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Pathophysiology of Takotsubo Syndrome

Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.116.027121Circulation. 2017;135:2426–2441

    Abstract

    Originally described by Japanese authors in the 1990s, Takotsubo syndrome (TTS) generally presents as an acute myocardial infarction characterized by severe left ventricular dysfunction. TTS, however, differs from an acute coronary syndrome because patients have generally a normal coronary angiogram and left ventricular dysfunction, which extends beyond the territory subtended by a single coronary artery and recovers within days or weeks. The prognosis was initially thought to be benign, but subsequent studies have demonstrated that both short-term mortality and long-term mortality are higher than previously recognized. Indeed, mortality reported during the acute phase in hospitalized patients is ≈4% to 5%, a figure comparable to that of ST-segment–elevation myocardial infarction in the era of primary percutaneous coronary interventions. Despite extensive research, the cause and pathogenesis of TTS remain incompletely understood. The aim of the present review is to discuss the pathophysiology of TTS with particular emphasis on the role of the central and autonomic nervous systems. Different emotional or psychological stressors have been identified to precede the onset of TTS. The anatomic structures that mediate the stress response are found in both the central and autonomic nervous systems. Acute stressors induce brain activation, increasing bioavailability of cortisol and catecholamine. Both circulating epinephrine and norepinephrine released from adrenal medullary chromaffin cells and norepinephrine released locally from sympathetic nerve terminals are significantly increased in the acute phase of TTS. This catecholamine surge leads, through multiple mechanisms, that is, direct catecholamine toxicity, adrenoceptor-mediated damage, epicardial and microvascular coronary vasoconstriction and/or spasm, and increased cardiac workload, to myocardial damage, which has a functional counterpart of transient apical left ventricular ballooning. The relative preponderance among postmenopausal women suggests that estrogen deprivation may play a facilitating role, probably mediated by endothelial dysfunction. Despite the substantial improvement in our understanding of the pathophysiology of TTS, a number of knowledge gaps remain.

    Originally described by Sato et al1 in the 1990s, Takotsubo syndrome (TTS) presents as an acute coronary syndrome (ACS) characterized by severe left ventricular (LV) dysfunction that typically recovers spontaneously within days or weeks. Patients may present with abrupt-onset chest pain or dyspnea. Several stressors have been identified to precede the onset of TTS in a substantial proportion of patients.2 Emotional or psychological stress caused by the unexpected death of a relative or a friend, suppressed terror, the occurrence of natural disasters, or strenuous physical stress usually precedes its onset.3 About 1 in 5 patients, however, does not report any form of stress preceding the onset of the condition. Recently, it has been shown that TTS can also occur after a positive life event, hence the recently proposed term happy heart syndrome.4

    Despite extensive research, the cause and pathogenesis of TTS remain incompletely understood. The aim of the present review is to discuss the pathophysiology of TTS, with particular emphasis on the role of the central and autonomic nervous systems.

    Clinical Presentation

    Symptoms, clinical signs, and echocardiographic and electrocardiographic findings in patients with TTS are suggestive of an ACS.5 The most common symptoms at presentation are chest pain and dyspnea. TTS can also present as syncope and pulmonary edema. Cardiac arrest, cardiogenic shock, and serious ventricular arrhythmias occur more rarely in patients with TTS. Symptoms such as generalized weakness, unexplained cough, and fever have also been reported.6

    ECG Patterns

    Abnormalities on the ECG are common at the time of presentation. The most frequent finding on the admission ECG is ST-segment elevation, which most often occurs in the precordial leads.7 The magnitude of ST-segment elevation and the number of leads with this pattern are usually smaller in patients with TTS than in patients with ST-elevation–elevation myocardial infarction (STEMI).8 It is interesting to note that reciprocal ST-segment changes and abnormal Q waves are often absent in TTS. Moreover, ST-segment depression is less common in TTS compared with coronary artery disease–related ACS.9 Some patients with TTS may present with diffuse T-wave inversion, particularly in the anterior and lateral leads of the ECG. A prolongation in the QT interval, corrected for heart rate, has been reported in a substantial proportion of patients with TTS. These ECG changes are often transient, and their presence or absence depends on when the ECG is recorded after symptom onset. However, it is challenging to distinguish TTS from an ACS on the basis of the ECG alone; therefore, access to emergency coronary angiography should not be delayed.5

    Biomarkers

    Typically, patients with TTS manifest modest increases in creatine kinase-MB and cardiac troponin concentrations compared with patients with STEMI. Of interest, in TTS, there is a disparity between the degree of biomarker elevation and the extent of myocardial dysfunction observed at left ventriculography. In a minority of patients with TTS, however, the elevation of biomarkers of necrosis can be substantial, probably reflecting more severe myocardial damage.5 Significantly elevated serum brain natriuretic peptide or N-terminal pro-B-type natriuretic peptide can also be detected during the acute phase of TTS.10 The production and release of these peptides appear to be related mainly to ventricular stretching.11 Because in most cases TTS is characterized by LV distension and relatively mild tissue necrosis, a greater increase in plasma natriuretic peptides compared with biomarkers indicative of necrosis can be detected.10

