Balkin, Daniel M.; Cohen, Lawrence S.
The Takotsubo Syndrome was first described by Japanese investigators approximately 20 years ago and has been increasingly recognized in all countries [1–10]. It occurs almost exclusively in postmenopausal women and is triggered by a severe emotional stress. Severe chest pain is common and the electrocardiogram often mimics that seen with an acute myocardial infarction. An echocardiogram or a left ventriculogram resembles a Takotsubo, a Japanese octopus fishing pot (Fig. 1). In Japanese ‘Takotsubo’ means a ‘fishing pot for trapping octopus.’ These traps have a round bottom with a narrow neck. When the octopus enters the Takotsubo it is most often trapped while the fisherman pulls the device to the surface. The syndrome is reversible and over the next several weeks to months all electrocardiographic and echocardiographic changes revert to normal. It is likely that the emotionally induced catecholamine surge in an estrogen-deficient woman causes a combination of epicardial coronary artery constriction, constriction of the myocardial microvasculature, and direct cardiomyocyte toxicity producing a temporary stunning effect on the left ventricular myocardium.
P.O. is a 68-year-old woman who had no cardiac history until May 2005, when she was 65 years of age. She had a history of surgical removal of uterine fibroids and the resection of a benign breast cyst. She was 10 years post menopausal and had a lifelong history of Raynaud's phenomenon.
During a routine yearly checkup in April 2005 an electrocardiogram was performed, which was totally normal. In early May 2005, she had a severely emotional and stressful afternoon at her mother's funeral. She had no chest pain but felt extremely weak and unwell. She was seen by her physician on 19 May 2005 during which an electrocardiogram was performed, which was quite abnormal. It showed deeply coved T waves in I, II, III, Avf, and V3–V6. The QT interval was prolonged with the QTc measuring 484 ms.
On 16 June 2005, the T wave coving was less, and the QTc was 450 ms. On 7 July 2005 the abnormalities started to abate, and the QTc was 445 ms. By 22 September 2005, the electrocardiogram was virtually normal with no T wave abnormalities. The QTc was 412 ms (Fig. 2).
Takotsubo cardiomyopathy is characterized by the acute onset of chest pain, dyspnea, and at times syncope. It is predominantly seen in postmenopausal women in their fifties or sixties. There is usually a severe emotional or physical event in the antecedent period leading to the clinical presentation. News of an unexpected death or other such emotional trauma is common. The patient may be hypotensive and may require circulatory pharmacological support. Similarly, the patient may present with severe dyspnea and at times pulmonary edema. With appropriate hemodynamic support, which at times may require an intra-aortic balloon pump, immediate prognosis is favorable.
Electrocardiogram may mimic closely that of an acute anterior wall myocardial infarction. There is ST-segment elevation, which may evolve into deeply coved T waves after the ST segment approaches the baseline. There is usually a prolonged QTc interval, which returns to normal somewhat more quickly as do the pathologic precordial Q waves if present.
The initial left ventricular ejection fraction is most often markedly depressed, at times as low as 20%. The typical contractile pattern shows preserved basal function, moderate-to-severe dysfunction in the mid ventricle and apical akinesis or dyskinesis. Within a week's time, the left ventricular ejection fraction is usually improved and the mid-ventricular and apical segments are only mildly hypokinetic.
There is frequently a mild elevation of tropinin T or tropinin I levels. This elevation is by no means invariable and the biomarkers often remain normal. Similarly, creatine kinase or creatine kinase MB levels may be normal or only minimally elevated.
Coronary angiography and ventriculography
Coronary angiography usually shows normal epicardial coronary arteries. At times there may be spasm recognized particularly in the left anterior descending coronary artery. The left ventriculogram usually shows typical apical ballooning and hypercontraction of the basal segments.
The link between emotion and chest pain has been noted for a long time. In 1896, Osler refers to the late surgeon scientist, John Hunter who used to say, ‘His life was in the hands of any rascal who chose to annoy and tease him’ . Incidentally, in 1793, Hunter died suddenly as a result of a myocardial infarction during a heated argument .
