Thursday, April 9, 2015

Dispersion of Repolarization and Arrhythmogenicity

If you ask 5 cardiologists and 5 toxicologists about the best way to predict the risk of Torsade de Pointes (TdP) in a patient with a prolonged QT, you will likely get 11 different answers. 

Here is what we know: 

  • A corrected QT (QTc) interval > 500 msec is associated with an increased risk of TdP (1). 
  • Not every patient with a QTc interval > 500 msec develops TdP (1). 
  • Not every patient with TdP has a QTc > 500 msec (1). 

You may be thinking this does not make sense, and you are right: there is certainly a gap in our understanding of this phenomenon. There must be many variables that determine a patient’s risk of TdP that are not explained by the QT interval, or even the QTc. And speaking of the QTc, which of the available correction methods provides the best estimation of risk? What about in patients with tachycardia? Bradycardia? Wide QRS? 

Obviously, there are many unanswered questions about predicting TdP. Yet the QTc is often regarded as a deciding factor for determining a patient’s risk of fatal ventricular arrhythmias and whether or not certain medications can be used. 

QT Dispersion

One of the potential explanations for the discrepancy between QTc prolongation and TdP risk is QT dispersion. The QT is typically measured in one lead on a 12-lead EKG (usually a limb lead) (1). Ideally, it is measured manually, and, in the perfect world, a patient-specific correction factor is used to adjust for extreme heart rates (2). But in actuality, if the QT were measured in all 12 leads, there could be significant intra-patient variation between the interval lengths (1). 

This variation is the result of regional heterogeneity of the action potentials occurring across the myocardium (3). This leads to areas of functional refractoriness within the cardiac tissue that creates the perfect environment for re-entrant ventricular arrhythmias or early afterdepolarizations (EADs), resulting in TdP (1). 

QT dispersion, or spatial dispersion, can be quantified:

QT Dispersion = max QT interval – min QT interval on a 12-lead EKG 

Theoretically, QT dispersion may be a better surrogate marker for ventricular repolarization abnormalities than standard QTc measurements (3). Reported normal values of QT dispersion vary from 10-70 msec, but in general extreme values (>100 msec) are associated with an increased risk of death (4). 

Select medications and their dispersion potentials are listed in Table 1 (5). One notable example is amiodarone; this drug is a notorious QT prolonger, but is rarely associated with TdP and is considered safe even in patients that developed TdP on other antiarrhythmic agents. This may be partially explained by amiodarone’s ability to decrease QT dispersion by causing a homogenous prolongation of repolarization across all types of ventricular cells (6).


However, although medications known to cause TdP have been shown to increase dispersion, increased dispersion has not been shown to correlate with the incidence of TdP (7). In a retrospective study by Yamaguchi et al. of 27 patients with acquired prolonged QT, patients with TdP were more likely to have increased dispersion, but in logistic regression analysis, QT dispersion was not identified as an independent risk factor for TdP (8). QT dispersion has, however, been shown to predict mortality in various disease states including chronic obstructive pulmonary disease and end-stage renal disease, with controversial prognostic value in patients with heart disease (4, 9, 10). Much of the excitement over the applicability of QT dispersion in the 1990s has simmered down, leading investigators to seek out other indexes of repolarization abnormalities.

Transmural Dispersion of Repolarization 

Of the three types of cells in the ventricle wall (endocardial, epicardial, and midmyocardial or M cells), the M cells are the most influential contributors to regional differences, especially those located within the intraventricular septum (11). M cells are known to prolong repolarization more than any other type of myocardial cell, and this is traditionally explained by differences in ion channel expression (11).

The refractoriness generated across the myocardial wall from the delayed recovery of M cells is called transmural dispersion of repolarization (TDR) (11). Experimental models have demonstrated that TdP risk may be the result of an enhancement of TDR rather than an overall increase in QT dispersion across the entire myocardium (12). This is because the M cells appear to be most sensitive to effects on the HERG K channel and some medications may selectively prolong repolarization there (12). In contrast, amiodarone (non-selective) may shorten repolarization in the M cells, leading to more uniformity (12). TDR can be represented by:

TDR = (Tpeak – Tend)/QT 

Here, Tpeak is the peak of the t-wave and Tend is the end of the t-wave, as measured in a precordial lead (13). Tpeak has been found to correspond to repolarization of epicardial cells, while Tend corresponds to repolarization of M cells (13). In the study previously mentioned by Yamaguchi et al., (Tpeak-Tend)/QT was identified as an independent risk factor for TdP, with a sensitivity of 80% and specificity of 88% (8). There is, however, still controversy over what this ratio represents and whether it can be clinically useful in risk stratification.

