Occurrence of Takotsubo cardiomyopathy and use of antidepressants

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Occurrence of Takotsubo cardiomyopathy and use of antidepressants Andre Dias a,b,⁎, Emiliana Franco a, Vincent M. Figueredo b, Kathy Hebert c, Henry C. Quevedo d a

Danbury Hospital, Internal Medicine Department, Danbury, Connecticut Einstein Medical Center, Department of Cardiology, and Jefferson Medical College, Philadelphia, PA, USA University of Miami, Department of Cardiology, Miami, FL, USA d Tulane University, Department of Cardiology, New Orleans, LA, USA b c

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Article history: Received 13 March 2014 Accepted 2 April 2014 Available online 13 April 2014 Keywords: Takotsubo cardiomyopathy Depression Selective serotonin reuptake inhibitors

Takotsubo cardiomyopathy (TTC), also known as stress-induced cardiomyopathy, is a peculiar reversible cardiovascular disease (CVD) that may mimic an acute coronary syndrome, often affecting postmenopausal women after a stressful event. The prevalence ranges between 1.7 and 2.2% in patients admitted with chest pain for suspected acute coronary syndrome [1,2]. Proposed pathophysiological mechanisms include: catecholamine cardiotoxicity, microvascular dysfunction and coronary artery spasm [3,4]. Major depression and comorbid anxiety disorders have been associated with elevated sympathetic activity and diminished reuptake of norepinephrine, which may be responsible for prolonged cardiac sympathetic stimulation [5]. As suggested by Ziegelstein et al. [6], the double impact effect of disproportional high catecholamine responses and increased cardiac sympathetic sensitivity may place depressed patients at higher risk for developing TTC when exposed to stressful situations. Several case reports [7–11] have suggested that the use of SSRIs (in both therapeutic and over dosage scenarios) is associated with TCC, potentially by increasing norepinephrine levels in neuronal tissue via reuptake inhibition. This retrospective descriptive study consisted of 78 patients who met the Modified Mayo criteria [12]: 1) akinesia or dyskinesia of the apical and/or midventricular segments of the left ventricle with regional wall motion abnormalities extending beyond the distribution of a single epicardial vessel, 2) absence of obstructive coronary artery disease, 3) new electrocardiographic abnormalities, and 4) absence of pheochromocytomas/myocarditis. The diagnosis of depression and anxiety was made based on clinical criteria by a primary care physician or psychiatrist before being admitted to the hospital. The diagnosis of anxiety included generalized anxiety disorder, panic disorder, post-traumatic stress disorder and social phobia. Clinical outcomes were assessed during the hospital admission and within 6 months after the index event, as follows: in hospital death (all cause-mortality), inpatient acute heart failure (HF), length of stay, and left ventricular ejection fraction (LVEF) determined by 2-D echocardiogram. Chi-squared and paired t-tests were used to assess statistical differences in categorical and continuous variables, respectively. A twotailed P b 0.05 was considered statistical significant. Cox-proportional hazard model was constructed to evaluate mortality. All analyses were ⁎ Corresponding author at: Western Connecticut Health Network — Danbury Hospital, 24 Hospital Avenue, Danbury, 06810, CT, USA. Tel.: +1 2037397000. E-mail address: [email protected] (A. Dias).

performed employing SPSS v 19.0, Chicago IL. This study was approved by the hospital’s institutional review board. Baseline characteristics of the study population as well as by SSRI use are reported in Tables 1 and 2 respectively. SSRIs use was strongly associated with all-cause mortality during index hospital admission (OR 7.6; 95% CI 1.1–50.3; P = 0.016). Mean LVEF on admission in patients taking SSRIs was 36.3 ± 11.4% and for patients not taking SSRIs was 36.7 ± 11.0%. Repeated echocardiogram within 6-months revealed statistically significant recovery of LVEF in each group (P b 0.05 for both comparisons) with a relatively lower LVEF in patients taking SSRIs (Fig. 1, P = 0.01). (See Table 3.) Mean LVEF on admission for patients without depression was 36.4 ± 11.2% and for patients with depression was 37.2 ± 10.6%. Repeated LVEF within 6-months revealed statistically significant recovery of LVEF in each group (P b 0.05 for both comparisons), although patients with depression had relatively lower LVEF compared to patients without depression (Fig. 2, P = 0.02). The survival curve (Fig. 3) showed that SSRIs patients had lower survival rate compared with patients not taking SSRIs (P = 0.04). In this study, the prevalence of depression and anxiety (21% and 31%, respectively) was consistent with previous reports [4,13,14] which reported a prevalence ranging between 20 and 40%. Several authors

