Epinephrine-induced T-wave notching in congenital long QT syndrome
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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Cited by (52)
The cardiovascular system as a target of chemical warfare agents
2020, Handbook of Toxicology of Chemical Warfare AgentsClinical Features of Genetic Cardiac Diseases Related to Potassium Channelopathies
2016, Cardiac Electrophysiology ClinicsCitation Excerpt :On top of the QT interval duration, the T-wave morphology is also beneficial for diagnosis of LQTS. Patients with LQT1 typically have a broad-based T wave and those with LQT2 a bifid T wave (Fig. 1),17 which may be apparent at rest or be uncovered by one of the aforementioned tests.18,19 Finally, genetic testing is beneficial in confirming the diagnosis, identifying the type of LQTS, and facilitating family screening.
Cardiovascular System as a Target of Chemical Warfare Agents
2015, Handbook of Toxicology of Chemical Warfare Agents: Second EditionT-wave morphology after epinephrine bolus may reveal silent long QT syndrome mutation carriers
2012, Journal of ElectrocardiologyCitation Excerpt :Instead, a kink is formed in the middle of T wave still leaving positive deflections at the beginning and at the end of the T wave. Similar multicomponent T waves were reported in patients with acquired bradyarrhythmias.24 In the light of experimental models, it has been suggested that the difference in time course of repolarization in the 3 predominant myocardial cell types (epimyocardial, endomyocardial, and midmyocardial M cells) and the voltage gradients between them contribute to the inscription of the T wave in ECG.25
The phenomenon of "qT stunning": The abnormal QT prolongation provoked by standing persists even as the heart rate returns to normal in patients with long QT syndrome
2012, Heart RhythmCitation Excerpt :Consequently, readily-applicable clinical tools to enhance the diagnosis of this dangerous disease are needed. Thus, many patients with suspected LQTS undergo additional diagnostic tests, including Holter recordings,5 exercise tests,6,7 and epinephrine8–11 or adenosine12 challenges. We recently described that patients with LQTS have an insufficient QT-interval shortening in response to the tachycardia provoked by abrupt standing and proposed this phenomenon as an easy bedside test for diagnosing LQTS.13
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).