The Takotsubo Syndrome has been recognized for only the past 20 years. What is known is that this condition is often precipitated by an acute emotional stress and that it occurs predominately in postmenopausal women. As the syndrome often occurs after a severe emotional disturbance (i.e. the death of a loved one), this condition has also been known as the ‘broken heart’ syndrome. In this discussion, we examine three areas that provide insight into the pathophysiology of this intriguing clinical syndrome: (i) the stress system; (ii) catecholamines and cardiotoxicity; and (iii) the effects of estrogen on vascular biology.
The stress system
The stress system is the body's physiological neural hormonal response to real or perceived threat. This system is activated when homeostasis is threatened. Whether a dangerous situation, an approaching deadline, or severe mental anguish, the body mounts a coordinated multiorgan response in an effort to increase arousal and alertness and to prepare for physiological demand. The stress system is a protective adaptation, allowing one to redirect behavior and refocus energy. However, it can also have deleterious physiological consequences when present in excess or activated at inappropriate times [13–16].
In 2005, Wittstein et al.  reported on 19 earlier healthy patients who presented with acute left ventricular dysfunction after an acute emotional stress. On hospital day one or two, patients' catecholamine levels (i.e. epinephrine, norepinephrine, and dopamine) were two-to-three times higher than patients with Killip class IV myocardial infarction. Plasma levels of metanephrine and normetanephrine were also elevated among patients with stress cardiomyopathy. In this study, patients' plasma catecholamine levels were measured up to 24–48 h after the onset of the disease. Therefore, at the onset of cardiovascular dysfunction, given a half-life of 2–3 min , epinephrine levels would have been immeasurable. This observation gives rise to a thesis that excessive catecholamine secretion and catecholamine-mediated cardiotoxicity play a fundamental role in the pathogenesis of this syndrome. Support for this theory is found in the neurological literature, which describes patients with subarachnoid hemorrhage developing profound electrocardiographic changes characterized by deep symmetrical T waves across the anterior precordium .
What could account for such a massive elevation in catecholamines in response to severe emotional stress? The stress system is a highly coordinated effort between the central nervous system and peripheral elements. The hypothalamic–pituitary–adrenal axis, the locus coeruleus (LC)–norepinephrine circuit, and the extrahypothalamic corticotrophin-releasing hormone system all respond enabling successful physiological adaptation to a stressful environmental insult [13–15,19].
The physiological response to the emotional stress depends in large part on an initial cognitive appraisal of the environment, occurring in the prefrontal and frontal cortices. The prefrontal cortex receives input from the motor, auditory, and visual regions along with the input from the hippocampus, cingulate gyrus, amygdala, and temporal regions (limbic system), areas involved in memory and emotion. This relay allows the brain to integrate and evaluate sensory input and process this information with regard to memory and emotion. The thalamus filters sensory information and has neuroanatomical connections with both higher cortical regions and with the hypothalamus, which links the nervous system with the endocrine system through the pituitary gland [15,16]. Specifically, in response to stressful stimuli, neurons of the paraventricular nucleus of the hypothalamus synthesize and secrete the 41 amino acid neuropeptide corticotrophin-releasing hormone into the portal capillaries, which elicits adrenocorticotropin hormone release from the anterior pituitary. Adrenocorticotropin, subsequently, triggers the synthesis and secretion of corticosteroids and androgenic steroids from the adrenal cortex (activation of the hypothalamic–pituitary–adrenal axis) .
