Transient left ventricular (LV) apical ballooning syndrome, Takotsubo cardiomyopathy, Takotsubo syndrome (TTS), broken heart syndrome, ampulla cardiomyopathy or stress-induced cardiomyopathy are interchangeable terms and have all been applied to define a syndrome characterized by transient left ventricular systolic and diastolic dysfunction, electrocardiographic features and myocardial enzyme elevation similar to the acute myocardial infarction but in the absence of obstructive epicardial coronary artery disease. First described in Japan in the 1990s, the syndrome has gained worldwide attention within the scientific community in the past few decades. The disease manifests predominantly in postmenopausal females in the presence of stressful triggers such as severe physical or emotional stress, natural disasters such as earthquakes, unexpected death of relatives, acute medical illnesses, etc. Initially thought to be a benign condition recent reports have demonstrated that TTS may be associated with severe complications and mortality similar to acute coronary syndrome. Concerted efforts have been made to define various pathophysiologic aspects of TTS; however, the precise etiologic understanding remains unclear. Some of the mechanisms proposed for the development of Takotsubo syndrome include elevated levels of circulating plasma catecholamines and its metabolites, microvascular dysfunction, inflammation, estrogen deficiency, spasm of the epicardial coronary vessels, and aborted myocardial infarction. Herein, we define each mechanism in further detail.
Takotsubo syndrome must be distinguished from other entities that involve cardiac enzyme elevation with non-obstructive coronary arteries. Symptomatic non-obstructive coronary artery disease (NOCAD) occurs with less than 50% coronary luminal stenosis.  Further functional and physiologic assessment of coronary endothelial function and the coronary microvascular system should be considered in these patients. Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease (MINOCA) occurs in as many as 5% of patients presenting with myocardial infarction who undergo coronary angiography.  Optical coherence tomography (OCT) and cardiac magnetic resonance imaging (MRI) are two imaging modalities which can play an important diagnostic role in the determination of MINOCA.   Both MINOCA and NOCAD should be considered once TTS and other entities have been excluded. Other entities to include in the differential diagnosis includes spontaneous coronary artery dissection, a non-traumatic, non-iatrogenic entity which occurs predominantly in young postpartum females .
Although the precise etiology of the syndrome is not known, the most plausible cause responsible for Takotsubo syndrome is the sudden release of stress hormones, such as norepinephrine, epinephrine, and dopamine, causing cardiac stunning. Stunning the heart triggers changes in the cardiac myocytes and coronary perfusion.
Although roughly about one-fourth patients have no clear triggers, Takotsubo syndrome is typically triggered by an unexpected emotionally or physically stressful event.
Events that have been reported to trigger TC include:
Researchers have no answer for the reasons why a specific stressful event will trigger this condition, but at a similar event may not do so at a different time. Post-menopausal women are most likely affected by TTS suggesting a possible role of estrogen deficiency. Patients with certain psychiatric conditions or mood disorders are also more likely to have Takotsubo syndrome. Recently reports have also described patients developing Takotsubo syndrome after a positive emotional experience the so-called term, Happy heart syndrome .
Supraphysiologic levels (two to threefold elevation) of plasma catecholamines and neuropeptides (norepinephrine, epinephrine, and dopamine) have been observed in patients with Takotsubo syndrome. Gs-mediated positive and Gi-mediated negative effects of beta-2-adrenoceptor stimulation on myocardial contractility has been reported previously in knockout mice. In Takotsubo syndrome, increased catecholamine levels stimulate beta-2 coupling from Gs to Gi leading to negative inotropy and resultant left ventricular contractile dysfunction. This effect has been called ‘Stimulus trafficking’ and can plausibly explain the apical forms of Takotsubo syndrome where beta-adrenergic receptors are the highest in numbers, however, does not elucidate the other forms of Takotsubo syndrome. Clinical features of Takotsubo syndrome are reproducible by intravenous administration of catecholamines and beta-adrenergic agonists. Accordingly, beta-blockers are useful in the management of Takotsubo syndrome. Catecholamine hypothesis is perhaps the most widely accepted pathophysiologic mechanism in Takotsubo syndrome.