    Coronary and LV Angiography

    Diagnostic coronary angiography shows normal coronary arteries or nonobstructive coronary artery disease in the vast majority of patients.5 However, ≈15% of patients with TTS have obstructive coronary atherosclerosis.6 In these patients, the diagnosis of TTS is suggested by the fact that the area of dysfunction detected on LV angiography extends beyond the territory subtended by a single coronary artery and by the reversibility of LV dysfunction. Hence, the mere presence of obstructive coronary atherosclerosis does not allow the exclusion of the diagnosis of TTS.12

    Different Types of LV Dysfunction

    Different patterns of LV dysfunction have been reported in TTS, including the classic apical variant, a midventricular variant, a basal or inverted variant, and regional variants.13 About 80% of patients exhibit the apical variant.14 Because the heart is densely innervated by sympathetic nerves that follow a regional distribution, it has been hypothesized that the typical apical pattern of LV dysfunction results from this anatomic substrate,3 as well as from the regional distribution of sympathetic adrenoceptors.15

    Clinical Outcome

    The prognosis of TTS was initially thought to be benign.16 Subsequent series, however, have demonstrated that both short-term mortality and long-term mortality are higher than previously recognized.17 Indeed, mortality reported during the acute phase in hospitalized patients is ≈4% to 5%, a figure comparable to that of STEMI in the era of primary percutaneous coronary interventions.18 Of interest, despite the recovery of LV function and the absence of significant coronary disease in most cases, mortality after hospital discharge is worse than that in an aged-matched healthy population.19 A recent meta-analysis of clinical correlates of acute mortality in TTS has reported that the average in-hospital mortality is 4.5%.20 Japanese investigators have recently pointed out that TTS is associated with an elevated in-hospital mortality resulting from coexisting chronic comorbidities and acute medical illnesses.21 In one of the largest published series (n=1750), Templin et al6 reported a 30-day mortality of 5.9% and a long-term death rate of 5.6% per patient per year. Major adverse events, including cardiogenic shock, cardiac arrest, and mortality, are more frequent in women than in men with TTS. There is uncertainty as to the real recurrence rate of TTS because of the paucity of data on the risk of a further episode after the index event. Available evidence points to figures ranging from 0% to 22%, depending on the size of the population investigated and the duration of follow-up.5

    TTS Phenocopies

    Generally, TTS is preceded by intense emotional triggers, although in up to one third of patients, no trigger can be identified. A TTS-like syndrome can be observed in several medical conditions, including sepsis, neurological disorders (eg, subarachnoid hemorrhage, seizures, stroke/transient ischemic attack, cerebral tumors, head trauma),22 and pheochromocytoma.23 Furthermore, a TTS-like syndrome can be triggered by drugs (dopamine, dobutamine, epinephrine, or norepinephrine in the setting of cardiovascular stress tests, anesthesia, etc).24 In our view, all these conditions should be differentiated from the classic phenotype of TTS and could be labeled TTS phenocopies.

    Epidemiology

    About 90% of patients with TTS are postmenopausal women, with a similar prevalence across ethnic groups.6 In recent years, the increasing number of patients referred to coronary angiography with suspected ACS has allowed better appreciation of the true incidence of TTS. At present, it is estimated that ≈2% of all patients undergoing emergency coronary angiography for a suspected ACS have TTS,12 and it has been calculated that the incidence of TTS is ≈100 new cases per 1 million population per annum.25 Indeed, the improved clinical characterization of the condition has led to a paradigm shift from what was initially the exclusion of STEMI to the recognition that TTS has a number of distinctive diagnostic features.

    Pathophysiology

    Sympathetic Activation in TTS and Its Mechanisms

    The environmental events experienced by the majority of these patients and perceived as threatening become profoundly stressful if one is not able to cope with them.26 Stress is a physiological response that mediates the action of a stressor on its target organ.27 The anatomic structures that mediate the stress response are found in both the central and autonomic nervous systems (Figure 1). Acute emotional stressors have been shown to induce brain activation, increasing bioavailability of cortisol, epinephrine, and norepinephrine.27 In a small series of patients in the acute phase of TTS, Suzuki et al28 have measured regional cerebral blood flow, a well-established index of brain activity, and demonstrated a significant cerebral blood flow increase in the hippocampus, brainstem, and basal ganglia, paralleled by a decrease in the prefrontal cortex. Although these changes subsided gradually, they were still present in the chronic phase of TTS even after the typical cardiac wall motion abnormalities had disappeared (Figure 2).

    Figure 1.

