Depression, Stress, and Heart Disease in Earthquakes and Takotsubo Cardiomyopathy

Depression, Stress, and Heart Disease in Earthquakes and Takotsubo Cardiomyopathy

REVIEW Depression, Stress, and Heart Disease in Earthquakes and Takotsubo Cardiomyopathy W. Victor R. Vieweg, MD,a,b Mehrul Hasnain, MD,e Briana Mezu...

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REVIEW

Depression, Stress, and Heart Disease in Earthquakes and Takotsubo Cardiomyopathy W. Victor R. Vieweg, MD,a,b Mehrul Hasnain, MD,e Briana Mezuk, PhD,c James R. Levy, MD,b,d Edward J. Lesnefsky, MD,b,d Ananda K. Pandurangi, MDa a

Department of Psychiatry, bDepartment of Internal Medicine, and cDepartment of Epidemiology and Community Health, Virginia Commonwealth University, Richmond; dMedical Service, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Va; e Sir Thomas Roddick Hospital, Stephenville and Memorial University of Newfoundland, St. John’s, Newfoundland, Canada.

ABSTRACT The preponderance of evidence links depressive disorder and coronary heart disease (CHD). Despite this evidence, multiple clinical trials have failed to show that effective treatment of depression favorably modifies the development, clinical course, or outcome of comorbid CHD. Possible reasons for these failures include the heterogeneity of depression, limitations of assessment instruments, limited understanding of the biology of depressive disorders, lack of biological markers, and the observation that depression may be more a product of CHD than a true risk factor for it. In this commentary, to better address the effects of externally provoked stress on physical health, we examine evidence about 2 specific examples of stress and subsequent heart disease: earthquake-induced adverse cardiac events among individuals with coronary artery disease, and stress-induced Takotsubo cardiomyopathy. In the former case, existing studies suggest that the stress and distress of earthquakes accelerate the development of poor cardiac outcomes for individuals with established coronary artery disease. In the latter example, existing case studies indicate that the profound left ventricular dysfunction of Takotsubo cardiomyopathy tends to quickly normalize once the acute stress is relieved. Together, these examples indicate that the presence or absence of prestress medical illness and its severity may better determine the outcome of the medical illness than the nature and severity of the stress, including depression. That is, any effort to look at depression among individuals with medical illness must look carefully at the medical illness itself and consider depression a possible nonspecific stress. In patients with comorbid depression and CHD, we propose using the more firmly established CHD outcome measurements to better understand how depression or other stressors and their associated treatments influence the prognosis and outcome of this medical illness. © 2011 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2011) 124, 900-907 KEYWORDS: Cardiovascular disease; Coronary heart disease; Depression; Earthquakes; Major depression; Major depressive disorder; Psychiatric measures; Takotsubo cardiomyopathy

We know that patients with coronary heart disease (CHD) are at increased risk for depression,1 and that depressed patients are at increased risk for various forms of cardiovascular disease (CVD) including CHD.2 However, we do not know if these associations are causal in nature.3 A series Funding: None. Conflict of Interest: No authors have a conflict of interest. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Victor Vieweg, MD, Departments of Psychiatry and Internal Medicine, Virginia Commonwealth University, 17 Runswick Drive, Richmond, VA 23238-5414. E-mail address: [email protected]

0002-9343/$ -see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2011.04.009

of large-scale studies over the past decade have failed to show that successful treatment of depression (or any other psychological condition), including both psychotherapy and pharmacotherapy, predicts favorable cardiac outcome in patients with comorbid CHD.4-8 Only a study9 based on a subanalysis of the Enriched Recovery in Coronary Heart Disease (ENRICHD) database showed a trend toward cardiac improvement associated with cognitive behavioral therapy among white men with comorbid depression or low perceived social support compared with usual care. We note that a variety of psychological states and traits including anhedonia,10 anger,11 anxiety,12,13 bereavement,14 generalized anxiety disorder,15 phobia,16 phobic anxiety,17

