Evaluation of Index of Cardio-Electrophysiological Balance (iCEB) as a New Biomarker for the Identification of Patients at Increased Arrhythmic Risk

Abstract

Background: Recently a new risk marker for drug-induced arrhythmias called index of cardio-electrophysiological balance (iCEB), measured as QT interval divided by QRS duration, was evaluated in an animal model. It was hypothesized that iCEB is equivalent to the cardiac wavelength λ (λ = effective refractory period (ERP) x conduction velocity) and that an increased or decreased value of iCEB would potentially predict an increased susceptibility to TdP or non-TdP mediated VT/VF, respectively.

Methods: First, the correlation between QT interval and ERP was evaluated by invasively measuring ERP during a ventricular stimulation protocol in humans (N = 40). Then the effect of administration of sotalol and flecainide on iCEB was measured in 40 patients with supraventricular tachycardias. Finally iCEB was assessed in carriers of a long QT syndrome (LQTS, N = 70) or Brugada syndrome (BrS, N = 57) mutation and compared them with genotype negative family members (N = 65).

Results: The correlation between QT interval and ERP was established (Pearson R(2) = 0.25) which suggests that iCEB≈ERPxCV≈QT/QRS. Sotalol administration increased iCEB (+ 0.23; P = 0.01), while it decreased with the administration of flecainide (-0.21, P = 0.03). In the LQTS group iCEB was increased (5.22 ± 0.93, P < 0.0001) compared to genotype negative family members (4.24 ± 0.5), while it was decreased in the BrS group (3.52 ± 0.43, P < 0.0001).

Conclusions: Our data suggest that iCEB (QT/QRS) is a simple but effective ECG surrogate of cardiac wavelength. iCEB is increased in situations that predispose to TdP and is decreased in situations that predispose to non-TdP mediated VT/VF. Therefore, iCEB might serve as a noninvasive and readily measurable marker to detect increased arrhythmic risk.

Keywords: cardiac wavelength; iCEB, risk stratification; index of cardio-electrophysiological balance; sudden cardiac death.

© 2015 Wiley Periodicals, Inc.

Figures

Figure 1

Schematic overview of iCEB. Balance and imbalance of the depolarization (QRS duration) and repolarization (QT interval) of cardiac electrophysiology. Schematic changes in the index of cardio‐electrophysiological balance (iCEB): significant increase/decrease (↑ or ↓) in iCEB by increase/decrease in QT interval or decrease/increase in QRS duration could potentially be proarrhythmic for TdP‐ and non‐TdP mediated VT/VF respectively (imbalance of cardiac electrophysiology). TdP = torsades de pointes; VT = ventricular tachycardia; VF = ventricular fibrillation.

Figure 2

Correlation between ERP and QT. Pearson correlation of invasively measured ERP during EPS and QT measured at the beginning of EPS (N = 40): data indicating that there is a moderate (R2 = 0.25) but highly significant correlation between ERP and QT‐interval (P = 0.001). ERP = effective refractory period; EPS = electrophysiological study.

Figure 3

Effect of sotalol and flecainide on iCEB. Effect of sotalol (left) and flecainide (right) on index of cardio‐electrophysiological balance (iCEB) in patients with paroxysmal supraventricular arrhythmias: data indicating that iCEB was significantly increased after administration of sotalol (mean daily dose 160 mg; N = 20; P = 0.01) and decreased after administration of flecainide (mean daily dose 158 mg; N = 20; P = 0.03).

Figure 4

iCEB in long QT syndrome and Brugada syndrome. Index of cardio‐electrophysiological balance (iCEB; upper panel) and its rate‐corrected values (iCEBc (middle panel) and JTc/QRS (bottom panel)) in carriers of (putative) pathogenic mutations in patients with the congenital long QT syndrome (LQTS) and Brugada syndrome (BrS): Data indicating that iCEB or heart‐rate corrected iCEB (iCEBc or JTc/QRS with Bazett's correction) is significantly increased in LQTS (N = 70; all P

Figure 5

iCEB as risk stratifier in long QT syndrome and Brugada syndrome. Index of cardio‐electrophysiological balance (iCEB) in symptomatic and asymptomatic carriers of (putative) pathogenic long QT syndrome (LQTS) mutations (left panel) and in symptomatic and asymptomatic carriers of (putative) pathogenic Brugada syndrome (BrS) mutations (right panel). Data indicating that there is a significant difference between the symptomatic (N = 15) and asymptomatic LQTS patients (N = 55; P = 0.0002), but no significant difference between the symptomatic (N = 10) and asymptomatic (N = 47; P = 0.32) BrS patients.

Figure 6

iCEB in controls. Index of cardio‐electrophysiological balance in a control population consisting of 65 genotype negative family members of long QT syndrome and Brugada syndrome probands and 40 patients with atrial arrhythmias prior to start of either flecainide or sotalol. Data demonstrating that iCEB is normally distributed in this control population with a reference range of 3.14–5.35.

Figure 7

iCEB according to gender and age. (A) Index of cardio‐electrophysiological balance (iCEB) according to sex. Females have a significantly increased value of iCEB compared to males (P