Mortality in patients with takotsubo syndrome (TTS), sometimes called broken heart syndrome or stress-induced cardiomyopathy is substantially higher than that in the general population and comparable with that in patients having myocardial infarction (MI), results of a new case-control study showed. The rates of medication use are similar for TTS and MI, despite no current clinical trials or recommendations to guide such therapies, the authors noted.
METHODOLOGY:
The study included 620 Scottish patients (mean age, 66 years; 91% women) with TTS, a potentially fatal condition that mimics MI, predominantly affects middle-aged women, and is often triggered by stress.
The analysis also included two age-, sex-, and geographically matched control groups: Representative participants from the general Scottish population (1:4) and patients with acute MI (1:1).
Using comprehensive national data sets, researchers extracted information for all three cohorts on prescribing of cardiovascular and noncardiovascular medications, including the duration of dispensing and causes of death, and clustered the major causes of death into 17 major groups.
At a median follow-up of 5.5 years, there were 722 deaths (153 in patients with TTS, 195 in those with MI, and 374 in the general population cohort).
TAKEAWAY:
All-cause mortality was higher in patients with TTS than in the general population (hazard ratio [HR], 1.78; 95% CI, 1.48-2.15; P < .001) and slightly lower than in patients having MI (HR, 0.76; 95% CI, 0.62-0.94; P = .012), with cardiovascular causes, particularly heart failure, being the most strongly associated with TTS (HR, 2.47; 95% CI, 1.81-3.39; P < .0001 vs general population), followed by pulmonary causes. Noncardiovascular mortality was similar in TTS and MI.
Prescription rates of cardiovascular and noncardiovascular medications were similar between patients with TTS and MI.
The only cardiovascular therapy associated with lower mortality in patients with TTS was angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy (P = .0056); in contrast, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, antiplatelet agents, and statins were all associated with improved survival in patients with MI.
Diuretics were associated with worse outcomes in both patients with TTS and MI, as was psychotropic therapy.
IN PRACTICE:
“These findings may help to lay the foundations for further exploration of potential mechanisms and treatments” for TTS, an “increasingly recognized and potentially fatal condition,” the authors concluded.
In an accompanying comment, Rodolfo Citro, MD, PHD, Cardiovascular and Thoracic Department, San Giovanni di Dio e Ruggi d’ Aragona University Hospital, Salerno, Italy, and colleagues said the authors should be commended for providing data on cardiovascular mortality “during one of the longest available follow-ups in TTS,” adding the study “suggests the importance of further research for more appropriate management of patients with acute and long-term TTS.”
Takotsubo syndrome mimics an acute myocardial infarction, typically in the aftermath of mental or physical stress.
Objectives
The mechanism by which emotional processing in the context of stress leads to significant cardiac injury is poorly understood, so a full exploration of brain structure and function in takotsubo syndrome patients merits investigation.
Methods
Twenty-five acute (<5 days) takotsubo patients and 25 control subjects were recruited into this observational cross-sectional study. Surface-based morphometry was carried out on magnetic resonance imaging (MRI) brain scans to extract cortical morphology based on volume, thickness, and surface area with the use of Freesurfer. Cortical morphology general linear models were corrected for age, sex, photoperiod, and total brain volume. Resting-state functional MRI and diffusion tensor tractography images were preprocessed and analyzed with the use of the Functional Magnetic Resonance Imaging of the Brain Diffusion Toolbox and Functional Connectivity Toolbox.
Results
There was significantly smaller total white matter and subcortical gray matter volumes in takotsubo (P < 0.001), with smaller total brain surface area but increased total cortical thickness (both P < 0.001). Individual gray matter regions (hippocampus and others) were significantly smaller in takotsubo (P < 0.001); only thalamus and insula were larger (P < 0.001). There was significant hyperfunctional and hypofunctional connectivity in multiple areas, including thalamus-amygdala-insula and basal ganglia (P < 0.05). All structural tractography connections were increased in takotsubo (P < 0.05).
Conclusions
The authors showed smaller gray and white matter volumes driven by smaller cortical surface area, but increased cortical thickness and structural tractography connections with bidirectional changes in functional connectivity linked to emotion, language, reasoning, perception, and autonomic control. These are interventional targets in takotsubo patients’ rehabilitation.
Introduction
Takotsubo syndrome is an acute heart failure cardiomyopathy mimicking an acute myocardial infarction in its presentation.1 Typically, it occurs in the aftermath of intense psychologic or physical stress, affecting women in more than 90% of cases. The mechanism by which emotional processing in the context of stress leads to significant cardiac injury and acute left ventricular dysfunction has yet to be elucidated. Therefore, a full exploration of the brain structure and function in takotsubo syndrome merits investigation.
