“Broken Heart Syndrome”: Catecholamine Surge or Aborted
Myocardial Infarction?

Takotsubo cardiomyopathy, also called transient left ventricular apical ballooning or “broken heart syndrome,” is a cardiac condition that mimics the clinical presentation of acute coronary syndrome but without any evidence of obstructive atherosclerotic coronary artery disease. Originally described in Japan, this syndrome is characterized by an akinetic left ventricular apex that takes an elliptical shape and resembles the source of its namesake, a Takotsubo. An episode of intense emotional or physiologic stress, serving as the nidus for a catecholamine surge, has been reported prior to presentation and is presumed to be the triggering factor playing the pathogenic role. Although Takotsubo cardiomyopathy is increasingly described in recent medical literature, we report a unique case without any known precipitating factors, which may provide more insights into the pathogenesis and nature of this poorly understood syndrome.

Case Presentation. A 63-year-old Caucasian female with a history of hypothyroidism presented to the emergency room with a 1-hour history of acute substernal chest pressure which began shortly after taking a hot shower. This pressure was 7 out of 10 in intensity, nonradiating, nonpleuritic and nonpositional. She denied any diaphoresis, palpitations or dizziness. The patient had no prior history of angina or coronary artery disease. She denied any history of smoking, alcohol or cocaine use. She also denied a history of diabetes, hypertension and dyslipidemia, and her family history was negative for premature coronary artery disease. The patient reported following a regular exercise regimen and denied any recent emotional stress. Levothyroxin was the patient’s only medication and she had never been on any estrogen therapy.
On presentation, the patient was in no acute respiratory distress, afebrile and mildly hypertensive (156/72 mmHg), with a heart rate of 92/minute and a respiratory rate of 16/minute with an oxygen saturation of 98% on room air. Carotid upstrokes were normal, and no jugular venous distension was noted. Cardiac examination revealed a nondisplaced point of maximal impact and normal heart sounds without murmurs. Her lungs were clear to auscultation. She had no clubbing, cyanosis or edema. The rest of the physical examination was completely benign.
The patient’s complete blood count, basic metabolic panel and liver function tests were all within the normal range. The initial and subsequent myocardial damage panel levels showed the following: troponin I of 6.73 ng/ml, 8.45 ng/ml and 4.03ng/ml (normal range < 0.04 ng/ml), and creatine kinase-MB fraction of 70.0 ng/ml, 65.1 ng/ml and 22.0 ng/ml (normal range < 5.9 ng/ml), respectively. Electrocardiography (ECG) showed a 2 to 3 mm STsegment elevation in the inferolateral leads (Figure 1).

The patient received aspirin, clopidogrel and heparin in the emergency room and underwent an emergent cardiac catheterization for acute ST-elevation myocardial infarction (STEMI). Surprisingly, coronary arteriography revealed only a 20% ostial circumflex coronary artery stenosis, a codominant right coronary artery with moderate diffuse disease at the very distal part of the posterior descending artery and a type 2 left anterior descending artery with no acute obstructions. No epicardial coronary spasm was identified. Left ventriculography showed severe hypokinesis of the apex with an estimated left ventricular ejection fraction (LVEF) of 25%. Follow-up ECGs showed complete resolution of the ST-segment elevation and subsequent development of diffuse T-wave inversion (Figure 2). The left ventricular dysfunction was clearly out of proportion to the identified coronary artery disease (Figure 3).

Transthoracic echocardiography showed similar wall motion to that observed by ventriculography with no valvulopathy, ventricular aneurysm or pericardial effusion. A diagnosis of Takotsubo cardiomyopathy was considered at this point. The patient was transferred to the cardiac unit for continuous cardiac monitoring. She was treated with supportive measures: aspirin, clopidogrel, metoprolol, heparin and angiotensin-converting enzyme inhibitors. After an uneventful 3-day hospital course, the patient underwent a repeat echocardiogram that showed a 20% increase in the LVEF to 45%. She was discharged home, and 6 weeks later a repeat transthoracic echocardiogram revealed complete recovery of the left ventricular dysfunction.