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quently developed cognitive behavioral therapy.26 The DBI Type D personality,18 and mixtures of anxiety and depres19 sion may worsen cardiac outcome. An argument has been was built around a series of questions asking subjects to advanced that a more general “distress” disorder may be the endorse statements (varying in severity) about how they felt best way to link mental disorders and CHD.19 about themselves and their relationships. Somatic features Depression is a syndrome of diverse symptoms and were far less important in the BDI than the HDRS. Because signs. These features may range two-thirds of Beck’s study pafrom affective symptoms of mood tients were women, it is not surand lack of pleasure to vegetative prising that the BDI more closely CLINICAL SIGNIFICANCE signs of sleep, appetite, and sexual approximated criteria for depresdisturbances, coupled with cognision in DSM-III and subsequent ● Depression, other forms of psychologitive changes and somatic features editions than did the HDRS. cal stress, and heart disease commonly of anergy, lassitude, aches, and interact reciprocally. pains. The 2 most popular scales DIMENSIONS OF ● Instruments assessing depression have used to assess depression are the DEPRESSION substantive limitations. Hamilton Rating Scale for DeEfforts to assign a dimensional pression (HDRS)20 and the Beck ● Earthquakes and Takotsubo cardiomyopunderstanding of depression have Depression Inventory (BDI),21 athy provide models to compare and been underway for many decades27-33 and they arrived almost simultacontrast the impact of stress on heart even though different dimensions neously at the beginning of the disease immediately and long term. are not necessarily equivalent 1960s—2 decades before the Didomains. De Jonge et al31 comagnostic and Statistical Manual ● Heart disease outcome variables may 22 pared 3 symptom/sign dimenof Mental Disorders (DSM-III) provide the best markers to assess and sions of depression (somatic/afappeared. understand depression and other forms fective, cognitive/affective, and of stress both directly and how they appetitive) seeking to establish HAMILTON RATING SCALE affect heart disease. the dimensional structure of deFOR DEPRESSION pression after acute myocardial This scale was devised by Max infarction (MI). Hoen et al33 sepHamilton at the University of Leeds arated the 9 features of major (United Kingdom) to be used “only on patients already diagdepressive disorder34 into cognitive and somatic donosed as suffering from affective disorder of depressive mains. Each somatic symptom was associated with 14% type” and assessed various features of depression while greater risk for an adverse CVD event after adjusting for emphasizing the somatic ones.20 It was designed for admindemographic data and cardiac risk factors. Fatigue, apistration by trained staff and included both staff observation petite problems, and sleeping difficulties were most and patient report of features, including depressed mood, strongly predictive of adverse CVD events. suicide, work and loss of interest, retardation, agitation, To move beyond these limitations of existing research, gastrointestinal symptoms, general somatic symptoms, hyhere we review the evidence linking stress, distress, and pochondriasis, insight, and loss of weight. Only a few items cardiac outcomes using 2 heuristic examples: earthquakes asked the patient how they felt, probably because the study and Takotsubo cardiomyopathy. These case examples propopulation comprised men, and men are generally less exvide a platform upon which to build a new strategy to assess pressive of their feelings than women.23,24 The HDRS bore the influence of interventions for depression and related little resemblance to DSM-III and subsequent editions of conditions on cardiac outcome in individuals with heart this manual. disease. The HDRS has advantages over the BDI for the pharmaceutical industry—not least of which is its nonproprietary nature. In 1967, Hamilton reassessed his rating scale25 EARTHQUAKES AND SUDDEN CARDIAC EVENTS and found important differences between male and female Probably the most compelling evidence that emotional scoring that were largely ignored in drug development.23,24 stress can trigger an acute cardiac event comes from studies His scale did focus on physiologic symptoms and signs of natural disasters—particularly earthquakes. We selected likely to be improved, reversed, or caused by antidepressant several well-studied earthquakes and their link to adverse drugs in various premarketing and postmarketing studies. cardiac outcomes to compare and contrast the effects of natural disasters on individuals with preexisting coronary BECK DEPRESSION INVENTORY artery disease (CAD) with Takotsubo cardiomyopathy subjects who were free of CAD and yet developed severe but The BDI21 was designed by Aaron Beck at the University of reversible cardiac complications following exposure to sePennsylvania for self-administration and focused much more on feeling states than did the HDRS. Beck subsevere acute stress and subsequent distress (Table 1).

