Electrophysiological Characterization of Subclinical and Overt Hypertrophic Cardiomyopathy by Magnetic Resonance Imaging-Guided Electrocardiography

Abstract

Background: Ventricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)-guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties.

Objectives: The purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]-), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G-LVH+) and structural phenotype.

Methods: This was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH-, 104 LVH+ (51 G+/53 G-), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (G_AT/G_RTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH- from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia.

Results: Compared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (G_RTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (G_AT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G-LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]).

Conclusions: In the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status.

Keywords: ECG imaging; cardiac magnetic resonance imaging; electrophysiology; hypertrophic cardiomyopathy.

Graphical abstract

Figure 1

ECGI Acquisition and Postprocessing (Top) A 256-lead electrocardiogram (ECG) is recorded using the fully re-useable capturECGI vest. The mirror vest is positioned to match the electrode vest and the participant wears this during the dark blood (HASTE [Half-Fourier Acquisition Single-shot Turbo spin Echo imaging]) anatomical stack acquisition. Heart-torso geometry is obtained using segmentation of the epicardium and the markers on the mirror vest using Amira-Avizo software (Thermo Fisher). The inverse solution is performed according to previously described protocols thereby obtaining 1,000 computed unipolar electrograms. (Bottom Left) Activation time (AT) is defined by the steepest QRS downslope. Repolarization time (RT) is defined by the steepest part of QRS upslope. Both are referenced to earliest epicardial activation. Activation recovery interval (ARI) is the difference between RT and AT. Three points (circle, triangle, square) on AT and ARIc maps are shown and their corresponding AT, RT, ARI are indicated on their computed unipolar electrograms (black arrows show ECGI intervals of the ‘circle’ UEG). RT (and ARI) are corrected for heart rate. (Bottom right) AT/RT gradients: (ΔAT/ ΔRT) between adjacent orange and blue unipolar electrograms (UEGs) are shown. Gradients are measured as the difference in AT/RT between neighboring electrograms divided by their inter-electrode distance (d).

Figure 2

Exemplar AT and ARIc Maps Electrocardiographic imaging (ECGI) detects slowed ventricular conduction (prolongation of activation) even in the absence of left ventricular hypertrophy (LVH) in subclinical hypertrophic cardiomyopathy (HCM) (genotype [G]+ left ventricular hypertrophy [LVH]−). Prolongation of repolarization predominantly occurs in overt HCM (LVH+). ∗Statistically significant, P < 0.05. HV = healthy volunteer; LAO = left anterior oblique; NS = nonsignificant; RAO = right anterior oblique.

Figure 3

Repolarization Gradient Maps ECGI identifies concealed repolarization gradients (G_RTc) occurring in a healthy volunteer and more steeply in subclinical HCM (G+LVH−). (Left) RTc maps and corresponding G_RTc gradient maps are shown with superimposed shape labels showing computed electrodes. (Right) Corresponding unipolar electrograms are shown for each of the 3 computed unipolar electrodes annotated across the gradient. Abbreviations as in Figure 2.

Figure 4

Exemplar Fractionation Maps in HCM G+LVH+ HCM expressing a large region of signal fractionation (A) despite no/minimal LGE (and mild LVH) by cardiovascular magnetic resonance imaging (B).

Central Illustration

Electrophysiological Abnormalities in Hypertrophic Cardiomyopathy and Their Relationship to Risk Markers Subclinical hypertrophic cardiomyopathy (HCM) individuals with pathogenic (P)/likely pathogenic (LP) sarcomeric variants are characterized by slowed ventricular conduction, even in the presence of a normal electrocardiogram (ECG), and spatially heterogenous repolarization. In overt HCM, conduction is regionally slowed and repolarization is prolonged and spatially heterogenous. In overt HCM, electrophysiological abnormalities relate to conventional risk markers: fractionation was worse in those with a sarcomeric mutation (G+LVH+) and more extensive scar, and spatially heterogenous conduction was related to scar extent and the presence of nonsustained ventricular tachycardia. Severity of left ventricular hypertrophy (LVH) associated with regionally slowed conduction and prolonged repolarization.