Differential Diagnosis Between Catecholaminergic Polymorphic Ventricular Tachycardia and Long QT Syndrome Type 1　― Modified Schwartz Score ―

Junichi Ozawa; Seiko Ohno; Yusuke Fujii; Takeru Makiyama; Hiroshi Suzuki; Akihiko Saitoh; Minoru Horie

doi:10.1253/circj.CJ-17-1032

Abstract

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) has been often misdiagnosed as long QT syndrome (LQTS) type 1 (LQT1), which phenotypically mimics CPVT but has a relatively better prognosis.

Methods and Results: The derivation and validation cohorts consisted of 146 and 21 patients, respectively, all of whom had exercise- or emotional stress-induced cardiac events. In the derivation cohort, 42 and 104 patients were first clinically diagnosed with CPVT and LQTS, respectively. Nine of 104 patient who had initial diagnosis of LQTS were found to carry RYR2 mutations. They were misdiagnosed due to 4 different reasons: (1) transient QT prolongation after cardiopulmonary arrest; (2) QT prolongation after epinephrine test; (3) absence of ventricular arrhythmia after the exercise stress test (EST); and (4) assumption of LQTS without evidence. Based on genetic results, we constructed a composite scoring system by modifying the Schwartz score: replacing the corrected QT interval (QTc) at 4 min recovery time after EST >480 ms with that at 2 min, or with ∆QTc (QTc at 2 min of recovery−QTc before exercise) >40 ms and assigning a score of −1 for ∆QTc <10 ms or documented polymorphic ventricular arrhythmias. This composite scoring yielded 100% sensitivity and specificity for the clinical differential diagnosis between LQT1 and CPVT when applied to the validation cohort.

Conclusions: The modified Schwartz score facilitated the differential diagnosis between LQT1 and CPVT.

Although sudden cardiac death in children is relatively uncommon, it is devastating and brings deep sorrow to the family and community as a whole. RYR2 and KCNQ1 mutations, which are susceptibility mutations for catecholaminergic polymorphic ventricular tachycardia (CPVT) and long QT syndrome (LQTS) type 1 (LQT1), respectively, have been frequently identified in children with exercise-induced death.¹ CPVT is a rare familial arrhythmogenic disorder characterized by adrenergic-induced bidirectional and polymorphic ventricular tachycardia (bVT and pVT) without any structural heart disease.² Approximately 50–60% of patients with CPVT have been found to carry RYR2 mutations, whereas only a small minority have CASQ2, CALM1, and TRDN mutations.³^–⁵ Patients with CPVT have normal resting electrocardiograms (ECG), including corrected QT interval (QTc). The first few episodes of cardiac events in CPVT usually occur during the first or second decade of life.²

Editorial p 2246

Meanwhile, LQTS is an inherited heart disease associated with increased propensity to syncope, pVT, namely torsade de pointes (TdP), and sudden arrhythmic death.⁶ Hundreds of mutations have been identified in >10 LQTS-susceptibility genes, while approximately 75% of patients clinically diagnosed with LQTS have been successfully genotyped. Of the genotyped patients, 30–35% have mutations in KCNQ1 (LQT1),³ and most of them have first cardiac events during exercise before 10 years of age.⁷

CPVT is often misdiagnosed as LQT1, because exercise or emotional stress triggers cardiac events at a similar age.⁸^,⁹ CPVT, however, is fatal in more cases than LQT1, unless it is properly diagnosed and treated.⁸^,¹⁰ Beta-blocker therapy, which is the first-line therapy for both CPVT and LQT1, has insufficient effects in reducing fatal or near-fatal event rates in patients with CPVT.¹⁰^,¹¹ In contrast, it has acceptable effects in those with LQT1.¹² More recently, left cardiac sympathetic denervation has also been reported to be an effective anti-fibrillatory intervention for CPVT and LQT1 although it could not entirely prevent cardiac events.¹³^,¹⁴ Flecainide, as an additional therapy for CPVT, has been proven to be effective in suppressing ventricular arrhythmia and preventing cardiac events.¹⁵^–¹⁷

Family members with CPVT have been reported to have similar cardiac event rates as probands,¹¹ while penetrance with regard to LQT1 is relatively low.¹⁸ Thus, family screening and genetic testing, as well as strategies for preventive therapy immediately after CPVT diagnosis in family members, should be considered.

