QT interval duration in apparently healthy men is associated with depression-related personality trait neuroticism

Journal of Psychosomatic Research 61 (2006) 19 – 23

QT interval duration in apparently healthy men is associated with depression-related personality trait neuroticism Piercarlo Minorettia,b, Pierluigi Politic, Valentina Martinellic, Enzo Emanuelea, Marco Bertonaa, Colomba Falconea,d, Diego Geroldia,4 a

Interdepartmental Center for Research in Molecular Medicine (CIRMC), University of Pavia, Viale Taramelli, 24, I-27100 Pavia, Italy b Department of Cardiology, Alessandro Manzoni Hospital of Lecco, Lecco, Italy c Department of Health Sciences, Section of Psychiatry, University of Pavia, Pavia, Italy d Department of Cardiology, IRCCS San Matteo Hospital, Pavia, Italy Received 23 September 2005; received in revised form 9 January 2006; accepted 10 January 2006

Abstract Objective: High levels of neuroticism and low self-esteem are markers for vulnerability to depression, a condition associated with a higher risk of arrhythmias. The question as to whether these depression-related personality domains are related to cardiac repolarization (duration of QT interval) in apparently healthy men has been addressed in this study. Methods: Participants were 658 clinically healthy males who underwent a health screening programme. QT interval duration was determined in the resting 12-lead electrocardiogram using an automated analysis program. Neuroticism was assessed by the short-scale Eysenck Personality Questionnaire and self-esteem by the Rosenberg self-esteem scale. Results: Heart-rate corrected QT interval {QTc, formula of Bazett

[Bazett HC. An analysis of time relations of electrocardiograms. Heart 1920;7:353 – 370]} progressively increased across quartiles of neuroticism ratings. By contrast, no differences in QTc were observed across different degrees of self-esteem. A multivariate regression analysis showed that neuroticism was a statistically significant, independent predictor of QTc duration. Conclusion: After adjustment for potential confounders, neuroticism scores independently predicted QT interval duration in apparently healthy men. These findings highlight the possibility that higher arrhythmic risk could be present not only in patients with clinical depression but also in depression-prone, otherwise healthy individuals. D 2006 Elsevier Inc. All rights reserved.

Keywords: Depression-related personality traits; Electrocardiogram; Men; Neuroticism; QT interval; Self-esteem

Introduction Ventricular repolarization is a complex electrical phenomenon, and as direct repolarization measurements obtained from epicardial monophasic action potential and body surface mapping have been found to be correlated with the QT interval on surface electrocardiograms (ECGs), simple measurements of the QT interval have been regarded as essential in monitoring cardiac repolarization [1,2]. During the past years, a bulk of published data has clearly shown that a prolonged QT interval is a risk marker 4 Corresponding author. Tel.: +39 0382 528341; fax: +39 0382 526259. E-mail address: [email protected] (D. Geroldi). 0022-3999/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jpsychores.2006.01.001

for cardiovascular morbidity and mortality in numerous different populations, including initially healthy subjects [3 –5], subjects referred for Holter monitoring [6], as well as clinical cohorts of patients with diabetes mellitus [7,8] and cardiovascular disease [9,10]. Among the pathophysiological mechanisms advocated to account for this relationship, cardiac autonomic imbalance with decreased parasympathetic and increased sympathetic modulations has emerged as one of the most intriguing pathways [11]. Working from the assumption that an altered autonomic function may also be a feature of different psychiatric disorders, some authors have recently demonstrated significant alterations of the QT interval in clinical cohorts of psychiatric patients, including subjects with social phobia [12], panic disorder [13], and major depression [14]. The

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P. Minoretti et al. / Journal of Psychosomatic Research 61 (2006) 19 – 23