Table 1 Baseline clinical characteristics of the study population (n = 78). Characteristic

Value

Age, years (mean) Female Coronary risk factors Hypertension Hyperlipidemia Diabetes mellitus Current Smoker Clinical presentation Chest pain Pre-/peri-/postmedical/surgical procedure Stressful event reported Emotional stressor Strenuous exercise activity before the event Substance abuse/suicide attempt/panic attack Depression Anxiety Troponin upon admission (ng/ml) Peak troponin during hospitalization (ng/ml) Electrocardiographic changes at presentation ST elevation T-wave inversion Nonspecific ST-T wave changes High-degree atrioventricular block Asystole Chronic/paroxysmal atrial fibrillation LV ejection fraction Initial ejection fraction (%) Follow-up ejection fraction (%) Medications on admission SSRI SNRI TCA SARI Benzodiazepines

68 69 (87%) 54 (70%) 34 (44%) 14 (18%) 28 (36%) 50 (64.1%) 3 (4%) 20 (26%) 2 (2.6%) 3 (3.9%) 16 (20.5%) 24 (30%) 2.41 5.16 26 (33%) 29 (37%) 47 (60) 1 (1.3%) 1 (1.3%) 5 (6.4%) 36.6% ±11 53% ±9 15 (19.2%) 2 (2.6%) 1 (1.3%) 3 (3.8%) 23 (30%)

SSRI — selective serotonin reuptake inhibitors; SNRI — serotonin and norepinephrine reuptake inhibitors; TCA — tricyclic antidepressant; SARI — serotonin antagonist/reuptake inhibitors.

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Table 2 Baseline clinical characteristics of SSRI/non-SSRI groups. Characteristic

SSRIs patients (n = 15)

Non-SSRIs patients (n = 63)

P value

Age (years), mean Female (%) LOS (length of stay, days) Cardiovascular risk factors Hypertension Hyperlipidemia Diabetes mellitus Current smoker Depression Anxiety Clinical presentation Chest pain In hospital heart failure In hospital death Stressful event identified Emotional stressor Troponin I upon admission (ng/ml) Peak troponins I during hospitalization (ng/ml) Electrocardiographic changes at presentation ST elevation T-wave inversion Nonspecific ST-T wave changes High-degree atrioventricular block Asystole Chronic/paroxysmal atrial fibrillation Left ventricular ejection fraction Initial ejection fraction (%) mean ± SD Medications on admission SSRI SNRI TCA SARI Benzodiazepines Beta Blockers on admission Angiotensin-converting enzyme inhibitors or angiotensin receptor Blockers on admission Statin on admission Aspirin on admission

61.5 13 (86.7%) 6.73

68.3 56 (88.9%) 5.36

NS NS NS

10 (66.7%) 8 (53%) 3 (20%) 8 (53%) 13 (86.7%) 6 (40%)

44 (68.25%) 26 (41.2%) 11 (17.4%) 20 (31.7%) 3 (4.7%) 18 (28.6%)

NS NS NS NS b 0.001 NS

10 (66.7%) 3 (20%) 3 (20%) 12 (80%) 4 (26.7%) 2.95 8.81

40 (63.5%) 13 (20.6%) 2 (3.2%) 55 (87.3%) 16 (25.4%) 2.26 4.28

NS NS 0.016

5 (33.3%) 7 (46.7%) 9 (60%) 0 0 1 (6.6%)

21 (33.3%) 22 (34.9%) 38 (60.3%) 1 (1.6%) 1 (1.6%) 4 (6.5%)

NS NS NS – – NS

36.3% ± 11.4 SSRIs patients (n = 15) 15 1 (6.6%) 0 1 6 (40%) 12 (80%) 8 (53%) 11 (73%) 14 (93.3%)

36.7 ± 11.0 Non-SSRIs patients (n = 63) 0 1 (1.6%) 1 (1.6%) 2 (3.2%) 17 (26.9%) 52 (82.5%) 30 (47.6%) 41 (65%) 55 (87.3%)

NS

NS NS NS

SSRI — selective serotonin reuptake inhibitors; SNRI — serotonin and norepinephrine reuptake inhibitors; TCA — tricyclic antidepressant; SARI — serotonin antagonist/reuptake inhibitors. NS = nonstatistically significant.

have already described depression as being more prevalent in patients with CVD than in the general population and independently associated with a poor prognosis [15–18]. Psychiatric comorbidities, such as depression and anxiety, may play an important role in TTC, given its high frequency among these patients. Several mechanisms have been proposed associating mood disorders with TCC [6,19,20].