902 Table 1

The American Journal of Medicine, Vol 124, No 10, October 2011 Earthquakes and Sudden Cardiac Death or Acute MI Sudden Cardiac Events before the Earthquake

Sudden Cardiac Events after the Earthquake

Northridge, California, January 17, 199435

During the 7-day period before the earthquake, the average number of deaths due to atherosclerotic heart disease (ASHD) was 15.6 ⫾ 3.9 per day. During the 7-day period before the earthquake, the number of sudden cardiac deaths (SCD) averaged 4.6 ⫾ 2.1 per day.

Hanshin-Awaji, Japan, January 17, 199538

The acute myocardial infarction (MI) control population comprised 13 patients treated for acute MI during the period January 17 to February 13 from 1992 to 1994. The control group for posttraumatic stress disorder reaction index (PTSD-RI)39 comprised 19 patients with active gastric or duodenal ulcers diagnosed following gastrointestinal endoscopy during the same 4 weeks following the earthquake.

Niigata-Chuetsu, Japan, October 23, 200440

Baseline mortality for acute MI 5 years before the earthquake was 47.3 per 100,000 person-years in the disaster area compared with 42.5 per 100,000 personyears in the control area.

On the day of the earthquake, the number of deaths related to underlying ASHD rose to 51. During the 6 days after the earthquake, the number of deaths related to underlying ASHD fell to 9.7 ⫾ 3.4 per day. On the day of the earthquake, there were 24 SCDs. During the 6 days after the earthquake, the number of SCDs fell to 2.7 ⫾ 1.2 per day. The study group comprised acute MI patients (n ⫽ 15) treated in the Awaji Hospital coronary care unit during the 4 weeks after the earthquake. The PTSD-RI39 was the assessment tool. The mean age of acute MI patients was 72.5 ⫾ 2.8 years, compared with control mean age of 66.5 ⫾ 3.8 years, and the 53% of the 1995 acute MI patients were women compared with 31% of controls. In the acute MI group, the mean PTSD-RI score was 40.1 ⫾ 4.1, consistent with severe stress (female score greater than male score). Among the controls, the PTSD-RI score was 26.2 ⫾ 1.2, consistent with moderate stress (male and female scores the same). Overall mortality for acute MI 3 years after the earthquake was 53.9 per 100,000 person-years in the disaster area, compared with 42.6 per 100,000 person-years in the control area.

Earthquake

A well-reported natural disaster was the Northridge earthquake that occurred in the Los Angeles, California area on January 17, 1994. Leor et al35 reported that the increased mortality after the earthquake occurred in residents already at risk for sudden cardiac death. More specifically, data supported the concept that the earthquake triggered sudden cardiac death (SCD) a few days early among residents at high risk of dying from atherosclerotic cardiovascular disease. In an accompanying editorial, Muller and Verrier36 hypothesized that both rupture of a coronary artery plaque and a primary arrhythmia are frequent causes of SCD and that approximately 40% of such deaths are due to sudden stimuli. A year after the initial report by Leor et al,35 their group37 conducted a subanalysis in which they argued that

the Northridge earthquake-induced increase in SCD was followed by a compensatory decrease in SCD in the remaining population transiently more resistant to SCD. Suzuki et al38 looked at the Hanshin-Awaji earthquake (January 17, 1995 in Japan) as a trigger for acute MI. Compared with a control period for the study population, the number of individuals with an acute MI increased by about 3.5-fold during the first 4 weeks after the earthquake, particularly among women. The authors applied the Posttraumatic Stress Disorder Reaction Index39 score to assess stress level, and as expected, the mean score for women was significantly higher than for men. The authors concluded that earthquake-induced emotional stress can trigger acute MI more often in women than normally expected.

