The investigation of takotsubo syndrome may occur either because it is the primary suspected diagnosis or, more commonly, after an initial investigation for acute coronary syndrome attributable to the marked overlap in clinical presentation. A multimodal imaging approach is often needed to discriminate between the differential diagnoses of the acute cardiac presentation (Table 1), with cardiac magnetic resonance playing an increasingly important role.
The ECG commonly demonstrates acute dynamic changes at presentation, resembling those of an acute coronary syndrome. The most common abnormalities are ST elevation, T-wave inversion, and left bundle-branch block. ST elevation and T-wave inversion are widespread and may not localize to a particular territory.[35,36] Three evolving electrocardiographic stages of takotsubo syndrome have been described. Stage 1 involves ST deviation occurring within the first few hours of symptoms onset. Stage 2 involves progressive deep T-wave inversion and QTc prolongation, occurring within 1 to 3 days and peaking at 2 to 6 days, although when corrected for sex, the QTc is not different from male patients with acute myocardial infarction. These T-wave inversions are usually widespread over the precordial (V1 through V6), bipolar (I, II), and lateral limb (aVL) leads and correlate with myocardial edema, which can persist beyond ventricular contractile recovery. During these first 24 to 48 hours, torsade de pointes and other ventricular tachycardias can occur. The association of ventricular arrhythmias with prolonged QTc segment in takotsubo syndrome is well established. However, ventricular arrhythmias in the hyperacute phase of takotsubo syndrome are unlikely to be related to QTc prolongation. It is also possible that patients present with ventricular arrhythmia and are only subsequently diagnosed with takotsubo syndrome, making it very difficult to understand which occurred first. Stage 3 involves gradual resolution of T-wave and QTc changes over subsequent weeks or months. The normalization of myocardial contractile function occurring before long-lasting electrocardiographic abnormalities is in stark contrast to the simultaneous recovery of both contractile function and the ECG seen after restoration of blood flow in ischemic myocardial stunning. Together with a relative absence of isolated ST depression on presentation ECG, these concepts would argue against classical myocardial ischemia playing a part in the pathogenesis of takotsubo syndrome.
Other electrocardiographic findings have also been reported. A J wave and fragmented QRS during the hyperacute period have been described and low-voltage QRS complexes, as well. In those presenting with ST-segment elevation, the elevation is more subtle or of lower voltage compared with patients with acute myocardial infarction. Q waves may also occur acutely and disappear rapidly with reappearance of the R wave. In conclusion, subtle differences in electrocardiographic changes exist between takotsubo syndrome and acute coronary syndrome. The presence of ST-segment elevation will affect whether the patient undergoes coronary angiography as an emergency, or the procedure is slightly deferred.
Cardiac and Inflammatory Biomarkers
Plasma cardiac troponin concentrations are typically raised, although peak values are lower than in patients with ST-segment–elevation myocardial infarction and are more comparable to those presenting with non-ST elevation.[39,40] The rise in cardiac troponin is often disproportionately lower than the associated degree of left ventricular contractile impairment would suggest. This likely reflects the absence of myocardial necrosis, which is more akin to myocardial infarction. In contrast, plasma BNP (B-type natriuretic peptide) and NT-proBNP (its N-terminal inactive molecule) concentrations are typically much higher than those seen in patients with myocardial infarction.[41,42] Moreover, NT-proBNP concentrations are particularly high in patients with apical compared with atypical variants, which may reflect the greater degree of acute left ventricular dilatation and myocardial stretch.
Several proinflammatory (interleukin-2, interleukin-4, interleukin-8, interferon and tumor necrosis factor-α) and anti-inflammatory (interleukin-10) cytokines are raised at presentation and can continue to remain elevated for several months thereafter, reflecting the inflammatory pathophysiology of takotsubo syndrome. It is interesting that interleukin-6 concentrations tend to be higher in patients with acute coronary syndrome, potentially reflecting the greater extent of myocardial necrosis.
Coronary Angiography and Left Ventriculography
The diagnosis of takotsubo syndrome is often made once an invasive coronary angiogram has been performed and normal or nonobstructive coronary artery disease documented. Coexisting coronary artery disease is present in ≈15% of patients with takotsubo syndrome,[10,13] and careful correlation between angiography and the wall motion abnormalities is required. Where doubt exists, advanced intravascular imaging techniques, such as optical coherence tomography and intravascular ultrasound, may help to exclude plaque rupture, which is not a characteristic of takotsubo syndrome. Other types of myocardial infarction with nonobstructive coronary artery disease or spontaneous coronary artery dissection also require exclusion in the basis of careful inspection of the coronary angiogram in combination with cardiac magnetic resonance imaging.
