The re-entry vulnerability index (RVI) is an activation-repolarization marker recently proposed to predict sites of ventricular tachycardia (VT) initiation. RVI is inversely related to the probability of establishing a re-entry. The aim of this study was to characterize the CL dependency of RVI, assess different methods for CL-dependency corrections and test the capability of RVI to predict ventricular arrhythmias. Twenty-four subjects underwent whole heart epicardial mapping using a multi-electrode sock enabling the recording of 240 unipolar electrograms. Ventricular pacing was delivered at CLs decreasing from 600 to 350 ms in steps of 50 ms. In a separate study, 1 patient went into VT during steady state pacing. Predisposition to VT was assessed by using the 10th percentile RVI, termed global RVI. The results show that own to CL dependency of local repolarization, there was a strong positive association between RVI and CL. Local repolarization detrending and correction with the Bazett's formula eliminated the CL dependency, while a weak association was found after correction with the Fredericia's formula. In the patient who developed VT, global RVI was significantly lower than in the patients who did not develop VT. Corrections for CL dependency enhanced these differences. In conclusion, de-trending and Bazett's corrections effectively compensated for the CL dependency of RVI and global RVI may reveal predisposition to ventricular arrhythmias. Further analysis is necessary to establish the role of RVI for risk stratification

Hayward, M

Lambiase, PD

Orini, M

Taggart, P

UCL Discovery

Optimization of the Global Re-entry Vulnerability Index to Minimise CycleLength Dependency and Prediction of Ventricular Arrhythmias during HumanEpicardial Sock MappingMichele Orini1,2, Peter Taggart1, Martin Hayward3, Pier D Lambiase11 University College London, London, United Kingdom2 Barts Heart Centre, St Bartholomew’s Hospital, London, United Kingdom3 University College London Hospitals, London, United KingdomAbstractThe re-entry vulnerability index (RVI) is an activation-repolarization marker recently proposed to predict sites ofventricular tachycardia (VT) initiation. RVI is inverselyrelated to the probability of establishing a re-entry. Theaim of this study was to characterize the CL dependencyof RVI, assess different methods for CL-dependency cor-rections and test the capability of RVI to predict ventric-ular arrhythmias. Twenty-four subjects underwent wholeheart epicardial mapping using a multi-electrode sock en-abling the recording of 240 unipolar electrograms. Ven-tricular pacing was delivered at CLs decreasing from 600to 350 ms in steps of 50 ms. In a separate study, 1 patientwent into VT during steady state pacing. Predisposition toVT was assessed by using the 10th percentile RVI, termedglobal RVI. The results show that own to CL dependencyof local repolarization, there was a strong positive associa-tion between RVI and CL. Local repolarization detrendingand correction with the Bazett’s formula eliminated the CLdependency, while a weak association was found after cor-rection with the Fredericia’s formula. In the patient whodeveloped VT, global RVI was signiﬁcantly lower than inthe patients who did not develop VT. Corrections for CLdependency enhanced these differences. In conclusion, de-trending and Bazett’s corrections effectively compensatedfor the CL dependency of RVI and global RVI may revealpredisposition to ventricular arrhythmias. Further analy-sis is necessary to establish the role of RVI for risk stratiﬁ-cation.1. IntroductionThe re-entry vulnerability index (RVI) is an activation-repolarization marker recently proposed to predict sites ofreentrant ventricular tachycardia (VT) initiation [1,2]. RVIcombines information from proximal electrical repolariza-tion and distal activation to assess the likelihood of estab-lishing the necessary conditions for a re-entrant circuit. Itis deﬁned as the interval between repolarization time (RT)at a site proximal to a line of functional conduction blockand activation time (AT) at an adjacent site [1]. A negativeRVI indicates that repolarization at a given site is fasterthan depolarization at an adjacent site and therefore thatwave-front propagation is possible along the axis betweenthe two sites. The lower the RVI, the more vulnerable thetissue. The primary scope of RVI is to predict sites vulner-able to re-entry and guide catheter ablation therapy withoutthe need of inducing and mapping VT, which for many