Patients with mood disorders may mount an exaggerated norepinephrine response to emotional stress and have unusually high cardiac sympathetic activity [21]. Barton et al. [22] showed patients with major depressive disorder have reduced cardiac neuronal norepinephrine reuptake and persistence of norepinephrine in the synaptic space which could lead to increased cardiac sympathetic response.

Table 3 Preceding stressful events. Events

Fig. 1. Mean LVEF on admission and at 6 months in patients taking SSRIs versus not taking SSRIs.

Emotional stressors Death or illness of a relative/friend/pet Interpersonal conflict Panic/fear/anxiety (emotional stress) Job issues Bad news Other Physical stressors Perisurgical or postsurgical Acute respiratory failure (chronic obstructive pulmonary disease exacerbation) Infection Strenuous activity Stroke Seizure Near drowning Other No identifiable stressors

No.(%) of participants (total n = 78) 6 5 5 2 1 2

(7.7%) (6.4%) (6.4%) (2.6%) (1.3%) (2.6%)

4 (5.1) 7 (8.9%) 8 (10.2%) 2 (2.6%) 2 (2.6%) 3 (3.8%) 1 (1.3%) 9 (11.5%) 18 (23.1%)

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patients with ischemic heart disease remained unclear. Sherwood et al. [25] studied the relationship of depression and mortality or hospitalization in patients with HF. An unexpected association of antidepressant medications with worse clinical outcomes in HF patients was found [25]. More recently, several case reports have associated new SSRIs agents with arrhythmias and marked cardiovascular negative inotropic effects, raising doubts about their safety profile. Fluoxetine and citalopram inhibited in animal models the activation of fast Na+ channels and L-type of Ca2+ leading to a reduced cardiac contractility and heart rate [26]. The arrhythmogenic effect of SSRIs, along with their negative inotropic capacity, could account for a reduced LVEF recovery at 6 months and higher inpatient mortality. Our results suggest that prior administration of SSRIs may increase the likelihood of in hospital death and affect survival; therefore physicians should consider TCC as a possible side effect of antidepressants, particularly SSRIs. These findings need to be confirmed in larger studies. Fig. 2. Mean LVEF on admission and at 6 months in patients with depression versus patients without depression.

Exacerbation of an underlying psychiatric illness has also been described as a potential trigger for TCC [19]. In this small cohort, no statistically significant difference was found between depression and hospital death, inpatient HF and TTC recurrence, possibly due to reduced sample size. We found patients taking SSRIs had a reduced LVEF recovery at 6months, and reduced survival. The cardiovascular toxicity of older generation of tricyclic antidepressants (TCAs) is well-established, and interestingly, SSRIs have been reported not be more effective than older agents, but to have fewer adverse cardiovascular side effects [23]. The Sertraline Anti-Depressant Heart Attack Trial (SADHART) [24] was the first trial to investigate the safety and efficacy of sertraline (SSRI) treatment of major depressive disorder in patients with CVD. Sertraline was found to be safe and effective in treating recurrent depression in patients with CVD; however since the study was not powered to detect differences in clinical events, the impact of sertraline treatment in

Fig. 3. Survival curve (Figure 3) shows that SSRIs patients had lower survival rate compared with patients not taking SSRIs (p = 0.04).

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depression in patients with acute MI or unstable angina. JAMA 2002 Aug 14;288(6):701–9. [25] Sherwood A, Blumenthal JA, Trivedi R, et al. Relationship of depression to death or hospitalization in patients with heart failure. Arch Intern Med 2007;167:367–73.

[26] Kurisu S, Sato H, Kawagoe T, et al. Tako-tsubo-like left ventricular dysfunction with STsegment elevation: a novel cardiac syndrome mimicking acute myocardial infarction. Am Heart J 2002;143:448–55.

