Validation of the V-index as a metric of ventricular repolarization dispersionusing intracardiac recordings

M Orini1, C Blasi2, M Finlay3, B Hanson4, P Lambiase1, R Sassi5, LT Mainardi2

1Institute of Cardiovascular Science, University College London, United Kingdom2Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Italy3William Harvey Research Institute, Queen Mary University of London, United Kingdom4Department of Mechanical Engineering, University College London, United Kingdom

5Dipartimento di Informatica, Universita degli Studi di Milano, Italy

Abstract

The spatial heterogeneity of ventricular repoalarization(SHVR) is an important factor in arrhythmogenesis andit is related to increased vulnerability to fatal arrhyth-mia. The V-index is a non-invasive estimator of SHVRbased on the analysis of the surface ECG. A significantcorrelation between the V-index and SHVR has been pre-viously demonstrated theoretically and by means of numer-ical simulations. Also, the V-index has been shown to trackexpected changes in SHVR after infusion of drugs that al-ter the cardiac electrophysiology. In this study, we com-pare for the first time estimates from the V-index with di-rect measures of SHVR derived from unipolar elecrogramssimultaneously recorded in the left and right ventricularendocardium and in the left ventricular epicardium. In 22recordings collected in 14 patients with normal ventricles,the V-index showed a tight and significant correlation withdirected measures of SHVR, with correlation coefficientsas high as r = 0.80, whereas other ECG-derived esti-mates of SHVR based on T-peak and T-peak to T-end mea-sures showed lower correlations (r ≤ 0.41 and r ≤ 0.36,respectively). The results of this study suggest that the V-index provides reliable estimates of SHVR.

1. Introduction

The coordination of the electrical excitation and repolar-ization throughout the ventricular myocardium allows theheart to contract and pump blood. An alteration of electri-cal conduction and repolarization can result in a deteriora-tion of the cardiac function or trigger dangerous arrhyth-mia. The spatial heterogeneity of ventricular repolariza-tion (SHVR) refers to a nonhomogeneous recovery of ex-citability and it is an important factor in arrhythmogenesis[1]. An increased dispersion of repolarization constitutes

an arryhthmogenic substrate, that in presence of a trigger(such as an ectopic beat) can lead to functional conduc-tion block, re-entry, ventricular tachycardia/fibrillation andeventually sudden cardiac death [2]. Therefore, to preventsudden cardiac death and better understand mechanismsof arrhythmia, a methodology that provides an accuratequantification of SHVR from non-invasive measurementsis needed. The surface ECG provides non-invasive andcheap measurements of the electrical activity of the heartand can be used to study cardiac repolarization [3, 4]. Inparticular, the morphology of the T-wave is associated withventricular repolarization [5] and parameters that quantifyits morphology have been shown to have a predictive value[6].Recently, the V-index has been proposed as an ECG-derived marker of SHVR [7], and has already shownpromising results [8–10]. With respect to the majority ofother non-invasive indices of SHVR, the V-index presentstwo advantages. Firstly, being based on a biophysicalmodel [11] it provides a clear interpretation of what it ismeasuring. Secondly, the methodology is robust againstnoise and artifacts because it analyzes the morphology ofthe T-wave instead of relying on the localization of fewfiducial points (as for instance the T-peak or T-end).The aim of this study is to provide a validation of the V-index as a marker of SHVR, by comparing it with measuresof dispersion obtained simultaneously from unipolar elec-trograms (UEG) recorded in the left and right ventricularendocardium as well as in the left ventricular epicardium.

2. Experimental protocol

Studies were performed in 14 patients undergoing car-diac electro-physiological studies with a view to diagnosisand ablation of supraventricular tachycardia as describedin [12]. All patients gave prior informed consent. Studies

673ISSN 2325-8861 Computing in Cardiology 2015; 42:673-676.

were performed under minimal conscious sedation in thepost-absorptive state. Antidysrhythmic drugs were discon-tinued for 5 days prior to the study. The study protocolhad local ethics committee approval and conformed to thestandards set by the Declaration of Helsinki. ECG wasrecorded in the standard 12-lead configuration. UEG wererecorded as follows. Decapolar catheters were placed inan epicardial coronary vein via the coronary sinus, at theright ventricular apex and retrogradely within the left ven-tricular cavity adjacent to the epicardial catheter (St JudePathfinder). A reference anodal electrode was placed inthe inferior vena cava. UEG and ECG were sampled at 2KHz (Bard Clearsign, MN, USA). Ventricular pacing wasdelivered from the right ventricular apex during baselineconditions, mental stress and after infusion of Ajmaline, adrug that slows electrical conduction and prolongs actionpotential duration. Only recordings including more than 45beats, and presenting high signal to noise ratio (SNR> 15dB) and few abnormal beats were considered. After selec-tion, 22 recordings (9 baseline, 9 stress, 4 Adjmaline) wereincluded in the study. Example of recordings are shown inFig. 1.