The accurate identification of CPVT in those with exercise- or emotional stress-induced cardiac events is therefore of clinical importance. Subsequently, the aim of this study was to examine the clinical details of RYR2 mutation carriers initially diagnosed with LQT1 and to propose a method for the accurate differential diagnosis between CPVT and LQT1.

Methods

Subjects

The study cohort consisted of 167 patients (138 probands and 29 family members from 149 families, all Japanese). A total of 146 patients formed the derivation cohort, while the remaining 21 patients, the validation cohort. All patients had exercise- or emotional stress-induced cardiac events from 1 to 20 years of age and had suspected of LQTS or CPVT. They were referred to either Shiga University of Medical Science or Kyoto University Graduate School of Medicine for genetic testing, including of CPVT- and LQTS-related genes, between 1996 and 2016. The patients in the derivation cohort were registered before May 2013, while the patients in the validation cohort, after June 2013.

The first clinical diagnosis we used for the classification of CPVT and LQTS was rendered by the referring physicians. Final diagnosis was performed according to genotype: RYR2 mutation carriers were diagnosed with CPVT and those with KCNQ1, with LQT1. The mutations were confirmed as pathogenic based on the American College of Medical Genetics and Genomics (ACMG) guideline for the interpretation of sequence variants.¹⁹

On enrollment, a complete history was obtained retrospectively from birth to the age at study entry. For those >20 years old upon enrollment, we used the clinical history from birth to 20 years. Cardiac events included syncope (n=144) and cardiopulmonary arrest (CPA; n=23). All patients who had CPA required external defibrillation as part of resuscitation.

All subjects or their guardians provided informed consent for genetic and clinical studies in accordance with each institutional review board’s guideline. The study protocol was approved by each institutional review board.

ECG Analysis

To measure QTc (with Bazett’s correction),²⁰ 12-lead ECG recorded upon onset were used. In the absence of ECG upon onset, the first recorded ECG after onset were used. For patients with CPA, ECG recorded before the cardiac event or >1 month after were used to avoid the influence of resuscitation. Bradycardia was defined as heart rate (HR) below the second percentile of the established age- and sex-appropriate norms for children aged <16 years²¹ and <60 beats/min on resting ECG for those aged ≥16 years. Moreover, 12-lead ECG were acquired during exercise stress test (EST) using the standard or modified Bruce protocol treadmill test.²²

Genetic Analysis

Genomic DNA was isolated from peripheral blood lymphocytes. A total of 82 probands were routinely screened for KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 mutations using polymerase chain reaction and denatured high-performance liquid chromatography analysis (WAVE system; Transgenomic, Omaha, NE, USA). Moreover, 23 of the 82 probands with clinically suspected CPVT were screened for all exons in RYR2 and CASQ2, while multiplex ligation-dependent probe amplification (MLPA) was performed in 2 probands to identify RYR2 exon 3 deletion. The probes used were those for MLPA analysis of RYR2 exons 3 and 97 (SALSA MLPA Kit P168, MRC-Holland, Amsterdam, the Netherlands).

We then analyzed 45 genes in the remaining 56 probands and 2 family members using MiSeq (Ilumina, San Diego, CA, USA), a benchtop next-generation sequencer. To confirm the detected mutations, subsequent direct DNA sequencing was conducted using a capillary DNA sequencer (ABI 3130 DNA Sequencer, PerkinElmer, Foster City, CA, USA).