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Nakagawa et al40 used the October 23, 2004 NiigataChuetsu earthquake in Japan to study long-term mortality from acute MI. In a large population study, they found that overall mortality rates from acute MI 5 years before and 3 years after the earthquake were statistically significant compared with control populations. The authors concluded that the Niigata-Chuetsu earthquake significantly increased mortality from acute MI. In an accompanying editorial, Steptoe41 supported this argument by noting substantial evidence that emotional stress can trigger acute cardiac events among vulnerable persons. In this setting, acute MI may be associated with acute pathophysiological changes, including autonomic dysfunction; inflammatory, neuroendocrine, and platelet activation; and disruption of a vulnerable plaque. Emotional stress and distress may continue after a natural disaster for a variety of reasons, including extensive property damage, reduced employment opportunities, delayed reconstruction, altered daily routines, and social disruption. A common feature of the analyses of the Northridge, Hanshin-Awaji, and Niigata-Chuetsu earthquakes was employing cardiac end points (sudden death and acute MI) to estimate the impact of emotional stress among vulnerable persons. We will revisit this principle when we discuss Takotsubo cardiomyopathy.

TAKOTSUBO CARDIOMYOPATHY Takotsubo cardiomyopathy (also known as left ventricular apical ballooning syndrome, stress-induced cardiomyopathy, and broken heart syndrome) is a reversible cardiomyopathy frequently precipitated by a stressful event.42,43 Takotsubo (or Tako-Tsubo) derives from the term for Japanese octopus traps and was first described in Japan in the early 1990s.44 Its clinical presentation is indistinguishable from an acute MI, with chest pain and dyspnea typical presenting features. Commonly, electrocardiographic transient ST-segment elevation may be present along with a small increase in cardiac troponin T. Echocardiography and left ventriculography will show hypokinesis or akinesis of the mid and apical segments of the left ventricle, with sparing of basal systolic function. Evidence of CAD is absent. Spontaneous and rapid recovery will occur in nearly all patients; therefore, prognosis is excellent. A second event occurs in ⬍10% of patients. Takotsubo cardiomyopathy is part of the differential diagnosis in patients with apparent acute coronary syndrome, left ventricular regional wall motion abnormality, and no obstructive CAD, especially when accompanied by a stressful trigger. Takotsubo cardiomyopathy is present in 1%-2% of patients presenting with an acute MI. Catecholamine-mediated myocardial stunning is the most likely pathophysiologic explanation to date.45 Table 2 shows 6 cases of stress-induced Takotsubo cardiomyopathy that derived from a PubMed search (July 19, 2010 using limits: Humans, Case Reports, English, and Core clinical journals, Young Adult: 19-24 years, Adult: 19-44 years, and Middle Aged: 45-64 years) yielding 34

