Pathophysiology of Takotsubo Syndrome

Issues of Concern

Diagnosis

The modified Mayo Clinic criteria are used to diagnose takotsubo cardiomyopathy and include the following: [6]

• Absence of coronary artery disease on angiography
• Transient dyskinesis, hypokinesis, or akinesis of the left ventricle midsegments with or without apical involvement
• ECG evidence of ST-segment elevation or T-wave inversion
• Modest elevation of troponin levels
• Absence of myocarditis or pheochromocytoma

Differential Diagnosis 

Takotsubo syndrome must be distinguished from other conditions involving cardiac enzyme elevation and nonobstructive coronary arteries.

• Myocardial infarction with nonobstructive coronary artery disease (MINOCA) can result from several causes, including coronary artery spasm, coronary microvascular dysfunction, and spontaneous coronary artery dissection. Optical coherence tomography and cardiac magnetic resonance imaging (MRI) are 2 imaging modalities that can play an important diagnostic role in determining MINOCA.[7][8][9]

• Type II myocardial infarction

• Myocarditis: This condition can present with chest pain, ECG changes, and elevated cardiac biomarkers similar to takotsubo. Cardiac MRI may help differentiate the 2 conditions, as myocarditis often shows characteristic patterns of inflammation and scarring.

• Hypertrophic cardiomyopathy with apical ballooning: Apical hypertrophic cardiomyopathy can sometimes mimic the ballooning observed in takotsubo syndrome and can be differentiated on imaging by a thickened myocardium at the apex.

Evaluation

• Electrocardiogram: ECG may show widespread ST-elevation, T-wave inversion, QT prolongation, or left bundle branch block. Three stages of ECG changes in takotsubo syndrome are known. In stage 1, ST deviation is observed, though it is not necessarily localized to a territory. These changes occur during the first few hours of symptoms. In stage 2, over the next 1 to 3 days, QTc prolongation and widespread T-wave inversion are observed in precordial, lateral, and lead I and II, corresponding to myocardial edema. These changes may last beyond the recovery of left ventricular function and peak around 2 to 6 days. During 24 to 48 hours, ventricular arrhythmia can occur in association with torsade de pointes. In stage 3, these ECG changes are resolved over weeks and months. There is a relative absence of isolated ST depression in takotsubo syndrome, which is in contrast with ischemic myocardial stunning.[10]

• Cardiac enzymes and biomarkers: Troponin-I is raised but the values are disproportionately lower than the degree of left ventricular dysfunction, reflecting the absence of necrosis. Pro-BNP and NT-Pro-BNP are markedly raised, which reflects the degree of left ventricular dysfunction and myocardial stretch.

• Echocardiography shows temporary left ventricular dysfunction with regional wall motion abnormalities depending on the variant—apical, basal, or focal. Echocardiography is also used to rule out complications, including thrombus or left ventricular outflow tract obstruction (LVOTO).

• Coronary angiogram and left ventriculography: Coronary angiogram shows nonobstructive coronary arteries. Concomitant coronary artery disease may be present in at least 15% of patients. Wall motion abnormalities and arterial lesions should be correlated. Optical coherence tomography or intravascular ultrasound can be used to rule out plaque rupture, which does not suggest takotsubo syndrome.

• Cardiac MRI typically shows the absence of late gadolinium enhancement, which is observed with acute myocardial infarction or myocarditis. Cardiac MRI also shows myocardial edema. Rarely, a transmural band of late gadolinium enhancement can be observed at the hinge points of hyperkinetic and dyskinetic segments.[10]

Causes

Although the exact etiology of takotsubo syndrome is fully understood, the most plausible cause responsible for takotsubo syndrome is the sudden release of stress hormones, such as norepinephrine, epinephrine, and dopamine, leading to cardiac stunning. Stunning the heart triggers changes in cardiac myocytes and coronary perfusion. Although roughly one-fourth of 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 takotsubo syndrome include domestic abuse or relationship conflict; sudden loss of a loved one; natural disasters; an accident or major trauma; a fierce argument; severe financial or gambling losses; a surprise, such as winning a lottery; a serious acute medical condition or medical illness, such as a stroke or terminal illness; exhausting physical effort; surgery; head trauma; public speaking; use of drugs, such as cocaine, excessive stimulants, or inadvertent overdose of catecholamines; or drug withdrawal.

