elevation myocardial infarction from two prospective observational studies of depression in ACS. Depressive symp-
toms were assessed with the Beck Depression Inventory (BDI), and depression was defined as BDI score ≥10, com-
pared with ,5. Patients with QRS duration ≥120 ms and/or who were prescribed antidepressants were excluded.
QT intervals were adjusted for heart rate by two methods. Our analyses included 243 men (40.0% with BDI ≥10)
and 139 women (62.0% with BDI ≥ 10). Among women, average QT corrected by Fridericia’s method (QTcF) was
435.4+26.6 ms in the depressed group, vs. 408.6+24.3 ms in the non-depressed group (P , 0.01). However,
among men, average QTcF was not significantly different between the depressed and non-depressed groups
(415.4+23.6 vs. 412.0+25.8 ms, P ¼ 0.29). In multivariable analyses that included hypertension, diabetes, ACS
type, left ventricular ejection fraction ,0.40, and use of QT-prolonging medication, there was a statistically significant
interaction between depressive symptoms and gender (P , 0.001).
In this ACS sample, prolongation of the QT interval was associated with depressive symptoms in women, but not in
men. Further investigation of the mechanism of the relationship between depression and abnormal cardiac repolar-
ization, particularly in women, is warranted to develop treatment strategies.
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Depression † QT interval † Sudden cardiac death † Acute coronary syndrome
Electrocardiology and Risk Stratification
Women, but not men, have prolonged
QT interval if depressed after an acute
William Whang1*, Howard M. Julien1, Laura Higginbotham1, Ana V. Soto1,
Nisha Broodie1, J. Thomas Bigger2, Hasan Garan2, Matthew M. Burg1,3, and
Karina W. Davidson1
1Center for Behavioral Cardiovascular Health, Columbia University Medical Center, New York, NY, USA;2Department of Medicine, Columbia University Medical Center,
New York, NY, USA; and3Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA
Received 3 May 2011; accepted after revision 29 June 2011; online publish-ahead-of-print 27 July 2011
Depression is a mortality risk marker for acute coronary syndrome (ACS) patients. We hypothesized that the QT
interval, a predictor for risk of sudden cardiac death, was related to depressive symptoms in ACS.
We performed an analysis of admission electrocardiograms from hospitalized patients with unstable angina or non-ST
Depression is a predictor of early mortality in patients after acute
coronary syndrome (ACS), despite adjustment for coronary artery
disease (CAD) severity.1,2Potential mechanisms for this mortality
risk include worse medical adherence, proinflammatory cytokine
activation, and reduced heart rate variability.3Furthermore, pro-
spective studies of individuals ranging from those without known
heart disease to those with implantable cardioverter–defibrillators
have suggested that depression is associated with sudden cardiac
death (SCD) and potentially fatal ventricular arrhythmia.4–7
More than 40% of all coronary heart disease-related mortality
can be attributed to SCD,8with arrhythmias such as sustained ven-
tricular tachycardia or ventricular fibrillation often the suspected
cause. Therefore, ventricular arrhythmia may contribute substan-
tially to the association of mortality with depression in ACS.
Prolonged QT interval, indicative of abnormal ventricular repo-
larization, has been documented to be a strong predictor of SCD
in recent large studies of unrelated individuals.9–11In a case–
control study of SCD in CAD, Chugh et al.11found that prolonged
QT conferred a five-fold risk of SCD among individuals without
diabetes and who were not on QT-prolonging medications.
*Corresponding author. PH9-321, 622 West 168th Street, New York, NY 10032, USA. Tel: +212 305 8620; fax: +212 305 3137, Email: firstname.lastname@example.org
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: email@example.com.
Europace (2012) 14, 267–271
The relationship between QT prolongation and SCD raises the
question of what factors contribute to QT prolongation in individ-
uals without known genetic syndromes. Interestingly, several small
studies have suggested that psychosocial factors may be related to
abnormalities in cardiac repolarization.12–15To our knowledge,
however, no prior study has evaluated the relationship between
depression and QT prolongation after ACS.
