 beat and the S2,defined as S1S2 interval, is decremented by 10 ms steps(from 400 ms to 30 ms). The time interval between theS2 impulse (I) and the following atrial depolarization (Ra)for each S1S2 interval was measured. The atrial effectiverefractory period was defined as the longest S1S2 intervalthat failed to depolarize the atrial tissue.The pacing protocol leading to sustained AF consists inintermittent sequences of burst pacing of 5-sec durationfollowed by 2-sec rest period. The pacing interval wasprogrammed at 10 ms above the atrial effective refractoryperiod.The experimental procedure was the following :1. measurement protocols (S1S1 and S1S2);2. two weeks of burst pacing protocol (induction ofelectro-anatomical remodeling);3. measurement protocols (S1S1 and S1S2).Measurements of atrial effective refractory period andpropagation velocity made before burst pacing activationwere taken as baseline conditions. Steps 2 and 3 were re-peated until the sheep developed sustained AF.3. ResultsNone of the four implanted sheep developed non-sustained AF at baseline (before burst pacing protocol ac-tivation), in spite of aggressive pacing rates during mea-surement protocols (S1S1 and S1S2).Paced rhythm Non sustained AFS2S1S1S1S1Figure 2. Non-sustained AF induced during the S1S2 pro-tocol. AF started at a S1S2 interval = 100 msThe burst pacing protocol was activated in two sheepin which sustained AF was successfully induced after re-spectively four and six weeks. Interestingly, both sheepdeveloped non-sustained AF after 2 weeks of burst pac-ing during S1S2 protocol for coupling intervals between140 ms and atrial effective refractory period (∼ 110 ms) asshown in figure 2.3.1. Propagation velocity kineticsActivation time restitution was determined in both burst-paced sheep on a 2-week basis. For long S1S2 intervals,activation time remained stable; an increase was noted954(a)(b)(c)S1S2 = 400 msS1S2 = 130 msS1S2 = 120 msS1 S1 S2Activation time = 46 msActivation time = 30 msNo capture = ERPS1S1S1 S1S2Figure 3. Illustration of the slowing of propagation veloc-ity with shortened S1S2 intervals. (a) Normal activationtime for long a S1S2 interval (400 ms). (b) Increase in ac-tivation time near effective refractory period (130 ms). (c)Effective refractory period (no atrial capture at 120 ms).(corresponding to a slowing of propagation velocity) as theS1S2 interval approached atrial effective refractory period(figure 3). Figure 4 shows a representative example of acti-vation time restitution kinetics at baseline (i.e. before burstpacing activation) and after 15 and 30 days of burst pacingbefore sustained AF was induced. Each activation timecurve was fitted by an exponential function using a mini-mum least-squares approach :y = a · exp (−xτ) + cwhere x is the S1S2 interval and y is the correspondingactivation time. The amplitude a, the offset c and the timeconstant τ are the parameters to be estimated.0 50 100 150 200 250 300 350 400051015202530354045S1S2 duration [ms]Activation time [ms]Baseline15 days of burst pacing30 days of burst pacingERP = 160 msERP = 110 msERP = 90 msFigure 4. Evolution of activation time curve during thetime course of burst pacingThe offset c, corresponding to the activation time at rest(400 ms cycle length), increased progressively during thetime curse of rapid pacing from 13 ms at baseline to 17 msand 21 ms after 15 days and 30 days of burst pacing, re-spectively. Also the amplitude a increased with burst pac-ing, which illustrates the slowing of propagation velocityfor coupling intervals close to the effective refractory pe-riod starting at a value of 25 ms at baseline, and increasingto 30 ms and 44 ms after 15 and 30 days of burst pacing,respectively. The corresponding propagation velocities forboth burst-paced sheep are summarized in table 3.1. Nosignificant evolution in the time constant τ was observedwith burst pacing.PVel at rest PVel near ERPSheep # 1 # 2 # 1 # 2Baseline 101 cm/s 110 cm/s 51 cm/s 63 cm/s2 weeks 88 cm/s 92 cm/s 44 cm/s 50 cm/s4 weeks 66 cm/s AF 33 cm/s AF6 weeks AF AF AF AFTable 1. Propagation velocity (PVel) measured for bothburst paced sheep, at rest and near effective refractory pe-riod, from baseline to sustained AF.Atrial effective refractory periods also showed a gradualdecrease during the time course of burst pacing (figure 4).Table 2 summarizes the values of atrial affective refractoryperiod.Sheep # 1 # 2 # 3 # 4Baseline 150 ms 160 ms 150 ms 160 ms2 weeks NA 110 ms 120 ms NA4 weeks NA 90 ms AF NA6 weeks NA AF AF NATable 2. Atrial effective refractory periods measured onfour sheep, from baseline to sustained AF3.2. Atrial repolarization alternansIn two of the four implanted sheep, we were able to re-liably identify alternans of atrial repolarization which wasobserved during S1S1 protocol at coupling intervals nearatrial effective refractory period. Figure 5 shows a rep-resentative example. The top row shows a bipolar sub-cutaneous ECG derivation with 4/1 