Takotsubo syndrome during the COVID-19 pandemic, state-of -the- art review.

The current coronavirus disease 2019 (COVID-19) presents an ongoing medical challenge with multiple organs involvement, including the cardiovascular system. Takotsubo syndrome (TTS) has been described in the context of COVID-19 in two different scenarios: as a direct complication of the infection, and as an indirect outcome secondary to psychological burden of quarantine and social isolation (i.e., stress induced cardiomyopathy). Confirming the diagnosis of TTS in COVID-19 may be challenging due to the limited use of coronary angiography consistent with the recommended guidelines aimed to minimize contact with infected individuals. The use of natriuretic peptide as a diagnostic and prognostic marker in this context may not be reliable since this peptide is already elevated in severe cases of COVID-19 regardless of TTS diagnosis. A relatively high incidence of complications has been reported in these cases, probably related to the severity of the underlying infectious disease. Although quarantine-induced stress cardiomyopathy is a reasonable outcome of the powerful stress during the current pandemic, conflicting results have been reported, and further studies are encouraged to determine the true incidence.

Takotsubo syndrome (TTS) is a type of acute reversible cardiac dysfunction that mainly affects postmenopausal women and is usually preceded by a physical or emotional stressor.1, 2, 3 Patients often present with chest pain, electrocardiogram (ECG) changes in the anterior leads, and elevated cardiac biomarkers. Typical echocardiographic findings in most cases are basal hypercontractility and apical ballooning, although other less common forms (ie, reverse and median types) have been reported., For definitive diagnosis, coronary angiography should be performed to exclude obstructive coronary disease. The pathophysiology of TTS is not fully understood, but it is well established that plasma catecholamines and neuropeptides have a central role.6, 7, 8 Key pathways involve coronary endothelial dysfunction, activation of various cytokines, impaired fatty acid metabolism in cardiac tissue, and multi-vessel spasm leading to demand–supply mismatch and myocardial stunning., TTS has been described as following various physical and emotional stressors such as anger, argument, surgery, natural disasters, grief, happiness, several medications, general anesthesia, and infectious disease., The novel coronavirus disease 2019 (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an ongoing challenge with several medical and economic implications. Multiple cardiovascular complications have been described during SARS-CoV-2 infection, including myocardial injury, myocarditis, arrhythmia, and exacerbation of chronic cardiac diseases such as heart failure.12, 13, 14 In the setting of the COVID-19 pandemic, TTS may be encountered as a complication of the acute infection or as an indirect outcome of quarantine-induced stress (stress-induced cardiomyopathy).

Takotsubo Syndrome as a Direct Complication of COVID-19

The first cases of COVID-19–associated TTS were reported during the acute phase of the infection, with a typical pattern of apical ballooning. Table 1 summarizes the basic characterestics of the cases.15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42

Table 1

Demographic and laboratory characteristics of patients with coronavirus disease 2019 (COVID-19) complicated by Takotsubo syndrome (TTS)