Statistical Analysis

All analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). Continuous and categorical variables are presented as mean±SD and number (percentage), respectively. Differences in characteristics were evaluated using unpaired Student’s t-test, Mann-Whitney U-test, or chi-squared test, as appropriate. P<0.05 was considered statistically significant. Data from the derivation cohort were used to modify the original Schwartz score to establish a differential diagnosis between LQT1 and CPVT, with genetic testing results serving as the gold standard. Optimal cut-offs were selected from 12-lead ECG acquired during the EST to achieve high sensitivity and specificity for clinical differential diagnosis based on receiver operating characteristics (ROC).

Results

Proband Clinical Characteristics

Table S1 lists the demographic and clinical characteristics of all probands participating in this study, while Figure 1 illustrates a flowchart of the clinical diagnosis and results of genetic testing. Of the 146 patients in the derivation cohort, 42 (28%) and 104 (72%) were initially clinically diagnosed with CPVT and LQTS by the referring physicians, respectively. Moreover, 75 patients with LQTS (51%) who were identified as carrying KCNQ1 mutations were genotyped as LQT1. They comprised 72% of patients clinically diagnosed with LQTS.

Figure 1.

Flowchart of the clinical diagnosis and results of genetic testing in the derivation cohort. CPVT, catecholaminergic polymorphic ventricular tachycardia; LQTS, long QT syndrome.

Of the 42 patients clinically diagnosed with CPVT, 35 had heterozygous RYR2 mutations, while one (patient 2) had double mutations in RYR2. Therefore, CPVT1 probands comprised 81% of those clinically diagnosed with CPVT.

The other patients included 7 CPVT patients who all had bVT or pVT on stress test, and 20 LQTS patients (Figure 1). One CPVT patient (patient 140) carried compound heterozygous CASQ2 mutations, one (patient 141) had a heterozygous CALM1 mutation, while five had no known mutations. One LQTS patient carried compound heterozygous KCNH2 and SCN5A mutations (patient 131), four had a heterozygous KCNH2 mutation (patients 127–130), and three had a heterozygous mutation in KCNE1 (patient 132), KCNJ2 (patient 133), or CACNA1C (patient 134). The other 12 patients had no known mutation in LQTS- or CPVT-causing genes.

Furthermore, nine probands initially clinically diagnosed with LQTS were found to carry RYR2 mutations (Table 1) and were thought to be misdiagnosed due to 4 different reasons: (1) transient mild QT prolongation in three CPA patients (patients 3,6,8; sequential ECG changes are shown in Figure 2); (2) QT prolongation after the epinephrine test in the chronic stage in two patients (patient 5, QT, 460 ms; QTc, 584 ms; patient 7, QT, 420 ms; QTc, 480 ms after the epinephrine test); (3) negative EST or epinephrine test wherein typical CPVT-related VT had not been induced, in three patients (patients 1,4,9); and (4) pVT and subsequent ventricular fibrillation after the epinephrine test in 1 patient who had been clinically diagnosed with LQTS without evident QT prolongation (patient 2).

Table 1. Patients With RYR2 Mutations Initially Diagnosed With LQTS

Patient ID no.	Sex	Onset age (years)	Age at diagnosis (years)	Most severe symptom	Gene	Nucleotide	Amino acids	Acute phase		Chronic phase		Ventricular arrhythmias evoked by exercise or epinephrine test
Patient ID no.	Sex	Onset age (years)	Age at diagnosis (years)	Most severe symptom	Gene	Nucleotide	Amino acids	HR (/min)	QTc (ms)	HR (/min)	QTc (ms)
1	M	13	16	CPA	RYR2	1258c>t	R420W	NA		61	430	Not evoked
					KCNH2	3095 g>a	R1032Q	NA		61	430	Not evoked
2	F	12	25	CPA	RYR2	2300c>g, 2301 g>t	S767C	NA		68	419	Polymorphic VT, VF
					RYR2	14298+2t>c	–	NA		68	419	Polymorphic VT, VF
3	M	3	3	CPA	RYR2	2719 g>c	V907L	115	527	98	448	Not tested
4	F	18	18	Syncope	RYR2	5764a>t	I1922L	NA		48	448	Not evoked
5	M	9	17	Syncope	RYR2	6511 g>a	V2171M	53	409	55	384	Polymorphic VT
6	M	13	13	CPA	RYR2	6574a>t	M2192L	114	467	83	365	Polymorphic VT
7	M	10	11	CPA	RYR2	7169c>t	T2390I	93	450	58	405	Not evoked
8	M	5	15	CPA	RYR2	7199 g>t	G2400T	70	477	46	412	Polymorphic VT
9	M	11	11	Syncope	RYR2	12458 g>t	S4153I	90	467	71	402	Not evoked