latter findings are of particular importance, because it is well-known that depressed patients show an increased risk for a number of cardiovascular complications, including ischemic heart disease [15], serious ventricular arrhythmias [16], and sudden cardiac death [17]. It has been therefore proposed that dysregulation of ventricular repolarization may be one of the mechanisms linking depressive mood states and cardiac risk [13,14,16,18]. At this time, however, no studies have assessed whether a relation exists between QT interval duration and personality-related vulnerability to depression. Nonetheless, this issue could be of interest in view of the strict interrelationships between the onset of major depressive episodes and personality traits in the domains of high neuroticism and low self-esteem [19]. Neuroticism is a dimensional measure of an individual’s tendency to experience negative emotions that are manifested at one extreme as anxiety, low mood, and hostility and at the other as emotional stability [20]. Reflecting a tendency toward states of negative affect, it, together with extraversion and psychoticism, constituted the three key dimensions of personality, according to Eysenck and Eysenck [20], and has been included in nearly all theories of personality. Neuroticism is also known to possess good psychometric properties of item and construct validity, stability, and cross-cultural validation [21]. Differently from neuroticism, self-esteem has been given a number of different definitions, each emphasising different aspects [22]. The most significant division remains between the view that self-esteem is a generalised feeling about the self and the view that it is the sum of a set of judgments about one’s value, worthiness, and competence in various domains [23]. In any case, different independent studies have clearly indicated that low self-esteem could be a marker for developing clinically relevant depressive episodes [24,25]. In the present report, we hypothesized that depressionrelated personality traits of neuroticism and self-esteem could be associated with QT interval duration as a possible pathway in the genesis of higher cardiovascular risk observed in depressive mood states. We addressed this issue by studying the relationships of neuroticism and self-esteem scores with QT interval in an Italian cohort of apparently healthy men undergoing a cardiovascular screening programme. We also reasoned that if these personality domains are independently related to QT interval duration, then effects should persist after statistical control for demographical, clinical, and biochemical characteristics of the study participants.

Methods Study subjects Participants were recruited from a general health survey (CardioTest Lecco) aiming to investigate the role of various genetic, biochemical, and psychological risk factors in the development of cardiovascular diseases and to initiate

appropriate primary prevention interventions in subjects at risk. All participating individuals were Caucasians of Italian descent, and the population was homogeneous with regard to ethnic background. For the current investigation, the study cohort was composed of 658 clinically healthy males (age range 34 – 66 years, mean age = 47.7, S.D.= 6.9) with no past or present history of any psychiatric disease as well as of medical conditions that could alter electrocardiographic parameters. Specifically, to be eligible for the present study, none of subjects were permitted to suffer from (1) any known cardiac or pulmonary disease; (2) hypertension (blood pressure N140/90 mmHg or taking antihypertensive medication); (3) diabetes mellitus/impaired fasting glucose (fasting blood glucose N6.1 mmol/l or taking hypoglycemic drugs); (4) angina pectoris; (5) atrial fibrillation, bundlebranch block, frequent supraventricular or ventricular premature beats (N10 beats/min), delta waves, paced rhythm, or any arrhythmia; (6) renal, hepatic, or thyroid diseases (as assessed by self-reports and laboratory analyses); and (7) serum electrolyte imbalances. None of the subjects reported taking medication known to affect QT interval duration (i.e., beta-blockers, digitalis, anti-dysrhythmic, or antidepressant medication). Additionally, none of the participants had ever taken medications for psychiatric conditions. Marital status, smoking status, and alcohol use of the study subjects were determined by questionnaire. We measured weight and height and calculated body mass index (BMI) as weight in kilograms divided by the square of the height in meters. Physical activity was determined using the multiple-choice question, b Which of the following statements best describes how physically active you have been during the last month, that is, done activities such as 15 –20 min of brisk walking, swimming, general conditioning, or recreational sports?Q Participants who answered fairly, quite, very, or extremely active (vs. not at all or little active) were considered physically active. Systolic (SBP) and diastolic blood pressure (DBP) values were determined in the sitting position from the right arm using a sphygmomanometer after a 10-min rest period, with the mean of three determinations being recorded; diastolic pressure was measured at the fifth Korotkoff sound. We assayed total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting plasma glucose using commercially available kits. The investigation conformed to the principles outlined in the Declaration of Helsinki, and the study protocol was approved by our local ethics committee. All participants provided their written, informed consent before entering the programme. Measurements of QT interval In order to reduce emotional stress and to avoid the possible influence of circadian patterns, all ECG recordings

P. Minoretti et al. / Journal of Psychosomatic Research 61 (2006) 19 – 23 Table 1 General characteristics of the 658 study participants Characteristic Continuous variables

MeanFS.D.