    Figure 1. Central and autonomic nervous system interplay. Right, Somatic nervous system (motor system and sensory systems) and environment. Left, Autonomic nervous system, neuroendocrine system, and body organs. Middle, Spinal cord, brainstem, hypothalamus limbic system, and neocortex. The afferent feedback from the body is neuronal, hormonal, and humoral (physicochemical; eg, glucose concentration, osmolality) and other types (eg, body temperature). Solid line arrows, neuronal; dashed line arrow, hormonal; and dotted, neuroendocrine system, hormonal and humoral feedback. Limbic system is anatomically descriptive and a collective term denoting brain structures common to all mammals that include the hippocampus, dentate gyrus with archicortex, cingulate gyrus, septal nuclei, and amygdala. These forebrain structures are functionally heterogeneous and not a unitary system (as the term limbic system may imply). They are involved in the generation of emotional and motivational aspects of behavior. Note the reciprocal communication between the hypothalamus, limbic system, and neocortex (shaded arrows), indicating that the centers of the cerebral hemispheres have powerful influence on all autonomic regulations. Reprinted from Janig26 with permission from the publisher. Copyright © 2006 Cambridge University Press.

    Figure 2.

    Figure 2. Brain activation in patients with Takotsubo syndrome (TTS).Left ventricular (LV) angiograms (top) and single-photon emission computed tomography images of the brain in 3 patients with TTS. In patient 1, LV angiograms showed typical apical ballooning in the acute phase (day of onset; A), which disappeared in the chronic phase (29 days after onset; B). Normalization of wall motion abnormality was confirmed by echocardiography in patients 2 and 3. In all patients, brain activation was noted in the acute phase (1, 1, and 4 days after onset; C, E, and G, respectively), which subsided in the chronic phase (28, 28, and 39 days after onset; D, F, and H, respectively). The yellow, red, green, and blue arrowheads indicate the hippocampus, brainstem, basal ganglia, and prefrontal cortex, respectively. Reprinted from Suzuki et al28 with permission from the publisher. Copyright © 2014 The Japanese Circulation Society.

    The fundamental anatomic structures involved in the stress response are the neocortex, limbic system, reticular formation, brainstem, and spinal cord.29 After the complex neocortical and limbic integrations that occur in the interpretation of a stimulus as threatening,30 the neural stress response first occurs through activation of brainstem noradrenergic neurons and sympathetic adrenomedullary circuits, stimulating the secretion of catecholamine.

    The principal site for the synthesis of norepinephrine in the brain is the locus coeruleus, which is located in the posterior area of the rostral pons in the lateral floor of the fourth ventricle.31 As a crucial homeostatic control center, the locus coeruleus receives afferents from the hypothalamus, cingulate gyrus, and amygdala, allowing emotional stressors to trigger noradrenergic responses. The locus coeruleus contains the largest cluster of noradrenergic neurons in the brain and innervates large segments of the neuroaxis.31 Its activation leads to increased norepinephrine secretion, which in turn stimulates the hypothalamic-pituitary-adrenal axis.29

    Adrenal medullary chromaffin cells synthesize, store, and release predominantly epinephrine and norepinephrine, which constitute the hormonal output of the neuroendocrine stress-response axis.32 Activation of the latter is crucial to maintain high levels of stress arousal for prolonged periods. The hypothalamic-pituitary-adrenal axis is a complex set of direct influences and feedback interactions among 3 endocrine glands: the hypothalamus, the pituitary gland, and the adrenal gland (Figure 1).

    Apart from the locus coeruleus, the neural impulses also descend into the posterior hypothalamus, that is, the pathway of sympathetic activation. From here, sympathetic neural pathways descend through the cranial and sacral spinal cord regions and trigger the release of norepinephrine.33 There are sympathetic preganglionic neurons that lay in the lateral gray column from T1 to L2-3 that synapse with their postganglionic neurons. Sympathetic cardiac innervation originates mainly in the right and left stellate ganglia. These fibers travel along the epicardial vascular structures of the heart into the underlying myocardium and end as sympathetic nerve terminals reaching the heart muscle and coronary circulation. The sympathetic nerve endings release norepinephrine directly into the synaptic cleft, activating α and β postsynaptic adrenoceptors.34 Thus, all the epinephrine in the body and a significant amount of circulating norepinephrine derive from the adrenal medulla, and the total amount of catecholamine presented to cardiac adrenergic receptors at any given time is composed of circulating norepinephrine and epinephrine coupled with norepinephrine released locally from sympathetic nerve terminals.35 In normal humans, under resting conditions, only ≈2% to 8% of the circulating norepinephrine is released by the adrenal medulla, and the rest is released by sympathetic nerve endings.26

    Increased Circulating and Myocardial Catecholamine Levels

    Akashi and colleagues36 were the first to report elevated serum catecholamine levels in patients with TTS. Wittstein et al37 subsequently showed that in the acute phase, patients with TTS have increased concentrations of plasma catecholamines (ie, epinephrine, norepinephrine, and dopamine) and stress-related circulating neuropeptides that are several times higher than those in patients with STEMI. These levels remain markedly elevated even a week after the onset of symptoms (Figure 3).

    Figure 3.