CPA, cardiopulmonary arrest; HR, heart rate; LQTS, long QT syndrome; NA, not available; QTc, corrected QT interval; VF, ventricular fibrillation; VT, ventricular tachycardia.

Figure 2.

Sequential electrocardiogram changes in catecholaminergic polymorphic ventricular tachycardia probands who had cardiopulmonary arrest and transient and mild QT prolongation.

QTc intervals in those with transient mild QT prolongation after CPA normalized in ≤1 month. Although patient 1 had an LQTS-related KCNH2 mutation (R1032Q, rs199473020), he had no ECG features of LQT2, such as prolonged QTc or notched T wave.

Clinical Characteristics of Genotyped Patients: CPVT vs. LQT1

We compared the clinical characteristics of genotyped patients: RYR2 (n=40) and KCNQ1 (n=71; Table 2). Owing to the presence of compound mutations, 4 CPVT and 4 LQT1 patients were excluded from the analysis. There were no significant differences in gender (P=0.59), onset age (P=0.68), or family history of sudden cardiac death (P=0.25) between the CPVT and LQT1 groups. Significantly more CPVT probands, however, had CPA as the first cardiac event compared with LQT1 probands (CPVT, 5 of 40, 13%; LQT1, 1 of 71, 1%; P=0.022). Furthermore, CPA occurred more frequently in the CPVT than in the LQT1 group over the entire observation period (CPVT, 15 of 40, 38%; LQT1, 1 of 71, 1%; P<0.001) although the median follow-up time was not significantly different (P=0.42). One CPVT patient received β-blocker therapy for episodes of CPA.

Table 2. Clinical Characteristics: CPVT vs. LQT1

	CPVT (RYR2) (n=40)	LQT1 (n=71)
Male	19 (48)	30 (42)
Onset age (years)	9 (6–12)	9 (6–10)
Follow-up (years)	14.7±4.9	15.5±5.0
β-blocker therapy	16 (40)*	15 (21)
CPA	15 (38)***	1 (1)
CPA as the first event	5 (13)*	1 (1)
Family history of SCD <30 years of age	5 (13)	3 (4)
Schwartz score, points	2.4±0.6	4.6±1.5***
Schwartz score ≥3.5	2 (5)	58 (77)***
ECG data (without β-blockers)	(n=24)	(n=56)
HR (beats/min)	61 (55–73)	64 (57–70)
Low HR for age	9 (38)	10 (18)
QTc (ms)	417 (403–428)	471 (448–500)***

Data given as mean±SD, median (IQR) or n (%). *P<0.05, **P<0.01, and ***P<0.001 CPVT (RYR2) vs. LQT1. CPVT, catecholaminergic polymorphic ventricular tachycardia; ECG, electrocardiogram; HR, heart rate; LQT1, long QT syndrome type 1; SCD, sudden cardiac death. Other abbreviations as in Table 1.

Schwartz score was significantly lower in the CPVT group (2.4±0.6) than in the LQT1 group (4.6±1.5, P<0.001). Only 2 patients in the CPVT group (5%), compared with 58 in LQT1 group (77%), had Schwartz score >3.5 (patients 128,146 had 5 points, P<0.001).

On ECG, the percentage of patients with low HR for age was not significantly different between the CPVT and LQT1 groups (CPVT, 9 of 40, 38%; LQT1, 10 of 75, 18%; P=0.085). IQR QTc at rest was significantly longer in the LQT1 group (471 ms; range, 448–500 ms) than in the CPVT group (417 ms; range, 403–428 ms, P<0.001). One CPVT patient had prolonged QT and QRS interval (patient 128, QTc 500 ms, QRS interval 110 ms) presumably due to an anti-arrhythmic drug (flecainide 100 mg/day for an 18-year-old boy).