Angiography	ECG	Peak NPs, pg/mL	Peak troponin (T/I), ng/L	LV function, %	PMH	Sex	Age, y	Study (first author)
N	Negative T in anterior leads	474	170	61	HTN; DM; asthma	F	67	Bapat15
N	ST elevation in anterior leads	8999	T-775	30	HTN; HPL	M	74	Bernardi16
Y	Inferolateral ST segment elevation	1312	I-37	38	Gestational HTN	F	32	Bhattacharyya17
N	ST elevation in anterior leads	17,379	T-176	25	—	F	76	Bottiroli18
N	Diffuse ST elevation	4573	526	40	Healthy	M	49	Chao19
N	Negative T in precordial leads	54,000	I-2410 l	40	Non ischemic cardiomyopathy	F	67	Dabbagh20
N	Nonspecific ST-T changes	110	9	26	HTN; COPD	F	59	Dave21
N	Nonspecific ST-T changes	—	I-4700	30	Healthy	M	40	Faqihi22
N	No ST-T changes	BNP-2060	I-10,090	25–30	Crohn's disease; emphysema	F	57	Gomez23
N	ST elevation in anterior leads	17,800	I-4250	—	HTN; HPL; DM; obesity	F	72	Kariyanna24
N	No ST-T changes	35,000	503	25–30	HTN; HPL; hypothyroidism	F	76	Khalid25
N	Negative T in anterior leads	9000	692	—	HTN; DM	F	54	Manzur-Sandoval26
Y	ST elevation in anterior leads	—	T-1142	—	HTN	F	83	Meyer27
Y	ST elevation in I AVL	—	I-11,020	20	HTN; DM; HPL	F	58	Minhas28
Y	Negative T in precordial leads	—	I-1137	40	HTN; DM; obesity	F	59	Moderato29
Y	Non specific ST-T changes	—	T-412	—	HTN; HPL; hydrocephalus	F	71	Nguyen30
Y	ST elevation in anterior leads	—	—	Poor	HTN; DM; HPL; CKD	F	82	Oyarzabal31
N	Non specific ST-T changes	—	T-610	—	HTN; DM; AF	M	65	Panchal32
Y	Negative T in precordial leads	1381	T-70	53	HTN; DM	M	84	Pasqualetto33
Y	—	3000	T-647	30	HTN	F	85
Y	—	12,586	T-621	42	HTN; DM	M	81
N	T wave inversion in precordial leads	—	I-5318	48	Breast cancer	F	87	Roca34
Y	ST elevation in v1-v2	512	T-135	43	Healthy	F	43	Sala35
N	Anterior ST elevation	299	I-2273	Poor	HTN; COPD; rheumatoid arthritis	F	58	Sang36
N	Negative T in inferolateral leads	—	T-423	30	HTN; DM	F	67	Sattar37
Y	ST elevation in inferolateral leads	790	64,000	—	Benign mediastinal tumor	M	50	Solano-López38
Y	ST elevation in inferior leads	—	I-0.015	45	HTN; DM; schizophrenia	M	52	Taza39
Y	ST elevation in anterior leads	—	—	Poor	HTN; HPL; COPD	M	83	Titi40
N	Negative T in precordial leads	—	T-94000	36	Obesity	F	59	Tsao41
Y	Negative T in precordial leads	—	I-454	30	AF	F	72	Van Osch42

AF, atrial fibrillation; AVL, augmented vector left; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; ECG, electrocardiogram; F, female; HPL, hyperlipidemia; HTN, hypertension; LV, left ventricle; M, male; N, no; NP, natriuretic peptide; PMH, past medical history; Y, yes; The type of cardiac troponin assay (T/I) is indicated if available

Epidemiology and Presentation

Most of the reported cases were typical TTS characetrized by apical ballooning and basal hypercontractility. Cases of reverse TTS (characterized by hypercontractility of the apical region and basal hypokinesia) have also been reported.,,,, The leading presenting symptom was chest pain with/without dyspnea, and one patient presented with acute ischemic stroke. Of note, several cases were diagnosed based on echocardiography and ECG features during investigation of hemodynamic compromise in critically ill patients with no option for history taking. In most cases, TTS was described during the acute phase, although late onset TTS, 16 days after admission, was also reported. Several studies aimed to determine the incidence of TTS during COVID-19. Hegde et al. investigated 169 laboratory-confirmed COVID-19 patients; of these, 3 had typical TTS, 2 had reverse TTS, 1 had biventricular TTS, and 1 was defined as having global TTS with apical sparing. Giustino et al. documented the echocardiographic features of 118 consecutive COVID-19 patients, and 5 (4.2%) had echocardiographic findings compatible with TTS, 4 of them with typical appearence, and 1 with the reverse variant. In another study, Dweck et al. captured echocardiographic findings in 1216 patients with presumed or confirmed COVID-19; of these, 19 (2%) had echocardiographic findings consistent with TTS. Based on these studies, the estimated incidence of TTS complicating SARS-CoV-2 infection is 2%-4%, probably with a higher prevalence in critically ill patients, compared to 1%-2% among patients presenting with suspected acute coronary syndrome in the general population. Although TTS traditionally predominates in postmenopausal women (about 90%), 30% of the currently reported cases are males. TTS has been previously reported in infectious diseases, mainly in bacterial sepsis, and rarely in the setting of viral infections., The influenza virus is recognized as one of the viruses most likely to cause TTS during acute infection or following vaccination.48, 49, 50, 51, 52, 53, 54, 55 However, the incidence of TTS in the setting of influenza or other viral infections is not known as no studies have been dedicated to investigating the echocardiographic findings in affected patients. Therefore, it would be difficult to determine whether TTS is more prevalent during COVID-19 than other infectious diseases, or whether it is simply more investigated in this setting.

