Keep the QT interval: It is a reliable predictor of ventricular arrhythmias

Abstract

The cardiovascular community understands that the QT interval is the surface electrocardiographic representation of ventricular repolarization. However, despite tremendous advances in our understanding of the molecular and cellular basis for cardiac repolarization and its surface ECG representation, clinicians, regulators, and drug developers are increasingly faced with uncertainty over the best way to interpret this parameter. The evidence described below demonstrates that• Prolongation of the QT interval is a reliable predictor of ventricular arrhythmias in some settings, and may be less predictable in others• The arrhythmogenic potential of a given degree of QT prolongation varies among individuals and drugs. Further, the relationship between QT prolongation and arrhythmia susceptibility is non-linear. Multiple mechanisms may underlie QT prolongation, and these may carry different arrhythmogenic potential.• There is little doubt that further understanding of the cellular and molecular mechanisms underlying repolarization hold the promise of developing better indices of the arrhythmogenic potential of abnormalities of repolarization, but that science has not yet matured A caveat: The QT interval is hard to measureMeasuring the QT is hard enough when it is normal, and it is almost impossible to come up with a workable number in the face of common disease-associated ECG changes such as diffuse ST segment changes, inverted T-waves, small or large U-waves, or pauses (see Figure 1). A second problem is rate: while there is absolutely no doubt that action potential durations in ventricular tissue, and the QT interval, are exquisitely dependent on previous cycle length or cycle lengths, the "best" method to correct for rate, and thus allow QT intervals recorded at different rates to be compared, is not known. Indeed, comparing two "rate-corrected" QT values presupposes that whatever the intervention between the two recordings -often a drug -itself has no effect on rate. Further, even if a drug has no direct effect on rate, common conditions for which drugs are prescribed may be associated with increases in heart rate (e.g. due to fever or to autonomic activation); any effective drug may thus affect heart rate indirectly.

Drug-Induced Arrhythmia

“…40 Despite its significant limitations as a surrogate marker, the QTc interval remains the best established clinical predictor of drug-mediated proarrhythmic risk. 41 …”

Novel Variant in the ANK2 Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome

“…A prolonged QT interval on electrocardiogram (ECG), corrected for heart rate (QTc), is a marker for increased risk for arrhythmia and sudden cardiac death 1 and may be a result of genetic and/or non-genetic factors. Congenital long QT syndrome (LQTS types 1–13) is caused by variants in at least 13 known genes that encode for or affect the stability of critical ion channel proteins 2 .…”

Corrected QT Interval Prolongation in Psychopharmacological Treatment and Its Modulation by Genetic Variation

“…The relationship between QT c and arrhythmia susceptibility is nonlinear, so that it may not correlate well with torsade de pointes and SCD until it reaches far beyond 500 ms [36]. This perspective may call into question the clinical bearing of the association between genetic variants and QT c elongation.…”