EST

Table 3 presents the EST results. We compared 18 patients with CPVT and RYR2 mutation and 14 patients with LQT1 whose EST ECG without β-blockers were available. In the CPVT group, QTc at 2 min of recovery after EST was calculated in only 10 patients, due to the inability to measure the remaining 8 patients due to EST-induced polymorphic ventricular arrhythmias.

Table 3. EST: CPVT vs. LQT1

	CPVT (RYR2) (n=18)	LQT1 (n=14)
Male	8 (44)	8 (57)
Age at EST (years)	12 (8–19)	11 (9–19)
QTc before exercise (ms)	416 (400–427)	459 (427–482)**
QTc at 2 min of recovery from EST (ms)	400 (378–418)	540 (511–579)***
Δ QTc (2 min of recovery−before exercise) (ms)	−27 (−34 to −5)	92 (43–117)***
Peak heart rate during EST (beats/min)	170 (153–173)	144 (135–153)**
Polymorphic ventricular arrhythmias	14 (78) [bVT, n=2; pVT, n=11; PVC, n=1]	0 (0)

Data given as median (IQR) or n (%). *P<0.05, **P<0.01, and ***P<0.001 CPVT (RYR2) vs. LQT1 groups. bVT, bidirectional ventricular tachycardia; EST, exercise stress test; PVC, paroxysmal ventricular contraction; pVT, polymorphic ventricular tachycardia. Other abbreviations as in Tables 1,2.

No significant difference in gender (P=0.48) or in age at EST (P=0.64) was found between the CPVT and LQT1 groups. IQR pre-exercise QTc was significantly longer in the LQT1 group (459 ms; range, 427–482 ms) than in the CPVT group (416 ms; range, 400–427 ms, P=0.002). IQR QTc at 2 min of recovery after EST was significantly longer in the LQT1 group (540 ms; range, 511–579 ms) than in CPVT group (400 ms; range, 378–418 ms, P<0.001). Moreover, median ∆QTc (QTc at 2 min of recovery−QTc before exercise) was positive in the LQT1 group (92 ms; range, 43–117 ms) but negative in the CPVT group (−27 ms; range, −34 to −5 ms, P<0.001). EST induced polymorphic ventricular arrhythmias in 14 patients with CPVT (78%) but not in those with LQT1.

In the derivation cohort, the predictive value of ECG parameters during EST was examined on ROC analysis (Figure 3). A cut-off of 480 ms was selected for QTc at 2 min of recovery, with 93% sensitivity and 100% specificity for the diagnosis of LQT1 (Figure 3A). Moreover, a cut-off of 40 or 10 ms was selected for ∆QTc (QTc at 2 min of recovery−QTc before exercise), with 86% or 100% sensitivity and 100% or 90% specificity for the diagnosis of LQT1, respectively.

Figure 3.

Receiver operating characteristic curves for the differential diagnosis between catecholaminergic polymorphic ventricular tachycardia and long QT syndrome type 1 with (A) corrected QT interval (QTc) at 2 min of recovery after exercise and (B) ∆QTc (QTc at 2 min of recovery−QTc before exercise). AUC, area under the curve.

Modified Schwartz Score for LQT1 Diagnosis

We calculated the original Schwartz score²³ without the EST because we had insufficient data on QTc at 4 min of recovery. For patients with CPA, ECG recorded before the cardiac event or >1 month after the event were evaluated. A score ≥3.5 points indicates a high probability for LQTS, although 17 patients with LQT1 (23%) in the present study had score <3.5 points. Moreover, despite adding tentatively 1 more point to the EST results of all patients with LQT1, 6 of the 17 patients (6 of 71, 8%) still had score <3.5 points.

