The relevance of Takotsubo cardiomyopathy as a stress-induced disease

Angelina A. Ganych, Ekaterina K. Oflidi, Anastasia Y. Zaitseva, Alla B. Myasnikova, Oksana V. Chernik. The Relevance of Ta- kotsubo Cardiomyopathy as a Stress-Induced Disease. Cardi-ometry; Issue No. 26; February 2023; p. 105-113; DOI: 10.18137/ cardiometry. 2023.26.105113; Available from:

In recent years, there has been a worldwide deterioration in mental health in the human population that has been significantly exacerbated during the COVID-19 pandemic. Against such an unfavorable background, the severity of mental symptoms increases in people with premorbid mental health problems, and the appearance of corresponding adverse symptoms in initially healthy people is also noted [1]. Limitation of social communication and forced loneliness resulted in a deterioration in the social well-being of the population [2].

There is a relationship between chronic non-communicable diseases and an increased (2.5 times) probability of a mental disorder in a human person. The risk of premature death in people with mental disorders elevates due to their chronic somatic diseases, the prevalence of which is 40-60% higher than that of the general population. These individuals often have their metabolic and behavioral risk factors. Along with other causes, some stressful social factors can act as a trigger for the development of stress-specific coronary syndromes, including stress cardiomyopathy (SCM) or Takotsubo syndrome (TTS) [3].

Takotsubo cardiomyopathy, also known as “broken heart syndrome”, or TTS, was first described by Hikaru Sato in 1990, and it is a stress-induced cardiomyopathy (apical ballooning syndrome), that is, a clinical condition characterized by a transient dysfunction of left ventricular wall motion, provoking the development of acute reversible heart failure (HF). TTS is not associated with an occlusion of coronary vessels [4].

The aim of this article is to study the features of Takotsubo myocardiopathy, or Takotsubo syndrome (TTS), including cases associated with taking antidepressants.

Occurrence of Takotsubo syndrome in the human population

The occurrence rate of TTS is about 2% of all patients with a clinical manifestation of acute coronary syndrome (ACS): if only women are considered, this value rises to 10% [5]. The Nationwide Inpatient Sample (USA) database identified 6837 patients with TTS among 33, 505, 402 hospitalized individuals. An analysis revealed that women were 8.8 times more likely to develop TTS than men, and women over 55 had an additional 4.8 times the incidence of the disease than young women. Smoking, alcohol consumption, anxiety, hyperlipidemia were associated with TTS. The peak hospitalization of the considered group of patients was recorded in the summer time [6].

Between 2006 and 2012, the incidence of TTS has increased 20-fold, which might partly be explained by improved diagnostics of this disease [Y-Hassan]. Takot-subo syndrome, according to the Cardiology Department of the Hospital of Milan, was observed in 1-3% of patients hospitalized with ST elevation myocardial infarction (MI) (STEMI): mostly elderly women with emotional stress or previous (hospitalization) acute illness. Experts note an increase in the number of cases of TTS in 2019-2020, especially during the quarantine period [7]. The staff at the University of London demonstrated similar rates of the in-hospital TTS prevalence, which was 2.1% compared with 97.9% in the STEMI patients [8]. In addition, compared with the STEMI group, the patients with TTS had a lower prevalence (42% vs 100%, p<0.05) and severity (the number of stenosing plaques covering more than 30% of the vessel diameter) of coronary heart disease (CHD); there was no in-hospital mortality, and the 2-year mortality (0% vs 5.5%) was reduced, as it was also the case with the incidence of adverse cardiovascular events (2.1% vs 3.7%). In a meta-analytic study summarizing data from 18 publications (n=55557), it has been shown that the incidence of life-threatening arrhythmias in TTS is 6.29%. In the presence of dangerous arrhythmias, these patients had a statistically significant increase in the risk of in-hospital mortality (OR=4.74; CI: 2.24–10.04; p<0.0001) and cardiogenic shock (OR=5.60; CI: 3.518.95; p<0.00001). At the same time, the presence of life-threatening arrhythmias in TTS was not significantly associated with long-term mortality (OR=2.23 CI: 0.94–5.28; p=0.07) [9].