Pathophysiology of TTS During COVID-19

The pathophysiology of TTS is not fully understood, although several mechanisms have been proposed. Catecholamines, cortisol, and natriuretic peptides (NPs) probably play a central role in the development of the specific type of cardiac stunning in the syndrome by mediating several cardiac processes, such as epicardial coronary spasm, microvascular dysfunction, and direct myocyte injury., Several findings indicate an essential role for catecholamines in TTS, including the high plasma levels in affected patients, and the induction of TTS-like disease following epinephrine or norepinephrin administration., During catecholamine surge, epinephrine triggers β2-adrenoreceptor in cardiac tissue to switch from Gs to Gi coupling, resulting in apical ballooning. Patients with COVID-19 may be exposed to high catecholamine levels secondary to endogenous excretion as a compensatory mechanism to prevent decompensation, and to exogenous intravenous infusion of adrenaline and noreadrenaline used to maintain adequate blood supply in critically ill patients. High catecholamine levels might act as a double-edged sword by increasing oxygen demand, and inducing vasospasm and direct myocardial injury. The hypothalamic-pituitary-adrenal (HPA) axis is another system that is activated in severe COVID-19, with subsequent dysregulations in cortisol and adrenocorticotrophic hormone (ACTH) metabolism. During acute illness, activation of the HPA axis, along with reduced metabolism and decreased breakdown of cortisol, contributes to hypercortisolism and hence corticotropin suppression. In the study by Tan et al., levels of cortisol were significantly higher in people with COVID-19 than in those without the infection, and survival was halved in people with the highest cortisol levels. Whether hypercortisolemia in COVID-19 is a marker of severe inflammation or a leading cause of impaired immunity and vulnerability for complications is not clear yet. The relation between high cortisol levels and TTS is not well established, as TTS has been described in cases of cortisol excess, and in cases of secondary adrenal deficiency. It is reasonable to assume that activation of the HPA axis during acute illness may mediate TTS by inducing catecholamine secretion. One of the key biomarkers in TTS is N-terminal pro-brain-type natriuretic peptide (NT-proBNP), which is released following increased ventricular wall stress as part of the neurohormonal activation in the setting of heart failure. As in other forms of heart failure, NT-proBNP levels in TTS have been shown to correlate with the severity of left ventricle dysfunction. Compared to patients with ST-segment elevation myocardial infarction (STEMI), TTS is associated with higher brain natriuretic peptide (BNP) and lower troponin levels at admission, at peak, and at discharge. This unique biomarker profile of a high BNP/troponin ratio provides a reliable parameter to use to differentiate TTS from STEMI, particularly when measured at peak. The use of NPs as a diagnostic and prognostic marker in the era of COVID-19 may not be reliable, as NP levels are already elevated in cases of severe COVID-19 regardless of TTS diagnosis. Finally, the release of interleukin-6, tumor necrosis factor-α, and other proinflammatory cytokines in severe COVID-19 (known as a cytokine storm) might be accompanied by a catecholamine surge and further contributes to the development of myocardial stunning.

ECG and Laboratory Findings

Common ECG findings in TTS include ST-segment elevation in the precordial leads, anterior T-wave inversion, and QT-interval prolongation. Reciprocal ST-segment depression and Q waves are often absent., In the current reported cases, QT prolongation was documented in 8 patients (27%), although ECG description was unavailable in 2 cases. However, it should be noted that patients with COVID-19 are already prone to QT prolongation due to concomitant use of proarrythmic drugs such as quinidine and azithromycin. Cardiac troponin and NT-proBNP levels have been reported to be high in severe COVID-19, reflecting myocardial injury and probably excess mortality., In one study, among 118 patients with laboratory-confirmed COVID-19, those with TTS (5 patients) had higher troponin I and lower BNP levels compared to patients with myocardial injury (defined as a troponin I level ≥0.04 ng/mL) but without TTS. As we suggested above, the combination of slight elevation in troponin with excessive NP levels, commonly seen in TTS, is not applicable as a diagnostic tool in the setting of COVID-19.

