Light phase-restricted feeding slows basal heart rate to exaggerate the type-3 long QT syndrome phenotype in mice

Long QT syndrome type 3 (LQT3) is caused by mutations in the SCN5A-encoded Nav1.5 channel. LQT3 patients exhibit time of day-associated abnormal increases in their heart rate-corrected QT (QTc) intervals and risk for life-threatening episodes. This study determines the effects of uncoupling environmental time cues that entrain circadian rhythms (time of light and time of feeding) on heart rate and ventricular repolarization in wild-type (WT) or transgenic LQT3 mice ( Scn5a+/ΔKPQ). We used an established light phase-restricted feeding paradigm that disrupts the alignment among the circadian rhythms in the central pacemaker of the suprachiasmatic nucleus and peripheral tissues including heart. Circadian analysis of the RR and QT intervals showed the Scn5a+/ΔKPQ mice had QT rhythms with larger amplitudes and 24-h midline means and a more pronounced slowing of the heart rate. For both WT and Scn5a+/ΔKPQ mice, light phase-restricted feeding shifted the RR and QT rhythms ∼12 h, increased their amplitudes greater than twofold, and raised the 24-h midline mean by ∼10%. In contrast to WT mice, the QTc interval in Scn5a+/ΔKPQ mice exhibited time-of-day prolongation that was flipped after light phase-restricted feeding. The time-of-day changes in the QTc intervals of Scn5a+/ΔKPQ mice were secondary to a steeper power relation between their QT and RR intervals. We conclude that uncoupling time of feeding from normal light cues can dramatically slow heart rate to unmask genotype-specific differences in the QT intervals and aggravate the LQT3-related phenotype.

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Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome

Heart ◽

10.1136/hrt.86.1.39 ◽

2001 ◽

Vol 86 (1) ◽

pp. 39-44

Author(s):

K J Paavonen ◽

H Swan ◽

K Piippo ◽

L Hokkanen ◽

P Laitinen ◽

...

Keyword(s):

Heart Rate ◽

Serum Potassium ◽

Long Qt Syndrome ◽

Qt Interval ◽

Mental Stress ◽

Physical Stress ◽

Exercise Stress ◽

Long Qt ◽

Qt Intervals ◽

Qt Syndrome

OBJECTIVETo study and compare the effects of mental and physical stress on long QT syndrome (LQTS) patients.DESIGNCase–control study.MAIN OUTCOME MEASURESQT intervals were measured from lead V3. Serum potassium and plasma catecholamine concentrations were also monitored.PATIENTS16 patients with type 1 LQTS (LQT1), 14 with type 2 LQTS (LQT2), both groups asymptomatic, and 14 healthy control subjects.INTERVENTIONSThree types of mental stress tests and a submaximal exercise stress test.RESULTSHeart rate responses to mental stress and exercise were similar in all groups. During mental stress, the mean QT interval shortened to a similar extent in controls (–29 ms), LQT1 patients (–34 ms), and LQT2 patients (–30 ms). During exercise, the corresponding QT adaptation to exercise stress was more pronounced (p < 0.01) in healthy controls (–47 ms) than in LQT1 (–38 ms) or LQT2 patients (–38 ms). During exercise changes in serum potassium concentrations were correlated to changes in QT intervals in controls, but not in LQTS patients. LQT1 and LQT2 patients did not differ in serum potassium, catecholamine or heart rate responses to mental or physical stress.CONCLUSIONSQT adaptation to mental and exercise stress in healthy people and in patients with LQTS is different. In healthy people QT adaptation is more sensitive to physical than to mental stress while no such diverging pattern was seen in asymptomatic LQTS patients.

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Faculty Opinions recommendation of Trafficking defects and gating abnormalities of a novel SCN5A mutation question gene-specific therapy in long QT syndrome type 3.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3209956.2896054 ◽

2010 ◽

Author(s):

Hugues Abriel ◽

Jean-Sébastien Rougier

Keyword(s):

Long Qt Syndrome ◽

Syndrome Type ◽

Long Qt ◽

Specific Therapy ◽

Qt Syndrome ◽

Trafficking Defects ◽

Type 3 ◽

Scn5a Mutation

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Intrapericardial and Retrocardial Implantation of Implantable Cardioverter-Defibrillator Lead in a Child with Type 3 Long QT Syndrome

Pediatric Cardiology ◽

10.1007/s00246-011-0065-y ◽

2011 ◽

Vol 32 (7) ◽

pp. 1048-1052 ◽

Cited By ~ 3

Author(s):

Yasuhiro Ichikawa ◽

Mari Iwamoto ◽

Sadamitsu Yanagi ◽

Munetaka Masuda

Keyword(s):

Implantable Cardioverter Defibrillator ◽

Long Qt Syndrome ◽

Long Qt ◽

Cardioverter Defibrillator ◽

Defibrillator Lead ◽

Qt Syndrome ◽

Type 3

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Diagnosis of epilepsy using an implantable loop recorder in a child with long-QT syndrome type 3

Pediatrics International ◽

10.1111/j.1442-200x.2012.03686.x ◽

2013 ◽

Vol 55 (2) ◽

pp. 251-253 ◽

Cited By ~ 2

Author(s):