In this study, we hypothesized that QT prolongation is related to
depressive symptoms in individuals after ACS. Given the known
differences in QT intervals between men and women,10we
tested whether the association was different for men vs. women.
Institutional Review Board approval for this study was obtained at each
of the participating institutions. We performed an analysis of admission
electrocardiograms (ECGs) among patients admitted to hospital with a
diagnosis of unstable angina (UA) or non-ST elevation myocardial
infarction (MI), using data from two studies that used the same ACS
inclusion criteria and that assessed depressive symptoms with the iden-
tical instruments. The first study was the Coronary Psychosocial Evalu-
ation Studies (COPES), a multi-site, observational cohort study
designed to investigate the aetiology and natural course of depressive
symptoms after an ACS event.16,17Coronary Psychosocial Evaluation
Studies participants were recruited from among patients admitted to
three universityhospitals (Mount
New York, and Yale–New Haven Hospital and Hospital of St
Raphael, New Haven, Connecticut) between May 2003 and June
2005. The second sample was from the first 500 patients enrolled in
an ongoing prospective cohort study of depression after ACS [Pre-
scription Use, Lifestyle, and Stress Evaluation (PULSE), NIH/NHBLI,
P01 HL088117, PI Karina Davidson]. Participants of this study were
recruited from among patients admitted to Columbia University
Medical Center between February 2009 and June 2010.
For both studies, ACS events were defined according to American
Heart Association/American College of Cardiology criteria18as
either acute MI or UA. All patients had symptoms consistent with
acute myocardial ischaemia and at least one of the following: ischaemic
electrocardiographic changes (i.e. ST depression and/or T wave
abnormalities), an angiogram indicative of CAD on current admission,
and/or documented history of CAD. Patients who presented with an
acute rise in serum cardiac enzyme levels were categorized as MI. A
study cardiologist confirmed ACS eligibility for all patients.
The Beck Depression Inventory (BDI),19a 21-item self-report
measure of depressive symptom severity, was administered within 1
week after the index ACS event. The BDI has repeatedly been
shown to be associated with long-term mortality after ACS.2,17,20,21
Patients who scored ,5 (indicative of no depressive symptoms) or
≥10 (indicative of significant depressive symptoms) were included in
the study. Patients with BDI scores from five to nine were excluded
to delineate more clearly depressed and non-depressed groups at
baseline.22Depressive symptoms were categorized according to BDI
score: ≥10, vs. ,5. In order to minimize possible confounding associ-
ated with antidepressant medication use, for our analyses we excluded
participants who were prescribed antidepressant medications at hospi-
tal admission or on discharge.
Admission ECGs were analyzed by researchers and then over-read
by a single cardiologist (W.W.), each of whom was blinded to
depression status. For this study, we excluded patients with QRS dur-
ation ≥120 ms. ECG measurements included heart rate, PR interval,
Sinai Hospital,New York,
presence of Q waves, and ST depression ≥1 mm in two or more con-
tiguous leads. Left ventricular hypertrophy (LVH) was defined accord-
ing to Cornell voltage criteria23(S in V3 + R in aVL ≥ 28 mm in men
and S in V3 + R in aVL ≥ 20 mm in women) and/or Solkolow-Lyon
criteria24(S in V1 + R in V5 or V6 ≥ 35 mm and R in aVL ≥
11 mm). The QT interval was measured from the onset of the QRS
complex to the end of the T wave, defined as the point of return of
the T wave to the isoelectric line or to the nadir between the T and
U waves in cases where a U wave was present.25QT intervals were
corrected for heart rate in two different ways: according to Fridericia’s
method (QTcF ¼ QT/RR1/3), and using the nomogram-based QT cor-
rection (QTNc) proposed by Karjalainen et al.26
Left ventricular ejection fraction (LVEF) was measured quantitatively
by left ventriculogram during cardiac catheterization, echocardiogram,
or radionuclide study. If multiple measures were available, the value
from the ventriculogram was used first, followed by the value from the
echocardiogram. Left ventricular ejection fraction was then classified
as normal-to-mild dysfunction (LVEF ≥ 0.40) and moderate-to-severe
dysfunction (LVEF ,0.40). Medication use was collected at hospital
pared with an online list of possible or known QT-prolonging medi-
cations maintained by the Arizona Center for Education and Research
on Therapeutics (www.qtdrugs.org).27Prescription of QT-prolonging
medications was included as an indicator variable in our analyses.
