Electrocardiographic Screening of Arrhythmogenic Cardiomyopathy in Genotype-Positive and Phenotype-Negative Relatives

Abstract

Background: Arrhythmogenic cardiomyopathy is a hereditary cause of ventricular arrhythmias and sudden death. Identifying the healthy genetic carriers who will develop the disease remains a challenge. A novel approach to the analysis of the digital electrocardiograms of mutation carriers through signal processing may identify early electrocardiographic abnormalities. Methods: A retrospective case-control study included a population of healthy genetics carriers and their wild-type relatives. Genotype-positive/phenotype-negative individuals bore mutations associated with the development of arrhythmogenic cardiomyopathy. The relatives included had a non-pathological 12-lead electrocardiogram, echocardiogram, and a cardiac magnetic resonance. Automatic digital electrocardiographic analyses comprised QRS and terminal activation delay duration, the number of QRS fragmentations, ST slope, and T-wave voltage. Results: Digital 12-lead electrocardiograms from 41 genotype-positive/ phenotype-negative (29 simple carriers and 12 double mutation carriers) and 73 wild-type relatives were analyzed. No differences in the QRS length, the number of QRS fragmentations, and the voltage of the T-wave were observed. After adjusting for potential confounders, double carriers showed an average ST-slope flatter than those of the simple carriers and wild type [5.18° (0.73-8.01), 7.15° (5.14-11.05), and 11.46° (3.94-17.49), respectively, p = 0.005]. There was a significant negative correlation between the ST slope and the age in genotype-positive/phenotype-negative relatives (r = 0.376, p = 0.021) not observed in their wild-type counterparts (r = 0.074, p = 0.570). Conclusions: A flattened ST segment may be an early sign of electrical remodeling that precedes T-wave inversion in healthy genetic carriers. A thorough analysis of the digital electrocardiographic signal may help identify and measure early electrical abnormalities.

Keywords: arrhythmogenic right ventricular cardiomyopathy; early diagnosis; electrocardiogram; familiar screening; genetic carrier.

Figure 1

Box plot showing the median and interquartile range of the ST slope in wild-type controls and single- and double-mutation carriers (p = 0.001).

Figure 2

Correlation between ST slope and age. Mutation carriers are presented on the right side and wild-type on the left side.

Figure 3

Example of the automatic measurement of the ST slope in the lead I. Y-Axis shows the voltage (mV). Red asterisks mark the QRS offset and the T-wave onset. The intersection line (green) determines the ST-slope angle with the isoelectric line. (A–C) shows the ST slope of an arrhythmogenic cardiomyopathy patient (−0.4°), a non-affected mutation carrier (1.9°), and a control (9.3°), respectively.