Editorials
They Are Not Monozygotic Twins ― Long QT Syndrome Type 1 (LQT1) and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) ―
2018 Volume 82 Issue 9 Pages 2246-2247
Details
2018 Volume 82 Issue 9 Pages 2246-2247
Patients with long QT syndrome (LQTS) frequently experience syncope during exercise, and sudden cardiac death can occur at that time in some patients. Beta-blocking agents are effective for reducing symptoms and the occurrence of lethal cardiac events. LQTS type 1 (LQT1), which is a genotype of LQTS, accounts for approximately 40% of all causes of LQTS, and the generalized features of LQTS are mostly caused by the sympathetic nerve sensitivity of LQT1.1 LQT1 is caused by mutations in KCNQ1, which encodes a slow component of the delayed rectifier potassium channel (IKs channel). IKs contributes to rapid repolarization during sinus tachycardia and its dysfunction causes QT prolongation and ventricular arrhythmias at the time of sympathetic nerve activation. LQT2 and LQT3 account for 30–40% and 10% of causes of LQTS, respectively. LQT1–3 are found in approximately 80–90% of patients with LQTS, and the genotype-phenotype correlations of LQT1–3 have been described in detail. Schwartz et al reported that triggers for arrhythmic events are different in LQT1–3.2 Syncope and lethal events occur in association with exercise in patients with LQT1, whereas they rarely occur at rest or when sleeping. Patients with LQT2 experience arrhythmic events from emotional stress, and in patients with LQT3, cardiac events frequently occur when the patients are at rest or asleep. Swimming is a specific arrhythmic trigger for LQT1 and it should be avoided. Emotional stress, especially auditory stimuli (e.g., loud noise, alarm clock or the telephone ringing), is a specific trigger for LQT2. Sympathetic activation is important as a trigger for LQT1 and LQT2. The genotype also determines T-wave morphology. Characteristic T-wave morphologies in LQT1, -2 and -3 are broad-based T-wave, low-amplitude bifid T-wave, and late-onset peaked T-wave, respectively.3,4 The QT interval is longer in patients with LQT2 or LQT3 than in patients with LQT1, and LQT1 patients frequently have borderline QT prolongation.5 Diagnosis of QT interval prolongation is sometimes missed in patients with mild QT prolongation and normal T-wave morphology.6 QT interval responses to an exercise test are also different in patients with LQT1–3. An exercise test does not shorten the QT interval and the QT interval after exercise sometimes becomes longer than at rest in patients with LQT1. This unique feature of LQTS is included in the Schwartz score of the diagnosis for LQTS.7
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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a relatively rare form of inherited arrhythmia. Patients with CPVT frequently experience syncope, convulsion and cardiac arrest during exercise, but have sinus bradycardia and a normal QT interval at rest. Exercise induces frequent premature ventricular contractions (PVCs), polymorphic and multifocal ventricular tachycardias (VTs), and bidirectional VT. If patients have been misdiagnosed as having a seizure, antiepileptic drugs can modify the QT interval, resulting in a misdiagnosis of LQTS. CPVT is caused by mutations in genes related to intracellular calcium handling. Mutations in the cardiac ryanodine receptor 2 gene (RyR2) are found in about half of the cases diagnosed as CPVT (CPVT1). The prognosis of CPVT is very poor and approximately 40% of patients die within 10 years of the diagnosis.8 Beta-blockers and calcium antagonists improve the prognosis but cannot prevent sudden death.9 Flecainide, which modulates the ryanodine receptor, reduces ventricular arrhythmic events and improves the prognosis of patients.
A diagnosis of CPVT is not difficult if patients have the characteristic polymorphic, bidirectional VTs during exercise. However, exercise-induced syncope is a common feature in both CPVT and LQT1. The QT interval in a patient with LQT1 is relatively mild among LQTS patients, and some LQT1 patients have a normal QT interval.5 Priori et al reported that approximately 30% of patients with CPVT were misdiagnosed as LQTS with a normal QT interval, because of exercise-related symptoms.10 Moreover, CPVT with mutations in RyR2 was found in 6% of geno-negative LQTS cases.11 Swimming is a specific trigger for LQT1, but it is also an important trigger for symptoms in CPVT. Swimming-related symptoms occurred in 11% of patients who consulted for a gene analysis of LQTS. Among patients with symptoms associated with swimming, LQT1 was found in 85% of patients who were diagnosed as having a high probability of LQTS by the Schwartz score, followed by geno-negative LQTS (9%) and LQT2 (6%). However, in 10 patients with a low probability of LQTS who had swimming-related symptoms, 9 patients had RyR2 mutations and should be diagnosed as having CPVT1.12 Molecular autopsies of 28 unexplained drowning victims related to swimming also showed a higher incidence of RyR2 mutations (21%) than that in LQT1 (7%).13 In this issue of the Journal, the authors of the present study also comment that patients had transient QT prolongation immediately after cardiac arrest or failure of polymorphic VT by catecholamine test.14 It is not surprising that the differential diagnosis of CPVT from LQT1 is difficult in some patients.
Baseline therapy using a β-blocker is common for both LQT1 and CPVT. Advanced therapies such as left cervical sympathetic nerve denervation and implantation of an implantable cardioverter defibrillator are also used for severe forms of both LQT1 and CPVT. Why should we perform a differential diagnosis of LQT1 and CPVT? The reason is that the mortality rate of CPVT is higher than that of LQTS. With adequate β-blocker therapy, the mortality rate of LQTS is less than 0.1%/year,15 whereas it is 4%/year in patients with CPVT.8 Patients with CPVT should receive advanced therapeutic options.
In the present study by Dr. Ozawa et al, the aim was to differentiate CPVT from LQT1 with a modified Schwartz score.14 The authors attached importance to the QT response to exercise testing in patients with LQT1 and the occurrence of arrhythmia during exercise testing in patients with CPVT. New items of the diagnostic score for differentiation between LQT1 and CPVT were (1) QTc 2 min of recovery after exercise test ≥480 ms or with ∆QTc (QTc at 2 min of recovery−QTc before exercise) ≥40 ms, (2) ∆QTc (QTc at 2 min of recovery−QTc before exercise) ≤10 ms, and (3) polymorphic ventricular arrhythmias. The first 2 items are specific characteristics of LQT1 and the last is specific for CPVT. Usually, exercise testing does not induce polymorphic VTs in LQT1. These authors could identify patients with CPVT from those with LQT1 by using the new modified Schwartz score. As the prognosis of patients with CPVT is very poor under basic β-blocker therapy, we can administer appropriate, advanced therapy to patients with CPVT diagnosed by the new modified score before the results of gene analysis. We should also remember that this score is used for different diagnosis between LQT1 and CPVT and do not use it for primary diagnosis of LQTS.
H.M. is affiliated with an endowed department by Japan Medtronic Inc.