Fisher exact x2tests and two-sample t-tests were used to compare
categorical and continuous measurements between the depressed
(BDI ≥ 10) and non-depressed (BDI , 5) groups. ECG measures
were compared between the depressed and non-depressed groups,
separately in men and women. Average QT interval was compared
with correction for heart rate in three different ways, as noted
above. Linear regression models of the QT interval were estimated
with inclusion of variables for the main effects of depressive symptoms
and gender, as well as a multiplicative interaction term. Other variables
included in the analyses were age, body mass index ≥25 kg/m2, non-
White race, hypertension, diabetes, type of ACS event, LVEF ,0.40,
heart rate, electrocardiographic LVH, and prescription of QT-
prolonging medication. In addition, multivariable models of the QT
interval were estimated separately for men and women. All analyses
were performed using SPSS, version 18 (SPSS Inc, Chicago, IL, USA).
A consort diagram describing the cohort, we studied is provided in
Figure 1. From a total of 548 COPES and PULSE participants with
ACS and technically adequate admission ECGs, we excluded 89
patients who were prescribed antidepressant medications at ACS
admission or discharge. Among this group, 30 patients who were
not in sinus rhythm, and 47 who had QRS duration ≥120 ms
were also removed from the analysis. This left a sample of 382
patients with UA/non-ST elevation ACS.
In our sample, 85 of 139 women (62.0%) and 97 of 243 men
(40.0%) had significant depressive symptoms (BDI score ≥10).
Table 1 shows the distribution of clinical characteristics by depress-
ive symptom category. Depressed patients were more likely to be
female (46.7 vs. 27.0%) and non-white (44.0 vs. 25.0%). The pro-
portion with body mass index ≥25 kg/m2, hypertension, diabetes,
presentation with non-STEMI (ST elevation myocardial infarction),
and LVEF ,0.40 was similar between the depressed and
W. Whang et al.
non-depressed patients. Overall, QT-prolonging medications were
prescribed in 10.5% of patients (anti-arrhythmic medications in 5%,
antibiotics in 3.4%, other QT-prolonging medications in 2.1%), and
a similar proportion of depressed and non-depressed patients
were prescribed such medications.
Table 2 shows unadjusted values for ECG indices by depression
status, in men and women. Average heart rate, PR interval, pro-
portion of patients with Q waves, and proportion with ST
depression .1 mm were similar between the depressed and non-
depressed patients for both men and women. However, average
QT interval was longer in the depressed group among women,
but not in men. For instance, using Fridericia’s correction for
heart rate (QTcF), among women average QTcF was 435.4+
26.6 ms in the depressed group, vs. 408.6+24.3 ms in the non-
depressed group (P , 0.01). However, among men average
QTcF was not significantly different between the depressed and
non-depressed groups (415.4+23.6 vs. 412.0+25.8 ms, P ¼
0.29). Also, among women, more patients in the depressed
group had LVH by voltage criteria (23.8 vs. 7.7%, P ¼ 0.02).
We estimated the relationship between QT interval and
depressive symptoms (BDI score ≥10) in analyses that included
both men and women, in multivariable linear regression models
that adjusted for gender, gender2depression interaction, age,
hypertension, diabetes, body mass index ≥25 kg/m2, type of
ACS event, LVEF ,0.40, heart rate, electrocardiographic LVH,
and prescription of QT-prolonging medication (Table 3). The inter-
action term between gender and depressive symptoms was statisti-
cally significant (for QTcF beta coefficient 22.9, 95% CI 12.3–33.5,
P , 0.001), indicating that the relationship between depressive
symptoms and prolonged QT interval was stronger in women.