pa-tients may be unfeasible and dangerous. However, sincelow RVI is mechanistically related to re-entry, the lowestRVI may also be used to assess patients susceptibility toreentrant arrhythmia. In this respect, cycle length depen-dency of repolarization [3,4] may constitute a limitation asit can bias RVI estimates, which can change due to heartrate rather than cardiac risk. This paper investigates cor-rections for RVI heart rate dependency. The aims of thestudy are to (1) Characterize the interaction between RVIand other important electrophysiological indices, includ-ing CL, in the intact human heart; (2) Propose and assescorrections to reduce RVI cycle length dependency; (3)Provide a preliminary assessment of RVIs ability to pre-dict VT.2. MaterialDuring cardio-thoracic surgery, 25 subjects underwentwhole heart epicardial mapping using a multi-electrodesock enabling the recording of 240 unipolar electrograms[3, 5]. Unipolar electrograms were recorded at a samplingfrequency of 2 KHz, band-pass ﬁltered beteen 0.05 − 500Hz, and referenced against the rib retractor. Drive trainsof ventricular pacing were delivered at cycle lengths (CL)decreasing from 600 ms to 350 ms in steps of 50 ms. Inone patient, ventricular pacing at CL = 650 ms was main-tained for about 90 s and discontinued afterwards becauseComputing in Cardiology 2017; VOL 44 Page 1 ISSN: 2325-887X DOI:10.22489/CinC.2017.039-243  of hemodynamic instability and ST changes appearing onelectrocardiogram. After 3 spontaneous sinus beats therhythm became unstable with short runs of VT that quicklydegenerated into ﬁbrillation [6]. The study was stoppedand the normal surgical intervention continued success-fully after cardioversion.3. Methods3.1. Electrophysiological measurementsData were exported and analyzed off line with bespokesoftware as in previous studies [3, 7, 8]. After remov-ing the pacing artifacts and band-pass ﬁltering between0.5 − 20 Hz, local AT and RT were measured as thetime of the maximum negative downslope during the QRScomplex and maximum positive upslope of during the T-wave, respectively [9]. The activation-recovery interval,ARI = RT − AT , was used as standard surrogate for thelocal action potential duration. For each drive train, themedian AT, RT and ARI were calculated and used to esti-mate RVI and other electrophysiological indices at the sixdifferent CLs.The RVI at each recording location i, RV Ii, was calcu-lated taking the minimum difference between RT at site i,and AT at neighboring sites j comprised within a 20 mmradius [1]:RV Ii = minj(RTi −ATj) (1)In this expression, the minimum value is taken to ensurehigh sensitivity to vulnerable sites. Local dispersion ofactivation, DAT, and repolarization, DRT, were estimatedas the range between the 10th and 90th percentile of ATand RT within the same radius, respectively. For each pa-tient, the global RVI, RV IG, was measured as the 10thpercentile of the RV Ii distribution, which represents a ro-bust estimate of the global minimum RVI.3.2. Corrections for CL dependencyFor each patient and cycle length, RVI corrected for CLdependency was estimated by modifying RT prior to RVIcalculation as follows:1. Detrended global RVI, RV IG,D: The median RT wassubtracted to all RT. This correction is based on the as-sumption that CL dependency of repolarization is spatiallyhomogeneous and does not affect the global dispersion ofrepolarization.2. Bazett’s correction, RV IG,B: Local RTs were cor-rected using the Bazett’s formula, RTc = RT/√CL.3. Fredericia’s correction, RV IG,F: Local RTs were cor-rected using the Fredericia’s formula, RTc = RT/3√CL.Figure 1. Cycle length dependency of intra-patient me-dian AT, RT and ARI (panels on the left) and global disper-sion of AT, RT and ARI (panels on the right). Circles andbars represent median and adjusted median absolute devi-ation. Asterisks represent pair-wise signiﬁcant differenceswith respect to distributions for CL = 600 ms. P-valuesobtained though group-wise test are given on top of eachpanel.3.3. Statistical AnalysisLinear correlation was measured with the Spearman’scorrelation coefﬁcient. Central moment and variabilitywere measured with median and adjusted median abso-lute deviation, estimated as the median absolute deviationmultiplied by 1.483 to approximate the standard devia-tion. The Wilcoxon signed-rank test was used for pair-wise comparisons, while the Kruskal-Wallis test was usedfor group-wise comparisons. P < 0.05 was consideredsigniﬁcant.4. ResultsAfter removing recordings with SNR< 