Depressive symptoms in the congenital long QT syndrome

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1 Annals of Medicine. 2009; 41: ORIGINAL ARTICLE Depressive symptoms in the congenital long QT syndrome TAINA HINTSA 1, LIISA KELTIKANGAS-JÄRVINEN 1, SAMPSA PUTTONEN 2, NIKLAS RAVAJA 3, LAURI TOIVONEN 4, KIMMO KONTULA 5 & HEIKKI SWAN 4 1 Department of Psychology, University of Helsinki, FIN-00014, Helsinki, Finland, 2 Finnish Institute of Occupational Health, FIN-00250, Helsinki, Finland, 3 Helsinki School of Economics, FIN-00101, Helsinki, Finland, 4 Department of Cardiology, Helsinki University Central Hospital, University of Helsinki, FIN-00029, Helsinki, Finland, and 5 Department of Medicine, University of Helsinki, FIN-00290, Helsinki, Finland Abstract Background. A proportion of patients with congenital long QT syndrome (LQTS) experience potentially life-threatening cardiac arrhythmias. Aim. To examine whether depressive symptoms are related to arrhythmic events among symptomatic and asymptomatic LQTS patients, and syncope events among their relatives not carrying the family s LQTS-causing mutation. Methods. The participants were 569 molecularly defined LQTS mutation carriers and 622 non-carrier relatives from the Finnish LQTS registry. Depressive symptoms were self-rated with a revised version of the Beck Depression Inventory. Results. LQTS patients with arrhythmic events scored higher on depressive symptoms than those without (P0.011) or the control group (P0.005). In addition, in the binary logistic regression analysis including symptomatic and asymptomatic LQTS mutation carriers, depressive symptoms showed an age- and sex-adjusted association of odds ratio (OR) 1.40 (95% confidence interval (CI) ) with symptomatic status of LQTS. In similar analysis including non-carriers of the LQTS mutation, there was no association between depressive symptoms and history of syncope events OR 1.23 (95% CI ). Conclusion. Our results from this relatively large genotyped LQTS patient cohort indicate that depressive symptoms are associated with arrhythmic events in LQTS patients. Whether depressive symptoms are causally related to arrhythmias in LQTS remains uncertain. Key words: Arrhythmia, depressive symptoms, long QT syndrome, mutation Introduction The congenital long QT syndrome (LQTS) is an inherited disorder characterized by prolongation of the QT interval and predisposes to ventricular arrhythmias and sudden death (1). The basic anomaly is defective sarcolemmal ion channel function due to mutations in the ion channel coding genes. The syndrome is divided into subtypes, most common of which are LQT1, LQT2, and LQT3, possessing mutations in the potassium channel genes KCNQ1 and KCNH2 and in the sodium channel gene SCN5A, respectively (2). Common environmental triggers precipitate ventricular arrhythmias in LQTS leading to syncope events or cardiac arrest (3). These include physical exercise and acute physical or psychological stress in LQT1, sudden arousal or startling auditory stimuli in LQT2, or rest or sleep in LQT3 (3,4). Behavioral aspects have been shown to be important contributors to a variety of cardiac derangements including arrhythmic events and sudden death (5,6). The role of depression is especially emphasized (5,7 9). A previous study has reported an association between higher QT interval variability and depression in cardiac patients (10). In addition, there is a study reporting QT interval prolongation in healthy males with personality-related vulnerability to depression (11). Despite these observations, the association Correspondence: Taina Hintsa, Department of Psychology, University of Helsinki, PO Box 9, FIN University of Helsinki, Finland. Fax: taina.hintsa@helsinki.fi (Received 10 February 2009; accepted 11 May 2009) ISSN print/issn online # 2009 Informa UK Ltd. DOI: /