This finding remained consistent regardless of the method used
Age . 65 36.0
BMI ≥ 25 kg/m2
Table 1 Demographic and clinical characteristics of
acute coronary syndrome patients by depressive
BDI < 5
(n 5 200),%
BDI ≥ ≥ 10
(n 5 182),%
BDI, Beck Depression Inventory; BMI, body mass index; STEMI, ST elevation
myocardial infarction; LVEF, left ventricular ejection fraction.
548 ACS events
30 not in sinus rhythm
47 with QRS duration
Figure 1 Consort diagram of ECG analysis.
Women (n ¼ 139)
Heart rate (bpm) 68.0 (11.2)
PR interval (ms) 168.0 (23.7)
QTcF (ms)408.6 (24.3)
ST depression ≥1 mm
Men (n ¼ 243)
Heart rate (bpm) 68.9 (13.7)
PR interval (ms)171.8 (33.1)
QTcF (ms)412.0 (25.8)
ST depression ≥1 mm
Table 2 Baseline electrocardiographic characteristics
of acute coronary syndrome patients according to
depressive symptoms by Beck Depression Inventory
BDI < 5 BDI ≥ ≥ 10
Numbers in parentheses represent standard deviation for continuous measures.
bpm, beats per minute; ms, milliseconds; LVH, left ventricular hypertrophy; QTcF,
QT corrected for heart rate using Fridericia’s method; QTNc, QT corrected for
heart rate using the nomogram-based method.
Depression and QT interval in ACS
to correct QT interval for heart rate. Next, we estimated separate
multivariable models of the QT interval for men and women. In
women, there was a statistically significant relationship between
depressive symptoms and QT interval. For QTcF, this corre-
sponded to a 24.5 ms difference for depressed patients compared
with non-depressed patients (95% CI 15.4–33.7, P , 0.001), and
results were similar using the nomogram-based method (beta coef-
ficient 22.1, 95% CI 12.8–31.3, P , 0.001). In men, however, the
relationship between depressive symptoms and QT was not stat-
istically significant (for models of QTcF, beta coefficient 3.5, 95%
CI 22.9 to 9.8, P ¼ 0.29). When depressive symptom severity
was treated as a continuous measure in multivariable analyses
using score on the BDI, the relationship between QT and
depression symptom severity was statistically significant in
women (for QTcF beta coefficient 0.85 per 1 point increment in
BDI, 95% CI 0.36–1.35, P ¼ 0.001), but not in men (beta coeffi-
cient 0.24, 95% CI 20.24 to 0.68, P ¼ 0.35).
In this study of patients admitted to hospital with UA/non-ST
elevation MI, we found that depressive symptoms measured by
BDI score were associated with increased QT interval in
women, but not in men. The incremental difference in QT interval,
we found in women with significant depressive symptoms, 24.5 ms
for QTcF in adjusted analyses compared with women without sig-
nificant depressive symptoms, was large and likely to be clinically
significant. Prolonged QT has been associated with a three to five-
fold increased risk of SCD in recent studies involving adults 55
years or older10and individuals with CAD.11We made efforts
not to include patients who might have prolonged QT due to
factors other than depression. For instance, we excluded those
who were prescribed antidepressant medications, some of which
are known to prolong the QT interval. In addition, we excluded
patients with prolonged QRS duration to prevent inclusion of
patients with left or right bundle branch block. Also, our results
remained consistent with use of two different methods for correc-
tion for heart rate, and we adjusted for use of QT-prolonging
medications. The results of our analysis suggest that arrhythmia
may play an important role in the poorer prognosis after ACS
associated with depression, particularly in women.