A recent retrospective analysis using 18F-fluorodeoxyglucose positron emission tomographic–computed tomographic examination of a patient cohort investigated for cancer showed higher amygdala activity (an area involved in the experiencing of emotions) in subjects who subsequently developed takotsubo syndrome after 2 years,2 suggesting the possibility of a premorbid state affecting the brains of patients with takotsubo syndrome. Several reports have shown structural and functional differences of the brain limbic system and areas involved in regulating the autonomic nervous system in patients with takotsubo syndrome, suggesting impaired interaction between centers responsible for processing emotional inputs and the autonomic nervous system.3-5 All of these studies, except one,5 included patients at variable later stages after the acute presentation, possibly masking phasic variations that occur thereafter that may be important markers of recovery or sustained predisposing risk. Furthermore, a large international registry reported a significant stroke outcome in takotsubo patients,6 and recently white matter hyperintensities (which reflect small vessel disease) have been linked to an increased risk of developing future stroke.7
In the present study, we explored a whole-brain magnetic resonance imaging (MRI) investigation of acute changes in takotsubo presenters. Specifically, we examined the cortical surface areas, cortical thickness, and white matter hyperintensity volumes as well as gray matter volumes, the structural connectivity network of gray matter centers (tractography) by means of diffusion tensor imaging, and their resting state connectivity with the use of functional magnetic resonance imaging (fMRI), compared with a matched control population.
Discussion
This is the largest cohort of takotsubo syndrome patients whose acute brain phenotype has been investigated. All cases were examined during the acute phase (within 5 days of presentation) to allow benchmarking of any changes that may have occurred before or during the subsequent convalescent phase because of medications or other interventions. We found no evidence of cerebral small vessel disease, as evidenced by similar number and volume of white matter hyperintensities compared with control subjects. In this study, takotsubo patients had greater cortical thickness but smaller cortical surface areas and smaller total white matter, total subcortical gray matter volume, and all individual gray matter brain centers except for the thalamus and insula, which were larger, in either hemisphere or combined. Distinct bidirectional changes in functional connectivity were seen compared with matched control subjects, and this occurred in the context of all structural tractography connections being significantly increased in takotsubo patients.
Anatomic changes in takotsubo syndrome
It is well understood that there are different genes responsible for the development of cortical surface area vs cortical thickness.15 The radial hypothesis suggests that during early development, the brain develops along columns, with each column being associated with a certain function. The surface area is determined by the number of columns, whereas cortical thickness is influenced by the number of cells within a column. Later in life, cortical thickness appears to be influenced by environmental factors such as alcohol consumption and smoking, whereas cortical surface area appears to be regulated by unique developmental factors.16,17 Therefore, both a genetic difference as well as an adaptive cortical reorganization could be responsible for the findings seen in the brain of takotsubo patients compared with control subjects.
Smaller cortical surface area and greater cortical thickness as noticed in takotsubo patients in the present study is also seen in patients with major psychiatric disease, such as major depression.18 In addition, smaller brain gray matter volumes, especially hippocampal volumes, that we observed in patients with takotsubo syndrome are also seen in patients with elevated levels of inflammation19 and have been previously reported in the amygdala by Hiestand et al,20 albeit at a later time after the index presentation. The reduction in gray matter volumes was also shown by Dichtl et al,5 confirming the involvement of the gray matter in patients who develop takotsubo syndrome. Hiestand et al20 showed reduced cortical thickness in a cohort of takotsubo patients 1 year after the acute event, which is contrary to our results and may be explained by the timeframe when scanning was performed in that study. Both depression and anxiety disorders are associated with elevated levels of inflammation.21 Systemic and myocardial inflammation is a well-recognized feature of takotsubo syndrome,22,23 which raises the possibility that the changes we observed in the brain of takotsubo syndrome patients are potentially adaptive and related to inflammation.
White matter hyperintensity findings in this cohort would suggest that takotsubo patients have a similar risk of cognitive impairment, dementia and stroke as a matched control population.24 If the increased risk of stroke suggested by the international takotsubo registry6 was assigned to the significant premorbid incidence of neurologic disease of the patients included in this registry, it could mean that in the absence of preexistent neurologic disease, the risk of subsequent stroke for takotsubo patients may not be as high as suggested by registries.
