Spectrum of clinical applications of interlead ECG heterogeneity assessment: From myocardial ischemia detection to sudden cardiac death risk stratification

Abstract

Heterogeneity in depolarization and repolarization among regions of cardiac cells has long been recognized as a major factor in cardiac arrhythmogenesis. This fundamental principle has motivated development of noninvasive techniques for quantification of heterogeneity using the surface electrocardiogram (ECG). The initial approaches focused on interval analysis such as interlead QT dispersion and T_peak -T_end difference. However, because of inherent difficulties in measuring the termination point of the T wave and commonly encountered irregularities in the apex of the T wave, additional techniques have been pursued. The newer methods incorporate assessment of the entire morphology of the T wave and in some cases of the R wave as well. This goal has been accomplished using a number of promising vectorial approaches with the resting 12-lead ECG. An important limitation of vectorcardiographic analyses is that they require exquisite stability of the recordings and are not inherently suitable for use in exercise tolerance testing (ETT) and/or ambulatory ECG monitoring for provocative stress testing or evaluation of the influence of daily activities on cardiac electrical instability. The objectives of the present review are to describe a technique that has been under clinical evaluation for nearly a decade, termed "interlead ECG heterogeneity." Preclinical testing data will be briefly reviewed. We will discuss the main clinical findings with regard to sudden cardiac death risk stratification, heart failure evaluation, and myocardial ischemia detection using standard recording platforms including resting 12-lead ECG, ambulatory ECG monitoring, ETT, and pharmacologic stress testing in conjunction with single-photon emission computed tomography myocardial perfusion imaging.

Keywords: ECG heterogeneity; T-wave alternans; heart failure; myocardial ischemia; sudden cardiac death risk stratification; ventricular arrhythmias.

FIGURE 1

Flowchart of signal processing and computing of the second central moment calculation of R‐wave heterogeneity (RWH) and T‐wave heterogeneity (TWH) in a representative patient with cardiomyopathy with ventricular tachycardia (VT) (left panel), who exhibited greater splay (heterogeneity) than did the patient with cardiomyopathy without VT (right panel). Electrocardiograms were simultaneously obtained from precordial leads V₄, V₅, and V₆. Reprinted with permission from Verrier and Huikuri (2017)

FIGURE 2

Crescendo in depolarization and repolarization heterogeneity [R‐wave heterogeneity (RWH) (□), T‐wave heterogeneity (TWH) (■)] (lower panel), culminating in T‐wave alternans (TWA) and ventricular tachycardia (VT) (upper panel) in lead V₅ in a patient enrolled in the Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Nesiritide Therapy (PRECEDENT) trial. Reprinted with permission from Nearing et al. (2012)

FIGURE 3

Upper panel: Superimposed left precordial lead electrocardiograms (leads V₄–V₆) recorded in a survivor (left) and in a subject who suffered sudden cardiac death (SCD) (right) during the follow‐up period from Health Survey 2000 illustrate R‐wave heterogeneity (RWH), J‐wave heterogeneity (JWH), and T‐wave heterogeneity (TWH). Black horizontal bars indicate the periods when RWH, JWH, and TWH were measured. Lower panel: Kaplan–Meier curves of RWH, JWH, and TWH for SCD with numbers of subjects. Reprinted with permission from Kenttä et al. (2016)

FIGURE 4

Arrhythmia‐free survival (upper panel) and total survival (lower panel) in all cardiomyopathy (CM) patients (n = 70) according to Kaplan–Meier plots. CM patients with arrhythmic events (n = 42) exhibited elevated interlead R‐wave morphology heterogeneity (RWH) (>160 µV) and/or T‐wave morphology heterogeneity (TWH) (>80 µV) compared with those without events (n = 28, p = .012). CM patients who died (N = 6) or were resuscitated (N = 7) had elevated RWH (>160 µV) and/or TWH (>80 µV) compared with survivors (n = 57, p = .011). Reprinted with permission from Tan et al. (2017)

FIGURE 5

Receiver operating characteristic (ROC) curves for the capacity of R‐wave heterogeneity (RWH) and QRS complex duration to predict mechanical super‐response to cardiac resynchronization therapy in patients without left bundle branch block (non‐LBBB). RWH in all lead sets showed significance in non‐LBBB patients. The p value is based on the difference between the areas under the curve (AUCs) and an AUC of 0.5 (random). Reprinted with permission from Bortolotto et al. (2020)

FIGURE 6

Left panel: Time course of effects of vagus nerve stimulation (VNS) therapy on heart rate turbulence (HRT) slope (upper panel), T‐wave alternans (TWA) (middle panel), and numbers of patients with nonsustained ventricular tachycardia (NSVT) >3 beats (lower panel) in the Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM‐HF) Pilot study. The increase in HRT slope is associated with the beneficial effect of increasing baroreceptor sensitivity. Mean TWA was reduced from >70 µV, a severely abnormal level (≥60 µV), to a normal range (<47 µV). The number of patients with NSVT was also significantly decreased by chronic VNS therapy. Middle panels: Significant improvement in R‐wave and T‐wave heterogeneity (RWH and TWH) occurred at 6 months following initiation of VNS and persisted throughout the study. Right panel: Substantial, sustained reductions RWH and TWH in a representative study patient. Tracings were obtained at baseline screening and at 6 and 36 months after VNS device implantation. Left panel: *p = .03 compared with screening; **p = .02 compared with screening; †p < .05 compared with prior. Reprinted with permission from Nearing et al. (2021)

FIGURE 7

Effects of chronic vagus nerve stimulation (VNS) therapy on indices of cardiac performance in the Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM‐HF) Pilot study. Significant increases in left ventricular ejection fraction (LVEF) (upper left panel) were documented across the 3‐year observation period. A beneficial effect was also observed during the 6‐min walk test (6MWT) (upper right panel). All patients exhibited an improvement in New York Heart Association (NYHA) Class status (lower panel). By 6 months, NYHA Class III patients (filled) were all reclassified to NYHA Classes I (open) or II (striped). Reprinted with permission from Nearing et al. (2021)

FIGURE 8

Areas under the receiver operating characteristic curve (AUCs) for an increase in T‐wave heterogeneity in leads V_4–6 (TWH_V4–6) for clinically significant flow‐limiting coronary artery stenosis were 0.737 for exercise tolerance testing (ETT) (left panel) and 0.818 for myocardial perfusion imaging (MPI) with dipyridamole (right panel). ST‐segment changes with ETT and MPI with dipyridamole did not discriminate cases from controls. Reprinted with permission from Silva et al. (2020)

FIGURE 9

True‐positive myocardial perfusion imaging (MPI) case confirmed by coronary angiogram showed a sizeable increase in TWH_V4–6. Regadenoson testing elicited a 30% increase in TWH_V4–6 to 83 µV in an 81‐year‐old woman with chest pain (upper panel). Positive MPI revealed a significant lesion in the right coronary artery territory (lower left panel). Coronary angiogram confirmed an 80% lesion in the right coronary artery (lower right panel). The clinical notes indicated reversible, medium‐sized, moderate severity perfusion defect involving the LAD territory; transient cavity dilation consistent with multi‐vessel or left main disease; and normal left ventricular cavity size and systolic function at rest with stress‐induced global hypokinesis. Reprinted with permission from Araujo Silva et al. (2020)