QT Interval Measurement in Congenital and
Acquired Prolonged Ventricular Syndromes:
Old Problems and New Perspectives

Emanuela H. Locati

Institute of Cardiology, Department of Clinical and Experimental Medicine,
University of Perugia, Perugia, Italy

Correspondence: Dr. Emanuela H Locati, Via Vittoria Colonna 40, 20149 Milano, Italy.
E-mail: emlocati@tin.it, fax (+39-02) 48512444

1.  Introduction

Prolonged ventricular repolarization, with abnormal configuration and increased dispersion of QT interval duration, has been associated with an increased risk of malignant arrhythmias in congenital and acquired conditions [1, 2]. The Q-T interval is modulated by multiple factors, such as heart rate level, circadian rhythm and autonomic nervous system activity that cannot fully be evaluated by a brief ECG tracing obtained in basal conditions [3]. Together with the long term analysis of heart rate variability, the long-term analysis of QT interval dynamicity can now be explored from 24-hour ECG Holter recordings by new computerized programs, in some cases already available for routine clinical use. However, the automatic measurement of QT interval by Holter techniques has several methodological limitations, due to the relatively low sampling rates utilized in Holter recordings, the shifting of the isoelectric baseline, the low signal-to-noise ratio, and the difficult determination of the T wave end. To overcome such problems, it has been proposed to utilize the interval from Q wave onset to T wave apex (QT_apex), since in most cases T wave apex can be more accurately identified than T wave end (QT_end) [4]. However, QT_apex cannot be considered equivalent to the total QT duration, particularly in prolonged QT syndromes, where the QT prolongation may affect specifically the terminal components of the T wave [2, 5], whereas the early phase, QT_apex, should mainly account for the rate dependency of ventricular repolarization [4].

Reliable long-term automatic measurements of both QT_apex and QT_end from Holter monitoring can be obtained by averaging procedures, in order to obtain a low-noise ECG signal; however averaging procedures necessarily ignore the instantaneous variations of the QT interval. In contrast, while the long-term beat-to-beat automatic analysis of QT duration can often be unreliable, short-term beat-to-beat procedures can explore the instantaneous fluctuations of QT duration and T wave morphology by sophisticated analyses requiring high quality ECG tracings in controlled conditions.

2.  Long-Term Relation Between Ventricular Repolarization and Heart Rate

Among the several methods proposed to evaluate the long-term modulation of ventricular repolarization by heart rate, one standard approach is to compute the linear regression between QT intervals and correspondent RR intervals, both on the entire 24-hours or on pre-selected time-periods. Of note, a steep slope may indicate a further prolongation of the QT interval at longer cycle lengths, whereas an adequate QT shortening at shorter cardiac cycles; conversely, a flat slope indicates that the QT interval is less dependent from the cardiac cycle, and it fails to shorten at shorter cycle (see Figure 1).

Figure 1. Schematic representation of two linear regressions (steep, solid line, and flat, dashed line) expressing two possible different relation between QT and RR interval.

Recent studies demonstrated that the QT-RR relation shows typical day-night differences [3], with flatter slope during night than during day-time. Also, the QT-RR relation is steeper in females than in males in normal adult subjects, in parallel with a longer duration of the corrected QT interval observed in adult females [6].

3.  Long-Term QT-RR Relation in Congenital Long QT Syndromes

The QT-RR relation can be impaired in conditions of congenital and acquired prolonged ventricular repolarization [4, 7-10]. In patients with congenital long QT syndrome (LQTS), where at least three distinct genotypes (LQT1, LQT2, and LQT3) have been identified, typical gene-specific differences in rate dependency of QT duration have been recently demonstrated [7,8]. Preliminary findings indicate that patients with K+ channel abnormalities (Iks for LQT1 patients with KVLQT1 gene mutations located on chromosome 11, and Ikr for LQT2 with HERG gene-mutations on chromosome 7) may have impaired shortening of QT duration at fast heart rate, i.e. a flat slope of the QT-RR relation. In contrast, LQT3 patients, with SCN5A gene-mutations on chromosome 3, with impaired inactivation of cardiac sodium channels, tend to have further QT prolongation at longer cardiac cycles, i.e. a steep slope of the QT-RR relation [6, 7]. Of note, preliminary findings indicate that distinct patterns of circadian QT variability may also be present in LQTS patients with different genotypes. Patients with LQT3 genotype, with further QT prolongation at low heart rate, have longer corrected QT duration during sleep [11] that may account for the increased incidence of cardiac event during sleep and at rest observed in these patients [7]. In contrast, patients with LQT1 genotype appear to have longer QTc during day time, consistent with an impaired shortening of QT duration at fast heart rate that may account for the higher incidence of cardiac events during activity or stress more often observed among these patients.

4.  Long-Term QT-RR Relation in Acquired Long QT Syndromes

In patients with acquired prolonged ventricular repolarization, the heart rate dependency of QT duration may vary according with the drug and the cardiac condition provoking the QT prolongation. Conflicting information has so far been provided concerning the heart rate dependency of the moderate QT prolongation observed in patients following a myocardial infarction. Recently, patients with malignant arrhythmias were showed to have a steeper QT/RR slope than patients with coronary artery disease but with no history of malignant arrhythmias [12]. Of note, patients with coronary artery disease, when compared to normal subjects, may show lack of circadian modulation of the QT dynamics [12]. Abnormal circadian patterns of prolonged QT interval may be associated with an increased incidence of malignant arrhythmias [13] and sudden cardiac death after myocardial infarction [14].

More consistent information is available on the rate-dependent effects of antiarrhythmic drugs prolonging QT interval duration. A study comparing four drugs with different sensitivity of blockade for potassium channel (d-sotalol, dofetilide, E4031 or MS551) showed differential profile of rate dependence in drug-induced QT prolongation. With the exception of d-sotalol, steeper slopes were present after drug administration when compared to baseline, an effect correspondent to the “reverse-use-dependency” induced by the drugs [9]. In a more recent study, we observed that quinidine not only prolonged ventricular repolarization, but also impairs QT interval shortenings at shorter cycle lengths, corresponding to a "use-dependent" effect [10] (Figure 2). Such lack of QT adaptation at faster heart rate, similar to what observed in LQTS patients with K+ channel abnormalities, may play a role in the genesis of proarrhythmias sometimes observed during quinidine therapy.

5.  Conclusions

The dynamic analysis of the heart rate dependency of QT interval obtained from long-term Holter monitoring can provide a global evaluation of the cardiac substrate and of the risk of arrhythmogenesis in the individual patient. Holter monitoring, being inexpensive and noninvasive, is the technique of choice for evaluating the effect of cardiac therapies, especially antiarrhythmic drugs. The combined analysis of ventricular repolarization dynamics, heart rate variability and mechanisms of onset of arrhythmias may transform Holter monitoring in a “non-invasive electrophysiological test”, can explore the interaction between autonomic nervous system and myocardial substrate, in order to identify subjects at high risk of malignant arrhythmias in congenital and acquired prolonged ventricular repolarization. By this global approach, Holter analysis becomes a real “noninvasive electrophysiological test”, to identify potential risk factors for life-threatening cardiac arrhythmias.

References

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