Functional and structural connectivity changes in takotsubo syndrome
Brain activity and functional connectivity networks are intricately linked to their structural connectivity patterns, such that brain regions with high structural connectivity normally exhibit high functional connectivity, whereas the converse is not necessarily true.25 In this study, we showed that both thalamic and insulae nuclei were greater in size and had increased structural connections. Some of these findings overlap with those seen in other conditions, such as greater thalamic volumes seen in patients with major depression and suicidal ideation26 or increased functional connectivity between thalamus and nucleus accumbens linked to emotional processing regulating the pain response27 as well as involved in attenuating cardiac injury during ischemic damage.28 We have previously noted that there are increased proinflammatory cytokines and inflammatory markers, such C-reactive protein, in patients with takotsubo syndrome.29 Again, increased inflammation has been associated with reduced functional activation of the thalamus and insular cortex,30 such as we observed here.
It is therefore intriguing to see a reduction in functional connectivity in the context of enhanced structural connections, which implies that the reduction in functional connectivity is not caused by abnormal structural connections. An inflammatory substrate hypothesis makes it easier to reconcile observations such as reduced functional connectivity from the right thalamus to the right inferior frontal gyrus (language center) or to the visual lateral cortex in takotsubo patients in this study. The first is also observed in schizophrenia and linked to aberrant encoding of semantic memory (abnormal processing of auditory stimuli, fixity of thinking with low flexibility, and high emotional distress),31 and the latter is also seen in patients with anorexia nervosa and linked to abnormal processing of visual stimuli and overvalued ideation.32
A noteworthy finding in the present study is the reduced functional connectivity between the left thalamus and the left insular cortex. Lesions in the left amygdala or left insular cortex are associated with a 5-fold increased risk of sudden cardiac death in patients with schizophrenia.33 In patients with left insular lesions, there is loss of parasympathetic control and sympathetic overactivity with an increased risk of cardiac injury and arrythmia.34 Stroke patients with left insular lesions had poorer cardiac outcomes and were more likely to have cardiac wall motion abnormalities on echocardiography in the absence of obstructive coronary artery disease.35 Left insular lesions induced in mice resulted in cardiac injury and elevated serum levels of noradrenaline. The extent of the insular injury corresponded with the degree of cardiac injury.36 A previous study of patients with takotsubo syndrome 2 years after the acute event, however, noticed increased functional connectivity in the left insular cortex. A biphasic response with initial reduced insular functional connectivity leading to loss of parasympathetic control followed by increased insular connectivity thereafter is a plausible explanation of maladaptive autonomic response in these patients.37 Dichtl et al5 showed similar findings, with reduced functional connectivity of the insula during the acute period, in keeping with the results seen in our study. Templin et al3 showed similar findings with reduced functional connectivity in the insular region. This recurring finding of abnormal insular function strongly suggests a role for this region in the pathogenesis of takotsubo syndrome.
Another interesting finding in takotsubo patients in this study is the reduced functional connectivity in the caudate, putamen, and pallidum with increased functional connectivity in the nucleus accumbens. These together form key parts of the basal ganglia. Abnormalities in the basal ganglia have been associated with altered vagal nerve function and an increased risk of both bradyarrhythmias and atrial fibrillation.38,39 Altered functioning in this area may contribute to arrhythmic presentations seen in acute takotsubo syndrome or in the development of subsequent atrial fibrillation.40
We also observed reduced functional connectivity in the amygdala of patients with acute takotsubo similarly to patients with a tendency to catastrophize events.41 Previous observations showed reduction in functional connectivity in the amygdala years after the acute event. Together these findings would imply that this area of emotional processing is abnormal during both the acute phase and long term.3
These findings would support the nitrosative stress theory of takotsubo syndrome whereby maladaptive brain responses to stress involving the thalamus-amygdala-insular pathways lead to loss of autonomic control over the nervous system, leading to sympathetic overactivity, nitrosative stress, and cardiac injury, which contributes to the acute and chronic heart failure phenotype seen in takotsubo syndrome (Central Illustration).22,29,42,43 The overlap of many of the anatomic and functional brain findings in takotsubo patients with those seen in psychiatric conditions is intriguing, particularly because patients with depression or schizophrenia also have decreased survival because of excess cardiac mortality.
tCentral Illustration Brain-Heart Axis in Takotsubo Syndrome(A) Increased cortical thickness and reduced surface area in takotsubo syndrome. (B) Larger volume thalamus and insula in takotsubo syndrome compared with control. (C) Structural and functional connectivity changes in takotsubo syndrome. (D) Functional hypoconnectivity in key pathways involved in autonomic control of cardiac function in takotsubo syndrome.
