Electrical and Structural Substrate of Arrhythmogenic Right Ventricular Cardiomyopathy Determined Using Noninvasive Electrocardiographic Imaging and Late Gadolinium Magnetic Resonance Imaging

Abstract

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a significant cause of sudden cardiac death in the young. Improved noninvasive assessment of ARVC and better understanding of the disease substrate are important for improving patient outcomes.

Methods and results: We studied 20 genotyped ARVC patients with a broad spectrum of disease using electrocardiographic imaging (a method for noninvasive cardiac electrophysiology mapping) and advanced late gadolinium enhancement cardiac magnetic resonance scar imaging. Compared with 20 healthy controls, ARVC patients had longer ventricular activation duration (median, 52 versus 42 ms; P=0.007) and prolonged mean epicardial activation-recovery intervals (a surrogate for local action potential duration; median, 275 versus 241 ms; P=0.014). In these patients, we observed abnormal and varied epicardial activation breakthrough locations and regions of nonuniform conduction and fractionated electrograms. Nonuniform conduction and fractionated electrograms were present in the early concealed phase of ARVC. Electrophysiological abnormalities colocalized with late gadolinium enhancement scar, indicating a relationship with structural disease. Premature ventricular contractions were common in ARVC patients with variable initiation sites in both ventricles. Premature ventricular contraction rate increased with exercise, and within anatomic segments, it correlated with prolonged repolarization, electric markers of scar, and late gadolinium enhancement (all P<0.001).

Conclusions: Electrocardiographic imaging reveals electrophysiological substrate properties that differ in ARVC patients compared with healthy controls. A novel mechanistic finding is the presence of repolarization abnormalities in regions where ventricular ectopy originates. The results suggest a potential role for electrocardiographic imaging and late gadolinium enhancement in early diagnosis and noninvasive follow-up of ARVC patients.

Keywords: arrhythmogenic right ventricular dysplasia; cardiac electrophysiology; early diagnosis; gadolinium; heart ventricles.

Figure 1

Electrical substrate in a healthy adult. (A) Sinus rhythm activation with a typical RV epicardial breakthrough (asterisk) and normal conduction. RV (1) and LV (2) unipolar EGMs have a normal morphology free of fractionation. (B) Schematic maps of normal electrical properties in anatomical regions based on 20 control subjects. Left: fractionation z-score. Right: Fridericia-corrected ARI. The maps show absence of fractionation and ARI values within the normal range. AT: activation time. RA: right atrium. LA: left atrium. RV: right ventricle. LV: left ventricle. ARI: activation-recovery interval. EGM: electrogram.

Figure 2

Electrical substrate of a patient (Patient 6) with advanced disease and a high PVC rate (18.69%). (A) Ventricular epicardial breakthrough during sinus rhythm was abnormal, with earliest activation originating from the basal inferior LV (asterisk). RV (1) and LV (2) unipolar EGMs had normal QRS morphology. (B) EGM fractionation was not abnormal compared to controls (top). Fridericia-corrected ARIs were prolonged compared to control values (middle). Concentrated LGE was visible in the inferior RV (bottom). (C) MRI image of extensive LGE, which was confined to the subepicardial RV (indicated by yellow arrows). PVC: premature ventricular contraction.

Figure 3

Electrical substrate of a patient (Patient 14) with biventricular disease and a moderate PVC rate (1.11%). (A) Sinus rhythm breakthrough was abnormal, with earliest epicardial activation originating from the basal lateral LV (asterisk). RV (1) and LV (2) unipolar EGMs were fractionated (note the voltage scale of low-amplitude EGM 1). (B) Regions of high fractionation were present in both ventricles (top), and Fridericia-corrected ARI values were prolonged compared to control values (middle). LGE was visible in both ventricles (bottom). (C) MRI image of LGE showing scar in both ventricles (yellow arrows).

Figure 4

Electrical substrate of a 26-year-old male (Patient 13) with early disease and no observed PVCs. (A) Sinus rhythm epicardial breakthrough occurred in the inferolateral RV (asterisk in inset) with early activation of the RV free wall. There was a region of non-uniform conduction and fractionated unipolar EGMs (1) between these sites. Remote LV unipolar EGM (2) had a normal morphology. (B) Fractionation in the RV was much greater than control values (top) while Fridericia-corrected ARI values were within the normal range of controls (middle). Minimal LGE was visible in the LV (bottom). (C) MRI showed minimal abnormalities (arrow).

Figure 5

Schematic diagram of earliest epicardial activation of all observed PVC morphologies. Each marker represents a unique PVC morphology, with the number indicating the number of times the morphology was observed during the study. Marker color and shape identify patient ID (indicated below diagram). Sites near the epicardial aspect of the septum are shown on the edge of the RV.

Figure 6

PVC onset and initiation sites of a patient (Patient 6) with a high PVC burden (18.69%). (A) Time-course of observed PVCs in relation to exercise and schematic map of PVC initiation sites. The different PVC initiation sites are labeled A, B, and C and color coded. PVCs occurred only after the onset of exercise, and morphology C appeared only once near peak HR (B) Activation isochrone maps of the three distinct PVC morphologies observed in this patient. Asterisks indicate PVC initiation sites. Morphology B showed very a broad region of early epicardial activation, indicating a possible sub-epicardial origin and possible conduction system involvement. HR: heart rate.

Figure 7

PVC onset and initiation sites of a patient (Patient 14) with a moderate PVC burden (1.11%). (A) Time-course of observed PVCs in relation to exercise and schematic map of PVC initiation sites. Note that morphology C is partially obscured in the post-exercise recording period. (B) Activation isochrone maps of the three distinct PVC morphologies observed in this patient. Asterisks indicate PVC initiation sites.