Pathogenesis of Takotsubo syndrome

The pathogenesis of TTS is triggered by sympathetic nerve stimulation and catecholamine storm. Studying the activity of the sympathetic nerve by recording its direct activity, A. Vaccaro et al. revealed 106 | Cardiometry | Issue 26. February 2023

reduced spontaneous baroreflex control of the sympathetic activity and increased activity of the sympathetic nervous system in patients with TTS [10].

Back in 2008, T. Kume et al. found an increase in the local concentration of norepinephrine in the aortic root and coronary sinus in 5 patients with Takotsubo syndrome [11]. Left ventricular (LV) dysfunction in TTS is the result of the toxic effect produced by catecholamines on cardiomyocytes. As a result from this effect, the cardiomyocyte viability decreases, intracellular calcium overloading occurs, as a result of suppression of the expression of the sarcoplasmic Ca2+-adenosine triphosphatase (SERCA2a) gene and an increase in the expression of the sarcolipin and phospholamban genes. Due to an increase in the ratio of phospholambam/ SERCA2a, the affinity of cardiomyocytes for Ca2+ falls, and the contractile activity of the myocardium declines. On the other hand, the activation of the PI3K-AKT signaling cascade protects cardiomyocytes from death and promotes their rapid regeneration in stress-induced cardiomyopathy [12, 13].

The effect of a 10-20-fold excess of catecholamine levels is a multi-vessel coronary spasm and impaired microvascular circulation that initiates a state of post-ischemic myocardial stunning. The sympathetic tone is regulated by estrogen-mediated expression of β-adrenergic receptors, and suppression of the expression of these receptors is observed in women of reproductive age. This explains the predominance of TTS in postmenopausal women cohort [14]. One of the vasoconstrictor agents in TTS may be α1 endothelium, the level of which in blood plasma is increased [15].

Clinical manifestations and classification

A typical patient with Takotsubo syndrome has a unique profile of a circular left ventricular contraction dysfunction extending beyond the coronary artery and likely corresponding to the anatomical sympathetic innervation of the heart. The syndrome is mostly found in menopausal women, and it is usually preceded by emotional or physical stress. Patients with malignant neoplasms and other concomitant chronic diseases are more likely to develop TTS [5].

TTS is divided into 4 types: apical, basal, midven-tricular and focal TTS types [4]. In a clinical study using magnetic resonance imaging, 4 different types of regional ventricular ballooning were distinguished: apical (82%), biventricular (34%), median (17%) and basal (1%) variants. Left ventricular (LV) ejection fraction was found to be reduced (48%) in patients with TTS [16].

The classification of Takotsubo myocardiopathy based on trigger events according to Inter TAK score includes the following classes:

Class I – TTS associated with emotional stress;

Class II – TTS associated with physical stress;

Class IIa – TTS secondary to physical activity, diseases, procedures;

Class IIb – TTS secondary with regard to neurological disorders;

Class III TTS – no identified trigger [17].

The TTS clinical course ranges mostly to benign outcome, but in some cases it is accompanied by life-threatening complications. The clinical picture of Takotsubo cardiomyopathy resembles acute coronary syndrome and acute LV failure. Most often, the patient complains of chest pain (67.9-75.9%), shortness of breath (46.9-51.8%). In some cases, heart beat racing (11-12%), syncopes (7.7%-8.9%), nausea and / or vomiting (14-49.5%) are recorded. Sometimes life-threatening arrhythmias are observed [18]. In rare cases, there may be cardiogenic shock, cardiac arrest, and cardiac rupture [19, 20].

In patients with TTS, on the ECG the following signs can be observed: ST segment elevation, especially involving the anterior leads; ST depression, T wave inversion, QT interval prolongation, ventricular fibrillation. All these signs, together with an increase in the level of serum myocardial enzymes, may resemble acute coronary syndrome [21]. Takotsubo syndrome (TTS) is characterized by transient dysfunction of the apical segment of the left ventricle (LV) in the absence of signs of coronary blood flow limitation. Prolongation of QTc (normalized QT to heart rate) on the ECG is associated with the risk of sudden death in TTS [22].