Study limitations
Because this was an observational study, it was not possible to apportion causality of the observations, which are merely hypothesis generating. Follow-up of the natural history of changes in the brain of takotsubo syndrome patients could provide further insight.
Conclusions
In the largest structural and functional brain study of acute takotsubo syndrome patients compared with matched control subjects we demonstrate smaller cortical surface area and greater cortical thickness, no increase in white matter hyperintensities, smaller gray matter centers except for the thalamus and insula, which were larger (in either hemisphere or combined), and enhanced structural tractography connections with distinct bidirectional changes in functional connectivity linked to emotion, mood, language, visual and auditory perception, and autonomic control.
Perspectives
COMPETENCY IN MEDICAL KNOWLEDGE: In the acute phase of illness, takotsubo syndrome patients demonstrate overall increased cortical thickness but smaller cortical surface areas, smaller white and gray matter volumes, and smaller individual brain center volumes, except thalamus and insula. Patients with takotsubo syndrome: 1) have no significant difference in white matter hyperintensities compared with control subjects, implying absence of small vessel disease; 2) show areas of functional hypoconnectivity in key brain regions involving the thalamus-amygdala-insula axis and basal ganglia, which are responsible for higher-level functions (emotion, reasoning, language, perception) as well as autonomic regulation of the brain-heart axis; and 3) have increased structural tractography connections compared with control subjects, suggesting that the abnormalities in functional connectivity are not caused by abnormalities in structural connections.
TRANSLATIONAL OUTLOOK: The abnormalities in the thalamus-amygdala-insula and basal ganglia support the concept of involvement of higher-level function centers in takotsubo syndrome, and interventions aimed at modulating these may be of benefit.
Takotsubo syndrome (TTS) is a condition characterized by acute heart failure and transient ventricular contractile dysfunction that is frequently precipitated by acute emotional or physical stress. Although the precise pathophysiologic mechanism underlying this syndrome remains unknown, enhanced sympathetic stimulation resulting in microvascular dysfunction and/or direct myocyte injury is believed to be central to the syndrome’s pathogenesis.1 Since its original description in the early 1990s, a consistent observation in all series of TTS has been the marked preponderance of older postmenopausal women. Women comprise approximately 90% of the cases reported in the literature with a mean age of 65-75 years in most series, and the risk of developing TTS increases 5-fold in women after the age of 55 years.2 The precise reason that older women are so disproportionately affected remains unknown, but it is believed that the declining beneficial effects of estrogen on cardiac microvascular function as women age make postmenopausal women particularly susceptible to microvascular ischemia and TTS during episodes of excessive sympathetic stimulation. Given the marked female predisposition to TTS, it is not surprising that most of the literature over the past 20 years has focused primarily on women with this disorder, and far less has been written about the clinical features and outcomes of men with TTS. Although men clearly make up the minority of reported cases, the available literature suggests that males with TTS may represent a particularly vulnerable population with increased rates of arrhythmia, cardiogenic shock, and mortality compared with females with the syndrome.3-5
In this issue of the Journal of the American College of Cardiology, Arcari et al6 provide much needed insight into the influence of sex on TTS by presenting a large population of both men and women with TTS enrolled in the GEIST (GErman Italian Spanish Takotsubo) registry. The investigators looked at 2,492 patients enrolled in this registry and compared the clinical features and short- and long-term outcomes between men and women with TTS. After examining sex differences in this large population, they then performed a propensity score analysis by matching men and women 1:1 based on several variables that included age, presence of diabetes, current smoking status, history of malignancy, and the type of trigger precipitating the syndrome (emotional vs physical). Several important observations were made in this study: 1) men comprised 11% of the total TTS population, a prevalence similar to what has been reported in other studies and registries; 2) physical triggers were more frequently reported in male patients, whereas emotional triggers were more common in female patients; 3) men were significantly sicker at the time of initial presentation and were more likely to have cardiogenic shock, to require catecholamine administration, and to require intubation both in the total population and after propensity score matching; 4) in-hospital mortality was significantly higher in men, both in the overall and matched cohorts; and 5) long-term mortality was higher in men in the overall population but was not different between men and women in the matched cohort. Some of these observations can be readily explained by looking at the demographics of the overall GEIST population. Men had a significantly higher prevalence of diabetes mellitus, tobacco use, pulmonary disease, malignancies, and coronary artery disease, comorbidities that one would expect to have an impact on in-hospital complications as well as short- and long-term survival. Men in the overall population were also more likely to develop TTS following physical triggers, which has been previously shown to be associated with worse outcomes compared with emotional triggers.7 Men were also less likely to be discharged from the hospital on beta-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, which may have also had an impact on long-term outcomes. Although there were significant demographic differences between men and women in the overall population, the study by Arcari et al6 is novel in that the relatively large size of the GEIST registry made it possible for the investigators to account for many of these confounding variables by performing a propensity score matching analysis. Interestingly, even after matching for age, comorbidities, and type of precipitating trigger, men with TTS remained much sicker than women with a higher incidence of cardiogenic shock, in-hospital death, and death at 60 days. Men also had a lower ejection fraction and a higher prevalence of the apical ballooning variant compared with women, echocardiographic features known to be associated with worse short-term outcomes.8 By contrast, long-term mortality was not affected by sex in the matched cohort. This last observation suggests that once left ventricular systolic function recovers, which typically occurs within days to weeks of initial presentation, long-term mortality in TTS is driven primarily by non-cardiac comorbidities and events.