Range

Age (y) BMI (kg/m2) SBP (mmHg) DBP (mmHg) Total cholesterol (mmol/l) LDL cholesterol (mmol/l) HDL (mmol/l) Triglycerides (mmol/l) Fasting plasma glucose (mmol/l) Heart rate (beats/min) QT (ms) QTc (ms) EPQ neuroticism score Rosenberg self-esteem score

47.7F6.9 25.2F3.1 123.3F10.1 78.7F6.6 5.1F1.1 3.4F1.0 1.2F0.4 1.9F0.9 4.5F0.6 59.6F6.5 404.6F22.2 402.7F19.1 4.9F2.6 20.5F4.1

34 – 66 17 – 34 105 – 140 59 – 90 2.4 – 8.4 0.2–7.5 0.3–2.5 0.4 – 6.9 3.3 – 6.1 40 – 101 332– 489 317–468 0 –12 11 – 28

Categorical variables

n

%

Married Current smokers Regular alcohol use Physical activity

421 177 203 434

64 27 31 66

were performed between 9:00 and 11:00 a.m. in the same quiet room during spontaneous breathing, following 10 min of adjustment in the supine position. Heart rate (beats/min) and QT intervals were assessed automatically from resting ECGs using the GE Marquette 12SL ECG Analysis Program (GE Medical Systems, Menomonee Falls, WI, USA). QT interval was corrected for heart rate by calculating corrected QT interval (QTc) according to the equation of Bazett [QTc= QT/RR1/2] [26].

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has been used extensively with internal consistency and 6-month test–retest reliability both greater than 0.70 [27]. Self-esteem was measured using the Rosenberg Scale [29], which is the most widely used scale to measure this personality trait in research studies. Self-esteem is quantified using a set of 10 questions. The scale ranges from 0 to 30. Scores between 15 and 25 are within the normal range, while scores below 15 indicate low self-esteem. In the original report, it showed a reproducibility of 0.90 and a scalability of 0.70. The Rosenberg Scale has previously been validated in other studies [30,31]. Statistical analysis The SPSS Version 11.0 (SPSS, Chicago, IL, USA) and MedCalc (Mariakerke, Belgium) packages were used for all calculations. Simple correlation analysis (Spearman’s rho) was used to assess the relationships between QTc interval duration and numerical variables [32]. The study sample was divided into quartiles based on neuroticism and selfesteem ratings, and the hypothesis that QTc interval duration differed across different neuroticism or self-esteem scores was tested using one-way analysis of variance (ANOVA) (including polynomial contrast analysis for trend), and by analysis of covariance (ANCOVA) after considering the confounding effects of demographical, clinical, and biochemical characteristics of the study participants. To analyze further the effects of potential confounders on the relationship between the degree of neuroticism and QTc, a stepwise multiple regression analysis was performed according to previous methodology [33]. A value of P b.05 (two-tailed) was considered statistically significant.

Assessment of neuroticism and self-esteem

Results

Immediately after the ECG recordings, two brief personality questionnaires were administered. Neuroticism was assessed using the Italian translation of the revised, shortscale Eysenck Personality Questionnaire (EPQ) [27,28]. This measure comprises 12 yes/no questions in which each b yes Q scores one point. Points are then summed to yield a total score which may range from 0 to 12. Higher scores indicate a higher degree of neuroticism. The questionnaire

The general characteristics of the 658 study participants are summarized in Table 1. As assessed by Spearman’s correlation analyses, the QTc interval in our study cohort showed a positive correlation with age (r =.129, Pb.001), fasting plasma glucose (r =.080, Pb.05), and EPQ neuroticism scores (r =.104, Pb.01). On the other hand, no association between QTc duration and Rosenberg selfesteem scores was discerned (r = 0.056, P=.15).

Table 2 QTc interval duration across neuroticism and self-esteem quartiles Neuroticism quartiles 1 (scores less than 3, n=164) QTc (ms) 397.3F28.5

2 (scores from 3 to 5, n=165) 403.6F28.2

3 (scores from 5 to 7, n=165) 404.0F26.7

4 (scores higher than 7, n=164) 404.9F28.5

Self-esteem quartiles 1 (scores less than 17, n=164) QTc (ms) 402.7F28.7

2 (scores from 17 to 21, n=166) 401.3F28.4

3 (scores from 21 to 24, n=165) 407.3F26.9

4 (scores higher than 24, n=163) 400.6F28.2

P (ANOVA)

P (ANCOVA)

.017

.029

P (ANOVA)

P (ANCOVA)

.15

.43

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Table 3 Results of multiple stepwise regression analysis of QT interval (dependent variable: heart-rate corrected QT interval) Predictor

Step

B

S.E.