12dB, 21,748RVI estimates were obtained pooling together estimatesfrom all non-VT patients and CLs. Median AT and globalAT dispersion were not associated with CL (Fig. 1A-B).Median RT signiﬁcantly decreased with CL, from 333±42ms for CL = 600 ms to 277 ± 22 ms for CL = 350ms (P << 0.05 for both group-wise and pair-wise,Fig. 1C), while global dispersion of RT only showed anon-signiﬁcant trend to decrease with CL (P = 0.29 forgroup-wise comparisons, Fig. 1D). This result suggeststhat RT detrending may compensate for the CL depen-dency of global RVI. Median ARI and global dispersion ofPage 2   Table 1. Spearman’s correlation coefﬁcients between local RV Ii and local electrophysiological parameters. Results arereported as median ± adjusted median absolute deviation.CL 350 ms 400 ms 450 ms 500 ms 550 ms 600 msAT 0.13 ± 0.24 0.25 ± 0.23 0.22 ± 0.26 0.18 ± 0.2 0.18 ± 0.19 0.14 ± 0.29ARI 0.68 ± 0.14 0.71 ± 0.16 0.65 ± 0.11 0.7 ± 0.092 0.68 ± 0.12 0.74 ± 0.1RT 0.58 ± 0.19 0.58 ± 0.15 0.56 ± 0.17 0.59 ± 0.21 0.62 ± 0.2 0.57 ± 0.27DAT -0.45 ± 0.073 -0.44 ± 0.083 -0.52 ± 0.1 -0.5 ± 0.11 -0.5 ± 0.078 -0.51 ± 0.095DARI -0.31 ± 0.13 -0.39 ± 0.12 -0.38 ± 0.15 -0.37 ± 0.1 -0.4 ± 0.13 -0.29 ± 0.21DRT -0.13 ± 0.13 -0.17 ± 0.086 -0.2 ± 0.087 -0.25 ± 0.13 -0.23 ± 0.079 -0.24 ± 0.15Figure 2. Cycle length dependency of global RVIs beforeand after CL correction. Circles and bars represent medianand adjusted median absolute deviation estimated amongpatients without VT. Dotted and dashed horizontal linesrepresent the global RVI of the patient who developed VT,at the onset of pacing and about 90 s later before VT on-set, respectively. Asterisks represent pair-wise signiﬁcantdifferences with respect to distributions for CL = 600 ms.Figure 3. RVI map in the one patient who developed VT atthe onset of pacing (top panels) and about 90 s later, beforeVT onset (bottom panels). The solid black line representsthe LAD.ARI presented similar association with CL as RT ( Fig. 1E-F).Local RVI,RV Ii, showed a moderate to strong correlationwith local ARI (about 0.7), RT (about 0.6) and local dis-persion of AT (about −0.5) for all CLs (Table 1). GlobalRVI was strongly associated with CL (ﬁg. 2A). The onepatient that went into VT showed low global RVI duringthe ﬁrst seconds of ventricular pacing (RV IG = 173.5 msdotted line), which further decreased toRV IG = 110.5msbefore discontinuing the pacing and the establishment ofVT (dashed line). During this interval, the RVI map for thispatient showed lower RVI in the apical-inferior LV region,which was therefore associated with higher vulnerabilityto re-entry (Fig. 3). As documented in a previous study,this region was also associated with undergoing acute is-chemia [6].Both detrending and Bazett’s correction compensated forCL dependency of RV IG (Fig 2B-C), while RV IG esti-Figure 4. Histograms showing the distribution of globalRVI before and after correction, pooling together all pa-tients without VT and CLs. Vertical lines represent globalRVI estimated in the VT patient before the onset of VT.The ranking of global RVI estimated in the VT patient withrespect to the entire distribution is reported above the line.Page 3   mated after Fredercia’s correction still presented a weakpositive association with CL (Fig 2D). After correctionsfor CL dependency, global RVI for the VT patient was stillsmaller than global RVI for the non-VT patients for all CLs(Fig 2). All corrections enhanced the differences betweenglobal RVI measured in the VT patient before the onset ofVT and the rest of patients (Fig 4).5. DiscussionThis study investigated the CL dependency of RVI, as-sessed three possible corrections and presented prelimi-nary results about the capability of the global RVI to pre-dict ventricular arrhythmia. The main results are: (1)Own to CL dependency of local repolarization, there was astrong positive association between RVI and CL. (2) Localrepolarization detrending and correction with the Bazett’sformula eliminated the CL dependency, while a weak as-sociation between RVI and CL remained after repolariza-tion correction with the Fredericia’s formula. (3) GlobalRVI calculated before VT onset in the patient that wentinto VT was signiﬁcantly lower than global RVI in the 24patients who did not develop VT. Corrections for CL de-pendency enhanced these differences. Interestingly, afterBazett’s correction, the global RVI calculated during theﬁrst seconds of ventricular pacing in the patient that wentinto VT was already lower than global RVI in the rest