The reason why a specific stressful event triggers this condition is not known, but a similar event may not do so at a different time. Postmenopausal women are most likely affected by takotsubo syndrome, 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.[11]

Clinical Pathology

Clinical Presentation

The clinical presentation of takotsubo syndrome is the same as that of a patient with an acute myocardial infarction or acute coronary syndrome. Common symptoms include chest pain and dyspnea, although patients may also present with nausea, palpitations, syncope, and vomiting. In many cases, patients may report a physical or emotionally stressful event before the onset of symptoms. Unlike acute coronary syndrome, which presents during the early morning hours, takotsubo syndrome tends to manifest in the mid-afternoon. The history also reveals that patients with takotsubo syndrome have a lower incidence of traditional coronary disease risk factors.

Physical Examination

The physical examination is often nonspecific and can include signs of heart failure such as pulmonary rales, S3, or systolic murmur of mitral regurgitation.

Mechanisms

The pathophysiology of stress cardiomyopathy is multifactorial, with several mechanisms implicated, including sympathetic system activation, excessive levels of adrenergic hormones, estrogen deficiency, endothelial dysfunction, and microvascular spasms.[12]

Sympathetic System Activation and Adrenergic Excess

Stress triggers a complex interaction involving the neocortex, brain stem, limbic system, and spinal cord. The locus coeruleus, the major site of noradrenaline synthesis, is stimulated by emotional triggers, leading to increased production of noradrenaline, which in turn stimulates a hypothalamic-pituitary-adrenal axis. The adrenal medulla plays a role in synthesizing, storing, and releasing catecholamines. Afferent signals to the locus coeruleus are received from the amygdala, hypothalamus, and cingulate gyrus. 

In patients with takotsubo syndrome, supraphysiologic levels of plasma catecholamines and neuropeptides, such as norepinephrine, epinephrine, and dopamine, are elevated to 2- to 3-fold higher than normal levels.[13] Gs-mediated positive and Gi-mediated adverse effects of beta-2-adrenoceptor stimulation on myocardial contractility have been reported previously in knockout mice. In takotsubo syndrome, increased catecholamine levels stimulate beta-2 coupling from Gs to Gi, resulting in negative inotropy and subsequent left ventricular contractile dysfunction.[14] This effect is called stimulus trafficking and can plausibly explain the apical forms of takotsubo syndrome, where beta-adrenergic receptors are the highest in numbers; however, they do not elucidate the other forms of takotsubo syndrome. Clinical features of takotsubo syndrome are reproducible by intravenous administration of catecholamines and beta-adrenergic agonists.[15] Accordingly, beta-blockers are useful in the management of takotsubo syndrome. The catecholamine hypothesis is perhaps the most widely accepted pathophysiologic mechanism in takotsubo syndrome. Catecholamine excess can also result in direct myocardial injury.

Brain-Heart Axis

Patients with takotsubo syndrome are more likely to have pre-existing psychiatric diseases, such as anxiety and depression. These patients have upregulated microRNA-16 and microRNA-26a, which leads to apical wall motion abnormalities when exposed to exogenous epinephrine in rodent models. Moreover, at least 20% to 30% of patients with acute neurological injury develop neurocardiogenic stunning. Patients with takotsubo syndrome have altered neuronal activity.[10] 

Microvascular Dysfunction and Coronary Vasoreactivity

Several catheter-based techniques can be used to demonstrate microvascular dysfunction in patients with takotsubo syndrome.[16][17] Quantitative coronary flow assessment with thrombolysis in myocardial infarction (TIMI) frame count (TFC) has shown prolonged corrected TFC in either the left anterior descending alone or all 3 coronary arteries.[12][18][19] The prolonged TFC is likely related to disordered resistance to the flow or microvascular dysfunction observed in patients with takotsubo syndrome.[20] Other parameters include reduced TIMI perfusion grade and quantitative flow ratio. Some noninvasive methodologies include myocardial contrast-enhanced echocardiography, which may show abnormal coronary flow velocity reserve, diastolic dysfunction, and deformation abnormalities (untwist rate and time to peak untwisting). Positron-emission tomography studies show reduced apical uptake of F-18 fluorodeoxyglucose and abnormal global longitudinal strain.[21] However, microvascular dysfunction may not be present in all cases of 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, coronary artery spasm and coronary vasoconstriction were reported in 23% and 54% of the patients, respectively.[22] More recent studies have also demonstrated coronary spasms on provocative testing with acetylcholine.[23][24][23]

