Both transmural dispersion of repolarization and of refractoriness are poor predictors of arrhythmogenicity: a role for iCEB (QT/QRS)?

We read the original article by Nuis, et al.[1] and the reply by Dogan, et al.[2] with great interest. Nuis, et al.[1] examined whether transcatheter aortic valve implantation (TAVI) in patients suffering from severe aortic stenosis led to changes in corrected QT dispersion (cQTD), previously used to predict arrhythmic risk. Dogan, et al.[2] proposed that a different marker, transmural dispersion of repolarization (TDR), has better accuracy in risk prediction. This stems from the observations that action potential duration (APD) varies between different cardiac regions, most notably across the myocardial wall. If the difference is exacerbated (i.e., increased TDR is present), then this can predispose to reentry via unidirectional conduction block. TDR can be approximated by the interval from the peak to the end of the electrocardiographic T wave (T_peak – T_end).[3] Indeed, increases in this interval reflecting TDR have been associated with increased arrhythmic risk in Brugada, long QT and short QT syndromes as well as myocardial infarction.[3]^–[5]

However, the use of TDR is based on the assumption that APD varies concordantly with the effective refractory period (ERP) of the myocardium, i.e. a delayed return of the transmembrane potential to baseline would lead to prolonged myocardial refractoriness. However, APD-ERP concordance may not hold true under all pathophysiological conditions. Experiments in animal models have been useful in studying the mechanisms of cardiac arrhythmogenesis and from these different markers for predicting arrhythmic risk have been formulated.[6]^–[12] Recent experiments in mouse models demonstrate that hypokalaemia, an acquired cause of long QT syndrome, increased APDs in the epicardium but not the endocardium, which led to an increase in TDR. It shortened both epicardial and endocardial ERP, and therefore did not alter the transmural dispersion of refractoriness. Yet, anti-arrhythmic effects produced by the gap junction inhibitor heptanol were observed despite prolonged APDs, an increased TDR.[13] These could be explained by increased ERP alone, but not by transmural dispersion of refractoriness, which remained unchanged.

By contrast, hyperkalaemia is an acquired cause of short QT syndrome. It decreased epicardial but not endocardial APD, leading to an increase in TDR. It decreased epicardial ERP but did not alter endocardial ERP, thereby decreasing the transmural dispersion of refractoriness. Administration of calcium, a known maneuver to electrically stabilize the myocardium, exerted anti-arrhythmic effects. It did so by prolonging epicardial ERP alone, without altering epicardial or endocardial APD, or endocardial ERP. It therefore did not correct for the increased TDR, or further influence transmural dispersion of refractoriness. Therefore, TDR and transmural dispersion of refractoriness were poor predictors of arrhythmogenicity in these models of LQTS and SQTS. Instead, excitation wavelength (λ) given by conduction velocity (CV) × ERP, accurately predicted the changes in arrhythmic tendency in all cases whether in the presence or absence of anti-arrhythmic treatment. λ represents the link between cellular depolarization and repolarization,[14]^,[15] and is the minimum path length that can support a reentrant circuit. Decreases in λ can therefore increase the likelihood of circus-type or spiral wave reentry, whereas increases in λ are associated with decreased likelihood of reentry. A major disadvantage of λ is that it must be determined invasively, but can be approximated by taking the ratio of the time taken for repolarization and depolarization, i.e., QT interval/QRS duration.[16] This was previously termed the index of Cardiac Electrophysiological Balance (iCEB), which can be easily derived from the electrocardiogram. It is firmly based on basic physiological principles and its use warrants further attention. Together, these studies demonstrate the translational value of applying pre-clinical findings to clinical scenarios.[13]^,[14]^,[16]^–[20]