Faculty Opinions recommendation of Vagal reflexes following an exercise stress test: a simple clinical tool for gene-specific risk stratification in the long QT syndrome.

Abstract Background/Introduction. Genetic abnormalities in heart ion channels can predispose life-threatening arrhythmias. Pathogenic genotype is found in the majority of individuals with phenotype of cardiac channelopathies of which long QT syndrome (LQTS) is the most common. However, incomplete penetrance and substantial heterogeneity in genotype-phenotype relationship results in broad clinical disease spectrum. Purpose. To review data gathered from Vilnius University Hospital Santaros klinikos (VUHSK) probands with LQTS and detect phenotypic differences between groups of individuals according to genetic testing results. Methods. We retrospectively reviewed data from clinical records of study participants with suspected LQTS who were clinically evaluated and treated at VUHSK in 2013-2019 year period. Probands with performed genetic testing were included for the final evaluation. Based on genetic testing results, the participants were divided into group I, involving patients with established genetic diagnosis, and group II, which included patients with no clinically relevant variants identified. Patients with variants of uncertain significance (VUS) were excluded from further analysis. Main characteristics of clinical manifestation (age during first symptoms, syncope, cardiac arrest, etc), results of instrumental examination (ECG, Holter monitoring, exercise stress test), Schwatz & Crotti score were compared between groups I and II. Results. LQTS was suspected for 137 patients; genetic testing was performed for 112 probands: 49 (43.8%) patients had pathogenic and likely pathogenic (P/LP) variant; 12 (10.7%) - VUS; 51 (45.5%) - no clinically relevant variant was determined. Phenotype differences of LQTS were compared between two groups: probands with P/PL variant (group I, n = 49); probands with no alteration found (group II, n = 51) (total of 100 patients). The median age of these two groups was 15 [6] years, 31 (31%) were adults, 56 (56%) were female. Most common P/LP variants among probands were identified in KCNQ1 (Type 1), KCNH2 (Type 2) and CACNA1C (Type 8) genes. Participants with P/PL variant had longer QTc interval on ECG (510 ms [37] vs. 500 ms [41], p = 0.011), 24-hour Holter monitoring (510 ms [34] vs. 500 ms [42], p = 0.013) and during 4th minute of recovery from exercise stress test (485 ms [35] vs. 458 ms [52], p = 0.021), compared to individuals without genetic alterations in LQTS genes. The Schwartz & Crotti score was higher in group I than in group II (3.5 [1.5] vs. 3 [1.25], p = 0.026). Other clinical findings did not differ statistically significantly. Conclusions. Probands with P/PL variants of LQTS had longer QTc intervals and higher Schwartz & Crotti score than patients with no alteration found. Genotype can affect clinical manifestation in patients with LQTS and consequently determine patient’s prognosis and further medical care. Larger scale study is required for more detailed analysis of genotype-driven phenotype differences.

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Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome

ACC Current Journal Review ◽

10.1016/s1062-1458(03)00202-2 ◽

2003 ◽

Vol 12 (3) ◽

pp. 81 ◽

Cited By ~ 1

Author(s):

K. Takenaka ◽

A. Tomohiko ◽

W. Shimizu

Keyword(s):

Long Qt Syndrome ◽

Stress Test ◽

Exercise Stress Test ◽

Exercise Stress ◽

Phenotype Correlation ◽

Long Qt ◽

Genotype Phenotype Correlation ◽

Qt Syndrome

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Exercise Training-Induced Repolarization Abnormalities Masquerading as Congenital Long QT Syndrome

Circulation ◽

10.1161/circulationaha.120.048916 ◽

2020 ◽

Vol 142 (25) ◽

pp. 2405-2415 ◽

Cited By ~ 1

Author(s):

Federica Dagradi ◽

Carla Spazzolini ◽

Silvia Castelletti ◽

Matteo Pedrazzini ◽

Maria-Christina Kotta ◽

...

Keyword(s):