Diagnostic Challenges

The COVID-19 outbreak necessitates special patient care considerations consistent with the need to minimize physical contact. These considerations make history-taking somehow limited, particularly in critically ill patients. Use of handled echocardiography devices rather than the large machines is recommended to obtain parameters such as left ventricular function, wall motion abnormailities, and valvular pathologies. One of the more sensitive modalities that was shown to detect early subtle myocardial contractility changes and predict mortality in TTS is left ventricular strain echocardiography. This modality may help to differentiate TTS from acute coronary syndrome. In the COVID-19 setting, Stöbe et al. demonstrated a reduced basal longitudinal strain in 10 of 14 patients (70%) with SARS-CoV-2 infection, a pattern that may be found in reverse TTS. However, it should be noted that strain echocardiography is not applicable for routine use during the COVID-19 pandemic, as it is a time-consuming modality. Despite being obligatory for confirming TTS, coronary angiography was performed in only 14 of the reported cases (47%), reflecting the need to minimize physical contact with infected patients. A clinical disgnostic score was developed based on the International Takotsubo Registry (InterTAK) for assessing the probability of TTS. The InterTAK diagnostic score consists of the following 7 variables with and corresponding points: female sex, 25; emotional trigger, 24; physical trigger, 13; absence of ST-segment depression (except in lead aVR), 12; psychiatric disorders, 11; neurologic disorders, 9; and QTc prolongation, 6. Using a cutoff value of 40 score points, sensitivity was 89% and specificity was 91%. The InterTAK score was recently proposed as a diagnostic tool during the COVID-19 outbreak. Here, we suggest a simplified algorithm for managing COVID-19 patients with suspected TTS (Fig. 1).

Figure 1

Suggested algorithm for managing patients with suspected Takotsubo syndrome (TTS) who also have COVID-19. CAD, coronary artery disease; CT, computed tomography; ECG, electrocardiogram; InterTAK, International Takotsubo Registry; LV, left ventricular. WMA, wall motion abnormality.

In unstable patients, ECG, echocardiography, and angiography when indicated are essential for ruling out obstructive coronary artery disease. In stable patients and those with wall motion abnormality consistent with Takotsubo, appropriate management depends on risk profile. When high-risk features are present (ongoing chest pain or dyspnea, episodes of ventricular tachycardia, or extremely elevated NPs), cardiac computed tomography is recommended for assessing the coronary arteries. Observation and follow-up echocardiography seem reasonable in low-risk patients (without the above-mentioned features).

Major complications and outcomes are provided in Table 2. About 60% of the patients were on inotropic or ventilatory support. Mechanical circulatory support (venous–venous extracorporeal membrane oxygenation) was provided in only one patient. Thromboembolic events occured in 2 cases,, arrhythmia in another 2 cases,, and shock in 7 cases.,,,,,, Given that sepsis and cytokine storm accompany the clinical course of severe COVID-19, it might be difficult to separate the hemodynamic effects of the underlying sepsis from TTS. Thromboembolic (venous and arterial) events have been reported in COVID-19, particularly in severe cases. In one large registry, major arterial or venous thromboembolic events occured in 35.3% of COVID-19 patients admitted to an intensive care unit (ICU), and in 2.6% of hospitalized non-ICU patients, and symptomatic venous thromboembolism was documented in 27% and 2.2% of ICU and non-ICU patients respectively. Septic shock with the need for vasopressors has been reported in about 70% of COVID-19 patients admitted to an ICU., Despite the fact that TTS is described mainly in severe COVID-19, complete recovery was observed in 24 of the cases (80%). The treatment of TTS in COVID-19 should not be different from the usual management of TTS, with emphasis on the underlying disease. Because angiotensin-converting enzyme 2 (ACE2) was recognized early in the pandemic as a potential receptor for SARS-CoV-2 entry, the use of ACE inhibitors was postulated to cause deleterious effects in affected patients. However, recent trial results do not support the routine discontinuation of these drugs among patients with mild or moderate COVID-19. For this reason, the use of ACE inhibitors and beta blockers in TTS in the setting of COVID-19 seems to be reasonable when indicated.