P

Age Fasting plasma glucose EPQ neuroticism score

1 2 3

0.485 4.519 0.909

0.157 1.845 0.424

.002 .015 .032

To further analyze the relationships between depressionrelated personality traits and QT interval duration, subjects were divided into quartiles based on neuroticism and selfesteem ratings. As shown in Table 2, QTc duration increased across neuroticism (one-way ANOVA: Pb.05, Pb.01 for trend), but not across the self-esteem quartiles (one-way ANOVA: P =ns, P =ns for trend). The association between QTc duration and neuroticism ratings remained significant ( Pb.05) even when analyzed by ANCOVA after adjustment for all variables listed in Table 1. Similarly, after statistical control for demographical, clinical, and biochemical characteristics of the study participants, stepwise multiple regression analysis showed that age ( Pb.01), fasting plasma glucose ( Pb.05), and neuroticism ( Pb.05) were statistically significant, independent predictors of QTc interval duration (Table 3).

Discussion The purpose of the present investigation was to relate a computerized measurement of the QT interval to two depression-related personality traits—neuroticism and selfesteem—at the time of risk assessment in a cardiovascular screening programme. Our results showed that, in an Italian sample of apparently healthy adult males, the QTc interval duration was positively associated with neuroticism scores but not with self-esteem measurements. This association was not affected by other potential confounders of the QTc interval as demonstrated by ANCOVA, as well as by stepwise multiple regression analysis. The QTc represents the interval between ventricular excitation and repolarization and can be easily obtained using a simple ECG recording [1]. This interval reflects the myocardial refractoriness and electrical stability and is thought to be influenced by cardiac autonomic activity [11]. Although the presence of a cardiac sympathovagal imbalance has been suggested in patients with clinical depression [13,14,16], to date, no data are available on the possible relationship between cardiac repolarization and depression-related personality domains. Our data on a significant positive association between the degree of neuroticism and the duration of QT/QTc intervals indicate that this personality trait, which gives an indication of the emotional stability of a person, might be of some relevance in affecting ventricular repolarization. Subjects with high scores on neuroticism scales tend to be more anxious and to have more worries in general, and

neuroticism has proven to be an important predictor of psychological distress, both in the presence and the absence of stressful circumstances [19]. In view of our results, it seems reasonable to hypothesize that high neuroticism, which reflects a pervasive tendency toward states of negative emotions [20,21], may lead to a condition characterized by a decreased cardiac vagal function and a relatively increased sympathetic drive. Although autonomic imbalance seems to be a plausible explanation for our present findings, it should be acknowledged that no definite conclusion on the mechanisms behind the association between QTc and neuroticism can be directly inferred from the present observational study. Therefore, we believe that future investigations on cardiac autonomic function in subjects with high neuroticism scores are needed for confirming this hypothesis. Similarly, longitudinal prospective studies initiated before the onset of depression are required to untangle the relationship between neuroticism, QT interval prolongation, and cardiac risk. In any case, it is also important to emphasize that our group had no past or current history of depression, suggesting that QT prolongation is a marker for vulnerability, rather than a consequence of depression. Additionally, it should be noted that our research design was aimed to investigate the relationships between cardiac repolarization and two depression-related personality traits, rather than depression per se. We therefore believe that further studies on the possible interrelationships between QT/QTc duration and depression, as well as other negative affective states, are required to confirm and expand our findings. Our report has several important limitations that merit consideration. First, errors in the measurement of QT interval could have resulted in some misclassification. Although we used a computerized measurement of the QT interval, a single measurement may be insufficient to assess an individual’s long-term QT interval length, and heart-rate adjustment according to Bazett [26] may be inadequate for both low and high heart rates [3]. Nevertheless, the positive relationship between neuroticism scores and QT duration persisted even when QTc was analyzed using different correction formulae [5] (data not shown), making confounding by heart-rate adjustment an unlikely explanation of our results. Second, due to the epidemiological approach on which the data analysis was based, it is not possible to state whether an association of neuroticism and QT interval duration exists in a single individual. Third, the current study cohort is confined to Italian males without ethnical diversity. Further studies with an ethnically and geographically diverse cohort therefore need to be performed. Fourth, as significant gender effects have been reported both with regard to neuroticism [34] and the QT/QTc intervals [35,36], additional investigations in female subjects would be desirable. Additionally, we did not investigate the relation of neuroticism and QTc dispersion, which is also an important predictor of future adverse cardiovascular events [37,38]. Finally, the present investigation shares the

P. Minoretti et al. / Journal of Psychosomatic Research 61 (2006) 19 – 23

limitations of cross-sectional, observational studies. We therefore observed associations, not prediction or causation. Given the study caveats, we nonetheless found evidence that high neuroticism tends to be associated with prolonged QTc intervals in a study of 658 apparently healthy males. This finding may be of clinical relevance inasmuch as it highlights the possibility that higher arrhythmic risk could be present not only in patients with clinical depression [16,17] but also in depression-prone, otherwise healthy individuals.

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