Dynamic conduction and repolarisation changes in early arrhythmogenic right ventricular cardiomyopathy versus benign outflow tract ectopy demonstrated by high density mapping & paced surface ECG analysis

Abstract

Aims: The concealed phase of arrhythmogenic right ventricular cardiomyopathy (ARVC) may initially manifest electrophysiologically. No studies have examined dynamic conduction/repolarization kinetics to distinguish benign right ventricular outflow tract ectopy (RVOT ectopy) from ARVC's early phase. We investigated dynamic endocardial electrophysiological changes that differentiate early ARVC disease expression from RVOT ectopy.

Methods: 22 ARVC (12 definite based upon family history and mutation carrier status, 10 probable) patients without right ventricular structural anomalies underwent high-density non-contact mapping of the right ventricle. These were compared to data from 14 RVOT ectopy and 12 patients with supraventricular tachycardias and normal hearts. Endocardial & surface ECG conduction and repolarization parameters were assessed during a standard S1-S2 restitution protocol.

Results: Definite ARVC without RV structural disease could not be clearly distinguished from RVOT ectopy during sinus rhythm or during steady state pacing. Delay in Activation Times at coupling intervals just above the ventricular effective refractory period (VERP) increased in definite ARVC (43 ± 20 ms) more than RVOT ectopy patients (36 ± 14 ms, p = 0.03) or Normals (25 ± 16 ms, p = 0.008) and a progressive separation of the repolarisation time curves between groups existed. Repolarization time increases in the RVOT were also greatest in ARVC (definite ARVC: 18 ± 20 ms; RVOT ectopy: 5 ± 14, Normal: 1 ± 18, p<0.05). Surface ECG correlates of these intracardiac measurements demonstrated an increase of greater than 48 ms in stimulus to surface ECG J-point pre-ERP versus steady state, with an 88% specificity and 68% sensitivity in distinguishing definite ARVC from the other groups. This technique could not distinguish patients with genetic predisposition to ARVC only (probable ARVC) from controls.

Conclusions: Significant changes in dynamic conduction and repolarization are apparent in early ARVC before detectable RV structural abnormalities, and were present to a lesser degree in probable ARVC patients. Investigation of dynamic electrophysiological parameters may be useful to identify concealed ARVC in patients without disease pedigrees by using endocardial electrogram or paced ECG parameters.

Figure 1. Sinus rhythm electrogram analysis (A) and 3D virtual electrode locations on reconstructed RV shell (B).

A) Activation time in sinus rhythm is taken from the earliest discernable ventricular activation (i.e. start of QRS complex) in any lead, and is measured to the local activation from the unipolar electrogram (most negative dV/dt, red circle). Local repolarization is given as the sharpest upstroke of the T wave, as with paced measurements. Time for activation of the RV is thus calculated as the difference between the local AT of the earliest activating electrode (AT_early) to the local AT of the latest activating electrode (AT_late). B) Virtual electrodes were placed in four rows corresponding to anterior, lateral, medial and posterior aspects of the RV. They thus covered apex (8 electrodes, 4 segments), outflow tract (8 electrodes, 4 segments) and mid-ventricle (8 electrodes, 8 segments). This enabled global electrograms to be collected without overwhelming quantities of data.

Figure 2. Intracardiac signal analysis.

Unipolar electrograms showing the three final activations following a S1S2 train are shown. Timings of stimulus artifact are indicated by S₁, S₂. The moment of local activation (A) is taken as the steepest downsloping point of the electrogram complex (A₀ – A₂). Repolarisation time (RT) is calculated as the time from stimulus to activation. Local repolarization is taken as the most rapid upstroke of the unipolar T-wave (R₀ - R₂) and repolarization time is calculated as the time from stimulus to local repolarization. The ARI is the time between activation and repolarization. Diastolic interval was calculated as A₁A₂ – A₀R₀ (i.e. local activation interval minus the steady state ARI). AT: Activation Time, RT, Repolarization Time, ARI: Activation Repolarisation Index.

Figure 3. Paced ECG analysis.

The final three paced limb-lead ECG complexes following a S1S2 train are shown, with the measurements taken marked. Stim: Stimulus.

Figure 4. Dynamic changes in activation time.

A. Example 3D colormaps showing activation times in steady state and pre-VERP. The change in activation delay in ARVC patients is greater than in Normal Controls & RVOT Ectopy (RVOTE) patients. Color scale represents local activation time relative to pacing stimulus. B. Notched box plot of change in activation times from steady state to ERP. Values are normalized to steady state. Notches indicate approx. 95% confidence intervals.

Figure 5. Dynamic changes in repolarization time.

A. Loess regression plots of Absolute Repolarisation times within the right ventricle are shown, plotted against coupling interval. There is a marked increase in repolarization times throughout the ventricle at short coupling intervals in the definite ARVC group compared to other groups. B. Change in repolarization time at ERP compared to steady state. There is a significantly greater change in definite ARVC groups than in other groups.

Figure 6. Global fractionation.

Panel A shows a notched boxplot of global mean fractionation index. Fractionation is significantly increased in RVOT ectopy and ARVC patients compared to normals. Panel B shows example electrograms (light grey) and their mathematical differentials, from which fractionation index (FI) was calculated. Panel C shows three example colormaps of distribution of fractionation. Higher levels of fractionation are seen in both RVOT ectopy (RVOTE) and ARVC.

Figure 7. 3D color maps of fractionation measured pre-ERP-distribution in Normal individuals, RVOTE and definite ARVC.

There is a patchy distribution of fractionated electrograms in both RVOTE and in ARVC ventricles.

Figure 8. Receiver-operator characteristic (ROC) curves derived from logistic models of electrophysiological criteria.

ROC curves are shown for the individual determinants of the most predictive model for definite ARVC derived from electrogram data. AT: Activation time, VERP: Ventricular effective refractory period, Repol Time: Repolarisation Time.

Figure 9. Typical ECG examples of J-point hysteresis.

Three representative paced ECGs are shown with stimulus to J-point timings of steady state and pre-VERP beats. The ARVC patient has a markedly extended J-point hysteresis pre-VERP than either normal patient or the RVOT ectopy patient.

Figure 10. CART analysis

. Panel A shows the optimum recursive partition tree. An increase in the time from the stimulus to the end of the paced QRS complex (J-point) of >48 ms gave a sensitivity of 67% and specificity of 88% for definite ARVC. B and C show raw data for the principal branches. These measurements were able to distinguish any ARVC patient from RVOT ectopy (RVOTE)/Normal patients with a sensitivity of 67% and specificity of 84%.