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Broken Heart Syndrome
April  2019

In contrast to other cardiomyopathies that are usually not transient in nature, TTS is characterized by a temporary wall motion abnormality of the LV, and shares common features with acute coronary syndrome (ACS) with similar symptoms at presentation, ECG abnormalities, elevated cardiac biomarkers as well as a comparable in-hospital mortality.

Epidemiology
Actually, 90% of cases involve women, most of whom are post-menopausal with mean age being 68 years.

Takotsubo syndrome is estimated to represent approximately 1–3% of all and 5–6% of female patients, presenting with suspected ST elevation myocardial infarction (heart attack).

Women older than 55 years have a five-fold greater risk of developing TTS than women younger than 55 years and a 10-fold greater risk than men.

Figure 1: Age and Sex Distribution of Patients with TTS



TTS-Figure2.jpgMechanisms
A hallmark of TTS is its association with a preceding stressful event. Physical triggers are more common than emotional stress factors retrieved respectively in 35 % and 30% of cases. Interestingly, male patients are more often affected from a physical stressful event, while in women an emotional trigger can be more frequently observed.

Recognition that TTS may occur spontaneously in 30% of cases has demonstrated the inappropriateness of the term ‘stress cardiomyopathy’ to describe the entire spectrum of TTS.

Psychological triggers represent a range of traumatic emotions including grief (death of a family member, friend, or pet), interpersonal conflicts (divorce or family estrangement), etc. Natural disasters such as earthquakes and floods are also associated with an increase in TTS events.

However, emotional triggers are not always negative, as positive emotional events can also provoke TTS (e.g., surprise birthday party, winning a jackpot and positive job interview). This is called “Happy Heart Syndrome.“

The most recent evidence supports the concept that in the acute phase of TTS there is an increased concentration of circulating catecholamines (several times higher than in myocardial infarction). Acute emotional stressors have been shown to induce brain activation, increasing bioavailability of cortisol, epinephrine, and norepinephrine.

Mechanisms by which this surge of cathecolamines impact the heart are not completely understood and different explanations are discussed such as multivessel coronary spasm, microvascular impairment, direct cathecolamines toxicity, estrogens deficiency and endothelial dysfunction.

Diagnosis
TTS generally presents as an acute myocardial infarction characterized by severe left ventricular dysfunction.

To assess the diagnosis, the Mayo Clinic Diagnostic Criteria are the most widely known but they exclude an obstructive coronary disease and pheochromocytoma.

Nonetheless, concomitant Coronary Artery Disease is reported with a prevalence ranging from 10–30%, and pheochromocytoma is considered a TTS-like myocardial dysfunction by Japanese authors; that’s why new international diagnostic criteria (InterTAK Diagnostic Criteria) have been developed and may help to improve identification and stratification of TTS: 
  • Patients show transient left ventricular dysfunction (hypokinesia, akinesia or dyskinesia) presenting as apical ballooning or midventricular, basal or focal wall motion abnormalities. Right ventricular involvement can be present. 
  • An emotional, physical or combined trigger can precede the takotsubo syndrome event, but this is not required.
  • Neurologic disorders (e.g., subarachnoid hemorrhage, stroke/transient ischemic attack or seizures) as well as pheochromocytoma may serve as triggers for TTS.
  • New ECG abnormalities are present (ST-segment elevation, ST-segment depression, T-wave inversion and QTc prolongation)
  • Levels of cardiac biomarkers (troponin and creatine kinase) are moderately elevated in most cases; significant elevation of BNP is common.
  • Significant coronary artery disease is not a contradiction in TTS.
  • Patients have no evidence of infectious myocarditis.
  • Postmenopausal women are predominantly affected.

During the acute phase, in the majority of cases, wall motion abnormalities typically involve the apical and midventricular segments, which appear akinetic or dyskinetic (defined as ‘‘apical ballooning’’) in contrast to the basal segments, which are often hyperkinetic.

Apical ballooning is often associated with other suggestive features, such as Left Ventricular Outflow Tract Obstruction due to basal hypercontractility, and Mitral Regurgitation due to systolic anterior movement of the anterior leaflet of the mitral valve.

In the acute phase, LV ejection fraction is reduced and recovers with resolution of myocardial stunning.

The magnitude of myocardial dysfunction is wide and irrespective of single coronary artery territory distribution, while the degree of biomarker release (troponin) is quite small in proportion to the extent of Wall Motion Abnormalities, in contrast with the situation in acute MI.

Figure 3: In Hospital Complications with TTS

Source: JR Ghadri et al European Heart Journal (2018) 39, 2047–2062

Complications of TTS
While TTS is usually a reversible condition, hemodynamic and electrical instability during the acute phase expose patients to the risk of serious adverse in-hospital events which occur in approximately one-fifth of TTS patients.

A multivariate analysis of the data from the International TTS registry, revealed that older age and the presence of emotional triggers independently predicted a lower incidence of the combined end point. 

In contrast, the presence of physical triggers, acute neurologic or psychiatric disease, a first troponin measurement of more than 10 times the upper limit of the normal level and a left ventricular ejection fraction of less than 45% each predicted a higher incidence of adverse in-hospital outcome.

Figure 4: Long-term Outcome of Patients with TTS
Source: Templin C et al N Engl J Med 2015;373:929–938

Figure 5: Long-term Mortality of Triggering Groups
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Source: Ghadri, J.R. et al. J Am Coll Cordiol. 2018;72(8):874-82

Long term outcome
According to the InterTAK Registry report, which represents a consortium of 26 cardiovascular centers from Europe and the United States, thus the largest TTS registry to date, death rates are estimated to be 5.6%. The rate of major adverse cerebrovascular and cardiac events is 9.9% per-patient year. This suggests that TTS is not a benign disease with a 10 year mortality of 20 to 25%.

Although it is reasonable to expect TTS mortality to be related to primary LV pump failure, TTS events are frequently preceded by acute medical or surgical illnesses, which independently have poor prognosis. In this regard, mortality in TTS is likely related to both the magnitude of myocardial injury, the nature of the triggering event and comorbidities.

Overall, TTS patients had a similar long-term outcome compared with age- and sex-matched Acute Coronary Syndrome patients. TTS patients with events-related to emotional stress had a favorable short- and long-term prognosis. TTS secondary to neurologic diseases had the worst short-term prognosis.

TTS secondary to neurologic diseases and TTS secondary to physical activities, medical conditions, or procedures had significantly higher mortality rates compared with ACS during long-term follow-up.

References
  • Ghadri JR et al European Heart Journal (2018) 39,2032–2046
  • Ghadri JR et al J Am Coll Cardiol.2018; 72(8):874-882
  • Templin C et al N Engl J Med 2015;373:929–938
  • Pellicia F et al Circulation. 2017;135:2426–2441
  • Sharkey W et al J Am Coll Cardiol.2018; 72(8):883-884
  • Templin C et al European Heart Journal (2019) 00,1-5