Tako-Tsubo cardiomyopathy (TTC), also known as transient left ventricular apical ballooning syndrome,1 is a reversible, stress-induced cardiomyopathy that predominantly affects post-menopausal, elderly women during emotional or physical stress.1,2 Although it is an increasingly recognized and reported syndrome, the syndrome remains uncommon, occurring in <1% of patients referred for coronary angiogram. Because the electrocardiogram (ECG) classically depicts ST-segment elevations and cardiac biomarkers can often be raised, it can be a challenge to differentiate TTC from an acute myocardial infarction (AMI). Therefore, TTC generally remains a diagnosis per exclusionem, i.e. a diagnosis of exclusion, where an acute coronary syndrome usually needs to be ruled out. Ogura et al.,3 however, proposed specific ECG criteria to aid in the diagnosis of TTC (see Table 1). They suggested that the absence of reciprocal changes, absence of abnormal Q-waves, and a ratio of ST-segment elevation in leads V(4–6)/V(1–3) ≥1 all showed a high sensitivity and specificity for diagnosing TTC versus anterior AMI. In addition, they demonstrated that the combination of the absence of reciprocal changes and the ratio of ST-segment elevation in leads V(4–6)/V(1–3) ≥1 on a standard 12-lead ECG had a greater specificity (100%) and overall accuracy (91%) than either criterion (see Table 1). We present a case series where, although such ECG criteria had been specifically employed, TTC remained a diagnosis of exclusion, necessitating coronary artery catheterization to rule out myocardial infarction.
Case 1. A 76-year-old female without known coronary artery disease presented following a fall with severe, atypical chest pain that had resolved on arrival to the emergency room. Initial ECG and serum biochemistry were unremarkable. She was initially treated for musculoskeletal pain, but when repeated cardiac biomarkers were elevated, cardiac telemonitoring was continued. Her ECG during a similar recurrence of chest symptoms demonstrated ST-segment elevations in leads V1, V2, and V3 and flattening of the T-wave in lead aVL (see Figure 1). The ratio of ST-segment elevations in leads V(4–6)/V(1–3), therefore, was not ≥1.3 Cardiac catheterization did not reveal significant coronary artery stenoses (see Figure 2).
However, her left ventriculogram showed left ventricular apical akinesis (ballooning) and basal hyperkinesis (see Figure 2). Subsequent ECGs, following supportive treatment, showed inversion of T-waves that continued to deepen for several days without recurrence of symptoms. However, ST-segment elevations persisted well into day 10, contradictory to that proposed by Kurisu et al.4 2D transthoracic echocardiogram (TTE) 10 days after her initial presentation showed normalization of the left ventricular wall motion abnormality.
Case 2. A 79-year-old female with small bowel obstruction was referred for cardiological evaluation when her ECG had revealed precordial ST-segment elevations (see Table 2) with elevated cardiac biomarkers. Once again, the ratio of ST-segment elevation in leads V(4–6)/V(1–3) was <1,3 necessitating coronary angiographic referral to exclude an AMI. Cardiac catheterization was unremarkable except for apical akinesis on the left ventriculogram. Again, contradictory to that proposed by Kurisu et al.,4 ST-segment elevations persisted well into day 10. Interestingly, urinary metanephrine and vanillylmandelic acid excretion levels were not elevated.
Case 3. A 48-year-old female presented with atypical, constant, substernal chest pain following trauma to her back during a row with a co-worker. Her ECG did not reveal impressive ST-segment elevations precordially but showed that repeat cardiac biomarkers were persistently elevated. She was treated for a myo-pericarditis initially, but when subsequent ECGs showed T-wave inversions, a TTE was performed. Her study revealed akinesis of the apex with preserved left ventricular function. Although TTC was suspected, ECG as per the criteria proposed by Ogura et al.3 remained non-diagnostic (see Table 1). Subsequent coronary angiogram confirmed normal coronary arteries, but left ventriculogram confirmed the echocardiogram findings consistent with a diagnosis of TTC. Urinary metanephrine and vanillylmandelic acid excretion levels were borderline elevated.