    Figure 3. Plasma catecholamine levels in patients with Takotsubo syndrome (TTS) and patients with myocardial infarction.In the acute phase, patients with TTS have increased concentrations of plasma catecholamine (ie, epinephrine, norepinephrine, and dopamine) and stress-related circulating neuropeptides that are several times higher than those in patients with myocardial infarction and remain markedly elevated even a week after the onset of symptoms. Modified from Wittstein et al37 with permission from the publisher. Copyright © 2005 Massachusetts Medical Society.

    A recent study in a murine model has demonstrated that the infusion of high concentrations of epinephrine can produce the characteristic reversible apical LV ballooning coupled with basal hypercontractility observed in patients with TTS.38

    Indeed, in the acute phase of TTS, along with an increased concentration of circulating catecholamine,37 there is evidence of increased catecholamine at the myocardial level. Kume et al39 have demonstrated increased norepinephrine spillover in the coronary sinus in a small series of patients with TTS, suggesting increased local myocardial release of catecholamine. An increase in local catecholamine levels has been demonstrated also in the so-called neurogenic stunned myocardium that appears to be mediated by neuronally transmitted norepinephrine.40 The clinical presentation of this condition, which is found in patients with aneurysm-related subarachnoid hemorrhage, closely resembles that of TTS and is characterized by a fully reversible form of acute LV dysfunction.41 Accordingly, experimental work has shown that elevated activity of the sympathetic nervous system in the acute phase of subarachnoid hemorrhage induces myocardial damage and contributes to the development of cardiac dysfunction.42

    The local release of catecholamine from cardiac nerve endings results in an elevated norepinephrine concentration in the synaptic cleft owing to increased exocytosis of norepinephrine from presynaptic vesicles, paralleled by a decrease in terminal nerve axon norepinephrine reuptake through the specific uptake-1 transporter (Figure 4).43 This process has been originally demonstrated by means of iodine-123 meta-iodo-benzyl-guanidine, that is, a γ-emitting norepinephrine analog used to image myocardial sympathetic nerve terminals with single-photon emission computed tomography. Akashi et al44 examined 8 patients with TTS within 3 days of admission and at a 3-month follow-up after normalization of LV dysfunction. The early scan showed a pattern of cardiac sympathetic hyperactivity with improvement at follow-up.44 The evidence of reduced iodine-123 meta-iodo-benzyl-guanidine retention in dysfunctional segments is consistent with a regional disturbance of sympathetic neuronal activity that can persist for months.45 Recently, Christensen et al46 have demonstrated myocardial sympathetic hyperactivity in the subacute phase of TTS paralleling plasma epinephrine levels, which were also elevated compared with follow-up concentrations.

    Figure 4.

    Figure 4. Autonomic nervous system (ANS) activation and cardiovascular system.ANS activation is mediated by release of norepinephrine (NE) and epinephrine (Epi) and occurs via the following mechanisms: (1) Release of norepinephrine by cardiac sympathetic nerve terminals (resulting in tachycardia and an increased force of contraction); (2) release of epinephrine into the circulation by the adrenal medulla, modulating both myocardium and peripheral vessels; and (3) local release of norepinephrine and epinephrine by various peripheral ANSs that can synthesize and release these catecholamines in an autocrine/paracrine manner and are located in blood vessels and in cardiac myocytes themselves. AC indicates adenylyl cyclase; Ach, acetylcholine; AT1R, angiotensin type 1 receptor; α2AR, α2-adrenergic receptor; βAR, β-adrenergic receptor; β2AR, β2-adrenergic receptor; GRK2, G protein–coupled receptor kinase 2; MR, mineralcorticoid receptor; NET, norepinephrine transporter; and PKA, protein kinase A. Reprinted from Lymperopoulos et al43 with permission from the publisher. Copyright © 2013 American Heart Association, Inc.

    Role of Endothelial Dysfunction and Estrogen Deficiency

    New information has shed additional light on the pathogenesis of TTS, supporting the concept that the condition differs markedly from cardiomyopathies as currently defined. Specifically, recent data show that endothelial dysfunction is common in patients with TTS, which could explain the propensity for epicardial and/or microvascular coronary artery spasm, which are 2 likely pathogenetic mechanisms for TTS.47 Indeed, endothelial dysfunction, a pathological state of the endothelium characterized by an imbalance between vasoconstricting and vasodilating factors, may represent an important link between stress and myocardial dysfunction in TTS.47 Therefore, transient myocardial ischemia followed by stunning might be the cause underlying the typical, reversible LV dysfunction.