The study by Arcari et al6 shows convincingly that although men are far less likely to develop TTS than women, they have more serious complications and are more likely to die than women presenting with the syndrome. Although these observations may seem paradoxical at first, they may actually provide important clues about the pathophysiologic mechanisms of this disorder. There is increasing evidence that the transient myocardial dysfunction observed in TTS is the result of sympathetically mediated microvascular ischemia.1Figure 1 illustrates how TTS susceptibility may be dependent on the delicate balance between resting sympathetic tone and microvascular function. In this paradigm, individuals with normal basal sympathetic tone and normal microvascular function may be at low risk for developing TTS, whereas individuals with elevated resting sympathetic tone and significant microvascular dysfunction may be highly vulnerable. This paradigm helps to explain why older women are particularly susceptible to TTS. Resting sympathetic tone appears to be particularly elevated in older women,9 and as women age, there are significant decreases in cardiac vagal tone and baroreflex sensitivity with an associated increase in sympathetic activation.10 Estrogen is also an important regulator of endothelial function and vasomotor tone, and can attenuate catecholamine-mediated vasoconstriction, making older postmenopausal women potentially more susceptible than men to stress-related microvascular ischemia.11Figure 1 further illustrates that the sympathetic stimulus required to precipitate TTS is inversely related to susceptibility. Only mild sympathetic stimulation may be needed to precipitate TTS in highly susceptible individuals such as older women, and whereas older women may be more likely to develop the syndrome following acute stress, the smaller sympathetic stimulus may result in less myocardial injury and fewer cardiac complications. By contrast, significant noradrenergic stimulation may be necessary to precipitate TTS in men who have lower resting sympathetic tone and less microvascular dysfunction, thus resulting in more myocardial injury (eg, higher troponin, more contraction band necrosis, lower ejection fraction) and a higher incidence of cardiovascular complications and death in the acute period.
Download FigureDownload PowerPointFigure 1Proposed Inverse Relationship Between Stimulus Needed to Precipitate TTS and Syndrome SusceptibilityProposed paradigm illustrating the inverse relationship between takotsubo syndrome (TTS) susceptibility and the degree of sympathetic stimulation needed to precipitate the syndrome. Individuals with normal microvascular function and basal sympathetic tone (eg, young healthy individuals) have low susceptibility to TTS and will therefore require a large sympathetic stimulus to precipitate the syndrome. Individuals with mild-to-moderate abnormalities in microvascular function and basal sympathetic tone (eg, middle-aged men) will require at least a moderate amount of sympathetic stimulation to precipitate TTS. The people most susceptible to TTS are those with high resting sympathetic tone and significant microvascular dysfunction (eg, older women) and even mild sympathetic stimulation can precipitate the syndrome in these individuals.
The proposed paradigm in Figure 1 helps to explain an interesting and recurrent theme that has emerged in the Takotsubo literature, and that is that groups with the lowest prevalence of TTS appear to be the sickest at the time of presentation. African Americans made up <10% of the reported cases of TTS in one series but had a greater number of in-hospital complications compared with Caucasians.12 Young individuals (aged <50 years) comprised only 11% of the InterTAK (International Takotsubo) registry but were more likely to have cardiogenic shock and to require inotrope and ventilator support than older patients.13,14 Once again in the current study, men accounted for only 11% of the total GEIST registry but were significantly sicker than their female counterparts. These observations not only shed light on possible pathophysiologic mechanisms of this disorder, but also serve as an important reminder to clinicians that the patients least likely to get TTS are perhaps the most likely to die from it.
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