The recently developed Inter TAK score, which has a sensitivity of 89% and a specificity of 91%, allows distinguishing TTS from acute coronary syndrome. In a clinical test, 95% of patients with TTS had a positive scale score for this disease. In addition, the Inter TAK score makes possible to stratify the patients with a high risk of adverse outcomes [23].

Diagnostics of Takotsubo syndrome

The main tools for the diagnostics of TTS are coronary angiography, left ventricular angiography, transthoracic echography, and magnetic resonance imaging (MRI) of the heart.

Transthoracic ECHO-cardiography (TTE) is a highly informative non-invasive examination method. It makes it possible to delineate the area of dysfunctional myocardium and allows assessing the left ventricular function using speckle tracking and tissue Doppler velocity. In TTE in patients with TTS, there is a decrease in global longitudinal LV deformity, which is most pronounced in the middle-inferior lateral, middle-inferior, apical-lateral and apical-inferior segments. Compared with patients with infarction of the left anterior descending coronary artery, patients with TTS have a more pronounced lesion of the right ventricle (RV). Echo-CG predictors of TTS are pathological TAPSE (tricuspid annular plane systolic excursion) and RV LS (right ventricular longitudinal strain) in the apical segment. A decrease in the ejection fraction and the general LV deformity are also observed. The lesion of the right ventricle and the pattern of regional left ventricular abnormalities help to differentiate between TTS and infarction of the left anterior descending coronary artery [24]. Conducting a 2-dimensional Echo-CG makes it possible to distinguish between variants of TTS with the RV damage and without it. In the latter case, changes in the left ventricle are less pronounced [25]. The measurement of the peak velocity of systolic tension has been shown to assess the dynamics of the left ventricle during volumetric loading with suppression of the LV function [26]. The increased mortality and incidence of cardiac events in patients with TTS may be related to the localization of the global longitudinal deformation of the left ventricle during systole. Thus, patients with worse profiles of the basal-lateral and mid-lateral segments, and altered global longitudinal deformity have greater in-hospital mortality rate. An increased occurrence rate of cardiac events has been associated with disorders in the basal-lateral and mid-lateral segments [27]. The diastolic function is also impaired in TTS, but however it is restored almost simultaneously with systolic function [28].

The Mayo clinical criteria are widely used in the TTS diagnostics procedure. All of them are necessary to confirm the diagnosis as listed below:

• 1.    Transient hypokinesis, akinesis or dyskinesia in the middle LV segments with or without involvement of the apex, regional wall motion abnormalities.

• 2.    Single epicardial vascular extension and the frequent presence of a stress trigger.

• 3.    Absence of coronary vessel occlusion or angiographic evidence of plaque rupture.

• 4.    New ECG abnormalities (ST-segment elevation and/or T-wave inversion) or moderate increase in cardiac troponin.

• 5.    Absence of pheochromocytoma and myocarditis [29].

MRI is very important for a comprehensive analysis of the condition of patients with TTS. In addition to detecting local abnormalities in the motion of the walls of the ventricles of the heart, MRI determines the functional characteristics of the ventricles, evaluates additional abnormalities and complications (pericardial/pleural effusion, blood clots), and characterizes myocardial tissues considering edema, inflammation, necrosis, fibrosis, if any. MRI allows differentiation between TTS and other pathologies, including myocarditis, myocardial infarction that is critical for prescribing appropriate medication [30]. Positive late gadolinium enhancement can determine segments with low perfusion, contraction bands in akinetic zones of the myocardium, small foci of fibrosis, accumulation of interstitial fluid in cardiomyocytes etc. [4, 31, 32].