903 case reports. We then selected those cases due to psychological stress/distress that provided an adequate description of the stressor and the patient’s initial symptoms and signs. We limited age range from 19 to 64 years to minimize old age as a confounding variable. All of the 6 cases in Table 2 were women, and ages ranged between 35 and 61 years. Events precipitating stress were 1) chased by 2 large terrier dogs, 2) brother’s unexpected death, 3) fierce argument with a close family member, 4) physically threatened by a parent of one of her 5th-grade students, 5) learned that her daughter had a brain tumor and was admitted for surgery, and 6) heated argument with her family. Cardiac complaints began shortly after stressor onset. Psychological symptoms such as anxiety and depression were not described in any of the narratives. However, this absence does not necessarily mean that anxiety and depression syndromes were not operative in these patients before the onset of the acute stressor. Psychological stressors were characteristic of those associated with Takotsubo cardiomyopathy. Wittstein et al,46 in their review of 19 cases describing the neurohumoral features of myocardial stunning due to sudden emotional stress, reported that in half of their patients, news of an unexpected death precipitated cardiac dysfunction. Other stressors included automobile accident, surprise reunion, surprise party, fear of procedure, fierce argument, court appearance, fear of choking, public speaking, armed robbery, and tragic news. All stressors were of very recent onset. The patients’ mean age was 63 years, and 95% were women. Their data supported the concept that exaggerated sympathetic stimulation was central to syndromic causation. As in previously reported cases, patients did well over the course of 4 years’ follow-up. Ionescu et al47 conducted a retrospective analysis of all patients diagnosed with Takotsubo cardiomyopathy (27 patients; 2%) from a database of 1374 cases of emergency left heart catheterization admitted to the Hospital of Saint Raphael, New Haven, Connecticut between 2003 and 2008. The mean age was 68 years and 96% were women, all postmenopausal. The authors found a precipitating stress in 74% of the patients (30% gastrointestinal triggers). Over one half (14 patients; 52%) met a combined end point of all-cause death, cardiogenic shock, sudden cardiac death, and rehospitalization for cardiac cause. Ionescu et al47 concluded that the long-term outcome of patients with Takotsubo cardiomyopathy is worse than previously reported. A series of 3 strong earthquakes with about 90 large aftershocks during the following week in central Niigata, Japan on October 23, 2004 provided Watanabe et al48 the opportunity to retrospectively investigate the incidence of acute cardiac events including Takotsubo cardiomyopathy, acute coronary syndrome, and SCD from September 25, 2004 to November 19, 2004 in 8 hospitals that treat most patients with such conditions in the area impacted by the earthquake. Twenty-five cases of Takotsubo cardiomyopathy appeared during the 4 weeks following the earthquake, compared with no cases reported during the 4 weeks before the earthquake. Similarly, no cases were reported in 2003

904

Table 2

Case Reports of Takotsubo Cardiomyopathy

Case

Heart Disease and Clinical Course

2008 Parulekar et al

61-year-old woman arrived via ambulance at her local emergency department complaining of chest pain after being chased by 2 large terrier dogs.

2008 Can et al62

35-year-old woman developed chest pain following the unexpected death of her brother.

2008 Hassan et al63

59-year-old woman developed shortness of breath and severe left-sided chest pain after a fierce argument with a close family member.

2009 Tsai et al64

57-year-old female teacher with history of hypertension presented to an urgent-care center in the evening with cardiac complaints developing soon after she was physically threatened by a parent of one of her 5th-grade students that morning. She had no psychological or psychiatric complaints during or after hospitalization. 56-year-old woman was under severe emotional stress after she learned that her daughter had a brain tumor and was admitted for surgery. The night before surgery, she developed cardiac complaints. Her serial improvement and subsequent asymptomatic status appears in the next panel over.

