Takotsubo (Stress) Cardiomyopathy (Broken Heart Syndrome)

Takotsubo cardiomyopathy, also known as stress cardiomyopathy and "broken heart syndrome," is a sudden, transient cardiac syndrome that involves dramatic left ventricular apical akinesis and mimics acute coronary syndrome (ACS). It was first described in Japan in 1990 by Sato et al.

Patients often present with chest pain, have ST-segment elevation on electrocardiography (ECG), and have elevated cardiac enzyme levels consistent with myocardial infarction (MI). ^[1]  (See the images below.) ^{[2, 3]}  However, when the patient undergoes cardiac angiography, left ventricular (LV) apical ballooning is present, and there is no significant coronary artery stenosis. (See Presentation and Workup.) ^[4]

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Electrocardiogram of a patient with takotsubo cardiomyopathy demonstrating ST-segment elevation in the anterior and inferior leads.

View Media Gallery

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Electrocardiogram (ECG) from the same patient discussed in the previous ECG, obtained several days after the initial presentation. This ECG demonstrates resolution of the ST-segment elevation, and now shows diffuse T-wave inversion and poor R-wave progression.

View Media Gallery

The Japanese word takotsubo translates to "octopus pot," which refers to the resemblance of the LV shape during systole to this pot on imaging studies. Although the exact etiology of takotsubo cardiomyopathy remains unknown, the syndrome appears to be triggered by a significant emotional or physical stressor. ^{[1, 5]}  (See Etiology.)

The modified Mayo Clinic criteria for diagnosis of takotsubo cardiomyopathy ^[6]  can be applied to a patient at the time of presentation. The diagnosis requires the presence of all four of the following (see Workup):

• Transient hypokinesis, dyskinesis, or akinesis of the LV midsegments, with or without apical involvement; the regional wall-motion abnormalities extend beyond a single epicardial vascular distribution, and a stressful trigger is often, but not always, present
• Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture
• New ECG abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in the cardiac troponin level
• Absence of pheochromocytoma or myocarditis ^[6]

Normal myocardium utilizes approximately 90% of its energy from fatty acid metabolism at rest and with aerobic activity. During ischemia, this pathway is suppressed, and glucose is largely utilized instead, which results in impaired cardiac function. Patients with takotsubo (stress) cardiomyopathy (broken heart syndrome) are found to have a shift toward the glucose pathway despite relatively normal myocardial perfusion and a lack of ischemia in the left ventricular (LV) segments. ^[7]

The most commonly discussed possible mechanism for takotsubo cardiomyopathy is stress-induced catecholamine release, with toxicity to and subsequent stunning of the myocardium. ^[5]  Endomyocardial biopsy of patients with takotsubo cardiomyopathy demonstrates reversible focal myocytolysis, mononuclear infiltrates, and contraction band necrosis. The sympathetic/catecholamine theory is gaining momentum, because takotsubo cardiomyopathy was induced in rats exposed to physical stress and, in some instances, was prevented by pretreatment with an alpha blocker or beta blocker. Other evidence for this theory has been demonstrated through myocardial imaging studies using catecholamine analogues that evaluated cardiac sympathetic activity.

Some authors have proposed a unifying hypothesis stating that in susceptible individuals, notably women, neurohormonal stimulation results in acute myocardial dysfunction, as reflected by the characteristic LV wall-motion abnormality of takotsubo cardiomyopathy. Whether this is triggered by multivessel spasm, thrombosis, epicardial vessel occlusion, or direct myocardial toxicity remains to be seen. These authors point out that the wall-motion abnormality of takotsubo cardiomyopathy can be seen in other conditions, including those with certain left anterior descending lesions, ^[8]  making wall motion alone insufficient for the diagnosis of takotsubo cardiomyopathy. ^[9]

Cases of takotsubo cardiomyopathy have been reported in the literature following cocaine, methamphetamine, and excessive phenylephrine use. ^{[10, 7]}  Exercise stress testing, which is known to cause increased levels of catecholamines, has resulted in false positives attributable to takotsubo cardiomyopathy. ^[11]  Studies have found that patients with takotsubo cardiomyopathy have, by a statistically significant margin, higher levels of serum catecholamines (norepinephrine, epinephrine, and dopamine) than do patients with myocardial infarction. ^[12]  The apical portions of the LV have the highest concentration of sympathetic innervation found in the heart and may explain why excess catecholamines seem to selectively affect its function. ^[7]