Left ventriculography usually confirms the diagnosis because of the characteristic ballooning of the left ventricle. In the majority (50%–80%) of cases, there is a typical pattern of apical and midventricular dyskinesis, akinesis, or hypokinesis with basal sparing (Figure 1). The second most common form affects the midventricle as a circumferential midventricular wall motion abnormality with basal and apical hyperkinesis; this pattern is pathognomonic for takotsubo syndrome (Figure 1). Patients may occasionally present with a reverse takotsubo syndrome where the basal segments are affected with sparing of the mid and apical segments. The incidence of right ventricular involvement can vary (10%–30%) and is associated with more severe disease and complications. Last, other rarer variants have been described, involving isolated right ventricular or focal (segmental) left ventricular takotsubo syndrome.
Echocardiography can be used to help support the diagnosis (extent, severity, and location of the wall motion abnormalities) and to identify potential complications of takotsubo syndrome. Approximately 20% of patients have evidence of left ventricular outflow tract obstruction. This usually occurs in patients with the typical apical to mid cavity ballooning with basal hyperkinesia and can be associated with mitral regurgitation secondary to systolic anterior motion of the mitral valve apparatus. Ultrasound contrast agents can be useful to delineate wall motion abnormalities and assess for left ventricular thrombus formation, which can occur acutely or later in the disease course. More advanced techniques, such as speckle-tracking echocardiography, can also show abnormalities of left ventricular twist and lower mean values of systolic peak velocity, strain, and strain rate. Although left ventricular twist and deformation indices typically improve during the recovery phase, persistently abnormal cardiac deformation indices suggest a phenotype of heart failure with preserved ejection fraction.
Cardiac Magnetic Resonance
Cardiac magnetic resonance with gadolinium contrast administration distinguishes takotsubo syndrome from acute myocardial infarction and myocarditis. Unlike these latter conditions, fibrosis depicted by late gadolinium enhancement is usually not a feature of takotsubo syndrome. A characteristic pattern of takotsubo syndrome rarely appears as a thin transmural band of fibrosis at the hinge points between the hyperkinetic base and dyskinetic apex or midcavity. This can be seen both acutely (at the time of presentation) and 4 to 5 months later at follow-up (Figure 2). This possibly results from the opposing strong shear forces applied to the left ventricular wall. Cardiac magnetic resonance also provides a reliable assessment of right ventricular involvement, identification of left and right ventricular thrombi, and often shows the presence of a small pericardial effusion (and pleural effusions, as well), in particular, if the test is performed early after presentation.
Cardiac magnetic resonance imaging and computed tomography findings in takotsubo syndrome.
Short-axis T2 maps (A), T2 polar map (B), and short-axis T1 maps (D), demonstrating elevated T2 and T1 values circumferentially in the mid and apical regions (outside a coronary territory). C, Long-axis 2-chamber view demonstrating transmural fibrotic band pattern typical of takotsubo syndrome 4 months after the index event. Long-axis 4-chamber and short-axis views of midventricle demonstrating elevated left ventricular mass in acute phase (E and F) and normalization during convalescence (G and H). Hybrid positive emission tomography with cardiac computed tomography angiography depicting a small left ventricular thrombus in a patient with takotsubo syndrome with no clinically apparent thrombus on conventional imaging. There is subtle hypoattenuation on the computed tomography angiogram (insets) and increased uptake of an activated platelet and thrombus-specific radiotracer (18F-GP-1; yellow-red) in long-axis 4-chamber (I and J) and short-axis (K and L) views on positron emission tomography.
Intense myocardial edema is an important feature of takotsubo syndrome (Figure 2). Edema is not only confined to regions of abnormal contractility but is present to a lesser extent within the entirety of the ventricular myocardium. Myocardial edema resolves gradually over weeks or months after the index event, typically taking much longer to recover than myocardial contractility. Reflecting this, left ventricular mass is markedly elevated and native T1 and T2 mapping values are increased during the acute phase, gradually resolving over 5 to 6 months during convalescence (Figure 2). Both myocardial edema and acute inflammation are detectable at presentation, but it remains unclear whether they are a consequence of takotsubo syndrome or if they represent a primary, causal inflammatory stimulus.
Circulation. 2022;145(13):1002-1019. © 2022 American Heart Association, Inc.