ofpatients, suggesting that global RVI could provide an earlyassessment of the predisposition to ventricular arrhythmia.The underlying hypothesis of this study is that RVI couldbe used as a risk stratiﬁcation marker. The RVI has beendesigned to capture the interplay between premature ac-tivation, conduction slowing and repolarization time thatis critical for the establishment of re-entrant tachycardia[1, 10]. It is function of both repolarization and conduc-tion dynamics and partially correlates with ARI, RT andlocal dispersion of AT. To compare global RVI among pa-tients with different heart rates, a correction to compensatefor the CL dependency of repolarization is necessary. Theresults of this study suggest that detrending and Bazett’scorrection eliminate CL dependency in the range from350 ≤ CL ≤ 600 ms. However, these results may notapply for different CLs and in particular for CL < 350ms, when both dispersion of AT and RT show CL depen-dency making the interaction more complex [3]. As onlyone patient who developed VT was included in the study,the results about the predictive value of global RVI shouldbe considered as preliminary and further analysis is neces-sary to establish the role of RVI as a stratiﬁcation marker.References[1] Child N, Bishop MJ, Hanson B, Coronel R, Opthof T,Boukens BJ, Walton RD, Eﬁmov IR, Bostock J, Hill Y,Rinaldi CA, Razavi R, Gill J, Taggart P. An activation-repolarization time metric to predict localized regionsof high susceptibility to reentry. Heart rhythm 2015;12(7):1644–53.[2] Hill YR, Child N, Hanson B, Wallman M, Coronel R, PlankG, Rinaldi CA, Gill J, Smith NP, Taggart P, Bishop MJ. In-vestigating a Novel Activation-Repolarisation Time Metricto Predict Localised Vulnerability to Reentry Using Com-putational Modelling. PLoS ONE 2016;11(3):e0149342.[3] Orini M, Taggart P, Srinivasan N, Hayward M, Lambi-ase PD. Interactions between activation and repolariza-tion restitution properties in the intact human heart: In-vivowhole-heart data and mathematical description. PLoS ONE2016;11(9):e0161765.[4] Srinivasan NT, Orini M, Simon RB, Provideˆncia R, KhanF, Segal OR, Babu G, Bradley R, Rowland E, Ahsan S,Chow AW, Lowe M, Taggart P, Lambiase P. Ventricu-lar Stimulus Site Inﬂuences Dynamic Dispersion of Repo-larization In The Intact Human Heart. American Journalof Physiology Heart and Circulatory Physiology 2016;ajp-heart.00159.2016.[5] Taggart P, Orini M, Hanson B, Hayward M, Clayton R, Do-brzynski H, Yanni J, Boyett M, Lambiase PDP. Develop-ing a novel comprehensive framework for the investigationof cellular and whole heart electrophysiology in the in situhuman heart: Historical perspectives, current progress andfuture prospects. Progress in Biophysics and Molecular Bi-ology 2014;115(2-3):252–260.[6] Orini M, Taggart P, Hayward M, Lambiase PD. Spatiotem-poral characterization of the transition from sinus rhythmto ventricular ﬁbrillation during an acute ischemic eventin the intact human heart by whole-heart sock-mapping.HeartRhythm Case Reports 2017;3(5):253–257.[7] Orini M, Hanson B, Monasterio V, Martı´nez JP, HaywardM, Taggart P, Lambiase P. Comparative evaluation ofmethodologies for T-wave alternans mapping in electro-grams. IEEE Trans Biomed Eng 2014;61(2):308–316.[8] Orini M, Citi L, Hanson BMB, Taggart P, Lambiase PDP.Characterization of the Causal Interactions Between Depo-larization and Repolarization Temporal Changes in Unipo-lar Electrograms. In Computers in Cardiology, volume 40.IEEE, 2013; 719–722.[9] Coronel R, de Bakker JMT, Wilms-Schopman FJG, OpthofT, Linnenbank AC, Belterman CN, Janse MJ. Monophasicaction potentials and activation recovery intervals as mea-sures of ventricular action potential duration: Experimen-tal evidence to resolve some controversies. Heart Rhythm2006;3(9).[10] Coronel R, Wilms-Schopman FJ, Opthof T, Janse MJ. Dis-persion of repolarization and arrhythmogenesis. HeartRhythm 2009;6(4):537–543.Address for correspondence:Name: Michele OriniFull postal address: University College London, Gower Street,London, UK.E-mail address: m.orini@ucl.ac.ukPage 4   

Optimization of the global re-entry vulnerability index to minimise cycle length dependency and prediction of ventricular arrhythmias during human epicardial sock mapping

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Optimization of the global re-entry vulnerability index to minimise cycle length dependency and prediction of ventricular arrhythmias during human epicardial sock mapping

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