Coronary angiography in TTS should be performed in order to exclude the myocardial infarction diagnosis. If the Inter TAK score is less than 70, coronary angiography (CAG) with left ventriculography should be completed. In patients with high Inter TAK scores, TTE is preferable, and in the absence of circular ballooning, CAG is recommended. Stable patients with circular ballooning should undergo CT angiography to exclude CAD. In unstable patients with TTS, typical complications (such as left ventricular outflow tract obstruction) are assessed using CAG and TTE to exclude the AMI diagnosis [33].

Serum levels of troponin and CK-MB may be elevated in TTS [34]. In a clinical test, the troponin T levels in these patients correlated with the initial ejection fraction and, as a rule, troponin T and troponin I values did not exceed 6 ng/mL and 15 mg/mL, respectively [35]. The NT-proBNP (ng/L) /myoglobin (μg/L) ratio of 3.8 makes possible to differentiate TTS from STEMI (sensitivity 89%, specificity 90%), while the NT-proBNP (ng/L) /myoglobin ratio (mcg/L), equal to 14, makes it possible to differentiate TTS from MI without ST elevation (sensitivity 65%, specificity 90%) [36].

Iatrogenic TTS

Many works have been published that reported on the iatrogenic causes of the development of TTS. They 108 | Cardiometry | Issue 26. February 2023

mainly referred to some consequences of treatment with catecholamines [37, 38]. So, in an article by A. Azouzi et al. a case with an 18-year-old North African male delivered by the emergency ambulance upon his β-blocker acebutolol intoxication is treated. Physical examination revealed signs of circulatory failure and cardiac conduction disturbances. The patient’s hemodynamic status was stabilized by fluid administration and ephedrine infusions. The next day after the hospital admission, the patient developed chest pain with shortness of breath. The ECG showed an ST segment elevation and an increase in troponin up to 8.4 ng/ mL was recorded. Transthoracic echocardiography (TTE) revealed a decrease in the LV ejection fraction (40%) and apical akinesia. According to the emergency coronary angiography, the coronary vessels were found to be intact, and ventriculography showed apical ballooning with unchanged basal contraction. The patient was diagnosed with TTS. Supportive therapy improved his hemodynamics [37].

An unusual case of TTS resulting from combined sympathetic simulation was observed in a hospital in Coimbra (Portugal). A 47-year-old woman was admitted to the hospital with severe gastrointestinal symptoms and sinus tachycardia; the β-blocker (esmolol) medication was prescribed in that case. Shortly after taking esmolol, the patient developed cardiogenic shock and elevated levels of cardiac biomarkers. The respective instrumental examination made it possible to exclude the presence of an occlusion of the coronary vessels, but it found basal akinesis with preserved apical myocardial contractility that corresponded to the non-apical variant of TTS. The authors of that clinical report believed that the above case of TTS was associated with sympathetic simulation against the background of a gastrointestinal disorder, linked with the administration of esmolol [39].

Some antidepressants can also cause TTS. In the article by E. V. Shubnikova et al. the following antidepressants have been identified as being capable of provoking TTS:

– venflaxine (an antidepressant of the group of selective norepinephrine and serotonin reuptake inhibitors);

– duloxetine (a serotonin and norepinephrine reuptake inhibitor);

– milnacipran (antidepressant of the group of selective norepinephrine and serotonin reuptake inhibitors) [40].

Another case has been described with a patient who used an excessive amount of venflaxine and developed cardiogenic shock with clinical and echocardiographic signs of Takotsubo syndrome. Since venflaxine, like other norepinephrine and serotonin reuptake inhibitors, increases the content of catecholamines, it was considered a trigger for the development of the described clinical condition [41]. One more study showed an association between TTS and the antidepressant use in patients with depressive disorders. However, that study was based on a small group analysis (n=17), so that an extended cohort study is needed to confirm these findings [42]. It is obvious that antidepressants, due to their pharmacokinetic features, are able to increase the content of catecholamines in blood.