The initial electrocardiogram showed anterolateral ST-segment depression. Troponin T was elevated at 1.25 micrograms/L. Coronary arteriography showed normal coronary arteries. Left ventriculography showed a large area of apical hypokinesis with moderately decreased ejection fraction. Several weeks later, left ventricular systolic function had returned to near normal. Initial electrocardiogram showed ST-segment elevation in the anterior leads and there was a small increase in cardiac enzymes and troponin. Selective coronary arteriography was normal. An echocardiogram showed left ventricular apical akinesia and basal-segment hyperkinesia. By Day 10, left ventricular function was normal. Initial electrocardiogram showed T-wave inversion in the inferior and anteroseptal leads consistent with an acute coronary syndrome. Troponin T was elevated at 0.43 micrograms/L (normal ⬍.03). Selective coronary arteriography was normal. Left ventriculography showed a large apical wallmotion abnormality. At 6 weeks, an echocardiogram showed improved apical contraction. There was a loud, crescendo systolic murmur loudest at the right upper sternal border. An electrocardiogram showed 1-2 mm ST-segment elevation V2-V4, biphasic T-wave in V3; and deep, symmetric T-wave inversions in leads V4-V6. Coronary arteriography showed only minimal luminal irregularities. Left ventriculography revealed severe distal anterolateral, apical, and diaphragmatic dyskinesis with hypercontractile basal segments. The estimated ejection fraction was 35% and moderate mitral regurgitation was present. One month after discharge, left ventricular hypertrophy was present with normal function. The initial electrocardiogram showed sinus tachycardia but was otherwise normal. Three hours later, it showed 2-mm ST-segment elevation in leads V3-V5 and T-wave inversion in leads I, aVL, and V1-V6. Serial creatinine kinase MB fraction levels were 11.5 and 5.2 ng/mL (normal upper limit 10.4 ng/ mL) at 0 and 10 hours, respectively. Emergency coronary arteriography showed a right dominant system with no luminal narrowing, but 1-mm-long significant myocardial bridging causing a 70% narrowing in the left anterior descending artery distal to the origin of the first diagonal branch. Left ventriculography showed an ejection fraction of 45%-50% with moderate hypokinesis of the anterior, inferior, and lateral walls. Initial electrocardiogram showed ST-segment elevation in leads V2-V6. Treatment troponin T was increased at 1.16 ␮g/L (normal ⬍.01). Chest radiograph was normal. Selective coronary arteriography was normal. Left ventriculography showed the apical portion had “ballooned” out and was akinetic. Her ejection fraction was 48%. Three weeks later, an echocardiogram showed an ejection fraction of 56%.

2009 Boktor65

2010 Lateef66

55-year-old woman became symptomatic 10 minutes after a heated argument with her family. She was immediately brought to the hospital.

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and one case was reported in 2002. The first case presented immediately after the earthquake. An additional 10 cases developed a few hours after the earthquake. New cases developed until Day 19 following the original earthquake (16 during the first week, 5 during the second week, and 4 during the third week). Ten of the 25 Takotsubo cardiomyopathy cases developed life-threatening heart failure. All 25 patients recovered within several weeks after left ventricular apical dysfunction improved.

DISCUSSION A variety of psychological states including anhedonia,10 anger,11 anxiety,12,13 bereavement,14 depression,2 generalized anxiety disorder,15 natural and unnatural stress (such as naturally induced earthquakes and blizzards and unnaturally induced holiday season events such as Christmas and New Year),49 phobia,16 phobic anxiety,17 Type D personality,18 and mixtures of anxiety and depression19 may cause or contribute to adverse cardiac events. Thus, efforts to find the components of depression that most strongly predict CHD may prove very difficult, particularly if CHD itself contributes to aspects of depression (or other stressors) or when investigators gather information about depression and depressive symptoms using retrospective interviews or other instruments not temporally concordant with the adverse cardiac event. Acute emotional stress during natural disasters such as earthquakes may accelerate the poor prognosis for individuals with established CAD.35,37 That is, among persons with advanced CAD, the added stress of the earthquake may trigger a fatal cardiac event (acute MI or cardiac arrhythmia such as ventricular fibrillation) sooner than might otherwise occur. The earthquake may induce a nonfatal cardiac event such as an acute MI in individuals with CAD.38 Not only may a natural disaster such as an earthquake induce an adverse cardiac event temporally proximate to the disaster, but psychological reverberations from the disaster may continue for several years, triggering additional adverse cardiac events such as acute MI.40 Various forms of stress may stimulate the body’s reaction initially developed to increase survival. However, until very recently, Homo sapiens lived for 20-30 years and died largely from trauma and infections. Psychological stress influences cardiovascular health by triggering neuroendocrine (hypothalamic-pituitary-adrenocortical axis, sympathetic-adrenal-medullary system, reduced vagal tone, and endothelial dysfunction) responses and behavior associated with high-risk (smoking, medication noncompliance, excess alcohol intake, and improper diet) activities.49-52 When advanced CAD is present, various forms of stress, including depression followed by distress usually well tolerated, may provoke adverse cardiac outcomes. Such stresses may include early morning activity,53 winter weather including heavy snowfall,54-56 summer in a very warm climate,57 holiday events such as Christmas and New Year’s Day,56,58 Mondays for working men and Saturdays for