The LC–norepinephrine system is a critical component of the stress response as it is thought to be the integrating site for the autonomic nervous system response to the stress. The LC is a concentrated cluster of norepinephrine-producing neurons located in the lateral floor of the fourth cerebral ventricle. The LC cell bodies receive input from diverse neuroanatomical sites: the medullary reticular formation, prefrontal cortex, amygdala, and hypothalamus. This collection of norepinephrine-producing neurons also receives input from the paraventricular nucleus [14,21–23]. The LC, therefore, is a common node for highly processed cognitive and emotional stimuli. Activation of the LC results in norepinephrine release from a dense network of neurons throughout the brain  (Fig. 3). This initiates a neuronal signaling cascade from the preganglionic sympathetic neurons of the intermediolateral cell column of the thoracolumbar spinal cord to the prevertebral or paravertebral ganglia, which, in turn, project to the end organs and to the chromaffin cells of the adrenal medulla . The adrenal medulla converts L-tyrosine into norepinephrine and then epinephrine and secretes these catecholamines into the circulation, enhancing cardiovascular and respiratory output while inhibiting digestive and metabolic demands. In the early 1900s, Walter Cannon first described this most rapid response to stress, the so-called fight-or-flight response .
What causes the massive catecholamine surge in patients with the Takotsubo Syndrome? There is a tremendous interaction between different components of the stress system. Functionally, the hypothalamic corticotrophin-releasing hormone and brainstem LC–norepinephrine systems participate in a positive feedback loop . In addition, the LC participates in a feedback loop with the adrenal medulla and the limbic system. Specifically, epinephrine is secreted by the adrenal gland and stimulates the LC to release norepinephrine, which then sends signals to the hippocampus and amygdala. In turn, the amygdala can re-stimulate the LC .
There exists a feedback mechanism in these physiological stress pathways when stressful stimuli cease. However, this complex and intricate interaction of stress response systems lays the groundwork for a reverberating positive feedback loop in the presence of a sustained stressful stimulus. In the case of the ‘broken heart syndrome,’ unrelenting emotional stress is one such stimulus that could result in sustained activation of the positive feedback stress response systems, resulting in marked elevation of plasma catecholamine levels.
Catecholamines and cardiotoxicity
The circadian release of norepinephrine and epinephrine results in elevated catecholamines in the early morning hours upon awakening. It is interesting to note a significant spike in acute coronary events during this time of day [19,26]. Experimentally, in 1905, myocarditis in rabbits after adrenaline stimulation was reported. In patients, similar cardiac lesions, coined as norepinephrine myocarditis, are observed in patients treated with epinephrine and norepinephrine and these lesions are quite common in patients with a diagnosis of pheochromocytoma . The pathophysiology of catecholamine-induced cardiomyopathy is not fully understood. Elevated catecholamine levels can alter cardiac physiology by direct toxicity of norepinephrine/epinephrine and their metabolites on cardiac tissue, through excessive adrenergic stimulation of the coronary arterial vasculature and/or at the level of the cardiomyocyte β-adrenergic receptors (β-ARs).
Toxicity of norepinephrine/epinephrine and metabolites on cardiac tissue
It was not long after the discovery of epinephrine when, in 1907, Josué et al. [28,29] showed its cardiotoxicity. From then, a wealth of research has been carried out in an effort to define the mechanism of catecholamine-induced cardiac injury. The integrity of the cell membrane is critical for cellular homeostasis and viability . In the mid 1970s, Rona et al. [31,32] carried out a series of morphological investigations using light and electron microscopy to define the effects of catecholamines on the cardiomyocyte plasma membrane, termed the sarcolemma. In rats, they injected saline or catecholamines intravenously followed by the extracellular macromolecular tracer horseradish peroxidase (HRP). Then, at different time intervals, they assessed the localization of HRP in the heart. In a normal physiological state (i.e. saline injection), the sarcolemma presented an effective barrier to the macromolecular tracer, HRP. In other words, HRP remained in the extracellular environment. However, after norepinephine injection, the sarcolemma integrity was compromised and HRP became localized to intracellular compartments. The compromised sarcolemma then allowed for heightened calcium influx, which is thought to underwrite the pathological changes within cardiomyocytes. In particular, elevated levels of intracellular calcium result in diminished cellular ATP and are thought to cause sarcomere super contraction, cellular disorganization, and subsequent myocardial death [27,33].
