Long-Term Prognosis of Short QT Interval in Asian Patients: Multicenter Retrospective Cohort Study

Background: Short QT syndrome is a rare, inherited channelopathy associated with sudden cardiac arrest (SCA) but characteristics and prognosis of short QT interval (SQTI) in Asian patients remain unclear. This study aimed to determine clinical characteristics of and outcomes in patients with SQTI in an Asian population. Methods: Consecutive patients with SQTI were recruited. SQTI was dened as a Bazett’s formula-corrected QT interval (QTc) ≤ 340 ms in serial electrocardiograms. Age- and sex-matched patients with a normal QTc and without overt cardiovascular disease were included at a 1:4 ratio. Clinical and ECG features and outcomes were compared between patients with and without SQTI. Results: Thirty-four patients with SQTI [age, 23.5 (21–30.5) years; 31 male] were followed up for 4.8 (2.0– 7.8) years. Early repolarization, tall T wave, and U wave were signicantly more frequent in patients with SQTI than the patients without SQTI. QT dispersion [44.0 (28.0–73.0) vs. 20.0 (12.0–35.0) ms, P<0.001] was signicantly wider and heart rate [52.0 (47.0–58.0) vs. 70.0 (62.3–84.0) /min, P<0.001] was signicantly slower in patients with SQTI than patients without SQTI. Atrial brillation (AF, 11.8% vs. 2.2%, P=0.030) and ventricular arrhythmia (VA)/SCA (8.7% vs 0%, P=0.007) were signicantly more frequent in patients with SQTI than patients without SQTI. SQTI was signicantly associated with AF [odds ratio, 5.911; 95% condence interval, 1.257–27.808; P=0.025] and VA/SCA. Conclusions: In this Asian population, SQTI was associated with AF and VA/SCA. The results are presented as median (interquartile range) for continuous data and as frequency (percentage) for categorical data.


Background
Short QT syndrome (SQTS) is a rare, life-threatening, inherited channelopathy associated with ventricular arrhythmia (VA) and sudden cardiac arrest (SCA). 1 The rst reported clinical case was of familial short QT interval < 300 ms accompanied by arrhythmia. 2 After a while, familial sudden cardiac death (SCD) accompanied with short QT interval and a history of syncope or palpitations was reported. 3 Later, SQTS was found to increase the risk of SCD, especially in young patients who were not previously diagnosed with any disease. The clinical and electrocardiogram (ECG) features, as well as clinical outcomes, remain unclear in Asian patients with SQTS. That is due to the rarity of the condition and the time since its discovery in Western countries. The aim of our study was to determine the clinical characteristics and outcomes of patients with short QT interval (SQTI) in an Asian population.

Study population
This was a multicenter retrospective cohort study. The study design was approved by the institutional review board (IRB number: 4-2019-0644), and the study was conducted in accordance with the Declaration of Helsinki. The institutional review board waived both the need for the acquisition of informed consent from patients to be included in the analysis and the need for review by a critical event committee owing to the study's retrospective nature and the absence of patient identi cation data.
We included consecutive patients with SQTI from January 1999 to March 2019 in three university hospitals in South Korea. SQTI was de ned as a Bazett's formula-corrected QT interval (QTc) ≤340 ms in serial ECGs. For estimating the QT interval, we used GE Healthcare's 12SL software. A representative beat was generated from the selected segment of each lead, and then a composite beat was formed by the representative beats of all independent leads. The global QT interval was considered as the longest QT interval in the multiple leads. Patients of all ages who met the SQTI de nition were included into the SQTI group, even in cases without related symptoms or history of familial SCD (Figure 1). Exclusion criteria were as follows: temporary SQTI due to electrolyte imbalance (e.g. hypercalcemia, hyperkalemia) related to clinical impairments, especially during hospitalization, structural heart disease, and signi cant atrioventricular block (AVB). Age-and sex-matched subjects in the normal QT group were recruited at a 1:4 ratio and had at least three ECGs with normal QTc which were performed from January 1999 to March 2019 in the outpatient clinic. Patients with overt cardiovascular disease, de ned as cardiomyopathy, coronary artery disease, and signi cant bradyarrhythmia, were excluded. Clinical outcomes included arrhythmia outcomes and all-cause death. Arrhythmia outcomes included atrial brillation (AF), VA/SCA, and Mobitz type 2 second-, high-, and third-degree AVB.

Data analysis
The following clinical variables were collected from all recruited subjects: age, sex, height, weight, systolic and diastolic blood pressure, clinical history of loss of consciousness, palpitation, chest pain, SCA, and familial history of SCA, accompanied arrhythmias (AF, VA, premature ventricular complex, supraventricular tachycardia, rst-degree AVB, second-degree AVB, high-degree AVB, third-degree AVB), and ECG parameters (PR interval, QT interval, QT dispersion, heart rate, JT interval, biphasic negativepositive T wave, early repolarization, and tall T waves). Tall T waves were de ned as > 10 mm (1 mV) in any of the precordial leads. 4 QT dispersion was calculated as the difference between the maximum and minimum QT interval in the 12-lead ECG. JT interval was measured from the J point to the T wave peak.
Early repolarization was de ned as an elevation of the QRS-ST junction (J point) in leads other than V1-V3. 5 We compared the baseline characteristics including symptoms, family history, ECG ndings, and clinical outcomes between the two groups.