Discussion. Originally described in Japan,¹ Takotsubo cardiomyopathy is becoming increasingly recognized around the world. “Tako-tsubo” is the Japanese name for a fishing pot used in trapping octopus. The word-for-word translation is “octopus-trap” (the octopus is “tako” and the pot is “tsubo”).

Takotsubo cardiomyopathy has been observed most commonly in women over 60 years of age, closely associated with an intense emotional occurrence, physiological stress or an acute medical illness. A pneumothorax, natural disasters, an unexpected death of a close relative and devastating financial losses are some of the stressors reported with high frequency.^2,3 A possible association with cocaine use and opioid withdrawal has also been described.^4,5 Our patient, a postmenopausal Caucasian female, did not have any of the above described precipitating events.
This unique type of heart failure has distinct clinical features which include the following: (i) most common in women aged > 60 years; (ii) symptoms at onset similar to those of an acute STEMI; (iii) ventricular dysfunction shaped like a Takotsubo; (iv) no critical coronaryartery lesions; and (v) dysfunction which improves rapidly within a few weeks.^2,3,6
Universally accepted criteria for diagnosis are not yet established. Bybee et al⁹ suggested, in their systematic review, the four following inclusive criteria to establish the diagnosis of the transient left ventricular apical ballooning: (i) transient akinesis or dyskinesis of the left ventricular apical and mid-ventricular segment s; (ii ) absence of obstructive coronary dise ase or acute plaque rupture; (iii) new ST-segment elevation or T-wave inve rsion; and (v) absence of recent significant head trauma, intracranial bleeding, pheochromocytoma , myocardit is and hypert rophic car - diomyopathy.

The classical presentation involves acute susbsternal chest pain,although some patients may present with dyspnea, tachydysrhythmias, bradydysrythmias or hypotension. ST-segment elevations are the most commonly reported electrocardiographic abnormalities. Additional ECG changes have also been described, including ST-segment depression, T-wave inversion, Q-T interval prolongation and abnormal Q-waves.^2,3
Traditionally, cardiac biomarker levels are mildly elevated, typically less than those observed in acute STEMI. Ventriculography or echocardiography show the characteristic apical ballooning with akinesis of the apical one-half to two-thirds of the left ventricle with an overall decrease of the LVEF and basal hyperkinesias.^1,2,7 The coronary arteriogram reveals no critical coronary artery disease: the left ventricle dysfunction is classically described as out of proportion to the coronary artery disease and not consistent with any particular coronary artery territory.
The optimal treatment of the transient left ventricular apical ballooning, beyond standard supportive care for congestive heart failure and arrhythmias, remains largely empirical due to the limited availability of controlled data. Follow-up echocardiographic evaluation is routinely performed to ensure the resolution of the left ventricular dysfunction. Our patient recovered rapidly: the follow-up echocardiograms at day 3 of hospitalization showed a nearly 20% increase in the LVEF and complete recovery at 6 weeks.