3. Methods

3.1. V-index calculation

The V-index is derived from a simplified version of thebidomain model of the myocardium [13], in which the po-tential recorded at the body surface during a cardial cyclek can be written as [7, 9]:

Ψ(t) = A

D1(t)· · ·

DM (t)

≈ A∆ρ︸ ︷︷ ︸w1

Td(t) + 0.5A∆ρ2︸ ︷︷ ︸w2

Td(t)

(1)In this expression, A = [Ai,m] is the transfer matrixfrom the transmembrane potentials Dm(t) evaluated at in-tracrdiac sources m = 1, . . . ,M and the potentials Ψi(t)recorded on the body surface in correspondence of cardiacleads i = 1, . . . , L. The model assumes that the repo-larization phase of each transmembrane potential can bewritten as Dm(t) = D(t − ρm), i.e. it is obtained bytranslating a constant D(t) by the local repolarization timeρm(k) = ρ(k) + ∆ρm(k), where ρ(k) is the mean repo-larization time calculated across the M sources. In (1),Td(t) = −Dm(t − ρm). In [7], the spatio-temporal dis-tribution of repolarization delays ∆ρm(k) across cardiacsites m and heart beats k was modeled as:

∆ρm(k) = ϑm + φm(k) (2)

where ϑm and φm(k) represent spatial and temporal vari-ability, respectively. The V-index is an estimate of the stan-dard deviation of ϑm, sϑ, which according to the model is

0 0.5 1 1.5 2 2.5 3Time (s)

EC

GR

VLV

EP

IFigure 1. Illustrative example of data (high pass filteredto remove baseline trends), including 12-leads ECG andunipolar electrograms from the right (RV) and left (LV)ventricular endocardium, as well as from left ventricularepicardium (EPI). Spikes represent RV pacing, deliveredat t0i (k).

a measure of SHVR. In particular, as shown in [7], the V-index is obtained as:

Vi =stdk[w2,i(k)]

stdk[w1,i(k)]≈ sϑ (3)

In this study, the standard deviations calculated acrossheart beats k were estimated in a robust way by us-ing the median of absolute differences, defined asmediank[X(k)−median[X(k)]]. The average of Vi acrossleads i was taken as final measure of SHVR.

3.2. Repolarization analysis

The analysis of UEG and ECG was carried out by meansof bespoke algorithms as in previous studies [14–16]. Asshown in the diagrammatic example of Fig. 2, local re-polarization times were measured as the maximum of thefirst derivative of the i-th UEG channel, i.e. tRi (k) =arg max(dVi(t)/dt) [17]. In the ECG, T-peak tPi (k) wasdefined as the apex of the T-wave, and T-end tEi (k) as theinstant for which the tangent of the T-wave at the pointof maximum downslope crosses the baseline (Fig. 3).T-peak and T-peak-end intervals were defined as IPi =tPi (k) − t0i (k) and IEi = tEi (k) − tPi (k), while local re-polarization intervals were IRi = tRi (k) − t0i (k). In theprevious expressions, t0i (k) are the time at which the pac-ing stimuli were delivered (Fig. 1 and Fig. 3). Two metrics

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0 100 200 300 400

−80

−60

−40

−20

0

Time (ms)

AP

(m

V)

0 100 200 300 400

−5

0

5

Time (ms)

UE

G (

au)

Figure 2. Measure of repolarization time of the actionpotential at maximum upslope in the local unipolar elec-trogram (diagrammatic).

were used to calculate reference values for SHVR from theUEGs as:

∆ΣR1 = medk[p

80i [IRi (k)]]; ∆ΣR

2 = stdi[meank[IRi (k)]]

(4)while ECG-derived indices of SHVR were estimated as:

∆ΣP1 = medk[p

80i [IPi (k)]] (5)

∆ΣE1 = medk[p

80i [IEi (k)]] (6)

In (4)-(6), medk and p80i represent the median across heartbeats and the interval from 10th to 90th percentile calcu-lated across leads, respectively.