905 women in a traditional Japanese culture,59 and levels of air pollution.60 Assessment of depression or depressive symptoms in patients with comorbid CHD should take these stressors into account when attempting to link depression with this cardiac disease. Acute emotional stress also may induce adverse cardiac events in subjects free of CAD, as exemplified by Takotsubo cardiomyopathy.61-66 For reasons that are unclear, women are much more vulnerable than men to develop stress-induced Takotsubo cardiomyopathy. Also for unclear reasons, women are more likely than men to develop such psychiatric conditions as depression. However, the stress associated with Takotsubo cardiomyopathy is not thought to be depression as might be described in DSM-IV-TR34 because, among other reasons, only a very short time separates the onset of stress from the cardiac event. However, this does not preclude depression as a steady-state condition when a superimposed acute stressor induces the immediate adverse cardiac event. The generally rapid and favorable recovery from Takotsubo cardiomyopathy warrants comment.42,43 A dynamic state such as sudden release of catecholamines or coronary artery spasm appears to explain this condition, rather than a static state such as a ruptured vulnerable atherosclerotic coronary artery plaque with subsequent thrombus formation. Full recovery from Takotsubo cardiomyopathy may occur in as short a time as 2 days.67 Morel et al68 argue that myocardial adrenergic receptor distribution may be a dynamic process that contributes importantly to stress-induced Takotsubo cardiomyopathy. The authors describe an elderly woman with recurrent Takotsubo cardiomyopathy followed by recovery in each instance. As demonstrated by single-photon emission computed tomography in 2006, there was marked reduction in tracer uptake in the left ventricular apex associated with echocardiographic demonstration of typical apical ballooning. In contrast, in 2008 positron emission tomography showed reduced uptake in mid-left ventricular segments associated with echocardiographic evidence of ballooning in mid-left ventricular segments. Vasospasm could not explain this second instance of Takotsubo cardiomyopathy with compromised mid-left ventricular contraction and preservation of left ventricular apical contraction. The authors pointed out that canine heart studies have shown a higher concentration of beta-adrenergic receptors in left ventricular apical segments.68 This model fits nicely with stress-induced increased adrenal gland secretion of catecholamines with subsequent cardiac involvement and production of Takotsubo cardiomyopathy followed by recovery in subjects free of CAD. We have proposed69,70 and continue to propose using cardiac end points to assess various psychiatric and psychological interventions used to treat depression and other such stressors in individuals with comorbid CHD. This strategy may be more promising than current ones.

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CONCLUSIONS At present, we lack any biological or psychological markers of factors underlying depression (or other psychiatric conditions) and thus are limited in improving our understanding of the link between depression and comorbid CHD. Both CAD and depression and CAD among earthquake victims point to the potential for stress, distress, and suffering to induce major morbidity and mortality among individuals with existing CAD. In contrast, patients with Takotsubo cardiomyopathy may be exposed to severe stress with induction of major cardiac impairment that rapidly improves over the several weeks following stress reduction. Together, our observations about the effects of natural disasters on individuals with preexisting advanced CAD and the effects of stress-induced Takotsubo cardiomyopathy indicate that the presence or absence of prestress medical illness and its severity may better determine the outcome of the medical illness than the phenomenological components of the stress or distress, including depression. Thus, we must look carefully at the medical illness and at the psychiatric condition as one form of stress. In patients with comorbid psychiatric conditions (particularly depression) and CHD, we propose using the more firmly established CHD outcome measurements to best understand and manage both conditions. In advancing our proposal, we do not intend to eliminate current methods, scales, and instruments used to assess various psychological disturbances linked to CVD.

ACKNOWLEDGMENT Dr. Mezuk is supported by the Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) Program at Virginia Commonwealth University (K12-HD055881).

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