In order to establish a method for the differential diagnosis between LQT1 and CPVT, we constructed a composite scoring system by modifying the original Schwartz score based on genetic data from the derivation cohort. As shown in Table 4, we replaced QTc at 4 min of recovery after EST >480 ms (1 point) with QTc at 2 min of recovery >480 ms or with ∆QTc (QTc at 2 min of recovery−QTc before exercise) >40 ms (2 points). Moreover, we assigned a score of −1 for the presence of polymorphic ventricular arrhythmias or ∆QTc <10 ms and a history of CPA. In addition, we excluded 3 items from the original Schwartz score: (1) TdP; (2) low HR for age; and (3) unexplained sudden cardiac death at <30 years of age among immediate family members. A score ≥3.5 points indicated high probability for LQTS, whereas a score ≤3 points indicated high probability for CPVT in those with exercise- or emotional stress-induced cardiac events.

Table 4. Original vs. Modified Schwartz Score for the Differential Diagnosis Between CPVT and LQT1

Original Schwartz score		Modified Schwartz score
ECG data		ECG data
A. QTc^†		A. QTc^†
≥480 ms	3	≥480 ms	3
460–479 ms	2	460–479 ms	2
450–459 ms (male patients)	1	450–459 ms (male patients)	1
B. EST		B. EST
QTc at 4 min of recovery after EST ≥480 ms	1	1. QTc 2 min of recovery after EST ≥480 ms or with ΔQTc (QTc at 2 min of recovery−QTc before exercise) ≥40 ms	2
		2. ΔQTc (QTc at 2 min of recovery−QTc before exercise) ≤10 ms	−1
		3. Polymorphic ventricular arrhythmias	−1
C. Torsades de pointes	2
D. T wave alternans	1	C. T-wave alternans	1
E. Notched T wave in 3 leads	1	D. Notched T wave in 3 leads	1
F. Low heart rate for age	0.5
Clinical history		Clinical history
A. Syncope with stress	2	A. Syncope with stress	2
Syncope without stress	1	B. Cardiopulmonary arrest	−1
B. Congenital deafness	0.5	C. Congenital deafness	0.5
Family history		Family history
A. Family members with definite LQTS	1	A. Family members with definite LQTS	1
B. Unexpected sudden cardiac death age <30 years in immediate family members	0.5
Score ≤1 point: low probability of LQTS 1.5–3 points: intermediate probability of LQTS ≥3.5 points: high probability of LQTS		Score ≥3.5 points: high probability of LQTS (LQT1) (Score ≤3 points: high probability of CPVT)

^†Calculated using Bazett’s formula. Abbreviations as in Tables 1–3.

This composite scoring was applied to 5 patients with LQT1 and 16 patients with CPVT and RYR2 mutation in the validation cohort, yielding 100% sensitivity and specificity for the clinical differential diagnosis between LQT1 and CPVT.

Discussion

The present study examined why patients with CPVT had been initially diagnosed with LQT1 and proposed a composite scoring system by modifying the original Schwartz score to improve the sensitivity and specificity for the clinical differential diagnosis between LQT1 and CPVT. Differential diagnosis between CPVT and LQT1 appears to be straightforward in most cases, especially when reviewed retrospectively after genetic testing. We, however, identified 4 points that required attention: (1) transient QT prolongation after CPA; (2) QT prolongation after epinephrine infusion test; (3) absence of ventricular arrhythmia after EST; and (4) assumption of LQTS without evidence.

Regarding the first point, 3 patients had CPA requiring external defibrillation as part of resuscitation, while 2 had transient prolonged QTc and T-wave inversion, which normalized after several days. In the patients who were resuscitated and received therapeutic hypothermia, QT prolongation was observed after resuscitation and during hypothermia therapy. Although the sequential changes were unclear, the QT prolongation was shortened after the therapy.²⁴ Similar sequential changes in ECG have been generally observed in acute myocardial infarction.²⁵ We suspect that similar mechanisms had caused the transient QT prolongation accompanied by T-wave inversion in the present patients. Physicians should be aware of transient QT prolongation accompanied by T-wave inversion after resuscitation, and assess the QT interval correctly in order to diagnose accurately.