Long Qt Syndrome ◽

Stress Test ◽

Diagnostic Errors ◽

Exercise Stress ◽

Medical Visit ◽

Long Qt ◽

Qt Syndrome ◽

Congenital Lqts ◽

Ecg Abnormalities ◽

Repolarization Abnormalities

Background: The diagnosis of long QT syndrome (LQTS) is rather straightforward. We were surprised by realizing that, despite long-standing experience, we were making occasional diagnostic errors by considering as affected subjects who, over time, resulted as not affected. These individuals were all actively practicing sports—an observation that helped in the design of our study. Methods: We focused on subjects referred to our center by sports medicine doctors on suspicion of LQTS because of marked repolarization abnormalities on the ECG performed during the mandatory medical visit necessary in Italy to obtain the certificate of eligibility to practice sports. They all underwent our standard procedures involving both a resting and 12-lead ambulatory ECG, an exercise stress test, and genetic screening. Results: There were 310 such consecutive subjects, all actively practicing sports with many hours of intensive weekly training. Of them, 111 had a normal ECG, different cardiac diseases, or were lost to follow-up and exited the study. Of the remaining 199, all with either clear QTc prolongation and/or typical repolarization abnormalities, 121 were diagnosed as affected based on combination of ECG abnormalities with positive genotyping (QTc, 482±35 ms). Genetic testing was negative in 78 subjects, but 45 were nonetheless diagnosed as affected by LQTS based on unequivocal ECG abnormalities (QTc, 472±33 ms). The remaining 33, entirely asymptomatic and with a negative family history, showed an unexpected and practically complete normalization of the ECG abnormalities (their QTc shortened from 492±37 to 423±25 ms [ P <0.001]; their Schwartz score went from 3.0 to 0.06) after detraining. They were considered not affected by congenital LQTS and are henceforth referred to as “cases.” Furthermore, among them, those who resumed similarly heavy physical training showed reappearance of the repolarization abnormalities. Conclusion: It is not uncommon to suspect LQTS among individuals actively practicing sports based on marked repolarization abnormalities. Among those who are genotype-negative, >40% normalize their ECG after detraining, but the abnormalities tend to recur with resumption of training. These individuals are not affected by congenital LQTS but could have a form of acquired LQTS. Care should be exercised to avoid diagnostic errors.

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Mutation and gender-specific risk in type 2 long QT syndrome: Implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome

Heart Rhythm ◽

10.1016/j.hrthm.2011.03.049 ◽

2011 ◽

Vol 8 (10) ◽

pp. 1537-1543 ◽

Cited By ~ 84

Author(s):

Dimitry Migdalovich ◽

Arthur J. Moss ◽

Coeli M. Lopes ◽

Jason Costa ◽

Gregory Ouellet ◽

...

Keyword(s):

Risk Stratification ◽

Long Qt Syndrome ◽

Cardiac Events ◽

Long Qt ◽

Specific Risk ◽

Life Threatening ◽

Qt Syndrome ◽

And Gender ◽

Gender Specific

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Systematic Evaluation of KCNQ1 Variant Using ACMG/AMP Guidelines and Risk Stratification in Long QT Syndrome Type 1

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.002926 ◽

2020 ◽

Author(s):

Asami Kashiwa ◽

Takeshi Aiba ◽

Hisaki Makimoto ◽

Keiko Shimamoto ◽

Kenichiro Yamagata ◽

...

Keyword(s):

Risk Stratification ◽

Long Qt Syndrome ◽

Multivariable Analysis ◽

Clinical Aspects ◽

Syndrome Type ◽

Long Qt ◽

Specific Risk ◽

C Terminus ◽

Qt Syndrome

Background - Mutation/variant-site specific risk stratification in long-QT syndrome type 1 (LQT1) has been well investigated, but it is still challenging to adapt current enormous genomic information to clinical aspects caused by each mutation/variant. We assessed a novel variant-specific risk stratification in LQT1 patients. Methods - We classified a pathogenicity of 141 KCNQ1 variants among 927 LQT1 patients (536 probands) based on the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines and evaluated whether the ACMG/AMP-based classification was associated with arrhythmic risk in LQT1 patients. Results - Among 141 KCNQ1 variants, 61 (43.3%), 55 (39.0%), and 25 (17.7%) variants were classified into pathogenic (P), likely pathogenic (LP), and variant of unknown significance (VUS), respectively. Multivariable analysis showed that proband (HR = 2.53; 95%CI = 1.94-3.32; p <0.0001), longer QTc (≥500ms) (HR = 1.44; 95%CI = 1.13-1.83; p = 0.004), variants at membrane spanning (MS) (vs. those at N/C terminus) (HR = 1.42; 95%CI = 1.08-1.88; p = 0.01), C-loop (vs. N/C terminus) (HR = 1.52; 95%CI = 1.06-2.16; p = 0.02), and P variants [(vs. LP) (HR = 1.72; 95%CI = 1.32-2.26; p <0.0001), (vs. VUS) (HR = 1.81; 95%CI = 1.15-2.99; p = 0.009)] were significantly associated with syncopal events. The ACMG/AMP-based KCNQ1 evaluation was useful for risk stratification not only in family members but also in probands. A clinical score (0~4) based on proband, QTc (≥500ms), variant location (MS or C-loop) and P variant by ACMG/AMP guidelines allowed identification of patients more likely to have arrhythmic events. Conclusions - Comprehensive evaluation of clinical findings and pathogenicity of KCNQ1 variants based on the ACMG/AMP-based evaluation may stratify arrhythmic risk of congenital long-QT syndrome type 1.

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