1. A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration
Melissa Busovsky-McNeal, MD, Frank Cecchin, MD, Meghan Farrell, CPNP-AC, Michelle Ramirez, MD, Puneet Bhatla, MD, Ralph Mosca, MD, and Sujata Chakravarti, MD
Congenital Cardiovascular Care Unit
12/12/2014

2. History of Present Illness
A full term female infant was delivered by emergency cesarean section for non-reassuring fetal heart rate
Mother was a gravida one with limited prenatal care
At birth, the patient was noted to be bradycardic with a heart rate of beats per minute
An ECG was performed and it demonstrated 2:1 AV block with a corrected QT interval of 620 milliseconds with multiple episodes of TdP
She was treated with IV magnesium and emergently transferred to our institution for further management
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

3. Electrocardiogram on arrival
T wave appearance was suggestive of sodium channel defect
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

4. Electrocardiogram on arrival
2:1 block QTc 669
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

5. Hospital Course
On arrival to our institution, she was noticed to be in cardiogenic shock
She developed Multi-Organ Dysfunction Syndrome including:
Acute lung injury
Acute kidney injury
Necrotizing enterocolitis (NEC) requiring exploratory laparotomy
Due to unstable hemodynamics, she was emergently intubated and mechanically ventilated, and inotropic and vasopressor support was initiated
Repeat ECG showed a QTc of 690 milliseconds
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

6. Echocardiography
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

7. Echocardiography
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

8. Echocardiography
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

9. Echocardiography
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

10. Echocardiography
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

11. Hospital Course (cont.)
Due to the inability to administer enteral antiarrhythmics after her episode of NEC, the patient was initiated on IV infusions of Isoproterenol and Magnesium
In spite of these, she continued to have multiple prolonged, but self-terminating episodes of TdP with persistent 2:1 block requiring frequent chest compressions
Once her bowel healed and her gut was tolerating enteral feeds, Propranolol and Mexiletine were initiated
Propranolol: Beta blocker, non-selective, beta blockers have a ~ 70% reduction of cardiac events in LQT
Mexiletine: Class IB antiarrhythmic, sodium channel blocker, structurally related to lidocaine, which inhibits inward sodium current, decreases rate of rise of phase 0, increases effective refractory period/action potential duration ratio
TIGHT ELECTROLYTE CONTROL
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

12. Hospital Course (cont.)
A trial of Flecainide was also attempted to help control persistent TdP
The patient developed increased frequency of TdP as well as widened QRS complex consistent with Flecainide toxicity
Flecainide was discontinued
At 1 week of age, the patient underwent insertion of a transvenous atrial pacing lead which was externalized to allow for atrial pacing
This resulted in decreased frequency of TdP
Epicardial PM/ICD placement was precluded due to recent laparotomy
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

13. Hospital Course (cont.)
The patient continued to have periods of 2:1 block and TdP in the setting of a persistent, severely prolonged QTc despite improved ventricular function, end organ function and overall clinical status
Ranolazine was added at 4 mg/kg/day
At two weeks of age, the patient underwent LCSD and placement of an epicardial dual chambered PM/ICD.
Weight at this time was 3.28 kg.
Periods of 2:1 block and TdP continued
Three days later Ranolazine was increased to 8 mg/kg/day.
Ranolazine dosing: 500mg for 75kg person. Divided for 3kg baby, took 3rd of that dose
Transient Horner’s
Pneumothorax
Hemothorax
Early post-op proarrhythmia
One death reported from Netherlands
Arrhythmic storm in LQT8 patient
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

14. Hospital Course (cont.)
Subsequently, she was weaned off the Isoproterenol and Magnesium infusions
Due to persistent 2:1 block and periods of Torsades with atrial pacing, the patient’s pacemaker mode was changed to VVI 100 with a hysteresis of 30
Although her QTc remains prolonged, she now persistently has 1:1 conduction and she has been free of TdP
Studies confirmed the diagnosis of type III LQTS
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

15. Long QT Syndrome Channelopathies
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

16. Genetic Testing Mutation of SCN5A
mutation in SCN5A reduces peak I(Na) while augmenting late I(Na), and may thus underlie the development of atrial tachycardia, intraventricular conduction delay, and QT interval prolongation in an infant.
Presentation TA Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