    Endothelial dysfunction can also explain why TTS is more common in postmenopausal women; they have been shown to have both age-related and estrogen deficiency–related coronary vasomotor abnormalities.4850 Under physiological circumstances, estrogen beneficially affects the coronary microcirculation via endothelium-dependent and -independent mechanisms, improving coronary blood flow.50 During menopause, both increased sympathetic drive and endothelial dysfunction are a consequence of reduced estrogen levels.49 In an elegant experimental study in animals, Ueyema et al51 have shown that stress-induced LV apical ballooning can be prevented by pretreatment with α- and β-adrenoceptor blockers and estrogen. Estrogen supplementation attenuated the stress-induced hypothalamo-sympatho-adrenal outflow from the central nervous system to the target organs. In addition, estrogen treatment upregulated the cardiac levels of cardioprotective substances such as atrial natriuretic peptide and heat shock protein 70. These data suggest that estrogen deficiency after menopause might facilitate the occurrence of TTS, particularly that linked to emotional stress, either by indirect action on the nervous system or by direct action on the heart. Moreover, impairment of endothelial function is associated with the presence of traditional risk factors and has been described in the setting of various systemic inflammatory disorders with high cardiovascular morbidity and mortality.49 Recently, data in large cohorts have shown that patients with TTS have a nonnegligible prevalence of cardiovascular risk factors, that is, hypertension, hypercholesterolemia, and smoking.2,6,18 In addition, there is now evidence that most cases of TTS occur in patients with various comorbidities, including neurological, psychiatric, pulmonary, kidney, liver, and connective tissue disease,2 that are associated with endothelial dysfunction and might therefore constitute a previously unrecognized predisposing factor for TTS.52

    From these multiple observations, the possibility exists that endothelial dysfunction might constitute a crucial link between a sympathetic surge and myocardial ischemia in TTS.

    Mechanisms of LV Dysfunction Induced by Sympathetic Hyperactivity

    Although there is agreement that TTS is characterized by increased circulating and cardiac catecholamine levels, how this translates into the typical LV dysfunction remains incompletely understood.53 Multiple mechanisms have been postulated to explain the cardiotoxicity of catecholamines.54 The surge in stimulation of adrenoceptors enhances heart rate and cardiac contractility with a secondary imbalance in the ratio of oxygen supply to oxygen demand, thus creating areas of myocellular hypoxia.55 Myocyte hypoxia can be further aggravated by metabolic changes56 such as excessive deposition of lipid droplets in cardiomyocytes. These changes might result in an uncoupling of oxidative phosphorylation in mitochondria, which inhibits the coupling between the electron transport and phosphorylation reactions, which in turn will interfere with ATP synthesis.57 Changes in membrane permeability might also lead to electrolyte changes. These include hypokalemia, hypocalcemia, and hypomagnesemia, with resultant elevations in parathyroid hormone, and hypozincemia with hyposelenemia, which are antioxidant defenses. Altered cationic homeostasis might affect several cellular processes and contribute to myocardial toxicity.58 Norepinephrine and epinephrine are also potential sources of free radicals. These oxygen-derived free radicals may interfere with calcium and sodium transporters, which may result in additional myocyte dysfunction.3

    Direct Catecholamine Toxicity

    Some authors favor the hypothesis of direct catecholamine-induced myocardial toxicity in TTS. For instance, myocardial necrosis can occur in patients with acute neurovascular events, and this is caused by direct toxicity of endogenous catecholamine released into the heart via nerve terminals.59 Catecholamine released directly into the myocardium via sympathetic nerves has been suggested to have a greater “toxic” effect than that reaching the heart via the bloodstream.60 Indeed, norepinephrine spillover from the cardiac sympathetic nerve terminals can decrease myocyte viability through cAMP-mediated calcium overload, resulting, histologically, in contraction band necrosis, which is one of the pathological hallmarks of TTS,61 along with increased production of extracellular matrix, leading to a rapid increase in fibrosis and mild neutrophil infiltration. Nef et al62 studied serial myocardial biopsies in 8 patients with TTS during the phase of severe LV dysfunction and found histological signs of catecholamine toxicity, that is, focal mononuclear inflammatory cells, areas of fibrotic response, and characteristic contraction bands. They noted that TTS can be accompanied by “severe morphological alterations potentially resulting from catecholamine excess followed by microcirculatory dysfunction and direct cardiotoxicity.” They continued, “However, the affected myocardium represents a high potential of structural reconstitution which correlates with the rapid functional recovery.”62

    Contraction band necrosis is a unique form of myocyte injury characterized by hypercontracted sarcomeres, dense eosinophilic transverse bands, and an interstitial mononuclear inflammatory response and is distinct from the polymorphonuclear inflammation seen in infarction.61 Contraction band necrosis has been found in patients with pheochromocytoma23 and those with subarachnoid hemorrhage,40 both characterized by a catecholamine excess. It has also been observed postmortem in people who died under terrifying circumstances such as fatal asthma and violent assault, suggesting that catecholamine excess represents an important link between emotional stress and cardiac injury.63 The lack of persistent, significant morphological changes in most cases of TTS is further demonstrated by data accrued so far with cardiac magnetic resonance (CMR). Different studies have pointed out that the acute phase of the disease is characterized only by remarkable myocardial edema with no evidence of significant late gadolinium enhancement (Figure 5).64 These findings are of major importance because they exclude the possibility that TTS is mainly the consequence of a catecholamine-mediated myocarditis, which commonly occurs in pheochromocytoma.23 Although TTS and pheochromocytoma are both characterized by increased catecholamine concentrations, this causes a distinct entity in pheochromocytoma only, leading to degenerative changes in muscle fibers, foci of necrosis, acute inflammation, chronic interstitial inflammatory exudation, and reparative fibrosis.65 At CMR, these abnormalities may be observed noninvasively as myocardial necrosis (late enhancement), edema, and focal and diffuse fibrosis that may lead to short- or long-term LV dysfunction.23 A different pattern is observed in patients with TTS. Testa and Feola66 performed serial CMR scans in patients with TTS and found no evidence of delayed enhancement either in the acute phase or at the 3-month follow-up, suggesting that the damage in dysfunctional myocardium was transient and did not include significant tissue fibrosis.