Estrogen Deficiency

Estrogen provides direct cardioprotective effects, including vasodilation, vascular protection, and effects against atherosclerosis and endothelial dysfunction.[25] More than 90% of patients with takotsubo syndrome are postmenopausal women, suggesting that estrogen deficiency may correlate with an increased risk of takotsubo syndrome.[26] Studies have shown that a lack of estrogen replacement therapy may predispose women to takotsubo syndrome.[27][28] Furthermore, the cardioprotective effects of estrogen are further elucidated in murine models. In these studies, ovariectomy was associated with a loss of cardiac protection and the development of takotsubo syndrome in response to a stressful trigger. However, this protective effect was restored following long-term estradiol replacement therapy. In addition, estrogen downregulates beta-adrenergic receptors. The lack of direct cardioprotective effects of estrogen may also predispose men to develop takotsubo syndrome and its associated complications. Although takotsubo syndrome is less prevalent in males, they generally have a worse prognosis compared to females.[29] Estrogen deficiency leads to endothelial dysfunction, which is linked to coronary epicardial and microvascular spasm—the 2 mechanisms known to cause takotsubo syndrome. 

Inflammation and Stress Cardiomyopathy

Inflammation is believed to play a critical role in the development of takotsubo syndrome.[30][31][32] Cardiac MRI has shown myocardial edema, necrosis, and fibrosis in patients with takotsubo syndrome. Previously believed to be absent, late gadolinium enhancement is present in up to 10% of patients with takotsubo syndrome.[31] The enhancement patterns for takotsubo syndrome are focal or patchy following a segmental distribution. These patterns are in contrast with late gadolinium enhancement observed in myocarditis (mid-wall or sub-epicardial) or ischemia (subendocardial or transmural), which aids in differentiation. Moreover, the late gadolinium enhancement noted in takotsubo syndrome is present in the acute phase and typically 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.[32] 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 takotsubo syndrome.[33][34][35] This finding is in contrast with practice guidelines (The Mayo Clinic criteria and the European Society of Cardiology - Heart Failure Association), which mandate the absence of myocarditis as one of the diagnostic criteria to fulfill the diagnosis of takotsubo syndrome.[36][37] Histologic specimens of patients with takotsubo syndrome show areas of contraction band necrosis, inflammatory cell recruitment, and focal fibrosis, which possibly develop due to the cardiotoxic effects of catecholamines and their metabolites.

Clinical Significance

Prognosis or Clinical Significance

Stress cardiomyopathy is frequently encountered in clinical practice and constitutes 2% of the acute coronary syndromes. Initially believed to be a benign condition, recent reports have demonstrated that takotsubo syndrome may be associated with severe complications and mortality, such as acute coronary syndrome.[38] The in-hospital mortality rate of takotsubo syndrome is comparable to that of ST-elevation myocardial infarction. Patients with takotsubo syndrome, after the acute event, have an all-cause death rate of 5.6% per patient-year and 9.9% per patient-year rate of major adverse cardiovascular events. One in eight patients has a recurrence of takotsubo syndrome on a 5-year follow-up of the index event. Symptoms of exercise intolerance and dyspnea or chest pain may persist for >2 years despite normalization of left ventricle function.[10] The left ventricular function returns on an average of 21 days. Approximately 95% of patients recover from left ventricular dysfunction over several weeks.[4] The overall long-term prognosis for takotsubo syndrome is excellent, with nearly complete recovery within 6 to 8 weeks. About 1% to 2% of patients experience recurrence. Mortality rates of 3% to 4% have been reported.[24]

Management

Takotsubo syndrome is a diagnosis of exclusion. Evaluation of coronary artery disease is often one of the initial investigation goals. Initial management is aimed at addressing hemodynamic and electrical instability. Patients are initially managed on lines of acute coronary syndrome and heart failure, depending on clinical presentation. Once coronary artery disease is ruled out, standard guideline-directed heart failure therapy is initiated and titrated. Subsequent recovery of ejection fraction confirms the clinical diagnosis of takotsubo syndrome. Cardiac MRI plays a crucial role in defining the etiology and ruling out other mimickers of acute coronary syndrome, such as acute myocarditis. In hemodynamically unstable patients, echocardiography is performed to rule out LVOTO. If LVOTO is present, inotropes cannot be used. Patients should be treated with intravenous fluids and beta-blockers. Vasopressors can be used. In the absence of LVOTO, inotropes, vasopressors, or left ventricular assist devices can be used if indicated.[4]

Complications

Complications occur in at least one-fourth of patients and include the following:

• Recurrence
• Ventricular and atrial arrhythmias
• Cardiac arrest
• Mitral regurgitation
• Cardiogenic shock
• Left ventricular outflow tract obstruction
• Development of left ventricular mural thrombus
• Rupture of the ventricular wall
• Death