Case 4. A 70-year-old female presented to the emergency room following a fall. She described chest tightness and difficulty breathing. Her ECG revealed gross tombstoning of the ST segments, with maximal ST-segment elevations in leads V3 and V4. Although she met the criteria proposed by Ogura et al.,3 where the ratio of ST-segment elevation in leads V(4–6)/V(1–3) was ≥1,3 coronary angiogram was performed in view of the concerning ECG changes. Again, angiogram did not reveal occlusive coronary artery disease and the left ventriculogram was classically descriptive of that seen with TTC. However, on the ECG, the first inversion of T-waves occurred almost one week later. This contradicted the evolutionary criteria proposed by Mitsuma et al.5
Case 5. A 62-year old female smoker with a history of hypertension, diabetes, and family history of coronary artery disease presented with crushing chest pain after jogging. She readily admitted to severe mental stress at her work and home environment. The ECG showed upsloping ST-segment elevations in predominantly lateral precordial leads, and cardiac biomarkers were elevated. TTE demonstrated apical ballooning with basal left ventricular hyperkinesis. Again, although the ratio of ST-segment elevation in leads V(4–6)/V(1–3) was ≥1,3 because of her family history, risk factors, and TTE findings, cardiac catheterization was performed. Her angiogram showed only luminal irregularities and the left ventriculogram suggested TTC. Repeat TTE four weeks later showed no abnormalities.
Case 6. A 76-year old female with a previous episode of witnessed syncope was brought to the emergency room after being found unresponsive on her apartment floor. Her ECG showed ST-segment elevations in V3, V4, V5, and V6 and flattening of the T wave in aVL. Creatinine kinase and troponins were grossly elevated (>100-fold), while other serum laboratory values were within the normal range. Computed tomography of her brain revealed mild atrophy and no intracranial abnormalities. Again, although the criteria proposed by Ogura et al.3 (see Table 1) were met, grossly elevated cardiac biomarkers prompted cardiac catheterization. Her angiogram showed mild atherosclerotic changes in the left circumflex and right coronary artery without focal occlusion. Her left ventriculogram was suggestive of TTC. Serial TTEs during her admission showed gradual recovery of her apical hypokinesis. However, phase 4, as described by Mitsuma et al.5 (see Table 1), was never achieved, and “deepening of the T-waves with increase of QT interval by about two-fold,” as described by Kurisu et al.,4 was not observed.
Discussion and Conclusion
TTC is an increasingly recognized entity but its prevalence of 0.7% suggests that the disorder remains quite underestimated.6 The pathogenesis of this disorder remains unclear, although excess catecholamine and pre-existing (left) ventricular dysfunction precipitated by acute emotional or physical stress have been proposed. A recent study showed evidence that the primary cause of TTC could in fact be anomalies in cardiac sympathetic conduction and innervation.7 Ventricular arrhythmias can also occur in almost 9% of patients with TTC.
QT-interval prolongation has been purposed as a culprit, but the exact mechanism for these arrhythmias is not completely understood. In addition, it has been found that there may be an association of TTC with long-QT syndrome.8 Complications associated with the apical akinesis in TTC such as left ventricular clot, myocardial rupture, shock, and arrhythmias are also associated with AMI. Indeed, clinicians should be aware of not only the wide spectrum of manifestations of TTC but also its potential sequelae. However, for the most part, TTC runs a benign course and treatment regimens remain supportive.
Several recent studies have proposed guidelines to assist in the diagnosis of TTC, i.e. The Guidelines for Diagnosis of Tako-Tsubo Cardiomyopathy9 and The Proposed Mayo Clinic Criteria for the Clinical Diagnosis of the Transient Left Ventricular Apical Ballooning Syndrome.10,11 Collectively, these comprise:
- transient akinesis or dyskinesis of the left ventricular apical segment;
- absence of significant coronary artery disease;
- ECG demonstrating ST-segment elevation (typically after onset) and/or T-wave inversion, and/or minimal myocardial enzymatic release; and
- absence of recent significant head trauma, intracranial bleeding, cerebrovascular diseases, pheochromocytoma, myocarditis, or hypertrophic cardiomyopathy.