    Figure 5.

    Figure 5. Cardiovascular magnetic resonance identification of myocardial edema in Takotsubo syndrome.T2-weighted images (short-axis view, top) demonstrating normal signal intensity of the basal myocardium (left) but global edema of the mid and apical myocardium (middle and right). Computer-aided signal intensity analysis (bottom of the T2- weighted images with color-coded display of relative signal intensity normalized to skeletal muscle [blue indicates a signal intensity ratio of myocardium to skeletal muscle of ≥1.9, indicating edema; green/yellow indicates a normal signal intensity ratio of 1.9]) confirms the presence of global mid and apical edema. Reprinted from Eitel et al64 with permission from the publisher. Copyright © 2009 European Society of Radiology.

    In summary, it may be hypothesized that direct catecholamine toxicity plays a role in both TTS and pheochromocytoma but with important quantitative differences. The myocardial damage in pheochromocytoma is probably more extensive because of the persistent exposition of patients to elevated catecholamine levels. In TTS, the elevation is transient and generally results in less evident damage, as demonstrated by the relatively mild elevation of necrosis biomarkers5,6 and absence of late enhancement at CMR in most cases.66 The latter in particular might be a consequence of the limited spatial resolution of CMR, that is, 0.6 to 1 cm3, which may not detect smaller or patchy areas of damage that are present in TTS.67

    Microvascular Spasm

    A further vascular pathogenetic mechanism that could be involved in TTS is acute, transient myocardial ischemia. Since the first description of TTS, coronary vasospasm has been suggested as a plausible causative factor. In their original report, Dote et al68 hypothesized that TTS was caused by multivessel coronary vasospasm because 4 of 5 patients in their series had spontaneous or induced coronary vasospasm at coronary angiography. Sato et al1 reported epicardial coronary artery spasm in 8 of 35 patients (23%) and diffuse coronary vasoconstriction in 19 (54%). Similarly, Tsuchihashi et al69 reported epicardial coronary spasm in 10 of 48 patients with TTS (21%). Although the causative role of coronary spasm has been questioned by many authors, in a prospective study, Angelini70 confirmed the development of coronary spasm in patients with TTS who underwent acetylcholine testing. Indeed, severe, subocclusive epicardial coronary artery spasm occurred in these patients, which was associated with echocardiographic evidence of transient LV dysfunction, as classically observed in TTS. Another epicardial coronary abnormality that might cause TTS is spontaneous coronary artery dissection, which is a form of TTS triggered by an ischemic insult leading to postischemic myocardial stunning.71

    In addition to abnormalities of the epicardial arteries, coronary microvascular dysfunction could play a pathogenetic role in TTS (Figure 6).72

    Figure 6.

    Figure 6. Mechanism of myocardial ischemia.In addition to the classic mechanisms (ie, atherosclerotic disease and epicardial coronary vasospasm) that lead to myocardial ischemia, coronary microvascular dysfunction has recently emerged as a third potential mechanism of myocardial ischemia. As in the case of the other 2 mechanisms, coronary microvascular dysfunction (alone or in combination with the other 2) can lead to transient myocardial ischemia as in patients with coronary artery disease (CAD) or cardiomyopathy (CMP) or to severe acute ischemia as observed in Takotsubo syndrome. CFR indicates coronary flow reserve. Reprinted from Crea et al72 with permission. Copyright © 2013 The Author.

    Abnormal coronary microvascular responses have been documented in TTS with invasive and noninvasive diagnostic tools.73 Reduced TIMI (Thrombolysis in Myocardial Infarction) frame count in most patients undergoing emergency coronary angiography with spontaneous improvement of coronary flow reserve at a 1-month follow-up has been reported by some authors,16 although this has not been a universal finding.74,75 It is interesting to note that using myocardial contrast echocardiography, Galiuto et al76 demonstrated reversible coronary microvascular dysfunction in patients with TTS. A clear perfusion defect was observed in the LV segments showing reduced contractility. In contrast to what is commonly observed in patients with STEMI, the perfusion defect in patients with TTS transiently improved after the infusion of intracoronary adenosine and recovered permanently at 1 month of follow-up (Figure 7). The close relationship between the improvement of myocardial perfusion and LV dysfunction observed in this study suggests a pathogenetic role for the coronary microvascular dysfunction in this condition.76 Several single-photon emission computed tomography perfusion studies have shown a decrease in tracer uptake during the acute phase of TTS and a return to normal at follow-up, suggesting a role for coronary microvascular dysfunction as a trigger of myocardial ischemia in this condition.7779

    Figure 7.

