A Case of Long QT Syndrome Type 3 Aggravated by Beta-Blockers and Alleviated by Mexiletine: The Role of Epinephrine Provocation Test
A 15-year-old female middle school student was referred to our hospital because of multiple syncopal episodes. She had experienced four syncopal episodes at school during the last three years. All of these episodes occurred while resting or in class. Her mother noticed the patient's very unusual snoring sound with transient loss of consciousness twice at night, and what seemed like agonal respiration. After that, she had palpitations with presyncope while writing in class. She had a past history of patch repair surgery for ventricular septal defect (VSD) at the age of 5 months old, however, there was no abnormality in the physical examination or laboratory findings, and echocardiography showed her heart to be completely normal morphologically and functionally. The only abnormal finding was prolonged QTc (629 ms) in surface 12 lead electrocardiography (ECG) (). She had no family history of sudden death or other genetic heart disease (). At the time when she was referred to our hospital, she was taking low dose of propranolol. Because ECG at the time of presyncope or syncope had not been documented and her clinical presentation was unusual, we stopped propranolol and performed an epinephrine test.\nAfter skipping propranolol for 5 times its half life, an epinephrine provocation test was performed and mean QTc was measured after epinephrine test., Mean QTc was significantly prolonged (637.0-48.6 ms; between 585 and 646 ms), and frequent single or couplets of ventricular premature beats appeared (). We then repeated the epinephrine test with β-blocker medication. With propranolol 120 mg per day, mean QTc was prolonged as 628.5±62.7 ms (between 618 and 634 ms), and non-sustained polymorphic ventricular tachycardia (VT; 200 bpm) appeared following R-on-T phenomenon and spontaneously ended within 8 sec without syncopal event (). There were two different premature ventricular contraction (PVC) morphologies, and non-sustained VT initiating PVC was localized by 12 lead ECG (). The origin of PVC seems to be left ventricular (LV) high septum just below the (left) distal HIS bundle. QRS duration is relatively narrow and purely negative in lead aVR and aVF, but initially positive in all other leads, suggesting LV peri-Hissian PVC related to membranous VSD repair. After increasing the dosage of propranolol to 160 mg per day for 3 days, sustained polymorphic VT was induced spontaneously, requiring external defibrillation, and syncope and tonic clonic seizure were documented during the epinephrine provocation test (). Mean QTc was prolonged as 644.0±33.7 ms (between 619 and 668 ms). However, after stopping propranolol for 4 days, no arrhythmic event was reproducible during the epinephrine provocation test ().\nBecause the patient's arrhythmia could not be controlled by β-blocker, she underwent ICD implantation. She returned to the emergency room due to ICD shock in the 3rd month after ICD implantation. ICD EGM documented sustained polymorphic VT with cycle length 220 ms and successful ICD therapy. Therefore, we repeated the epinephrine provocation test while medicating with mexiletine 600 mg per day, and there was no event except for QTc lengthening >30 ms (). She was discharged with mexiletin 600 mg per day and an increase in atrial pacing rate to higher than 70 bpm. During mexiletine medication, there was no VT episode in ICD interrogation for 3 months. However, she arbitrarily stopped the anti-arrhythmic drug due to weakness, and received appropriate ICD shock 8 months after stopping the medication. Therefore, she is presently taking mexiletine 600 mg a day.\nWe genotyped 155 loci from exon 2 to 28 of the SCN5A gene, and G>A, R1192Q (rs41261344; reference sequence: NM000335) was identified at the exon 20 sequence. However, same base pair change was found in SCN5A genetic analyses in her father and siblings who did not show the phenotypes of LQTs (ECG or symptom) (). Therefore, it seems to be genetic polymorphism in SCN5A, but not a mutation.