Table 2

Clinical course and outcomes

Outcome	Mechanical ventilation	Mechanical circulatory support	Inotropic support	Complications	Study (first author)
Recovery	Y	N	Y	QT prolongation	Bapat15
Recovery	N	N	Y	LV thrombi	Bernardi16
Recovery	N	N	N	—	Bhattacharyya17
Recovery	Y	N	Y	Shock	Bottiroli18
Recovery	Y	V-V ECMO	Y	QT prolongation	Chao19
Recovery	N	N	N	—	Dabbagh20
Death	Y	N	Y	Shock	Dave21
Recovery	Y	N	Y	Shock	Faqihi22
Recovery	Y	N	Y	QT prolongation	Gomez23
Death	N	N	Y	Shock, acute ischemic stroke	Kariyanna24
Recovery	Y	N	Y	Shock	Khalid25
Recovery	Y	N	Y	QT prolongation	Manzur-Sandoval26
Recovery	N	N	N	—	Meyer27
Recovery	N	N	Y	Shock	Minhas28
Recovery	N	N	N	QT prolongation	Moderato29
Recovery	Y	N	N	QT prolongation	Nguyen30
Recovery	N	N	N	—	Oyarzabal31
Death	Y	N	Y	Shock	Panchal32
Recovery	N	N	N	QT prolongation	Pasqualetto33
Death	Y	N	Y	—
Recovery	N	N	N	—
Recovery	N	N	N	—	Roca34
Recovery	N	N	N	—	Sala35
Death	Y	N	Y	—	Sang36
Recovery	N	N	N	Atrial fibrillation	Sattar37
Recovery	N	N	N	—	Solano-López38
Recovery	N	N	N	—	Taza39
Death	Y	N	Y	—	Titi40
Recovery	Y	N	Y	Ventricular tachycardia	Tsao41
Recovery	Y	N	N	QT prolongation	Van Osch42

LV, left ventricle; N, no; V-V ECMO, venous–venous extracorporeal membrane oxygenation; Y, yes.

Quarantine-Induced TTS

Another scenario in which TTS may be encountered in the COVID-19 era is related to the subsequent increase in mental stress, particularly during quarantine and self-isolation. People in quarantine report a high prevalence of depression, stress, insomnia, and anxiety, brought on by the long duration of quarantine, fear of infection, frustration, and inadequate supplies. The fact that many of the self-isolated individuals are elderly (with quarantining intended to protect themselves from the disease) may directly affect the incidence of TTS, as it predominantly affects elderly women. Three retrospective studies aimed to evaluate the changes in TTS incidence during the COVID-19 pandemic. Delmas et al. reported no increase in the incidence from March 1 to April 15, 2020 compared to the same period in previous years (5 patients vs 4-8 patients). In another single-centre study in Lombardy during the pandemic peak in Italy, 11 patients were diagnosed as having TTS from February to May 2020, compared to 3 cases during the same months of 2019. Finally, the study by Jabri et al. demonstrated a higher TTS incidence among patients admitted with suspected acute coronary syndrome between March 1 and April 30, 2020, with a total of 20 (7.8%), compared to the corresponding timeline in pre-pandemic years (5-12 patients; proportion range: 1.5%-1.8%) The difference in the results between the studies may be related to differences in quarantine policies, the social status of the study population, length of the study period, and the effect of the pandemic on the particular region (eg, Lombardy was a region with one of the worst COVID-19–related situations in Italy). It is reasonable to assume that the mental stress resulting from the COVID-19 pandemic and its medical, social, and economic implications may constitute a potential trigger for TTS. Further registries are needed to determine the true change in incidence of TTS during the current pandemic.

Conclusion

TTS may be encountered in COVID-19 as a complication of the infection, or secondary to the overwhelming stress. The high rates of complications reported may be related to the undelying severe infection and not directly to the cardiomyopathy. Diagnosis may be challenging in this era, as biomarkers are not reliable for this purpose, and coronary angiography is often avoided. We suggest performing echocardiography in patients with COVID-19, using handheld devices to minimize contact with infected patients. The use of coronary angiography may be appropriate in high-risk patients with ongoing chest pain or dyspnea, episodes of ventricular tachycardia, or extremely elevated NP levels. Otherwise, routine management and repeated echocardiography are recommended, as most reported cases exhibited full cardiac function recovery. Treatment of TTS should be based on managing the underlying disease. The use of ACE inhibitors is appropriate when indicated, as these medications were shown to be safe among COVID-19 patients. Stress-induced Takotsubo is likely a reasonable consequence of the COVID-19 pandemic, due to the accompanying stress of self-isolation and quarantine, but large studies from various countries are needed to determine the trend in TTS incidence worldwide.

Funding Sources

The authors have no funding sources to declare.

Disclosures

The authors have no conflicts of interest to disclose.