atrioventricular block.The bottom row shows the intracavitary EGM. Note thealternation of atrial repolarization (Ta), while the far fieldventricular depolarization takes place every 4 atrial beats.In general, atrial repolarization alternans and its thresholdcould not be reliably established during the time course ofburst pacing because of 2/1 atrioventricular block at mostrapid pacing rates.955TaTaTaTaTaRv RvI(a)(b)Figure 5. Example of atrial repolarization alternans duringan S1S1 protocol. (a) Subcutaneous ECG during a four-to-one atrioventricular block. The atrial EGM clearly showsthe beat-to-beat alternation in the repolarization wave am-plitude (Ta). The S1S1 cycle length is 140 ms.4. Discussion and conclusionsWe report here for the first time the observation of rightatrial repolarization alternans in a free-behaving sheepmodel of pacing-induced AF. Importantly, atrial repolar-ization alternans was observed near atrial effective refrac-tory period; its threshold, however, could not be reli-ably determined during pacing-induced electro-anatomicalremodeling because of far field ventricular interference.Also other important changes took place including:1. a gradual decrease in atrial effective refractory period;2. a progressive decrease in propagation velocity at anypacing rates, with a marked slowing near atrial effectiverefractory period.Allessie et al. [5] reported in a similar model the lackof any increase in dispersion of refractory periods with in-creasing susceptibility to AF. Their measurements, how-ever, were made during steady state conditions, i.e. withdelivery of a single premature beat to determine atrialeffective refractory periods. Our findings extend to thewhole heart previous works performed in single cellsshowing the susceptibility of atrial cells to repolarizationalternans (Huser et al [4]). Therefore, repolarization alter-nans might enhance dispersion of refractory periods onlyat pacing rates near atrial refractory periods. Interestingly,Qu et al. [3] showed in simulated tissues that propagationvelocity had to be engaged for discordant alternans to takeplace. Only discordant alternans, where islands of actionportential duration were out of phase, increased dispersionof repolarization. In the present study, propagation veloc-ity declined gradually during the time course of electro-anatomical remodeling, with a steep slowing near atrial re-fractory period. This steep slowing paralleled the suscepti-bility to AF as shown by bouts of non sustained AF at pac-ing rates near atrial refractory periods after 15 and 30 daysof burst pacing. Because atrial repolarization alternans wasmeasured in a single point, and because its threshold couldnot be determined reliably, the role of repolarization al-ternans and propagation velocity in enhancing dispersionof refractory periods and susceptibility to AF could not beestablished. Future studies are warranted in which ven-tricular rate will be controlled by producing atrioventric-ular block. In conclusion, these preliminary results showthe feasibility of measuring both atrial repolarization alter-nans and propagation velocity kinetics and their potentialin predicting susceptibility to AF.AcknowledgementsThis work was supported in part by The Fondation Vau-doise de Cardiologie, The Swiss National Fund for Scien-tific Research, The CardioMet Poˆle, and VitatronTM . Theauthors wish to thank Prof. A. van Oosterom for construc-tive criticism and suggestions on the manuscript.Address for correspondence:Yann PrudatEPFL – STI–ITS-LTS1 Station 11CH - 1015 Lausanne, Switzerlandyann.prudat@epfl.chReferences[1] Allessie MA, Bonke FI, Schopman FJ. Circus movement inrabbit atrial muscle as a mechanism of tachycardia. II. therole of nonuniform recovery of excitability in the occurrenceof unidirectional block, as studied with multiple microelec-trodes. Circ Res 1976;39:168–77.[2] Kuo CS, Munakata K, Reddy CP, Surawicz B. Character-istics and possible mechanism of ventricular arrhythmia de-pendent on the dispersion of action potential durations. Cir-culation 1983;67:1356–67.[3] Qu Z, Garfinkel A, Chen PS, Weiss JN. Mechanisms of dis-cordant alternans and induction of reentry in simulated car-diac tissue. Circulation 2000;102:1664–70.[4] Huser J, Wang YG, Sheehan KA, Cifuentes F, Lipsius SL,Blatter LA. Functional coupling between glycolysis andexcitation-contraction coupling underlies alternans in catheart cells. J Physiol 2000;524 Pt 3:795–806.[5] Wijffels MCEF, Kirchhof CJHJ, Dorland R, Allessie MA.Atrial fibrillation begets atrial fibrillation: A stydy in awakechronically instrumented goats. Circulation 1995;92:1954–1968.956

Propagation velocity kinetics and repolarization alternans in a sheep model of pacing-induced atrial fibrillation.

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Propagation velocity kinetics and repolarization alternans in a sheep model of pacing-induced atrial fibrillation.

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