A novel surface electrocardiogram-based marker of ventricular arrhythmia risk in patients with ischemic cardiomyopathy

Abstract

Background: Better sudden cardiac death risk markers are needed in ischemic cardiomyopathy (ICM). Increased heterogeneity of electrical restitution is an important mechanism underlying the risk of ventricular arrhythmia (VA). Our aim was to develop and test a novel quantitative surface electrocardiogram-based measure of VA risk in patients with ICM: the Regional Restitution Instability Index (R2I2).

Methods and results: R2I2, the mean of the standard deviation of residuals from the mean gradient for each ECG lead at a range of diastolic intervals, was measured retrospectively from high-resolution 12-lead ECGs recorded during an electrophysiology study. Patient groups were as follows: Study group, 26 patients with ICM being assessed for implantable defibrillator; Control group, 29 patients with supraventricular tachycardia undergoing electrophysiology study; and Replication group, 40 further patients with ICM. R2I2 was significantly higher in the Study patients than in Controls (mean ± standard error of the mean: 1.09±0.06 versus 0.63±0.04, P<0.001). Over a median follow-up period of 23 months, 6 of 26 Study group patients had VA or death. R2I2 predicted VA or death independently of demographic factors, electrophysiology study result, left ventricular ejection fraction, or QRS duration (Cox model, P=0.029). R2I2 correlated with peri-infarct zone as assessed by cardiac magnetic resonance imaging (r=0.51, P=0.024). The findings were replicated in the Replication group: R2I2 was significantly higher in 11 of 40 Replication patients experiencing VA (1.18±0.10 versus 0.92±0.05, P=0.019). In combined analysis of ICM cohorts, R2I2 ≥1.03 identified subjects with significantly higher risk of VA or death (43%) compared with R2I2 <1.03 (11%) (P=0.004).

Conclusions: In this pilot study, we have developed a novel VA risk marker, R2I2, and have shown that it correlated with a structural measure of arrhythmic risk and predicted risk of VA or death in patients with ICM. R2I2 may improve risk stratification and merits further evaluation. (J Am Heart Assoc. 2012;1:e001552 doi: 10.1161/JAHA.112.001552.).

Keywords: electrical restitution; electrocardiography; implantable cardioverter defibrillator; risk factors; sudden, death.

Figure 1.

Technique for measurement of diastolic interval surrogate: T_peak to QRS onset (TpQ) and APD surrogate: QRS onset to T_peak (QTp). A. When an S2 arrives after the T_peak the TpQ and QTp are measured as shown on the left of the diagram. B. If the S2 occurs before the T_peak the TpQ is effectively negative. In this case it is measured by subtracting the QTp_-1 interval (QTp for the last drive cycle beat) from the QQ, in the example above this would give a TpQ close to zero.

Figure 2.

Explanation of the R2I2 calculation and demonstration of the body surface restitution relation. A. Plot of QRS onset to T_peak (QTp) against T_peak to QRS onset (TpQ) for representative ECG leads: I (lateral), II (inferior) and V2 (anterior) to explain the Regional Restitution Instability Index (R2I2) calculation in a typical study patient. For each lead, the QTp/TpQ gradient (least-squares regression) was calculated over a 40 ms segment of TpQ range. This segment was then scanned over the range of TpQ with available data to produce gradients at 10-ms intervals (example gradients are shown for lead V2). The difference of the gradient from the mean gradient in each 40 ms segment was calculated. The standard deviation of these values was taken as a measure of APD restitution heterogeneity in each lead. The mean of this was then taken as the R2I2. B. Mean data points for the individual ECG leads from the combined ICM cohorts were calculated and an area graph of the standard error of the mean has been plotted for the same representative leads as in A.

Figure 3.

Endocardial and epicardial borders are drawn; then a large representative area of “normal myocardium” and a small area of “peak scar” are selected as shown in A. Software analysis identifies all voxels with signal intensity >2 standard deviations above “normal myocardium” mean intensity and voxels with signal intensity >50% of the “peak scar” are subtracted from this to obtain the PIZ. Identified voxels that are not in the region of an infarct are discarded.

Figure 4.

Scatter plot for Regional Restitution Instability Index (R2I2) in Control, Primary Study and Replication groups, the line indicates the value chosen to separate a positive and negative R2I2 result and filled squares identify patients who reached the endpoints of VA/death (Primary Study group) or VA (Replication group) during follow-up.

Figure 5.

Plot of Regional Restitution Instability Index (R2I2) against peri-infarct zone (PIZ) in each of the 19 Primary Study group patients for whom paired data were available. Lines are drawn at the optimal cut-off values for both parameters. A least-squares regression line demonstrates significant correlation (r=0.51, P=0.024).

Figure 6.

Receiver operating characteristic curve for Regional Restitution Instability Index (R2I2) in Primary Study group: VA/death versus VA-free survival.

Figure 7.

Kaplan-Meier survival curve for combined Primary Study and Replication groups showing a significantly higher rate of VA in a “high-risk” group with Regional Restitution Instability Index (R2I2)>=1.03 compared with the “low risk” group with R2I2<1.03 (P=0.003, log rank test).

Figure 8.

Diagram shows the last beat of the drive train and the S1 S2 coupling interval at 400, 380, 360 and 340 ms for leads V2 and III. Demonstration of regional heterogeneity in repolarization: little change is seen in V2 and the QRS onset to T_peak (QTp) is stable, while lead III is seen to fragment with 2 peaks and variable QTp. This Primary Study group patient had an R2I2 of 1.63 and had VA during follow-up.