The role of free radicals in the molecular pathogenesis of heart disease is also an active area of research. Activated oxygen species are chemically unstable, and therefore, highly reactive and toxic for tissues. In general, free radical-generated tissue injury involves lipid peroxidation, oxidation of protein thiol groups, and DNA strand damage. When present in high levels, catecholamines can auto-oxidize, which can, in turn, generate reactive oxygen species. These molecules, in the heart, have been suggested to have diverse physiological consequences, such as effects on the action potential, calcium availability, the Na+–K+–ATPase, and mitochondrial function, to name a few .
Coronary arterial spasm
The role of the coronary artery vasculature in the pathogenesis of the Takotsubo Syndrome is unclear. The α-adrenergic receptors located in the smooth muscle cells of the coronary vasculature are activated by both norepinephrine and epinephrine, and, in response, result in coronary vasoconstriction [30,35]. In 1995, Lacy et al.  published a study in which the coronary arterial vasculature of patients was angiographically monitored during a simulated public-speaking task. Specifically, they selected midcoronary segments free of angiographically demonstrable disease for analysis. Intriguingly, after this potent mental stress, investigators observed elevated heart rate and blood pressure combined with vasoconstriction of normal coronary artery segments. Angiographic studies on patients with the Takotsubo Syndrome provide evidence both for and against the role of epicardial coronary spasm .
Brief episodes of epicardial and/or myocardial microvasculature spasm as a result of catecholamine-induced sympathetic stimulation can result in altered delivery of oxygen to the myocardial muscle. Localized contractile dysfunction develops within seconds after decreased coronary blood flow to match energy expenditure with energy supply. This state is known as perfusion–contraction matching. If blood flow is restored before myocardial infarction develops, myocardial tissue and cardiac function can recover. In the literature, such heart muscle is termed stunned or hibernating . Although still viable, morphological changes can develop as a result of reduced perfusion in hibernating cardiac tissue. In long-term hibernating myocardium, myofibrils are reduced in number and become disorganized. Changes can also occur in the myocardial glycogen content and in the extracellular collagen network [38,39]. Thus, although myocardial tissue is still viable in the hibernating or stunned state and contractile dysfunction is reversible after blood flow restoration, it may take days or weeks for the cardiac tissue to fully recover . This phenomenon certainly phenocopies what is observed in patients with the Takotsubo Syndrome.
Toxicity of norepinephrine/epinephrine and their metabolites on cardiac tissue and excessive adrenergic stimulation of the coronary arterial vasculature are two potential factors in the pathogenesis of disease. Although both elements can alter cardiac function, it is of interest that the apex and not the base of the left ventricle is affected [9,10,40].
β-ARs are members of one of the largest family of cell-surface signaling proteins in both eukaryotes and prokaryotes, called G-protein-coupled receptors (GPCRs) (Fig. 4). The main function of GPCRs is to convert extracellular stimuli into intracellular signals. Structurally, GPCRs are long protein chains stitched seven times across the cell surface lipid bilayer. The seven helical transmembrane domains form a bundle in the membrane and are connected through floppy peptide loops, sticking both outside and inside of the cell [30,41,42].
Those portions of the GPCR that face the extracellular environment create a unique discriminating binding domain for external stimuli. The protein loops on the inward surface of the plasma membrane are responsible for interacting with specific intracellular signaling machinery. Tethered to the inner membrane, this signaling platform is made up of heterotrimeric guanosine 5-triphosphate-binding proteins, collectively called G proteins, consisting of three subtypes: G-α, G-β, and G-γ. In general, GPCRs function in the following manner: a ligand binds the extracellular domain of a GPCR; in response, the GPCR undergoes a conformational change; this conformational change activates the associated G-α protein, allowing it to exchange its bound nucleotide guanosine diphosphate for guanosine 5-triphosphate and dissociate from the G-βγ proteins; then, G-α and G-βγ are free to engage in downstream signaling events . The G-α subtype can exist in four varieties, namely, G-αs, G-αi, G-αq, and G-α12 .