Kazuhiro Takahashi ◽

Akira Miyake ◽

Yoshimitsu Otsuka ◽

Masaharu Ohfu ◽

Hitoshi Ganaha

Keyword(s):

Long Qt Syndrome ◽

Syndrome Type ◽

Implantable Loop Recorder ◽

Long Qt ◽

Loop Recorder ◽

Qt Syndrome ◽

Type 3

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Computational Analysis of Coronary Blood Flow: The Role of Asynchronous Pacing and Arrhythmias

Mathematics ◽

10.3390/math8081205 ◽

2020 ◽

Vol 8 (8) ◽

pp. 1205

Author(s):

Timur Gamilov ◽

Philipp Kopylov ◽

Maria Serova ◽

Roman Syunyaev ◽

Andrey Pikunov ◽

...

Keyword(s):

Heart Rate ◽

Blood Flow ◽

Coronary Blood Flow ◽

Long Qt Syndrome ◽

Premature Ventricular Contraction ◽

Cardiac Pacing ◽

Long Qt ◽

Computational Evaluation ◽

Qt Syndrome

In this work we present a one-dimensional (1D) mathematical model of the coronary circulation and use it to study the effects of arrhythmias on coronary blood flow (CBF). Hydrodynamical models are rarely used to study arrhythmias’ effects on CBF. Our model accounts for action potential duration, which updates the length of systole depending on the heart rate. It also includes dependency of stroke volume on heart rate, which is based on clinical data. We apply the new methodology to the computational evaluation of CBF during interventricular asynchrony due to cardiac pacing and some types of arrhythmias including tachycardia, bradycardia, long QT syndrome and premature ventricular contraction (bigeminy, trigeminy, quadrigeminy). We find that CBF can be significantly affected by arrhythmias. CBF at rest (60 bpm) is 26% lower in LCA and 22% lower in RCA for long QT syndrome. During bigeminy, trigeminy and quadrigeminy, respectively, CBF decreases by 28%, 19% and 14% with respect to a healthy case.

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FUNCTIONAL EFFECTS OF SCN5A CHANNEL MUTATIONS AND THE RISK OF LIFE-THREATENING EVENTS IN TYPE 3 LONG QT SYNDROME

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(16)32341-5 ◽

2016 ◽

Vol 67 (13) ◽

pp. 2340

Author(s):

Yitschak Biton ◽

Neils Otani ◽

Ilan Goldenberg ◽

Elsa Ronzier ◽

Jayson Baman ◽

...

Keyword(s):

Long Qt Syndrome ◽

Long Qt ◽

Life Threatening ◽

Qt Syndrome ◽

Type 3

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Abstract 14358: Treadmill Exercise Testing Improves Diagnostic Accuracy in Children With Concealed Congenital Long QT Syndrome

Circulation ◽

10.1161/circ.142.suppl_3.14358 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Trisha Patel ◽

Stanley Kamande ◽

Elizabeth Jarosz ◽

James Bost ◽

Sridhar hanumanthaiah ◽

...

Keyword(s):

Exercise Testing ◽

Long Qt Syndrome ◽

Stress Testing ◽

Normal Population ◽

Recovery Phase ◽

Exercise Stress ◽

Long Qt ◽

Qt Intervals ◽

Prolonged Qt ◽

Qt Syndrome

Introduction: Resting electrocardiogram (ECG) identification of long QT syndrome (LQTS) has limitations. Uncertainty exists on how to classify patients with borderline prolonged QT intervals. We tested if exercise testing could help serve as a guide for which children with borderline prolonged QT intervals may be gene positive for LQTS. Methods: Pediatric patients (n=139) were divided into three groups: Controls (n=76), gene positive LQTS with borderline QTc (n=21), and gene negative patients with borderline QTc (n=42). Borderline QTc was defined between 440 to 470 (male) and 440 to 480 (female) msec. ECGs were recorded while supine, sitting, and standing. Patients then underwent treadmill stress testing using the Bruce protocol followed by a 9-minute recovery phase. Statistical analysis was completed to compare the QTc intervals amongst all three of the groups using t-test, ANOVA, and the Youden method to calculate sensitivity and specificity cut points. Results: Supine resting QTc, age, and Schwartz score for the three groups were: 1) Gene positive: 446 ± 23 msec, 12.4 ± 3.4 yo, 3.2 ± 1.8; 2) Gene negative: 445 ± 20 msec, 12.1 ± 2.8 yo, 2.0 ± 1.2; and 3) Control: 400 ± 24 msec, 15.0 ± 3 yo. The three groups could be differentiated by their QTc response at two time points: standing and recovery phase at six minutes. Standing QTc ≥ 460 msec differentiated borderline prolonged QTc patients (Gene positive and Gene negative) from controls with a specificity of 90% for gene positive versus control and 83% for gene negative versus control. A late recovery QTc ≥ 480 msec at minute six distinguished Gene positive from Gene negative patients with a specificity of >97%. Conclusions: Exercise stress testing can be useful to identify Gene positive borderline LQTS from a normal population and Gene negative borderline QTc patients, allowing for increased cost effectiveness by selectively gene testing a higher risk group of patients with borderline QTc intervals and intermediate Schwartz scores.

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