© 2003 by European Society of Cardiology
Long QT syndrome patients may faint due to neurocardiogenic syncope
1Center for Sensory Motor Interaction, Department of Health Science and Technology, Aalborg University Denmark; 2Department of Cardiology, Aalborg Hospital, Ċrhus University Hospitals Aalborg, Denmark; 3Laboratory of Experimental Cardiology, University of Copenhagen Copenhagen, Denmark; 4Department of Medicine, Elsinore Hospital Helsingĝr, Denmark; 5Copenhagen Heart Arrhythmia Research Center (CHARC) Copenhagen, Denmark; 6Department of Clinical Biochemistry, Statens Serum Institut Copenhagen, Denmark; 7Gentofte University Hospital Copenhagen, Denmark
Manuscript submitted 3 December 2002. Accepted after revision 15 June 2003.
Correspondence: Egon Toft, MD, PhD, Department of Cardiology, Aalborg University Hospital, Postbox 365, DK 9100 Aalborg, Denmark. Tel.: +45-9932-2177; Fax: +45-9932-2361. E-mail: et{at}healthntech.dk
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Abstract |
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AIMS: Syncope in long QT syndrome (LQTS) is expected to be due to Torsades de Pointes ventricular tachycardia (TdP). Often these patients faint in situations with emotional stress. The aim of the present study was to evaluate whether neurocardiogenic syncope occurs in LQTS.
METHODS AND RESULTS: Ten untreated consecutive LQTS patients (age 11–72 years, median 37.5 years, five males and five females from five different families (one KvLQT1 mutation, two HERG mutations in three families and one without established genetic background)) were examined by a head-up tilt-table test (HUT). If syncope did not occur within 25 min, the patient received 0.25 mg nitroglycerine sublingually and the HUT was continued for 20 min. Nine out of 10 patients had a positive HUT. The syncope resulted from a combined vasodepressor and bradycardiac response. There were no cases of TdP. No syncope occurred in a 42-year-old asymptomatic male LQTS patient with a borderline prolonged QTc of 0.45 s and a HERG mutation. In 11 of 21 patients referred for syncope without LQTS a positive HUT was found (P<0.10).
CONCLUSION: Syncope in LQTS can be of neurocardiogenic origin and is not necessarily due to TdP. The reason for neurocardiogenic syncope in LQTS is unknown, but involvement of the autonomic nervous system outside the heart is possible.
Key Words: Long QT syndrome, tilt-table test, syncope, sudden death
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Introduction |
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Congenital long QT syndrome (LQTS) is a relatively uncommon disease characterized by syncope, ventricular tachycardia and sudden cardiac death. LQTS exists in three variants, a very rare autosomal recessive variant associated with congenital deaf muteness (Jervell Lange-Nielsen syndrome[1]
), a less rare autosomal dominant variant (Romano–Ward syndrome[2]) with normal hearing, and a recently described recessive variant of Romano–Ward syndrome[3,4].
It has been shown that stimulation of the left stellate ganglion or ablation of the right stellate ganglion prolongs the QT interval[5], leading to the original hypothesis that LQTS was due to a sympathetic imbalance with a lower than normal right cardiac sympathetic activity. Antiadrenergic therapy with betablockers has been shown to be effective in reducing the mortality and the numbers of syncopal attacks[6]. Left cardiac sympathetic denervation shortens the QT interval and prevents torsades de pointes tachycardia (TdP) in LQTS, and is used in carefully selected patients with syncope despite medication with betablockers[7].
LQTS has more recently been shown to be due to mutations in cardiac potassium[8,9] or sodium channel subunits[10] and the imbalance hypothesis was abandoned.
The heart rate at rest is lower in LQTS[11,12] and sinus pauses unrelated to respiratory sinus arrhythmia are known to occur frequently in LQTS[12]. The clinical history commonly include syncope in a setting of emotional stress, fear and when taking blood samples[13]. This is in common with vasovagal syncope, which is a frequently made erroneous diagnosis in LQTS patients, when the QT prolongation is overlooked. In a recent study all the six patients investigated with a head-up tilt-table test (HUT) had a positive test of mixed response[14]. No genetic classification was made in that study.