The β-AR, the prototypical GPCR, was originally found to interact exclusively with G-αs, giving rise to the idea that a given GPCR interacts with only one class of G proteins. Upon activation, G-αs interacts with and turns on the enzyme adenyl cyclase, which catalyzes the enzymatic formation of 3′,5′-cyclic adenosine monophosphate. This then turns on protein kinase A (PKA), an enzyme that phosphorylates effector proteins that play key roles in vascular and cardiac physiology, metabolism, cell cycle control, and intracellular protein trafficking events, to name a few . Specifically, in the heart, PKA phosphorylates proteins involved in energy metabolism and excitation–contraction coupling, such as glycogen phosphorylase kinase, the L-type calcium channel, the sarcoplasmic reticulum membrane protein phospholamban, and cytoskeletal proteins. These phosphorylation events result in enhanced cardiac contractility (inotropy), accelerated cardiac relaxation (lusitropy), and increased heart rate (chronotropy) [44,45].
There exist two subtypes of the β-AR in cardiac tissue: β1-AR and β2-AR. The β1-AR stimulates only the G-αs protein. In contrast, however, Xiao et al. [46,47] showed the dual coupling of β2-AR to both G-αs and G-αi (a G protein that antagonizes the G-αs-adenyl cyclase–3′,5′-cyclic adenosine monophosphate–PKA pathway). To study the β2-AR apart from the β1-AR, Xiao  isolated cardiomyocytes from β1-AR and β2-AR double-knockout mice. While in culture, they then reintroduced the β2-AR using an adenovirus expression system and again conclusively showed coupling to both G-αs and G-αi.
How might the cellular biology of the β-ARs and G-αs/G-αi contribute to the pathogenesis of Takotsubo Syndrome? Lyon et al.  provide an intriguing hypothesis. At both physiological and elevated plasma levels, norepinephrine released from sympathetic nerve endings binds preferentially to the β1-AR on ventricular cardiomyocytes, exercising both positive inotropic and lusitropic effects through the G-αs–adenyl cyclase–3′,5′-cyclic adenosine monophosphate–PKA pathway. Epinephrine also binds to the β1-AR, but has a higher binding affinity for the β2-AR. At physiological concentrations, epinephrine binds to the β2-AR and activates G-αs (positive inotropy, positive lusitropy, and positive chronotropy). While at higher plasma levels (e.g. Takotosubo Syndrome), epinephrine still binds to the β2-AR but instead activates G-αi (negative inotropy, negative lusitropy, negative chronotropy). Simply put, β2-AR potentiated signaling switches from G-αs to G-αi in response to intense stimulation. The process whereby a given ligand can bind to a single receptor and initiate distinct intracellular programs is an active area of research, described in the literature as stimulus trafficking, biased agonism, protean agonism, agonist-directed trafficking, or functional selectivity .
Visually, the left ventricular contractile pattern typical of Takotsubo Syndrome looks similar to that of the Japanese octopus trap: hypokinesis or akinesis of the left ventricular apical segments and hyperkinesis of the basal segments [5,50]. Assuming equal perfusion, how is it possible that extremely high levels of plasma epinephrine could result in dichotomous physiological states of the apical and basal segments of the left ventricle? In 1993, Mori et al.  carried out a study to address the responsiveness of the left ventricular apical myocardium to adrenergic stimuli. Their results suggest that the apical segments of the ventricle express a greater β-AR density, with decreasing receptor concentration extending from apex to base. This would then imply that the apex of the ventricle would be most sensitive to circulating catecholamines. Future studies are needed to support this hypothesis.
Estrogen and vascular biology
In 1995, Rosano et al.  examined unselected patients with chest pain and normal coronary arteries over a period of 18 months at two London Hospitals. During the study, 107 of 134 consecutive cases were women. Moreover, of the 107 female patients, 95 experienced chest pain either during the perimenopausal period or after menopause. Therefore, it seems that the presence of estrogen might prevent symptoms and that the lack of estrogen might be contributory to the syndrome . It is believed that the direct action of estrogen on the vasculature is responsible for most of its protective effects .
Estrogen has profound effects on vascular physiology. In sheep, 17-β-estradiol increases both cardiac output and arterial flow velocity and decreases vascular resistance. Hormone administration also increases myocardial perfusion. In postmenopausal women, transdermal estrogen treatment improves the pulsatility index scores of carotid artery Doppler ultrasound studies. Furthermore, 17-β-estradiol administration to patients suffering from migraine attacks can increase blood flow through affected cerebral arteries . These data provide evidence for a regulatory role of estrogen on vascular physiology.