Mitsuma et al.5 suggested a time-course to describe the evolutionary ECG changes in TTC. They classified the changes into four phases:
- phase 1 (after onset): initial ST-segment elevation;
- phase 2 (days one to three): first T-wave inversion after ST-segment elevation;
- phase 3 (days two to six): transient improvement in T-wave inversion in the subacute period; and
- phase 4: giant inverted T-waves with QT prolongation persisting until recovery.
However, Kurisu et al.4 had observed that:
- ST-segment elevations returned to normal within three days;
- T-wave inversion deepened and the QT interval was prolonged;
- the ECG changes were usually sustained, even after resolution of the TTC-like left ventricular dysfunction;
- TC and AMI shared similar ECG evolutionary time-courses; and
- the T-wave inversion was deeper and corrected QT-interval was longer with TTC compared with that of AMI at three days or later during the early phase.
The admission ECG of our first patient (see Figure 1) showed ST-segment elevations in leads II, III, aVF, V2, and V3, and T-wave inversions in leads I and aVL, which may fit the phase 1 descriptions of Mitsuma et al.5 However, the described transient improvement in T-wave inversions in the subacute period did not occur during days two to six. Therefore, the ECG changes of this patient did not, perhaps, ‘classically’ evolve through phases 1–4 as observed by those authors.4,5 Instead, T-waves progressively became deepened with QT-interval prolongation well into the recovery.
While this patient’s ECG evolution may have instead fitted with some of the observations made by Kurisu et al.4 (see Table 1), the ECGs of the second and third patients did not (see Table 2). We also could not employ the ECG criteria proposed by Ogura et al.,3 where the proposed ratio of the elevated ST segments in leads V(4–6)/V(1–3) ≥1 neither matched the ECG description for the diagnosis of TTC nor helped in differentiating it from anterior AMI in all three cases. Neither the degree of elevation of cardiac biomarkers nor that of urinary metanephrine and vanillylmandelic acid excretion levels, which can be elevated in TTC cases, were helpful.12 In case 4, the criteria of Ogura et al. were met, yet the tombstoned appearance of the ST segments were reason enough for further investigation. In case 5, again coronary angiogram was necessary because the clinical history and cardiac risk factors were concerning enough to suggest an acute coronary syndrome with underlying coronary artery disease. In case 6, instead of the history itself, the cardiac biomarkers were significantly high, perhaps tipping the scale in favor of an acute coronary syndrome.
Although several previously proposed ECG criteria (see Table 1) were employed, the diagnosis in each of our patients remained uncertain. Indeed, more specific ECG criteria are needed. However, even if a conclusive ECG criterion is developed, it may still be difficult to differentiate TTC from AMI, where cardiac biomarkers in both conditions can be elevated, as noted in case 6. According to the New Universal Classification of Myocardial Infarction,13 AMI is diagnosed by a rise and/or fall of cardiac biomarkers (preferably troponin) with either symptoms of myocardial ischaemia or ECG changes (new ST–T changes or new left bundle branch block or Q-waves) or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. Thus, our TTC cases could actually have been misclassified as AMIs.
Inoue et al.14 demonstrated that ECG findings cannot differentiate TTC from symptoms caused by a distal lesion of left anterior descending coronary artery. Moreover, ECG changes are often not specific and vary between TTC patients. Therefore, it would certainly be quite difficult to justify not employing good clinical judgment and the diagnosis of exclusion. Large clinical studies are required to elucidate specific ECG criteria that may assist in the diagnosis of TTC. Until then, TTC will probably remain a diagnosis per exclusionem where coronary artery catheterization may indeed be necessary to conclusively rule out AMI.
Acknowledgments/Conflict of Interest Statement
None of the authors received any funding for this investigation. Any affiliations or financial involvement within the past five years and foreseeable future with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript are completely disclosed. All authors have also disclosed otherwise any potential personal conflict of interest.