    Figure 7. Myocardial contrast echocardiography in Takotsubo syndrome (TTS).Under baseline conditions, a clear perfusion defect is present within the left ventricular apical myocardium (top left), whereas during adenosine, a significant decrease in the extent of the perfusion defect is evident (top right). Contrast score index (arbitrary units; A and B) and contrast defect length (C and D) at baseline (Bsl), at peak of 90-second adenosine infusion (Adn), and at 1-month follow-up (FUP) in patients with TTS (ABS) and patients with ST-segment–elevation myocardial infarction (STEMI). *P<0.001 vs baseline. Reprinted from Galiuto et al76 with permission. Copyright © 2010 The Author.

    Mechanisms of Myocardial Protection

    The severe wall motion abnormalities seen in TTS are transient in the vast majority of patients, which strongly suggests that protective mechanisms are likely to operate to preserve myocardial integrity. Overactive adrenoceptor signaling, in the presence of supraphysiological catecholamine concentrations, might be the trigger of LV dysfunction.80 It is well established that catecholamine signaling through β-adrenoceptors mediates endogenous regulation of chronotropic, inotropic, and lusitropic cardiac functions. There is general consensus that this “brain-cardiac” process occurs via the β-adrenoceptor–mediated cAMP-dependent protein kinase pathway.81 Regional differences in adrenoceptor density might explain the pattern of LV dysfunction often seen in TTS. Experimental data have shown that β2-adrenoceptors are more frequently expressed in apical than in basal segments of the LV, whereas a reverse distribution is present for norepinephrine β1-adrenoceptors and sympathetic nerve terminals of the neuro-cardiac axis, which are expressed much more at the base than at the apex of the LV.15

    With this background, it might be considered that both epinephrine and norepinephrine elicit positive inotropic responses through Gs-coupling protein, but they function differently when activating the β2-adrenoceptors. Indeed, supraphysiological levels of epinephrine trigger β2-adrenoceptor to switch from Gs to Gi coupling.82 The switch to Gi, which causes a negative inotropic response, thus contributing to the apical ballooning, may be a mechanism to protect myocytes from the cardiotoxic activation of β1- and β2-adrenoceptor Gs pathways, thus limiting the degree of acute myocardial injury in response to the catecholamine storm. This mechanism has been elegantly shown by Paur et al,38 who demonstrated that high-dose epinephrine can induce direct myocyte cardiodepression and cardioprotection in a Gi-dependent manner. In a rat model, these authors showed that high-dose intravenous epinephrine given quickly as a bolus, to mimic the catecholamine surge after acute stress, produced the characteristic reversible apical depression of myocardial contraction coupled with basal hypercontractility, whereas an equivalent bolus of norepinephrine did not.39 This implies that the mechanism is epinephrine specific and confirms the observation that dysfunction is not typically observed in the region with the highest density of norepinephrine-releasing sympathetic nerve terminals.83

    Besides the inhibition of Gs protein, a major signaling pathway regulated by β2-adrenoceptors in TTS seems to be the phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) signaling cascade.57 Gene expression profiling with the microarray technique has demonstrated that genes coding for the PI3K/AKT signaling pathway proteins are differentially expressed in TTS. Indeed, Nef et al84 analyzed biopsies from 16 patients and found that increased catecholamine levels in TTS activate the PI3K/AKT signaling pathway in the acute phase of the disease, as shown by an upregulation of PI3K, an increase in AKT phosphorylation, and a downregulation of the PI3K antagonist phosphatase and tensin homolog. AKT is critical for postnatal cardiac growth and coronary angiogenesis. In addition, its downstream targets, especially mechanistic target of rapamycin and glycogen synthase kinase 3, have been shown to play crucial roles in cell survival.85 It is noteworthy that mechanisms of myocardial protection seem to act differently in different patients as a consequence of genetic variability. Over the past decade, several studies analyzing polymorphisms potentially involved in the pathogenesis of TTS have demonstrated differences in the various subtypes of adrenoceptors86 and estrogen receptors.87 Genetic predisposition to TTS might explain why some patients may develop the disease even with no preceding stressor and are at risk of recurrence.88 Last, because myocardial ischemia seems to play a key role in the pathophysiology of TTS (see the next section), it could also be hypothesized that mechanisms triggered by transient ischemia could confer some additional myocardial protection.