2 Depressive symptoms in LQTS 517 Key messages. Depressive symptoms are associated with arrhythmic events in long QT syndrome patients. between depressive symptoms and arrhythmic events in congenital long QT syndrome has not been studied so far. The aim of the present study was to examine whether depressive symptoms are related to arrhythmic events among symptomatic and asymptomatic LQTS mutation carriers and syncope events among their relatives not carrying the family s LQTScausing mutation. Abbreviations CI KCNH2 KCNQ1 confidence interval gene that is responsible for LQTS subtype 2 gene that is responsible for LQTS subtype 1 LQT1 long QT syndrome subtype 1 LQT2 long QT syndrome subtype 2 LQT3 long QT syndrome subtype 3 LQTS long QT syndrome OR odds ratio QT interval a measure of the time between the start of the Q wave and the end of the T wave in the heart s electrical cycle SCN5A SD gene that is responsible for LQTS subtype 3 standard deviation Material and methods Study population The study was carried out on genotyped LQTS patients and their relatives who did not carry the family s LQTS-causing mutation. Subjects were recruited from the Finnish LQTS registry, which includes all patients referred for molecular genetic studies since 1993 to Helsinki University Hospital from all over the country (1400 mutation carriers and 1700 relatives). Registry subjects who fulfilled the following criteria were included: molecularly verified positive or negative mutation carrier status for the LQTS-causing mutation identified in the family, age 1665 years, living in Finland, and a written informed consent which conforms to the ethical guide-lines of Helsinki University Central Hospital. The mutations in KCNQ1, KCNH2, or SCN5A genes and their in vivo and in vitro consequences have been described in detail (1215). Mean follow-up time was 6 years since entering the registry. The psychological study questionnaire was sent in year 2006 to 1822 subjects (n814 carriers of LQTS mutation and n 1008 non-carriers of LQTS mutation), and 1443 (79%) of them responded. The reasons for attrition are not known. There were 252 participants who either responded only partly to the psychological questionnaire or information on their relevant LQTS variables was missing. Thus a total of 1191 subjects had adequate psychological and clinical data available for analysis. Of them 569 (367 women) had molecularly defined LQTS, and 622 (373 women) were control subjects. There were 410, 143, and 16 carriers of the KCNQ1, KCNH2, and SCN5A mutations, respectively. Measures Data regarding the occurrence of arrhythmic events were collected with a questionnaire when an individual was entered into the LQTS registry. These data were updated in year 2006 when the current survey was carried out. A sudden loss of consciousness, i.e. syncope, for any potentially arrhythmic reason, a documented LQTS-type ventricular arrhythmia, and cardiac arrest were defined here as an arrhythmic event in LQTS patients. The control subjects reported whether they had had syncope events. A typical vasovagal fainting was not regarded as syncope. The same information was collected from all participants. They all filled in the same questionnaire at the time of recruitment to the study. This means that when a family member joined the study, his/her mutation carrier status was not yet known. The questionnaire in Helsinki University Hospital included questions where participants were asked about the history of syncope events, e.g. if he or she has ever had a syncopal spell, how many times syncopal spells had occurred, and a detailed description of the preceding activities. Arrhythmic events of the LQTS patients and syncope events of the control subjects are not comparable because LQTS patients know the potentially lethal nature of their loss of consciousness. However, in order to know whether depressive symptoms would be LQTS-specific (and not eventrelated), we included a control group with the same genetic background (with the exception of the LQTS-causing mutation), even though the arrhythmic events in LQTS mutation carriers and syncope events in control subjects are not comparable as such.