17. Electrocardiogram QTc 569. 10/27/2014
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

18. QTc Progression During The Hospital Stay
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

19. Echocardiography
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

20. Why Ranolazine?
International Journal of Cardiology. 171(1):90-2, Jan 15, 2014
Antianginal, enzyme inhibitor, piperazine derivative
FDA approved for treatment of chronic angina pectoris
Alters the transcellular late sodium current
Extensively metabolized in the gut and liver and its absorption is highly variable
S/E: dizziness, headache, constipation, and nausea
Ranolazine exerts antianginal and anti-ischemic effects without changing hemodynamic parameters (heart rate or blood pressure). At therapeutic levels, ranolazine inhibits the late phase of the inward sodium channel (late INa) in ischemic cardiac myocytes during cardiac repolarization reducing intracellular sodium concentrations and thereby reducing calcium influx via Na+-Ca2+ exchange. Decreased intracellular calcium reduces ventricular tension and myocardial oxygen consumption. It is thought that ranolazine produces myocardial relaxation and reduces anginal symptoms through this mechanism although this is uncertain. At higher concentrations, ranolazine inhibits the rapid delayed rectifier potassium current (IKr) thus prolonging the ventricular action potential duration and subsequent prolongation of the QT interval
Ranolazine Shortens Repolarization in Patients with Sustained Inward Sodium Current Due To Type-3 Long QT Syndrome
Arthur J. Moss, MD, Wojciech Zareba, MD, PhD, Karl Q. Schwarz, MD, Spencer Rosero, MD, Scott McNitt, MS, and Jennifer L. Robinson, MS 2008
From the Cardiology Division of the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NYAddress for Correspondence: Arthur J. Moss, MD, Heart Research Follow-up Program, University of Rochester Medical Center, 601 Elmwood Avenue, Box 653, Rochester, NY , Tel: , Fax:
Author information ► Copyright and License information ►
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The publisher's final edited version of this article is available at J Cardiovasc Electrophysiol
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Go to:Abstract.Introduction
One form of the hereditary long QT-syndrome, LQT3-ΔKPQ, is associated with sustained inward sodium current during membrane depolarization. Ranolazine reduces late sodium channel current, and we hypothesized that ranolazine would have beneficial effects on electrical and mechanical cardiac function in LQT3 patients with the SCN5A-ΔKPQ mutation.
Methods
We assessed the effects of 8-hour intravenous ranolazine infusions (45mg/hr for 3 hours followed by 90mg/hr for 5 hours) on ventricular repolarization and myocardial relaxation in five LQT3 patients with the SCN5A-ΔKPQ mutation. Changes in electrocardiographic QTc parameters from before to during ranolazine infusion were evaluated by time-matched, paired t-test analyses. Cardiac ultrasound recordings were obtained before ranolazine infusion and just before completion of the 8-hour ranolazine infusion.
Results
Ranolazine shortened QTc by 26±3ms (p<0.0001) in a concentration-dependent manner. At peak ranolazine infusion, there was a significant 13% shortening in left ventricular isovolumic relaxation time, a significant 25% increase in mitral E-wave velocity, and a meaningful 22% decrease in mitral E-wave deceleration time compared to baseline. No adverse effects of ranolazine were observed in the study patients.
Conclusion
Ranolazine at therapeutic concentrations shortened a prolonged QTc interval and improved diastolic relaxation in patients with the LQT3-ΔKPQ mutation, a genetic disorder that is known to cause an increase of late sodium current.
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

21. LCSD-Efficacy: Symptom Relief and Sudden Death Protection
International Journal of Cardiology. 171(1):90-2, Jan 15, 2014
Background—The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite
-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group
of high-risk patients.
Methods and Results—We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged
(QTc, ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with -blockers
remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8
years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%,
and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (P0.001). Among 74 patients
with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc
500 ms predicted very low risk. The percentage of patients with 5 CEs declined from 55% to 8% (P0.001). In 5
patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased
by 95% (P0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more
effective in LQT1 and LQT3 patients.
Conclusions—LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in
high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing
cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with
recurrent syncope despite -blockade and in patients who experience arrhythmia storms with an implanted defibrillator.
(Circulation. 2004;109: )
~50% symptom free, 10% sudden death in 10 years, 5 to 1 decrease in cardiac events
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

22. Effect of Left Cardiac Sympathetic Denervation on QTc
Background—The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite
-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group
of high-risk patients.
Methods and Results—We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged
(QTc, ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with -blockers
remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8
years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%,
and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (P0.001). Among 74 patients
with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc
500 ms predicted very low risk. The percentage of patients with 5 CEs declined from 55% to 8% (P0.001). In 5
patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased
by 95% (P0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more
effective in LQT1 and LQT3 patients.
Conclusions—LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in
high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing
cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with
recurrent syncope despite -blockade and in patients who experience arrhythmia storms with an implanted defibrillator.
(Circulation. 2004;109: )
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

23. LCSD-Efficacy: Symptom Relief and Sudden Death Protection
Background—The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite
-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group
of high-risk patients.
Methods and Results—We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged
(QTc, ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with -blockers
remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8
years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%,
and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (P0.001). Among 74 patients
with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc
500 ms predicted very low risk. The percentage of patients with 5 CEs declined from 55% to 8% (P0.001). In 5
patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased
by 95% (P0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more
effective in LQT1 and LQT3 patients.
Conclusions—LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in
high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing
cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with
recurrent syncope despite -blockade and in patients who experience arrhythmia storms with an implanted defibrillator.
(Circulation. 2004;109: )
A Case of Neonatal Long QT Syndrome and Torsades de Pointes Requiring Novel Therapies and Multidisciplinary Collaboration

24. Thank You Questions?
Presentation Title Goes Here