Although the prognosis for most patients with this syndrome is favorable, with complete recovery of ventricular function within 1 to 4 weeks, several cases of fatal outcome have been reported.^2,6,7 The recurrence of this syndrome seems to be rare.⁸
The exact cause of the transient left ventricular apical ballooning is unknown. Many authors have reported, speculatively, that an exaggerated sympathetic stimulation or catecholamine excess may be central to the cause of this syndrome. Multiple hypotheses have been suggested, including epicardial coronary arterial spasm, catecholamineinduced microvascular spasm and catecholamine-mediated myocardial stunning.
The evidence supporting any of these pathomechanisms is not yet persuasive. Wittstein and colleagues³ described supraphysiological levels of plasma catecholamine and stress-related neuropeptides in patients with Takotsubo cardiomyopathy. In their report, the LVEF improved from 20% to 45% by day 4, but, unpredictably, epinephrine levels were still 20-fold higher than normal values. A causal relationship cannot be confirmed and the elevated catecholamine levels may have been a secondary phenomenon. One possibility is ischemia resulting from epicardial coronary arterial spasm. Increased sympathetic tone from mental stress can cause vasoconstriction in patients without coronary disease.^10,11 But angiographic studies that have evaluated coronary artery spasm in patients with Takotsubo, in response to intravascular provocative maneuvers, reported inconsistent data.^3,6 Our patient had minimal enzymatic evidence of myocardial necrosis and no angiographic evidence of epicardial coronary spasm. Furthermore, multiple vasospasms seem unlikely to be responsible for afflicting only the apical portion of the left ventricle.
Another proposed mechanism is a catecholamine-induced microvascular spasm. Abnormal coronary flow in the absence of obstructive disease has been described in patients with stressrelated myocardial dysfunction.^10,12 The intracoronary injection of neuropeptide Y has been shown to cause profound distal vessel constriction resulting in extremely slow-flow blood supply followed by massive myocardial ischemia.^13,14 However, the studies that evaluated coronary microcirculation in Takotsubo patients reported conflicting results.^12,15
A third possible mechanism of catecholamine-mediated myocardial stunning that has been described involves direct myocyte injury. Catecholamines are a potential source of free-radical formation and can decrease the viability of myocytes, potentially leading to contraction-band necrosis as observed on histologic examination.^12–14,16 Even though this unique form of myocyte injury has been described in multiple other clinical conditions,^16–19 it has been noted on an inconsistent basis in biopsy specimens of patients with Takotsubo syndrome.^3,15,20 An isolated report on 2 sisters suffering from transient left ventricular apical ballooning suggested a possible genetic predisposition to this disease.²¹
Curiously, men have higher levels of basal sympathetic activity and produce higher levels of plasma catecholamines; however, one of the more noteworthy epidemiological features of Takotsubo is that it is most common in postmenopausal women. The explanation for the strong female predominance remains unclear, although estrogen may play a role.^7,8
The cause of the morphological features that inspired the term Takotsubo also remains controversial. An often-cited report by Mori et al²² suggested that apical myocardium has enhanced responsiveness to sympathetic stimulation, potentially making the apex more vulnerable to a catecholamine surge. Other authors have suggested that a longitudinal, baseto- apex decline in left ventricular myocardial perfusion, as described in patients with coronary risk factors, may be an alternative cause.²³
Interestingly, there is an increasing frequency of published cases with a clinical presentation similar to that of Takotsubo cardiomyopathy, but with an inverse left ventricular contractile pattern called “inverted Takotsubo”.^24,25 This supports the rejection of a “catecholamine surge” as the primary event leading to Takotsubo cardiomyopathy.
Our patient presented with features typical of Takotsubo cardiomyopathy, but without a precipitating event, or any major emotional or physical stress prior to presentation. Our patient’s blood pressure and heart rate were near normal; this may suggest that a catecholamine surge, which is thought to be the main contributing or associated factor in many of the other reports of this condition, seems less likely for this particular patient.
Our patient’s cardiac catheterization showed atherosclerotic lesions that were not critical, however, an acute plaque rupture could not be established or ruled out based on thismodality alone. The enzymatic evidence of myocardial damage and the resolution of chest pain prior to cardiac catheterization points toward a transient coronary occlusion with spontaneous reperfusion. This phenomenon is called an aborted myocardial infarction (MI).²⁶ Although our patient did receive anticoagulants and antithrombotics upon admission, the endogenous fibrinolysis may have played a major role. Ibanez et al²⁷ have suggested that Takotsubo syndrome may be the result of a spontaneously aborted MI resulting from an acute atherothrombotic event with rapid and complete lysis of the thrombus. They performed intravascular ultrasound (IVUS) examination in 5 consecutive patients with Takotsubo syndrome, documenting a disrupted eccentric atherosclerotic plaque in the middle portion of the left anterior descending artery that was not visible on coronary angiography. However, in those cases, the myocardial enzyme levels were generally higher than those classically described with this syndrome.
Conclusion. The incidence of “broken heart syndrome” is uncertain, but it has been increasingly reported in the literature and recognized in clinical practice. Several authors support a catecholamine surge as the cause of this syndrome. After reviewing multiple case reports and review articles, the evidence supporting a “catecholamine surge” is empirically plausible; however, our case calls this theory into question. The “aborted MI” hypothesis is more convincing as an allinclusive nidus for the pathogenesis and clinical presentation described in Takotsubo syndrome. This does not exclude a catecholamine surge as part of the syndrome: it may in fact be a contributing factor. More detailed studies and research is needed to ascertain the pathogenesis and optimal management of this syndrome.