Currently, neither QT dispersion or TDR monitoring are mentioned as a strategy in the 2010 AHA/ACC guideline on the prevention of TdP in hospitals and are not considered standard of care (14). Regardless, clinicians should be aware that the QTc is not a definitive prognostic tool for evaluating repolarization abnormalities, and although the most reliable method of predicting TdP remains unknown, an assessment of dispersion of repolarization may prove to be more accurate than the familiar QTc interval.

Author:

Maria Cardinale, PharmD, BCPS
PGY-2 Critical Care Pharmacy Resident
Yale-New Haven Hospital, New Haven, CT

References:
  1. Bednar MM, Harrigan EP, Anziano RJ, Camm AJ, Ruskin JN. The QT interval.  Prog Cardiovasc Dis 2001; 43:1-45.
  2. Isbister GK. How do we assess whether the QT interval is abnormal: myths, formulae and fixed opinion. Clin Tox 2015; 53(4):189-91.
  3. Day CP, McComb JM, Campbell RW. QT dispersion: an indication of arrhythmia risk in patients with long QT intervals. Br Heart J 1990; 63(6):342-4.
  4. Malik M, Batchvarov VN. Measurement, Interpretation and Clinical Potential of QT Dispersion. J Am Coll Cardiol 2000; 36(6):1749-66.
  5. Krantz MJ, Lowery CM, Martell BA, et al. Effects of Methadone on QT-Interval Dispersion. Pharmacotherapy 2005; 25(11):1523-9.
  6. Hii JTY, Wyse DG, Gillis AM, et al. Precordial QT Interval Dispersion as a Marker of Torsade de Pointes: Disparate Effects of Class Ia Antiarrhythmic Drugs and Amiodarone. Circulation 1992; 86:1376-2.
  7. Celi A. QT Dispersion: Time for a Revival? Intern Emerg Med 2006; 1(4):262-3.
  8. Yamaguchi M, Shimizu M, Ino H, et al. T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity. Clin Sci (Lond) 2003; 105(6):671.
  9. Zulli R, Donati P, Nicosia F, et al. Increased QT dispersion: a negative prognostic finding in chronic obstructive pulmonary disease. Intern Emerg Med 2006; 1: 279-86.
  10. Guney M, Ozkok A, Caliskan Y, et al. QT dispersion predicts mortality and correlates with both coronary artery calcification and atherosclerosis in hemodialysis patients. Int Urol Nephrol 2014; 46(3):599-605.
  11. Antzelevitch C. M Cells in the Human Heart. Circulation Research 2010; 106:815-7.
  12. Said T, Wilson L, Jeyaraj D, et al. Transmural Dispersion of Repolarization as a Preclinical Marker of Drug-induced Proarrhythmia. J Cardiovasc Pharm 2012; 60(2):165-71.
  13. Arteyeva NV, Goshka SL, Sedova KA, et al. What does the Tpeak – Tend interval reflect? An experimental and model study. J Electrocardiol 2013; 46(4):296.e1-296.e8.
  14. Drew BJ, Ackerman MJ, Funk M, et al. American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology, Council on Cardiovascular Nursing, American College of Cardiology Foundation. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation.  J Am Coll Cardiol. 2010; 55(9):934.

Peer Reviewer Comments:
This well-written piece on factors that may contribute to the potential for arrhythmias definitely offers some food for thought in the clinical setting. These phenomena of QT dispersion and transmural dispersion of repolarization that Maria has described may help explain some disparities that we see in clinical practice associated with the QT interval and associated effects. One question that has to be answered include whether or not these same effects hold true not only when medications are used therapeutically, but also in the setting of a toxic ingestion as well. However, it seems that there are currently there are no rules or regulations put forth by the FDA related to evaluation of these effects prior to the approval of new agents, and whether or not this will change in the future in incorporating these (not so novel) phenomena remains to be seen. However, if equipped with the appropriate resources to further evaluate the effects of QT dispersion and transmural dispersion of repolarization, these effects may shed some light on the clinical conundrums in select patients who unexplainably experience Torsades de Pointes that we may manage in our day-to-day practice.
--Nadia Awad, PharmD, BCPS

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