Carrying out medical procedures, regardless of the prescription of drugs, in some cases may induce the development of TTS. Thus, two cases of development of stress cardiomyopathy after esophagogastroduodenoscopy (EGDS) were described. In a 45-year-old woman after the EGDS procedure and the appearance of the TTS characteristic symptoms (chest pain, shortness of breath, hemoptysis), TTE revealed a hypokinetic area in the middle part of the left ventricle with an ejection fraction of 45%; the level of the relevant cardiac markers in blood was found to be increased. In another patient, after the EGDS procedure, a similar TTE pattern was observed: hypokinesia of the middle part of the left ventricle with an ejection fraction of 58%. The level of CK-MB increased to 19.1 ng/ mL, and troponin I was 5.39 ng/mL. In both patients, the symptoms completely disappeared after 3 days [43]. In another report, after bronchoscopy, a patient according to Echo-CG was diagnosed with a dilated cardiomyopathy with an ejection fraction of 10-15%. On the ECG detected was an inversion of the T wave with respect to the anterior leads. After extubation, a re-examination was performed, and the signs of TTS persisted [44]. Thus, when carrying out invasive procedures, one should be aware of such a possible complication as TTS.

Treatment and prognosis of Takotsubo syndrome

Guidelines for the treatment of TTS are not available because prospective randomized data have not been published yet. In uncomplicated cases, treatment is limited to therapy for heart failure [4]. Most of the treatment is based on clinical evidence and expert consensus (Evidence level C). Patients with TTS, given the developing LV dysfunction, are usually prescribed β-blockers and ACE inhibitors, which have a cardioprotective effect, as well as lipid-lowering agents, aspirin [19, 29]. Disputes about the expediency of such administration remain still unresolved. So, administration of β-blockers had no effect on the 30-day in-hospital mortality in a clinical study [45]. However, patients taking β-blockers were less likely to experience a complication such as heart rupture [20]. H. Kim et al., analyzing some clinical data, showed that β-blockers and ACE inhibitors were not significant predictors of death in patients with TTS and that the mortality rate was mainly influenced by oncological diseases (RR 2.004; CI 1.334-3.012, p = 0.004), physical activity provocations (RR 1.882; CI 1.256–2.822, p=0.012), history of depression (RR 1.622; CI 1.085– 2.425, p=0.009), and age-related factors (RR 1.059; CI 1.037–1.081, p<0.001) [46].

The treatment regimen is determined by the clinical pattern in the patient in question and his/her hemodynamic status. Stable patients are prescribed cardioselective β-blockers and ACE inhibitors for 3-6 months with periodic monitoring with Echo-CG and determination of LVEF. Patients with confirmed ventricular thrombus (5% of the TTS cases) are medicated with anticoagulants. Hemodynamic instability is treated with inotropes, and sometimes, as an alternative, hemodynamic support is provided through intra-aor-tic balloon pumping. If an obstruction of LV outflow is determined in cardiogenic shock, inotropic drugs are avoided, and phenylephrine is administered in combination with β-blockers [29].

Taking into account the frequent stress trigger in the disease history of the patients with TTS, as well as the peculiarities of the pharmacokinetics of antidepressants, the question becomes acute: should patients with anxiety-depressive disorders take antidepressants or should they avoid taking them? It has been suggested that even a therapeutic dose of an antidepressant can cause the development of drug-induced tachycardia and TTS [47]. According to one study of the relationship between TTS and the use of antidepressants, the clinical manifestations of patients corresponded to the pattern of ACS. A total number of 78 individuals participated in that study, and all of them met the Mayo Clinic criteria for the TTS diagnosis. In addition, they were diagnosed with de pression and anxiety. The researchers found that the patients with major depressive disorder demonstrated a reduced reuptake of norepinephrine by neurons, which might alter the sympathetic innervation of the heart. It was also noted that in the patients taking selective serotonin reuptake inhibitors (SSRIs), the recovery of LV ejection fraction was decreased that reduced their chances of survival. A decrease in LVEF and higher mortality in the patients may be associated with a greater arrhythmogenic effect and a negative inotropic effect of the above drugs in the examined group [48]. The reference literature describes many cases of the development of TTS while taking antidepressants. Thus, R. Vasuded et al. reported on the case with a 52-year-old American woman hospitalized due to venlafaxine-induced TTS. The patient started taking venflaxine 75 mg 4 weeks before her admission. She denied stress. Examination revealed dyskinesia and ballooning of the LV apex, and the relevant cardiac markers were slightly elevated. The female patient was administered aspirin, Plavix, nitroglycerin, heparin drip. It was recommended to stop taking venlafaxine. After 6 weeks, the cardiac performance in the patient has been normalized [49]. Some cases of TTS developed after taking nortriptyline and lithium preparations have also been reported in the reference literature [50, 51]. Previously it has been suggested that patients with affective disorders are subject to a double negative impact due to the following factors: 1) an increased catecholamine response to stress and 2) an increased sympathetic sensitivity of the heart to catecholamines. This feature predisposes this group of patients to TTS [52]. When prescribing antidepressants, clinicians should be aware of the potential for developing TTS.

