Long QT syndrome type 1 and 2 patients respond differently to arrhythmic triggers: The TriQarr in vivo study

doi:10.1016/j.hrthm.2020.08.017

Heart Rhythm

Volume 18, Issue 2, February 2021, Pages 241-249

https://doi.org/10.1016/j.hrthm.2020.08.017 Get rights and content

Background

In patients with long QT syndrome (LQTS), swimming and loud noises have been identified as genotype-specific arrhythmic triggers in LQTS type 1 (LQTS1) and LQTS type 2 (LQTS2), respectively.

Objective

The purpose of this study was to compare LQTS group responses to arrhythmic triggers.

Methods

LQTS1 and LQTS2 patients were included. Before and after beta-blocker intake, electrocardiograms were recorded as participants (1) were exposed to a loud noise of ∼100 dB; and (2) had their face immersed into cold water.

Results

Twenty-three patients (9 LQTS1, 14 LQTS2) participated. In response to noise, LQTS groups showed similarly increased heart rate, but LQTS2 patients had corrected QT interval (Fridericia formula) (QTcF) prolonged significantly more than LQTS1 patients (37 ± 8 ms vs 15 ± 6 ms; P = .02). After intake of beta-blocker, QTcF prolongation in LQTS2 patients was significantly blunted and similar to that of LQTS1 patients (P = .90). In response to simulated diving, LQTS groups experienced a heart rate drop of ∼28 bpm, which shortened QTcF similarly in both groups. After intake of beta-blockers, heart rate dropped to 28 ± 2 bpm in LQTS1 patients and 20 ± 3 bpm in LQTS2, resulting in a slower heart rate in LQTS1 compared with LQTS2 (P = .01). In response, QTcF shortened similarly in LQTS1 and LQTS2 patients (57 ± 9 ms vs 36 ± 7 ms; P = .10).

Conclusion

When exposed to noise, LQTS2 patients had QTc prolonged significantly more than did LQTS1 patients. Importantly, beta-blockers reduced noise-induced QTc prolongation in LQTS2 patients, thus demonstrating the protective effect of beta-blockers. In response to simulated diving, LQTS groups responded similarly, but a slower heart rate was observed in LQTS1 patients during simulated diving after beta-blocker intake.

Introduction

Congenital long QT syndrome (LQTS) is an inherited cardiac disease associated with an increased risk of syncope and sudden cardiac death.¹ Genetic testing can identify a pathogenic variant in ∼75% of patients, with KCNQ1 (LQTS type 1 [LQTS1]) and KCNH2 (LQTS type 2 [LQTS2]) the most commonly involved genes.²

External triggers such as auditory stimuli, swimming, and physical stress can trigger potentially fatal ventricular arrhythmias. Interestingly, trigger susceptibility seems to be related to genotype, as ∼99% of arrhythmias that occur during swimming are observed in LQTS1 patients, whereas >80% of arrhythmias in response to auditory stimuli are observed in LQTS2 patients.3, 4, 5, 6

Still, the trigger mechanisms remain incompletely characterized. Wilde et al⁴ suggested that a “long–short” sequence based on ventricular extrasystoles in response to auditory stimuli may initiate arrhythmias in LQTS2 patients. Interestingly, LQTS patients have more hearing disabilities than the general population,⁷ and Moss et al⁵ speculated that LQTS1 patients may be protected from loud noises due to impaired expression of the KCNQ1 gene in stria vascularis in the inner ear. With regard to swimming, activation of the mammalian diving reflex in cold water has been suggested as being involved in the observed increased risk of sudden cardiac death.⁸

To protect against arrhythmias, beta-blockers have been effectively implemented as first-line treatment in most LQTS patients,¹ but the protective effect may differ between LQTS groups.⁹ The difference in the protective effect of treatment and the presentation of arrhythmic triggers observed between LQTS1 and LQTS2 may be explained by the relative activity of the sympathetic/parasympathetic nervous system during exposure to arrhythmic triggers. Therefore, we systematically compared how LQTS1 and LQTS2 patients responded to sudden loud auditory stimuli and simulated diving.

Section snippets

Study population

Genotyped LQTS patients with a KCNQ1 or KCNH2 variant who were older than 18 years and were taking a beta-blocker were invited to participate. Patients were matched 1:1 with controls on sex and age (±5 years). Only LQTS patients were tested on beta-blockers.

The study was performed in accordance with the Declaration of Helsinki and approved by the Danish National Committee on Health Research Ethics (H-17004681) (Exploring Mechanisms and Morphology of QT Interval Prolongation [TriQarr]; //Clinicaltrials.gov

Results

A total of 25 LQTS patients were included in the study. Two patients were excluded because of antibradycardia pacing in 1 and poor ECG quality in 1. Of the remaining 23 patients, 87% were female (mean age 39 ± 10 years) (Table 1). Nine patients (39%) carried a KCNQ1 (LQTS1) variant, and 14 (69%) were KCNH2 carriers (LQTS2). A list of unique variants is given in Supplemental Table 1. Seven patients (30%) were probands. Two patients (9%) had an implantable cardioverter-defibrillator, and 7 (30%)

Discussion

Since the 1990s, it has been known that LQTS patients have increased risk of sudden cardiac death while swimming or upon exposure to sudden auditory stimulation. This study is the first to experimentally examine these triggers in LQTS patients. We demonstrated 2 novel findings. (1) LQTS2 patients have QTc interval prolonged significantly more than LQTS1 patients and matched controls in response to a sudden loud noise. Importantly, after intake of beta-blocker, the exaggerated noise-induced QTc

Conclusion

When exposed to a loud sudden noise, LQTS2 patients had QTc interval prolonged significantly more than did LQTS1 patients. This corresponds well with clinical observations that LQTS2 patients are at increased risk for arrhythmias/sudden cardiac death in association with ringing alarm clocks, phone calls, etc. Importantly, we found that beta-blockers reduced this exaggerated noise-induced QTc prolongation in LQTS2 patients, thus demonstrating the protective effect of beta-blockers and calling

Acknowledgment

We thank professor Preben Homøe for creative input about reproducibility of auditory stimuli.

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: Funding sources: This research was made possible with support from the Danish Heart Foundation (Grant 17-R115-A7532-22065), Elite Research Scholarship by the Danish Ministry of Science, fondsbørsvekselerer Henry Hansen og hustrus legat, and the FUKAP Foundation. Disclosures: All authors have reported that they have no relationships relevant to the contents of this paper to disclose.

: Clinicaltrials.gov Identifier: NCT03291145.

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ClinicalSudden DeathLong QT syndrome type 1 and 2 patients respond differently to arrhythmic triggers: The TriQarr in vivo study

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Study population

Results

Discussion

Conclusion

Acknowledgment

J Am Coll Cardiol

Am J Cardiol

Mayo Clin Proc

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

Auton Neurosci Basic Clin

Heart Rhythm

Heart Rhythm

Clinical
Sudden Death
Long QT syndrome type 1 and 2 patients respond differently to arrhythmic triggers: The TriQarr in vivo study