3 518 T. Hintsa et al. Depressive symptoms were self-rated with a revised version of the Beck Depression Inventory (16). The original Beck Depression Inventory has 21 items with four alternative statements for each item (17). The original items were here transformed to a fivepoint Likert scale. This modified measure has been used in several previous Finnish studies, and it has been shown to identify the whole range of depressive symptoms in a non-clinical population (16,1820). The responses were given from 1 (totally disagree) to 5 (totally agree). The scale reliability was 0.93 (Cronbach s alpha). Each subject s mean score of responses was calculated. Statistical analyses The three LQTS subgroups were combined for the analyses because of high variance in group sizes and lack of difference in the depressive symptom score among subgroups. First the differences in levels of depressive symptoms between LQTS patients and non-carriers of LQTS mutation and control subjects were tested. Then the associations between depressive symptoms, arrhythmic events in LQTS mutation carriers, and syncope events in control subjects were examined by conducting multinomial and binary logistic regression analyses. All logistic regression analyses were adjusted to age and sex. Data analyses were carried out using SPSS 15.0 software. Results Of the 569 LQTS patients, 248 had experienced syncope or LQTS-related ventricular tachycardia or cardiac arrest. The reported number of arrhythmic events ranged from 1 to 100. Of the 622 control subjects, 191 reported that they had experienced syncope events. Their number ranged from 1 to 30. The characteristics of the LQTS patients and control subjects are shown in Table I. The LQTS patients with arrhythmic events scored more highly on depressive symptoms than the LQTS mutation carriers without arrhythmic events (2.22 versus 2.02, P-value 0.011). They also scored more highly than the control subjects (2.22 versus 2.03, P-value 0.005). In asymptomatic LQTS mutation carriers depressive symptoms were on the same level as in the control subjects (2.02 versus 2.03, P-value 0.991). We tested whether depressive symptoms were specific to LQTS gene carrier status by an analysis of variance. We found a significant main effect of symptom status (P-value B0.001), a non-significant main effect of LQTS mutation (P-value 0.248), and a non-significant interaction of mutation and symptom status (P-value 0.816). In other words, the level of depressive symptoms was not related to LQTS gene mutation but was associated with the clinical symptoms, i.e. both arrhythmic events among LQTS mutation carriers and syncope events among control subjects. Among controls, those with syncope events scored more highly on depressive symptoms than did those without (2.16 versus 1.97, P-value 0.007). The associations between depressive symptoms and LQTS symptom status were examined with multinomial and binary logistic regression analyses. In multinomial logistic regression analysis including LQTS patients with arrhythmic events, LQTS mutation carriers without arrhythmic events, and the control subjects, depressive symptoms showed an age- and sex-adjusted association of odds ratio (OR) 1.29 (95% confidence interval (CI) ) with symptomatic status of LQTS (Table II). In the binary logistic regression analysis including symptomatic and asymptomatic LQTS mutation carriers, depressive symptoms showed an age- and sex-adjusted association of OR 1.40 (95% CI ) with symptomatic LQTS (Table II). In the binary logistic regression analysis including control subjects, i.e. non-carriers of LQTS mutation, depressive symptoms showed no association Table I. The characteristics of the study subjects according to long QT syndrome (LQTS) status. n Mean SD Range Age 1665 Symptomatic LQTS patients Asymptomatic LQTS mutation carriers Control group Depressive symptoms Symptomatic LQTS patients Asymptomatic LQTS mutation carriers Control group Syncope events No syncope events

4 Depressive symptoms in LQTS 519 Table II. Relationship between depressive symptoms and long QT syndrome (LQTS) symptom status. Group by LQTS status Age-and sex-adjusted OR (95% CI) P-value (2-tailed) Control group 1.00 Asymptomatic LQTS 1.00 ( ) mutation carriers Symptomatic LQTS patients 1.29 ( ) Asymptomatic LQTS mutation carriers Symptomatic LQTS patients Non-carriers of LQTS mutation/no syncope events Non-carriers of LQTS mutation/with syncope events ( ) ( ) with history of syncope events (OR 1.23, 95% CI ) (Table II). Discussion This is to our knowledge the first study that examined the relationship between depressive symptoms and arrhythmic events in congenital long QT syndrome. The results showed that depressive symptoms were associated with arrhythmic events but not with being a carrier of LQTS disease as such. The association remained after adjustment for age and sex. There were no association between depressive symptoms and history of syncope events among control subjects. Depressive symptoms did not differ between asymptomatic LQTS mutation carriers and their non-carrier relatives. Thus, depressive symptoms were related to arrhythmic events in LQTS. Carrying a LQTScausing mutation and being at risk of