In 1980, Furchgott et al.  published a paper in the journal Nature identifying the vascular endothelium as necessary for acetylcholine-mediated vasodilatation. Subsequently, in 1984, Furchgott et al.  showed that acetylcholine causes the release of an unstable transferable factor called endothelium-derived relaxing factor, which acts through the enzyme guanylate cyclase. At the 1987 symposium in Rochester, Minnesota, USA, entitled Mechanisms of Vasodilation, Fuchgott then advanced his hypothesis that endothelium-derived relaxing factor is nitric oxide (NO) .
NO, a diatomic gas, is synthesized by the enzyme NO synthase (NOS). The NOS isoform III exists mainly in endothelial cells (called eNOS), while isoforms I and II are expressed predominately in nerves and inflammatory cells, respectively [58–60]. In the endothelium, eNOS is localized to plasma membrane caveolae [61,62] and produces NO from the semiessential amino acid L-arginine . NO then diffuses to the wall of the vessel in which it affects vascular smooth muscle function . In the smooth muscle cell, NO activates the enzyme-soluble guanylyl cyclase, which catalyzes the formation of 3′,5′-cyclic guanosine monophosphate from guanosine 5-triphosphate. Cyclic GMP-dependent protein kinase is a serine/threonine kinase activated upon binding of 3′,5′-cyclic guanosine monophosphate. Many targets of GMP-dependent protein kinase-mediated phosphorylation result in smooth muscle relaxation [59,60].
Estrogen has a significant impact on eNOS levels and activity [54,63]. In the endothelium, estrogen diffuses into the nucleus where it binds to the estrogen receptor. The estrogen–estrogen receptor complex then binds to a specific nucleic acid sequence in target gene promoters called an estrogen response element. Interaction between estrogen–estrogen receptor with estrogen response elements in target gene promoters allows for transcriptional activation . The eNOS gene promoter has in it an estrogen response element, and, in this manner, estrogen regulates eNOS levels [64,65]. In fact, laboratory investigations have shown increased eNOS protein in human coronary artery endothelial cells after 17-β-estradiol treatment . In addition, estrogen can induce a rapid release of NO from the vascular endothelium in a manner independent of gene transcription. The exact molecular mechanism of this activation remains an active area of research, likely involving a functional signaling unit localized to plasma membrane caveolae along with mitogen-activated protein kinase-dependent and tyrosine kinase-dependent signaling events. In addition, the phosphatidylinositol 3-kinase/AKT signaling pathway has also been implicated in driving rapid estrogen-mediated eNOS activation [54,61].
In the above-mentioned manner, estrogen plays an important role in regulating arterial tone and vasodilatation by eNOS. In the absence of estrogen, therefore, the coronary arteries might be primed for coronary spasm in the setting of exaggerated plasma catecholamine levels. It is a hypothesis not yet proven that the catecholamine excess associated with grief reacts on a coronary artery system primed for stunning and spasm because of estrogen lack.
Strong evidence points to a multifactorial pathogenesis in patients who develop the Takotsubo Syndrome. It is in many ways a physiological perfect storm: (i) an extreme unrelenting emotional event unleashes a catecholamine surge as a result of a positive feedback loop in the physiologic stress system; (ii) extraordinarily high levels of catecholamines disrupt cardiac function through direct cardiomyocyte toxicity, excessive coronary artery adrenergic stimulation or by β-AR-mediated stimulus-dependent G protein stimulus trafficking; and (iii) the postmenopausal estrogen-deficient female is particularly susceptible to the actions of the catecholamine surge (Fig. 5).
With supportive therapy, physiological abnormalities as a result of the Takotsubo Syndrome resolve and the syndrome abates. Recognition of this clinical syndrome leads to more rational and effective therapy.
D.M.B. is supported by an NIH MSTP TG T32GM07205.
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