In patients with TTS, the risk of long-term mortality is comparable to that in case of ACS and ranges from 0% to 8%. Their prognosis is influenced by the nature of the trigger, in connection with which TTS is divided into primary TTS (the result from stress) and secondary TTS (caused by the hospital conditions, sepsis, trauma, surgical interventions). The secondary Takotsubo syndrome is associated with worse long-term outcomes. In men with TTS, the prognosis is often poor, due to the prevalence of conditions with elevated levels of circulating catecholamines. An LV ejection fraction value under 35% is an independent predictor of short-term and long-term mortality in patients with TTS [29, 53].

Conclusions

Takotsubo cardiomyopathy, or Takotsubo syndrome, being a separate nosological entity has been described quite recently, and at present there is not enough clinical experience and appropriate prospective randomized trials to develop a unified strategy for the management and treatment of patients in the group in question. Contrary to the initial expectations, the causes and the risk factors for the development of this pathology turned out to be quite diverse and were not associated only with a stress trigger, but however, in most cases, one way or another, they provoked an increase in the level of catecholamines in the patient’s blood.

The pathogenesis of Takotsubo cardiomyopathy is rather complicated, but its result is a decrease in the contractility of the left ventricle and ballooning of its cavity that leads to ineffective hemodynamics and the appearance of complaints resembling acute coronary syndrome. The combination of transthoracic echocardiography and coronary angiography is the most effective diagnostic tool to differentiate Takotsubo syndrome from other diseases. These two methods make it possible to identify the characteristic symptoms of the disease (balloon dilatation, segmental hypokinesia, decreased left ventricular ejection fraction) and exclude the presence of the critical occlusion of the coronary arteries.

There is still no consensus on the treatment of Ta-kotsubo syndrome, and the main treatment methods are aimed at eliminating the provoking factor (especially for iatrogenic causes) and taking measures to maintain the cardiac activity. Particular attention should be paid to antidepressants, which, due to their pharmacokinetics, are able to increase the level of catecholamines in blood: it is obvious that such cases of Takotsubo cardiomyopathy should be classified as class IIA according to the Inter TAK score.

The prognosis in Takotsubo syndrome is generally favorable except for cases associated with a sharp decrease in the left ventricular ejection fraction.

Findings:

• 1)    Takotsubo syndrome develops as a result from mental or physical stress, as well as for iatrogenic reasons;

• 2)    For individuals with excessive sympathetic activation, catecholamine derivatives and antidepressants from the group of selective norepinephrine and serotonin reuptake inhibitors should be prescribed with caution under cardiac activity monitoring;

• 3)    Takotsubo syndrome, developed due to taking antidepressants, should be classified as class IIA according to the Inter TAK classification, which includes, among others, iatrogenic causes of the disease;

• 4)    A generally accepted strategy for the treatment of Takotsubo syndrome has not yet been developed, and the efforts of the medical experts are aimed at supporting cardiac activity, treating complications and eliminating the responsible trigger factors.