Regarding the second point, 2 patients with CPVT had QT prolongation after epinephrine infusion test, although one of them had no QT prolongation after EST, while the other did not undergo EST. Epinephrine infusion test has proven useful in unmasking latent RYR2 and KCNQ1 mutation carriers,¹⁸^,²⁶ but it has lower sensitivity, however, for CPVT diagnosis compared with EST.²⁷ Moreover, epinephrine-induced QTc changes have not been thoroughly elucidated in patients with CPVT. Therefore, when epinephrine infusion test is used as an alternative to EST for CPVT diagnosis, the result should be interpreted carefully.

The third point merits closer attention. Three CPVT probands had no ventricular arrhythmia during EST without β-blocker therapy and were misdiagnosed with LQTS despite normal or baseline QTc. This was probably because EST-induced ventricular arrhythmias are considered to be hallmarks of CPVT.¹ In previous studies, a number of patients with CPVT and RYR2 mutation had no ventricular arrhythmia during EST but had cardiac events during follow-up.²⁸^,²⁹ Therefore, even if the ventricular arrhythmias were not evoked by EST, the patient can be diagnosed with CPVT with RYR2 mutation. And genetic tests targeting CPVT-related genes would be helpful for the diagnosis of patients with exercise- or emotion-related cardiac events.

A very small number of patients with RYR2 mutations, however, were reported to have only a phenotype of LQTS or an overlapping phenotype of LQTS and CPVT.³⁰^–³² In the present RYR2 mutation carriers, QTc interval in the chronic phase in all the patients first diagnosed with LQTS were within the normal range. Therefore, we did not diagnose them with LQTS, although it might be difficult to diagnose CPVT if EST showed no ventricular arrhythmia.

The Schwartz scoring system offers diagnostic criteria for LQTS based on clinical and ECG features.²³ It has a high specificity but a low sensitivity for LQTS diagnosis,²⁹ which is consistent with the present results. Furthermore, the present CPVT patients had low Schwartz score, such that all but 1 patient (with prolonged QTc perhaps due to an anti-arrhythmia drug), had a score ≤3 points.⁹ Therefore, in an attempt to improve the sensitivity for LQT1 diagnosis, we modified the Schwartz score by emphasizing EST findings. This composite scoring yielded considerably high sensitivity and specificity for the clinical differential diagnosis between LQT1 and CPVT.

In patients with exercise- or emotional stress-induced cardiac events, those with modified Schwartz score ≤3 points may be recommended to receive genetic testing for CPVT despite the absence of EST-induced ventricular arrhythmia, especially because its phenotype is usually more malignant.

Study Limitation

In this study, non-arrhythmic syncope was excluded in all patients by the referring physicians, therefore, it was not possible to unify exclusion of non-arrhythmic syncope.

We could validate modified Schwartz score only in a small cohort of 5 LQT1 and 16 CPVT patients. Therefore, further studies are necessary to evaluate the modified score. In addition, although the difference in QTc change and the occurrence of ventricular arrhythmias during EST between CPVT and LQT1 was significant, the number of patients was small.

Conclusions

To the best of our knowledge, this is the first study to examine why CPVT is misdiagnosed as LQT1. Based on genetic results, the present modified Schwartz scoring system facilitated the differential diagnosis between CPVT and LQT1 in patients with cardiac events triggered by exercise or emotional stress.

Acknowledgments

The study was supported in part by MEXT KAKENHI grant numbers 15H04818 (to M.H.) and 15K09689 (to S.O.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and a grant from the Ministry of Health, Labor and Welfare of Japan for Clinical Research on intractable Disease (H27-032 to MH). This research was partially supported by AMED under Grant Number JP17ek0109202 (to S.O. and M.H.).

Disclosures

The authors declare no conflicts of interest.

Supplementary Files

Supplementary File 1

Table S1. Subject clinical and genetic characteristics

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-17-1032

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