Elsevier

Heart Rhythm

Volume 2, Issue 2, February 2005, Pages 141-146
Heart Rhythm

Epinephrine-induced T-wave notching in congenital long QT syndrome

https://doi.org/10.1016/j.hrthm.2004.11.008Get rights and content

Objectives

The purpose of this study was to characterize the effect of epinephrine on T-wave morphology in patients with congenital long QT syndrome (LQTS).

Background

QT prolongation is a paradoxical, LQT1-specific response to low-dose epinephrine infusion. At rest, notched T waves are more common in LQT2.

Methods

Thirty subjects with LQT1, 28 with LQT2, and 32 controls were studied using epinephrine provocation. Twelve-lead ECG was recorded continuously, and QT, QTc, and heart rate were obtained during each stage. Blinded to phenotype and genotype, T-wave morphology was classified as normal, biphasic, G1 (notch at or below the apex), or G2 (distinct protuberance above the apex).

Results

At baseline, 97% LQT1, 71% LQT2, and 94% control had normal T-wave profiles. During epinephrine infusion, G1- and G2-T waves were more common in LQT2 than in LQT1 (75% vs 26%, P = .009). However, epinephrine-induced G1-T waves were present in 34% of control. Epinephrine-precipitated biphasic T waves were observed similarly in all groups: LQT1 (6/30), LQT2 (3/28), and control (4/32). During low-dose epinephrine infusion (≤0.05 μg/kg/min), G1-T waves occurred more frequently in LQT2 (LQT1: 25% vs 3%; control 9%, P = .02). Low-dose epinephrine-induced G2-T waves were detected exclusively in LQT2 (18%). Low-dose epinephrine elicited G1/G2-T waves in 8 of 15 LQT2 patients with a nondiagnostic baseline QTc.

Conclusions

Biphasic and G1-T waves are nonspecific responses to high-dose epinephrine. Changes in T-wave morphology during low-dose epinephrine (<0.05 μg/kg/min) may yield diagnostic information. G2-notched T waves elicited during low-dose epinephrine may unmask some patients with concealed LQT2.

Introduction

The congenital long QT syndrome (LQTS) was the first genetically defined type of arrhythmia to be understood at the molecular level as a primary cardiac channelopathy.1, 2, 3 To date, six LQTS genes have been identified: KVLQT1(KCNQ1, LQT1), HERG (KCNH2, LQT2), SCN5A (LQT3), ANKB (Ankyrin-B, LQT4), KCNE1(minK, LQT5), and KCNE2 (MiRP1, LQT6).4, 5, 6, 7, 8, 9 Type 1 (LQT1) and type 2 (LQT2) LQTS compose at least 90% of identifiable LQTS-causing mutations.10

Clinically, LQTS affects approximately one in 5,000 to 10,000 persons and can cause syncope, seizures, or sudden death. Such cardiac events occur when the heart's rhythm degenerates into the trademark tachyarrhythmia of LQTS known as torsades de pointes. Natural history studies suggest 40% of patients remain asymptomatic, 50% have at least one cardiac event, and 5% to 10% present with aborted cardiac arrest as the sentinel event.11, 12, 13 Thus, accurate diagnosis of LQTS is of paramount importance. However, at least 25% of individuals with LQTS may have an ECG manifesting equivocal or borderline QT prolongation (“concealed LQTS”).14, 15 New diagnostic modalities are needed for accurate identification of individuals who may harbor this potentially lethal arrhythmogenic substrate.

In addition to QT prolongation, T-wave morphology often is abnormal and notched T waves have been included in diagnostic criteria.16 This pattern of T-wave morphology has been associated with a poor prognosis.17 Particular T-wave ECG patterns have been associated with specific underlying genotypes.18, 19, 20 Moss et al19 reported broad-based, prolonged T-wave pattern in LQT1 distinct from the low-amplitude, moderately delayed T wave observed in LQT2. T-wave humps may provide another ECG marker, in addition to QT interval prolongation to identify LQTS carrier status in an affected family.19 Lupoglazoff et al18 concluded that T-wave notching on a resting ECG was more indicative of LQT2 than LQT1.

We and others previously demonstrated that a paradoxical response to low-dose epinephrine (i.e., prolongation of the absolute QT interval) is an LQT1-specific response.21, 22 Besides the differential QT interval response to epinephrine (shortening vs prolongation), we postulate that epinephrine also affects T-wave morphology differentially because of the underlying genetic heterogeneity in LQTS. The objective of this study was to characterize the effect of epinephrine on T-wave morphology in patients with LQTS.

Section snippets

Study population

Between May 1999 and July 2002, 90 subjects [30 with LQT1 (20 female, 28.0 ± 10.7 years); 28 with LQT2 (14 females, 30.0 ± 13.5 years; 32 age- and sex-matched normal control subjects (20 females, 29.6 ± 11.9 years)] underwent an epinephrine QT stress test approved by the Mayo Foundation Institution Review Board. Retrospective analysis included 19 subjects with LQT1, 15 with LQT2, and 27 controls who were analyzed previously with respect to a paradoxical QT response during epinephrine infusion.21

Results

As expected, baseline QT intervals and calculated QTc were significantly longer in LQTS subjects compared to controls (P < .001)—QT: 466 ± 64 ms (LQTS) versus 410 ± 28 ms (controls, C); QTc: 479 ± 61 ms (LQTS) versus 425 ± 23 ms (C). In addition, baseline QT intervals and QTc in LQT2 subjects were significantly longer than in LQT1 subjects (P < .0002)—QT: 489 ± 80 ms (LQT2) vs 444 ± 35 ms (LQT1) and QTc: 497 ± 80 ms (LQT2) versus 463 ± 27 ms (LQT1). Interestingly, 17 of 30 (57%) LQT1 subjects

Discussion

KCNH2 (HERG; chromosome 7q35–36) encodes the alpha subunit underlying rectifier potassium channels (IKr) in the heart that mediate phase 3 repolarization.23, 24 Mutations of KCNH2 result in decreased IKr as the electrophysiologic phenotype in LQT2 patients.25 Similarly, IKr blockers reduce the slope of phase 3 repolarization and can yield T waves of smaller amplitude and a notched morphology.26 In a LQT2 model using d-sotalol, prolongation of M-cell action potential duration was observed in

Conclusion

Epinephrine-provoked changes in T-wave morphology must be interpreted with great caution. At a high dose (>0.05 μg/kg/min), biphasic and G1-T wave morphologies are nonspecific. Changes in T-wave morphology during low-dose epinephrine infusion may yield diagnostic information and direct strategic genotyping. G2 notching elicited during low-dose epinephrine may unmask some patients with concealed LQT2.

Acknowledgments

We are indebted to the patients and control subjects for participation in the study. We gratefully acknowledge the statisticians at the “Center for Patient Orient Research” (CPOR) for helping with statistics.

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    Dr. Ackerman's research program is supported by a Clinical Scientist Development Award from the Doris Duke Charitable Foundation and the National Institutes of Health (HD42569).

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