Our findings are consistent with prior studies that have noted
differences in cardiac repolarization associated with depression
and other affective states. For instance, a study by Takimoto
et al.12reported a positive correlation between QT interval cor-
rected by Bazett’s formula (QTC) and self-reported depression
in patients with bulimia nervosa, while in a comparison of 20
post-MI patients with major depression and 20 post-MI patients
without depression, Carney et al.13found that QT variability was
significantly higher in the depressed group. Studies involving
patients with congenital long QT syndrome have shown increases
in QT interval associated with ‘low-arousal’ emotional states,15as
well as a correlation between reported happiness and reduced risk
of arrhythmic events.28In a laboratory setting, Critchley et al.14
documented asymmetric right midbrain activity by positron
emission tomography scan during stress, and correlated these
changes with cardiac repolarization abnormalities by ECG.
To our knowledge, ours is the first study that has noted a unique
relationship between depressive symptoms and repolarization
abnormalities in women, and this observation has some correlates
to other findings in the literature. Depression is known to be more
prevalent in women, particularly after myocardial infarction.2,29,30
Still, compared with women without depression, those with elev-
ated depressive symptoms have higher mortality post-MI30and in
suspected CAD.21Women are also known to be at greater risk
for drug-induced torsades de pointes compared with men,31and
women have greater response in their QT intervals to isoproter-
enol compared with men.32Previous hypothesized mechanisms
of the association between depression and prognosis in cardiac
activity.33,34The concept of ‘repolarization reserve’ has been
developed where given the different possible mechanisms that
contribute to cardiac repolarization, more than one insult may
be necessary to influence arrhythmia risk significantly.35Sympath-
etic activation and differences in repolarization reserve may help
explain the differential relationship between depressive symptoms
and QT interval seen in our study. In addition, there has been
speculation that depression may make patients more susceptible
emotion-induced catecholamine surges that is often accompanied
by pronounced repolarization abnormalities by ECG37and that is
much more frequent in women. Further study of the mechanisms
abnormal cardiac sympathetic
Beta coefficient (95% CI)
Beta coefficient (95% CI)
BDI ≥ 10
23.4 (211.1, 4.4)
Female×BDI ≥ 10
Table 3 Multivariable linear regression analyses of QT interval in milliseconds, with correction for heart rate by two
3.3 (23.1, 9.6)0.31
2.5 (24.2, 9.2)
24.1 (212.2, 4.1)
20.9 (9.8, 32.0)
22.9 (12.3, 33.5)
Results are from models that also adjusted for age, hypertension, diabetes, body mass index ≥25 kg/m2, type of acute coronary syndrome event, left ventricular ejection fraction
,0.40, heart rate, electrocardiographic left ventricular hypertrophy, and prescription of QT-prolonging medication. Female× BDI ≥ 10 refers to the interaction between female
gender and BDI score category.
QTcF, QT corrected for heart rate using Fridericia’s method; QTNc, QT corrected for heart rate using the nomogram-based method; BDI, Beck Depression Inventory.
W. Whang et al.
underlying the depression2gender interaction in cardiac repolari- Download full-text
zation may help clarify potential therapies to address the mortality
risk associated with depression in ACS.
Our analysis has several limitations. We cannot rule out the
possibility of reverse causality, in which more severe cardiac
disease could result in worse depressive symptoms and a per-
ceived association both with our ECG markers and with mortality.
The depressed and non-depressed groups in our sample were
similar in terms of type of ACS event, proportion with Q waves
or ST depression on their ECG, and proportion with reduced
LVEF, but there may be other unmeasured confounders for
which we have not accounted. Also, our study involved secondary
analysis of two separately collected samples of patients, neither of
which was designed in advance to evaluate gender differences.
Finally, we did not have serial ECG collections, and so we
cannot estimate for any changes in repolarization associated with
changes in depressive symptoms.
In summary, we found in this ACS sample that QT interval pro-
longation was associated with depressive symptoms in women, but
not in men. Abnormal cardiac repolarization may be an important
mediator of the poor prognosis associated with depression, and
further investigation into the mechanism of this relationship, particu-
larly in women, is warranted to develop possible treatment strategies.
Conflict of interest: none declared.
This work was supported by grants HC-25197, HL-076857,
HL-088117, and HL-084034 from the National Institutes of Health,
and by a Scientist Development Grant to W.W. from the American
Heart Association Founders Affiliate.
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Depression and QT interval in ACS