Statistical Analysis
The results are presented as median (interquartile range) for continuous data and as frequency (percentage) for categorical data. To compare the clinical parameters between groups, we used the Mann Whitney U-test for continuous data and Fisher's exact test for categorical data since all data sets were non-normally distributed. Univariate and multivariate logistic regression analyses were performed to determine the odds ratio of arrhythmia in patients with SQTI. A p-value ≤0.05 was considered statistically signi cant. Data were analyzed using Statistical Package for the Social Sciences version 25.0 (IBM Corporation, Armonk, NY).   . Symptoms included palpitation (n = 4, 11.8%), loss of consciousness (n = 3, 8.8%), chest pain (n = 3, 8.8%). Palpitations (11.8% vs 2.2%, p = 0.030) were signi cantly more frequent in the SQTI group than in the normal QT group. Regarding ECG ndings, QT dispersion was signi cantly wider and heart rate was signi cantly slower in the SQTI group than in the normal QT group. Early repolarization (n = 25, 73.5%), tall T waves (n = 20, 58.8%), and U waves (n = 4, 11.8%) were signi cantly more frequent in the SQTI group than in the normal QT group. There were no signi cant differences in the frequencies of premature ventricular contraction and supraventricular tachycardia between groups. Among patients with SQTI, twelve patients underwent transthoracic echocardiography during the follow-up period, which revealed no structural cardiac abnormalities. had ventricular brillation and underwent cardioverter-de brillator implantation (Fig. 1). Another patient had ventricular tachycardia but he refused cardioverter-de brillator implantation and was lost to follow up. The other patient had SCD. There were no signi cant differences in the occurrence of signi cant AVB between the groups. Multivariate logistic regression analysis adjusted for age and sex, showed SQTI was independently associated with AF [odds ratio, 5.911; 95% con dence interval, 1.257-27.808; P = 0.025] and VA/SCA (statistical comparison could not be performed because the incidence of VA/SCA in the normal QT group was zero). The results are presented as median (interquartile range) for continuous data and as frequency (percentage) for categorical data. The main ndings of the present study are as follows: (1) the prevalence of SQTI was 0.001%; (2) QT dispersion was signi cantly wider and heart rate was signi cantly slower in patients with SQTI than patients with normal QT interval. Early repolarization, tall T waves, and U waves were more frequent in patients with SQTI than patients with normal QT interval; and (3) SQTI was signi cantly associated with AF and VA/SCA.

SQTS diagnostic criteria
Multiple studies have suggested diverse diagnostic criteria for SQTS; de nite diagnostic criteria for SQTS have not been properly established since the condition was rst identi ed. Initially, a constant QT interval ≤300 ms was regarded as a short QT interval. 3 After major population studies, the suggested diagnostic criteria for SQTS were a QTc ≤340 ms or a QTc ≤370 ms in the presence of a pathologic mutation; familial history of SQTS or SCA at <40 years of age; or history of VA in a structurally normal heart, AF in early life, or loss of consciousness that might be strongly related to a cardiac arrhythmia. 6 Sex differences in SQTI The majority of patients with SQTI were male and between 20 and 30 years of age. It is known that the QT interval is shorter in men than in women 7 , which may attributable to the effect of testosterone on the QTc. 89

Symptoms
Over 35% of patients with SQTI had symptoms at presentation; these included, in decreasing frequency, palpitations, loss of consciousness, and chest pain. A previous study showed that the most frequent symptoms were palpitation and syncope, which is in accordance with the present study. 10 The cause of loss of consciousness may be self-terminating VA in patients with SQTS. 11

ECG characteristics
A previous study demonstrated that early repolarization was associated with arrhythmias in patients with SQTS and could be used for identifying the risk of SCA in SQTS. 12 Tall T wave is one of the characteristic ECG ndings in SQTS. 12 QT dispersion was signi cantly wider in the SQTI group than in the normal QT group in the present study. It is known that increases in repolarization dispersion are the possible substrate for reentry, which may result in VA and SCA. 11 A previous study also found that patients with SQTS had signi cantly wider QT dispersion. 13 Arrhythmia outcomes AF was the most frequent arrhythmia in the SQTI group in the present study. A prior study reported that 18.0% of patients with SQTS had AF. 14 Given the close association between SQTS and AF, the latter is included in the SQTS diagnostic criteria. 17 This relationship was found to be attributable to a common KCNQ1 missense mutation (V141M), which caused AF and shortened the QT interval by altering the gating of I Ks channels. 15 Approximately 5.8% of patients experienced VA at the initial SQTI diagnosis.

Limitations
The present study has a number of limitations. First, a small number of patients was included in the present study because SQTI is a rare condition. Large-scaled prospective studies of patients with SQTI are needed. Second, genetic studies were not performed in the patients with SQTI. Third, subjects with normal QT interval were recruited not from the general population but from among hospital visitors; this was decided since ECG is not routinely performed in the general population. However, subjects with normal ECG ndings and without any cardiovascular disease were included to avoid selection bias.