    Putting It All Together

    The most recent evidence supports the concept that in the acute phase of TTS there is an increased concentration of catecholamine that might induce direct myocardial injury and coronary spasm, mostly at the microvascular level, together with an increased cardiac workload that contributes to an acute situation of supply-demand mismatch followed by postischemic stunning. The functional counterpart at the LV level would be the typical apical ballooning that persists as a result of the presence of stunned myocardium but is followed by complete functional recovery over relatively short periods of time in most cases (Figure 8).

    Figure 8.

    Figure 8. Key pathogenetic aspects in Takotsubo syndrome.The interplay among triggers, pathogenetic factors, mechanisms of cardiac injury, and clinical consequences. ANS indicates autonomic nervous system; CNS, central nervous system; LV, left ventricular; and MVo2, myocardial oxygen consumption.

    Physiologically, small coronary arteries and arterioles are the principal determinants of coronary vascular resistance. These vessels receive autonomic innervation, and their diameter is modified by activation of these nerves. In healthy subjects, the overall response to sympathetic activation is vasodilatation mainly through activation of coronary β2-adrenoceptors. Conversely, increased cardiac sympathetic activity can induce coronary microvascular constriction in the context of endothelial dysfunction instead of the vasodilatation observed normally because α-adrenergic vasoconstriction becomes unrestrained and powerful enough to reduce coronary blood flow, thus contributing to myocardial ischemia.8991 Both α1- and α2-adrenoceptors mediate coronary vasoconstriction, with α1-adrenoceptors predominant in larger vessels and α2-adrenoceptors more abundant in the microcirculation.92,93 In the context of endothelial dysfunction, both α1- and α2-adrenoceptors and microvascular constriction are augmented and can induce myocardial ischemia.94

    Cardiac sympathetic hyperactivity in the acute phase of TTS is accompanied by metabolic abnormalities appearing as a flow-metabolism mismatch.95,96 Specifically, cardiac positron emission tomography with [18F]2-fluorodeoxyglucose has demonstrated reduced glucose metabolism in the context of normal myocardial perfusion. Similar findings have been observed with free fatty acid analogs. This pattern, known as inverse metabolic perfusion mismatch, represents a transient metabolic abnormality despite preserved myocardial blood flow, which is typically observed in stunned myocardium.9799 Using positron emission tomography in the acute phase, Feola et al98 have demonstrated impairment of tissue metabolism in the dysfunctional myocardium, mainly at the apex and progressively less in the midventricular myocardium, which normalized at the 3-month follow-up. In the same study, hyperemic myocardial blood flow and coronary flow reserve were shown to be reduced in dysfunctional myocardium, and these abnormalities recovered at follow-up.

    There are some apparent discrepancies between the flow data obtained with echocardiography and single-photon emission computed tomography on one hand and positron emission tomography on the other. Two main reasons likely explain these differences. The first is the time in the course of the disease when the studies were performed, and the second is related to differences inherent to these techniques. In fact, positron emission tomography is the only technique that can provide absolute myocardial blood flow in milliliters per minute per gram of tissue. In contrast, echocardiography and single-photon emission computed tomography provide only relative regional differences in tracer concentration that, also for differences within the normal range, will appear as regional defects. For example, if one myocardial region has an absolute resting flow of 0.7 mL/min per gram and another has a flow of 0.9 mL/min per gram (both of these values are within the normal baseline flow range), single-photon emission computed tomography and echocardiography might show a defect in the former relative to the latter, whereas positron emission tomography will show that both flows are within the normal range.

    The possibility exists that ischemic stunning confers protection against subsequent episodes of ischemia and preserves energy metabolism by downregulating contractile function and metabolism, thus facilitating recovery of LV systolic function.100 It is likely that different pathogenetic mechanisms operate in different patients presenting with TTS; thus, further mechanistic research is required to appropriately unveil the different reasons responsible for this intriguing and complex condition.

    Conclusions and Perspectives

    In the past few years, several studies have clarified mechanisms responsible for TTS, showing that a catecholamine surge results in direct and indirect myocardial damage. The frequent spontaneous resolution of LV dysfunction appears to be related to the activation of survival pathways such as those observed in postischemic stunning. The high prevalence in postmenopausal women suggests that estrogen deprivation may play a facilitating role, probably mediated by endothelial dysfunction.

    Despite the substantial increment in our knowledge of TTS, a number of knowledge gaps remain, including (1) causes of the sympathetic surge in patients who have TTS in the absence of psychological or physical stress, neurological disorders, or pheochromocytoma; (2) mechanisms making patients, at a certain point in time of their life, susceptible to develop TTS in the presence of a catecholamine surge; (3) reasons for the different distributions of wall motion abnormalities in different patients; (4) causes of the poor outcome observed in a sizeable proportion of these patients; and (5) causes of the recurrence of TTS occasionally observed during medium-term follow-up.6 These important issues need to be carefully addressed in future studies, together with work to identify targeted therapies.

    Footnotes

    Circulation is available at http://circ.ahajournals.org.

    Correspondence to: Paolo G. Camici, MD, Vita-Salute University, Via Olgettina, 58, 20132 Milan, Italy. E-mail

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