The present report describes the occurrence of neurocardiogenic syncope in 10 consecutive LQTS provoked by HUT. Genetic testing was performed in all patients and the results were compared with syncope patients without LQTS referred for HUT.
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Methods |
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Patients
The 10 LQTS patients (age: 11–72 years (range), five males) were recruited from five families (Table 1). QTc was calculated from Bazett's formula.
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Genetics
Genetic testing was routinely performed at Statens Serum Institut with SSCP and PCR for the five known genes KvLQT1, HERG, SCN5A, MinK, and MiRP1 as described in detail elsewhere[15]
. One patient had a mutation in the gene coding for the KvLQT1 potassium channel, eight subjects from three different families had two different HERG mutations. In one subject no mutation was identified.
HUT
The patients were initially placed in supine position for at least 10 min to obtain baseline values of blood pressure and heart rate. The table was then raised to a 60° upright position for 25 min. If the subject did not have syncope during unprovoked HUT, nitroglycerine 0.25 mg was given sublingually[16] and the HUT was continued for another 20 min. No venous cannula was inserted and a footplate was used. Pulse rate was monitored continuously, whereas blood pressure was not. The results of HUTs in 21 patients without LQTS referred for syncope are shown for comparative purposes (age median 43 years, range 21–67 years, 13 males and eight females).
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Results |
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Nine of 10 LQTS patients had a positive result of the HUT with a mixed response of vasodepression and bradycardia. None of the subjects developed TdP during the HUT. All patients were tested before the initiation of treatment and two of the patients (nos. 2 and 3, Table 1) were later reexamined with a second HUT after starting antiadrenergic treatment with a betablocker and patient no. 2 had a second positive HUT. Five of the patients presented a history of vasovagal syncope on admission.
In two of the patients, changes in T wave morphology developed during syncope or pre-syncope (Fig. 1). In syncope patients without LQTS a positive HUT was found in 11 of 21 (P<0.10, when comparing with LQTS patients, Fisher's exact test).
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Discussion |
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TdP can cause syncope, which has led to the expectation that syncope in LQTS always is due to TdP. A recent[14]
and the present study show that neurocardiogenic syncope can be induced in a majority of LQTS patients demonstrating that other mechanisms may be important. There was a slight tendency towards HUT being more often positive in LQTS than in patients without LQTS referred for HUT due to syncope (P<0.10). There is no clear relation between the presence of an ion channel defect and induction of neurocardiogenic syncope.
When humans are changing position from supine to standing, the baroreceptors are unloaded. This results in a diminished pre-load and a fall in cardiac output giving rise to a compensatory increase in sympathetic activity. The consequence of augmented sympathetic tone is, besides making the heart more vulnerable to TdP in LQTS, vasoconstriction outside the brain and the heart. The result is a redistribution of blood, favouring flow to the brain. Since potassium channels are known to participate in cerebral vasodilatation[17], it could be speculated that LQTS patients with affection of potassium channels have impaired cerebral blood flow in response to orthostatic stress. This mechanism could not explain syncope in the LQT3 variant with mutation in the sodium channel gene SCN5A. LQT3 patients have fewer occurrences of syncope with a higher risk of a lethal syncope than HERG and KvLQT1 patients. It is possible that syncope in LQT3 patients is more likely to be due to TdP. During the last two decades researchers have tried to find provocative tests to guide treatment in LQTS, but none of these tests has been successful. In this small series the only LQTS patient that was HUT negative was also asymptomatic, it could be interesting to investigate whether the outcomes of HUT have any prognostic value regarding mortality and syncope in LQTS. Accurate history taking in LQTS patients might reveal symptoms suggestive of vasovagal syncope. However, in contrast with the benign course of vasovagal syncope, syncope in LQTS is associated with high mortality. Hence, the presence of vasovagal syncope in LQTS should not lead to any modification in the selection of treatment.
In conclusion, the present study showed that neurocardiogenic syncope occurs in a large majority of a small series of LQTS patients. Syncope in LQTS has to be evaluated with this possible explanation in mind.
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Footnotes |
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No financial support was obtained for the study.
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References |
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