Estrogen provides direct cardioprotective effects including vasodilation, vascular protection, and effects against atherosclerosis and endothelial dysfunction. More than 90% of the TTS patients are postmenopausal women suggesting that estrogen deficiency may correlate with increased risk of Takotsubo syndrome. Studies have shown that lack of estrogen replacement therapy may predispose women to TTS. Furthermore, the cardioprotective effects of estrogen are further elucidated in murine models in which ovariectomy correlated with loss of cardiac protection and development of Takotsubo syndrome in response to a stressful trigger; the protective effect returned after long-term estradiol replacement therapy. Also, there are suggestions that estrogen down-regulates beta-adrenergic receptors. The lack of direct cardioprotective effects of estrogen may also predispose men to develop Takotsubo syndrome and its associated complications; additionally, although Takotsubo syndrome is less prevalent in males they generally have a worse prognosis than females .
Inflammation is thought to play a critical role in the development of Takotsubo syndrome. Cardiac magnetic resonance (CMR) imaging has demonstrated myocardial edema, necrosis, and fibrosis in patients with Takotsubo syndrome. Previously thought to be absent, late gadolinium enhancement (LGE) is shown to be present in up to 10% of patients with TTS. The enhancement patterns for TTS are focal or patchy following a segmental distribution; this is in contrast to LGE observed in myocarditis (mid-wall or sub-epicardial) or ischemia (subendocardial or transmural) and can help differentiate. Moreover, the LGE noted in TTS is present in the acute phase and usually resolves on follow-up imaging. There have also been reports of macrophage recruitment, change in the balance of monocyte subtypes and increased circulating pro-inflammatory cytokines with some of these changes persisting beyond 5 months. Coexisting cases of myocarditis, pericarditis, or autoimmune conditions such as systemic lupus erythematosus or Sjogren’s syndrome have also been reported suggesting that chronic inflammatory conditions with acute flares may provide a substrate for the emergence of TTS. This is in contrast to practice guidelines (The Mayo clinic criteria and the European Society of Cardiology - Heart Failure Association) which mandate absence of myocarditis as one of the diagnostic criteria to fulfill the diagnosis of TTS. Histologic specimens of patients with Takotsubo syndrome show areas of contraction band necrosis, inflammatory cell recruitment, and focal fibrosis which possibly develop as a result of cardiotoxic effects of catecholamines and its metabolites.
Microvascular dysfunction has been shown in Takotsubo syndrome patients with several catheter-based and imaging modalities. Catheter-based techniques applied in the catheterization laboratory include placement of a coronary pressure-wire and measuring coronary flow reserve velocity. Quantitative coronary flow assessment with thrombolysis in myocardial infarction (TIMI) frame count (TFC) have shown prolonged corrected TFC in either the left anterior descending (LAD) alone or all three coronary arteries. The prolonged TFC is likely related to disordered resistance to the flow or microvascular dysfunction observed in patients with Takotsubo syndrome. Other parameters include reduced TIMI perfusion grade and quantitative flow ratio (QFR). Some of the non-invasive methodologies include myocardial contrast-enhanced echocardiography also demonstrating abnormal coronary flow velocity reserve, diastolic dysfunction and deformation abnormalities (untwist rate and time to peak untwisting), positron-emission tomography studies showing reduced apical uptake of F-18 fluorodeoxyglucose, and abnormal global longitudinal strain. However microvascular dysfunction may not be present in all cases of Takotsubo syndrome. An interesting phenomenon observed in patients with TTS is the low prevalence of diabetes mellitus. The risk factor profile of Takotsubo syndrome patients is similar to the patients with coronary artery disease; however, diabetes mellitus is much less prevalent in Takotsubo syndrome compared with age-matched controls. Some researchers have speculated that autonomic dysfunction in diabetes mellitus may blunt the catecholamine secretion in patients with Takotsubo syndrome which may play a protective role against the development of this disease.
There is a hypothesis that Takotsubo syndrome is a form of an aborted myocardial infarction in which there is indeed the formation of acute thrombus with quick and complete lysis of thrombus with spontaneous resolution of the infarct. Detailed intravascular imaging with intravascular ultrasound (IVUS) and OCT has shown eccentric atherosclerotic plaques in the mid LAD of patients with TTS that were thought to be normal on coronary angiography.  Presence of such plaques along with thin cap fibroatheromas without evidence of rupture was also present on OCT analysis of patients with Takotsubo syndrome. Coronary artery vasospasm has also been postulated as a credible causative factor for Takotsubo syndrome. In the original studies by Sato and colleagues, the rates of coronary artery spasm and coronary vasoconstriction were reported in 23% and 54% of the patients respectively. More recent studies have also demonstrated coronary spasm on provocative testing with acetylcholine.
Various pathophysiologic mechanisms have been proposed for Takotsubo syndrome. While considerable progress has been made, several knowledge gaps still do exist. Improved understanding of Takotsubo syndrome will help optimize patient outcomes in the future.
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