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Secular changes in rates of coronary heart disease, fatal coronary heart disease, and out-of-hospital fatal coronary heart disease☆ Emily B. Levitan a,⁎,1, Rikki M. Tanner a,1, Hong Zhao a,1, Paul Muntner a,1, Evan L. Thacker b,1, George Howard c,1, Stephen P. Glasser d,1, Vera Bittner e,1, Michael E. Farkouh f,g,h,1, Robert S. Rosenson f,1, Monika M. Safford d,1 a

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA Department of Health Science, Brigham Young University, Provo, UT, USA Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA d Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA e Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA f Division of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA g Peter Munk Cardiac Centre, University of Toronto, Toronto, Ontario, Canada h Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario, Canada b c

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Article history: Received 13 March 2014 Accepted 2 April 2014 Available online 13 April 2014 Keywords: Coronary disease Epidemiology Mortality

In the Atherosclerosis Risk in Communities (ARIC) surveillance study, out-of-hospital fatal coronary heart disease (CHD) declined more slowly than total fatal CHD over 1987–2008 [1]; however, the upper age limit was 74 and temporal changes in risk factors and preventive therapies were not considered. To evaluate secular trends in CHD, fatal CHD, and out-of-hospital fatal CHD in a broader age range accounting for changes in risk factors and therapies, we used data from the ARIC cohort study [2], the Cardiovascular Health Study (CHS) [3], and the REasons for Geographic And Racial Differences in Stroke (REGARDS) study [4]. ARIC and CHS data were obtained as limited datasets from the National Heart, Lung, and Blood Institute data repository. REGARDS data were obtained from study investigators. Institutional review boards at participating centers approved these studies, and participants provided written informed consent. The University of Alabama at Birmingham institutional review board approved this project which conforms to the ethical guidelines of the 1975 Declaration of Helsinki.

☆ The REGARDS project is supported by cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke and grants R01 HL 080477 and K24 HL111154 from the National Heart, Lung, and Blood Institute. The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at http://www.regardsstudy.org. This investigation, including the design and conduct of the study, was supported by Amgen, Inc. The authors conducted all analyses and maintained the rights to publish this manuscript. ⁎ Corresponding author at: Department of Epidemiology, University of Alabama at Birmingham, RPHB 230K, 1720 2nd Avenue S, Birmingham, AL 35924-0022, USA. Tel.: +1 205 975 7680; fax: + 1 205 934 8665. E-mail address: [email protected] (E.B. Levitan). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

ARIC recruited participants aged 45–64 years from 4 United States communities between 1987 and 1989. We excluded 60 participants not in the limited dataset (n = 15,732). CHS recruited participants aged ≥65 years from 4 United States communities between 1989 and 1993. We excluded 93 participants not in the limited dataset and 39 who were neither black nor white (n = 5756). REGARDS recruited black and white participants aged ≥45 years from the 48 continental United States between 2003 and 2007. We excluded 569 participants without followup data (n = 14,992 aged b65 years, n = 14,857 aged ≥65 years). With the exception of family history of CHD, participant characteristics were defined similarly across populations. Participants in ARIC and REGARDS were asked about CHD before age 65 in mothers and 55 in fathers, and participants in CHS were asked about CHD before age 55 in brothers and sisters. We included the first seven years of follow-up in each population. Participant follow-up and CHD adjudication were conducted by ARIC, CHS, and REGARDS study investigators as previously described [5–9]. Additional cases were identified in ARIC through hospital discharge records and in CHS through Medicare hospitalization records. Fatal CHD included all deaths within 28 days of the index CHD event. Out-ofhospital fatal CHD was defined as fatal CHD that occurred without a hospitalization. Participants were censored at the time of a non-fatal CHD event. Myocardial infarction (MI) diagnosis became more sensitive between the late 1980s/1990s and the 2000s due to transition from creatine phosphokinase to troponin assays [10,11]. Therefore, MIs with maximum troponin b0.5 μg/L in REGARDS, which may not have been detectable in ARIC or CHS, were considered non-cases unless there were diagnostic electrocardiogram findings. All analyses were stratified by age at baseline (45–64 or ≥65 years). Participant characteristics were summarized as means and standard deviations or percentages. We constructed Kaplan–Meier curves for CHD, fatal CHD, and out-of-hospital fatal CHD by time period. We calculated age-, race-, and sex-adjusted rates and 95% confidence intervals (CIs) by time period overall and by history of CHD at baseline using Poisson models with over-dispersion parameters and an offset of natural logarithm of person-time. We calculated hazard ratios and 95% CIs comparing time periods using Cox proportional hazards models adjusted for age, sex, race, diabetes, LDL cholesterol, lipid-lowering therapy, systolic blood pressure, antihypertensive medications, smoking, HDL cholesterol, family history of CHD, body mass index, and baseline history of CHD. The proportional hazards assumption was tested using an