subsequent, potentially life-threatening arrhythmias might increase psychological distress and tendency to depression (21). A previous study showed that the uncertainty related to unconfirmed LQTS diagnosis can cause transient distress in suspected cases (22,23). However, our observation on asymptomatic LQTS mutation carriers suggests that being aware of the disorder in the family and knowledge of being a mutation carrier may not alone lead to depressive symptoms. On the other hand, it has been repeatedly documented that depression increases the probability of various cardiac events (69). Depression seems to contribute to the risk of arrhythmias such as ventricular premature beats, ventricular tachycardia, and ventricular fibrillation (5). Depressive symptoms may induce allostatic load on the individual confronting stress by activating neural, neuroendocrine, and neuroendocrine-immune mechanisms (24,25). Chronic allostatic load resulting from the inability to shut off allostatic activity after stress (24) has been linked to myocardial infarction (8,26). Sustained allostatic load could also add to the probability of LQTS-related arrhythmic events. A possible explanation for the relationship between depressive symptoms and arrhythmic events may be altered autonomic nervous system function. Imbalance between sympathetic and parasympathetic activity has been reported among depressed subjects (5,27). Decreased parasympathetic and/or increased sympathetic activity has been associated with ventricular tachycardia, ventricular fibrillation, and sudden cardiac death (28,29). Depressive symptoms may lower the capacity to cope with acute psychosocial stress and also lower the threshold for arrhythmias and prolong the QT interval (27,29). Further, a higher QT variability has been associated with depression (30). Depressive symptoms and QT interval were not interrelated among LQTS mutation carriers in the present sample. Depressed postmyocardial infarction patients have significantly higher QT interval variability in the early morning hours (10), which is the diurnal period with highest incidence of sudden death (31). The greater risk might be due to sympathetic nervous system dysfunction that may both increase QT variability (31) and be associated with depression (32). Depressive symptoms may trigger LQTS-related arrhythmic events and may partly explain why some carriers of the LQTS mutation gene have symptoms and others do not. The present results imply that depressive symptoms are associated with LQTS-related arrhythmic events. A limitation of the study is that a cross-sectional design does not allow conclusions about causalities. We measured depressive symptoms at one time point using the revised version of the widely used Beck Depression Inventory. Although it has been suggested to be the most effective in measuring depressive symptoms in the normal population (16,33), replicating our study with several measurement points of depressive symptoms would strengthen the evidence and help in defining the clinical significance of our findings. Furthermore, the selfreported events in LQTS mutation carriers include some not due to disease-specific ventricular arrhythmias, the proportion of which remains uncertain. More important than the exact underlying mechanism is that the study subjects may interpret the importance of arrhythmic events or syncope events

5 520 T. Hintsa et al. differently, depending on whether the particular individual is a LQTS mutation carrier or not. Finally, as information on medically treated psychiatric diagnoses was not available for this study, possible antidepressive medication may have influenced the association. The use of antidepressive medication has been associated with both increased sudden cardiac death risk and the presence of clinical depression (34). Instead of clinical depression, we measured depressive symptoms. As the level of depressive symptoms was not markedly higher than in a previous Finnish population-based study (19), it is possible that there were only few users of antidepressive medication among LQTS mutation carriers. Therefore, it is not very likely that the possible use of antidepressive medication has caused a major bias in our study. The special strength of this study is that the LQTS mutation carriers and the family members (i.e. control subjects) were molecularly genotyped and the study cohort is rather extensive in size. Depressive symptoms seem to be associated with increased risk of LQTS-related arrhythmic events but the causal relationship remains unclear. Prospective studies are needed to address a potential causality in the association between depressive symptoms and LQTS. Furthermore, whether attending to psychological conditions can improve quality of life and reduce morbidity in these patients remains to be addressed. Acknowledgements This study was supported by The Finnish Cultural Foundation and the Finnish Foundation for Cardiovascular Research (TH); the Academy of Finland, project , The Jansson Foundation (LK-J). We thank research nurses Hanne Ranne and Mauri Niiniaho for their valuable contribution in questionnaires and mailings-related procedures. 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