Underlying coronary endothelial dysfunction may also play a role in takotsubo cardiomyopathy, wherein an abnormal tendency toward spasticity in the coronary tree can manifest as angina and as takotsubo cardiomyopathy. ^[13] One theory indicates that "substantially increased coronary spasticity may lead to diffuse, transient spastic obliteration of coronary arteries and to critical ischemia, which can be reproduced by acetylcholine testing early after" an episode of takotsubo cardiomyopathy. ^[13]

The exact etiology of takotsubo (stress) cardiomyopathy (broken heart syndrome) is still unknown, but several theories have been proposed and are under investigation. ^[14] These include the following ^{[10, 15]} :

• Multivessel coronary artery spasm
• Impaired cardiac microvascular function
• Impaired myocardial fatty acid metabolism
• Acute coronary syndrome (ACS) with reperfusion injury
• Endogenous catecholamine-induced myocardial stunning and microinfarction
• Underlying coronary endothelial dysfunction ^[13]

Risk factors for takotsubo cardiomyopathy

A significant emotional or physical stressor or neurologic injury typically precedes the development of the takotsubo cardiomyopathy. ^{[1, 5]}  Stressors include the following:

• Learning of a death of a loved one
• Bad financial news
• Legal problems
• Natural disasters
• Motor vehicle collisions
• Exacerbation of a chronic medical illness
• Newly diagnosed, significant medical condition
• Surgery
• Intensive care unit stay
• Use of or withdrawal from illicit drugs

Takotsubo cardiomyopathy has also been reported after near-drowning episodes. ^[16]

Seizures may also trigger takotsubo cardiomyopathy, ^[17] but it is rare for takotsubo cardiomyopathy to result in sudden unexpected death in epilepsy (SUDEP). ^[18]

In a systematic review of 104 cases of takotsubo cardiomyopathy (1965-2013), investigators noted that young patients with takotsubo cardiomyopathy were more likely to be female and physical stress was more likely to exacerbate takotsubo cardiomyopathy than mental stress was. ^{[19, 20]}  The clinical presentation of takotsubo cardiomyopathy in this patient population was similar to that of other cardiac diseases (eg, coronary heart disease) but could be differentiated from them by means of echocardiography in conjunction with ventriculography. ^[19]

Similarly, the International Takotsubo Registry reported that patients with takotsubo cardiomyopathy, as compared with ACS patients, were more likely to be female (89.8%) and that physical triggers were more common than emotional triggers (36% vs 27.7%), although more than one quarter (28.5%) had no clear triggers. ^[20] Patients with takotsubo cardiomyopathy also had higher rates of neurologic or psychiatric disorders and a significantly lower left ventricular ejection fraction (LVEF). Both groups (takotsubo cardiomyopathy and ACS) had similar rates of severe inpatient complications (eg, shock, death), and independent predictors of such complications included physical triggers, acute neurologic/psychiatric diseases, elevated troponin levels, and low LVEF. ^[20]

Controversy exists regarding whether or not takotsubo cardiomyopathy is associated with malignancy. ^[13]  Although it appears that takotsubo cardiomyopathy occurs more frequently than would be expected in noncancer patients, ^{[13, 21]} it is unclear whether chemotherapy itself is a more significant risk factor for takotsubo cardiomyopathy than the cancer itself. ^[13]

Studies reported that 1.7-2.2% of patients who had suspected acute coronary syndrome were subsequently diagnosed with takotsubo (stress) cardiomyopathy (broken heart syndrome). ^{[22, 23]} Patients are typically Asian or white. In a literature review of cases in which race was reported, 57.2% of patients were Asian, 40% were white, and 2.8% were other races. ^[24]

Literature reviews report a mean patient age of 67 years, although cases of takotsubo cardiomyopathy have occurred in children and young adults ^{[10, 12]} Nearly 90% of reported cases involve postmenopausal women. ^[25]  

The prognosis in takotsubo (stress) cardiomyopathy (broken heart syndrome) is typically excellent, with nearly 95% of patients experiencing complete recovery within 4-8 weeks. ^{[26, 27]} A study by Singh et al indicated that the annual recurrence rate is approximately 1.5% but that the frequency of ongoing symptoms is greater. ^[28] Estimates of mortality have ranged from 1% to 3.2%. ^{[24, 25]}

Complications occur in 20% of cases of takotsubo cardiomyopathy, particularly in the early stage, ^[3] and include the following:

• Left heart failure with and without pulmonary edema
• Cardiogenic shock
• Left ventricular (LV) outflow obstruction
• Mitral regurgitation
• Ventricular arrhythmias
• LV mural thrombus formation
• LV free-wall rupture
• Death ^{[29, 30]}