4. Results

Reference measures of SHVR from endo- and epicar-dial UEG were ∆ΣR

1 = 110.8 ± 25.7 ms (mean ± std),66.4− 105.9− 157.5 ms (min-median-max) and ∆ΣR

2 =44.9±9.85 ms (mean ± std), 30.4−45.5−62.0 ms (min-median-max).Figure 4 shows correlations between ECG-derived mea-sures of SHVR (V , ∆ΣP and ∆ΣE) and reference mea-sures ∆ΣR. Pearson’s (rp) and Spearman’s (rs) corre-lation coefficients were in between 0.71 and 0.80 for V(P < 5·10−4), 0.29 and 0.40 for ∆ΣP (0.10 < P < 0.05),and 0.22 and 0.36 for ∆ΣE (P > 0.10). In comparison,correlation coefficients within intracardiac measures ∆ΣR

1

and ∆ΣR2 , were equal to 0.94.

0.1 0.6 1.1 1.6 2.1 2.6

0.1 0.6 1.1 1.6 2.1 2.6Time (s)

aVLV4TpeakTend

RVLVEPATRT

Figure 3. Illustrative example of data (band pass filtered)and markers of repolarization from the ECG, T-peak tPi (k)and T-end tPi (k) (top panel) and from the UEG, local re-polarization time tRi (k) (bottom panel).

60 100 140

V(m

s)

20

40

60

rp =0.72‡ rs =0.75‡

60 100 140

∆Σ

P 1(m

s)

20406080

100rp =0.41 rs =0.29

∆ΣR1 (ms)

60 100 140

∆Σ

E 1(m

s)

020406080

rp =0.22 rs =0.32

40 60

20

40

60

rp =0.71‡ rs =0.8‡

40 60

20406080

100rp =0.4 rs =0.36

∆ΣR2 (ms)

40 600

20406080

rp =0.26 rs =0.36

Figure 4. Correlation between ECG-derived measuresof dispersion of repolarization V , ∆ΣP and ∆ΣE andmeasures of dispersion of repolarization from intracardiacUEG, ∆ΣR

1 . Pearson’s (rp) and Spearman’s (rs) coeffi-cients are also shown, with (‡) significant correlation. Cor-relations for V were significant (P < 5 · 10−4), while for∆ΣP 0.1 < P < 0.05 and for ∆ΣE P > 0.1. N=22recordings were analyzed.

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5. Discussion and Conclusion

Spatial heterogeneity of ventricular repolarization is animportant factor influencing the arrhythmogenic propertiesof the ventricles. The V-index is an metric recently pro-posed to estimate SHVR non-invasively from the surfaceECG [7]. A tight relation between V-index and the disper-sion of repolarization has been demonstrated theoreticallyand using numerical simulations [9], and it has been con-firmed in studies where patients were given drugs knownto alter the dispersion of repolarization [8].In this study, the V-index was compared with directestimates of SHVR provided by unipolar elecrogramsrecorded in contact with the cardiac tissue, in the left andright ventricle and in the endo- and epicardium. The resultsof this study demonstrate that the V-index significantly cor-relates with direct measures of SHVR.This study present some limitations. The relative smallnumber of patients and recordings was mainly due to theinvasiveness and cost of the procedure. Only recordingduring cardiac pacing were analyzed. This reduces theheart rate dependent temporal variability of repolarization,but it also alter the normal electrical conduction and recov-ery of the heart and it increases SHVR. Finally, althoughthe reference values for SHVR included the dispersion ofrepolarization along the major axes (apex-base, right-leftventricles and endo-epicardium), direct measures of totalSHVR ranging from the sites of earliest to the site of latestrepolarization throughout the entire cardiac muscle mayhave been slightly different.Altogether, this study adds further evidence regarding thereliability of the V-index as a non-invasive estimator ofSHVR.

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Address for correspondence:

M. OriniInstitute of Cardiovscular Science / University College London132 Hampstead Road, London, United Kingdomm.orini@ucl.ac.uk

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