Takotsubo Syndrome from Coronavirus Disease 2019

Takotsubo syndrome (TTS) or stress-induced cardiomyopathy is a rare form of acute, reversible left ventricular dysfunction. Catecholaminergic surge, myocardial inflammation, impaired microvascular perfusion, and electrophysiologic derangements may all contribute to its clinical manifestations of myocardial stunning and apical ballooning.¹

The novel coronavirus disease 2019 (COVID-19) has been associated with various cardiovascular manifestations, known as acute COVID-19 cardiovascular syndrome (ACovCS), which include but are not limited to acute coronary syndrome, myocarditis, microvascular disease, and TTS. The pathophysiology of myocardial injury seen in COVID-19 is thought to be secondary to a robust inflammatory response, including cytokine storm, which often is associated with elevated inflammatory markers (e.g., D-dimer, ferritin, lactate dehydrogenase, C-reactive protein, and erythrocyte sedimentation rate).^{2 , 3} The aim of this study was to explore the prevalence of TTS in patients with COVID-19.

We conducted a retrospective study of consecutive patients with polymerase chain reaction–confirmed COVID-19 who underwent a transthoracic echocardiogram (TTE) at a single academic center between April 2020 and March 2021. The TTE reports of patients with confirmed COVID-19 were queried for the term “takotsubo,” “stress,” or “stress-induced cardiomyopathy” as well as for the presence of any regional wall motion abnormality (i.e., “hypokinesis,” “akinesis,” or “dyskinesis”). These TTEs were reviewed by three independent Core Cardiovascular Training Statement level III echocardiographers to confirm TTS on the basis of the characteristic presence of basal segment hyperkinesis with associated apical hypokinesis or “apical ballooning,” or atypical variants of TTS. Patients were excluded if they had preexisting epicardial coronary artery disease or acute myocardial infarction by chart review.

During our study period, a total of 1,308 patients were admitted with COVID-19, of whom 476 (36.4%) underwent a TTE during their index hospitalizations. Our query resulted in 47 TTEs, of which nine met echocardiographic criteria for typical TTS. Four were excluded because of the presence of coronary artery disease. The remaining five patients with COVID-19 and TTS had a mean age of 73 years, and three patients were women. The mean time from COVID-19 diagnosis to TTE was 1.6 days (1-3 days). Laboratory test results revealed elevated inflammatory markers and elevated cardiac biomarkers, in addition to the typical abnormalities seen on electrocardiogram and reduced left ventricular ejection fraction on TTE (Table 1 ). TTE demonstrated the typical “apical ballooning” pattern often seen in TTS (Figure 1 ). We did not find any atypical variants of TTS. The ischemic electrocardiographic findings improved over time in all patients, and in the three patients with ST-segment elevation, ST segments returned to baseline an average of 13 days after the initial electrocardiographic examination. In our cohort, the prevalence of typical TTS in patients with COVID-19 was 1%.

Table 1.

Patient characteristics, peak laboratory values, electrocardiographic findings, and transthoracic echocardiographic findings of patients meeting criteria for TTS

Patient	Gender	Race	Age, y	Lactic acid, mmol/L	hs-TnT, ng/L	WBC count, 103/μL	D-dimer, μg/mL	LDH, U/L	Fibrinogen, mg/dL	ESR, mm/h	CRP, mg/L	ECG	Previous TTE LVEF, %	Takotsubo TTE LVEF, %
1	M	Black	63.0	2.8	429.0	39.2	3.6	510.0	483.0	120.0	314.0	Sinus tachycardia, 2-mm STE in leads V3–V6	70.0	35.0
2	F	White	68.0	1.9	92.0	17.9	—	341.0	—	—	61.0	Sinus tachycardia, poor R-wave progression	64.0	36.0
3	F	Black	91.0	3.7	140.0	14.0	—	—	—	—	—	NSR, LBBB, lateral TWI	70.0	42.0
4	F	White	79.0	8.7	2,325.0	10.4	1.2	—	434.0	68.0	20.0	AF; 2- to 4-mm STE in leads V2–V6, <1-mm STD in leads II, III, and aVF	65.0	29.0
5	M	Black	65.0	4.3	2,221.0	10.3	2.9	687.0	578.0	31.0	301.0	Sinus tachycardia, lateral STE, inferior and anterolateral TWI	60.0	33.0
Mean			73.2	4.3	1,041.4	18.4	2.6	512.7	498.3	73.0	174.0		65.8	35.0

Reference values: lactic acid, 0.5 to 2.0 mmol/L; hs-TnT, <22 ng/L; WBC count, 3.5 to 11.0 × 10³/μL; D-dimer, <0.40 μg/mL; LDH, 116 to 245 U/L; fibrinogen, 180 to 409 mg/dL; ESR, 0 to 33 mm/h; CRP, <5 mg/L.

AF, atrial fibrillation; CRP, C-reactive protein; ECG, electrocardiogram; ESR, erythrocyte sedimentation rate; F, female; hs-TnT, high-sensitivity troponin T; LBBB, left bundle branch block; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; M, male; NSR, normal sinus rhythm; STD, ST-segment depression; STE, ST-segment elevation; TWI, T-wave inversion; WBC, white blood cell.

Figure 1.

Transthoracic echocardiograms of two patients with confirmed COVID-19 with TTS. Basal segment hyperkinesis and apical hypokinesis or “apical ballooning” can be seen on contrast-enhanced apical two-chamber views.

Our single-center retrospective review adds to the growing literature on ACovCS. A systematic review of all published cases describing TTS in patients with COVID-19 found only 12 cases at the time of publication.⁴ Our study highlights the association between COVID-19 and TTS and how TTS may be appreciated more readily by reviewing TTEs with attention to typical wall motion abnormalities seen in TTS. At our center alone, we found five patients with presumed TTS compared with only 12 cases previously published in the literature. We also had a high percentage of hospitalized patients with COVID-19 who underwent a TTE (36.4%), often because of elevated high-sensitivity troponin T levels. To increase specificity, we excluded coexisting coronary artery disease, which may confound the true prevalence of TTS.

Although the pathophysiology of TTS is not fully understood, most TTS occurs in the setting of severe emotional, medical, or physical stress and is driven by excessive sympathetic nervous system activation and a heightened catecholamine state.⁵ Studies have shown that serum levels of epinephrine and norepinephrine are higher in patients with TTS compared to those experiencing myocardial infarction, but this has not yet been studied in patients with COVID-19.⁶ Furthermore, patients with COVID-19 could also have some degree of microvascular dysfunction that predisposes them to TTS.⁷ COVID-19 is known to be associated with a severe inflammatory response, including cytokine storm, which is manifested by high fevers and significantly elevated inflammatory markers; this may be another possible mechanism for the development of TTS.²

Our data suggest that patients with COVID-19 and elevated cardiac biomarkers as well as elevated inflammatory laboratory testing consistent with ACovCS should undergo TTE and ischemic evaluation to rule out stress-induced cardiomyopathy or acute coronary syndrome.

Given the clinical context and limited resources during the height of the COVID-19 pandemic, acute myocardial infarction was not excluded in all patients by coronary angiography. Also, repeat TTE for left ventricular recovery was not performed in all of the patients, as two of the patients died and two have pending outpatient TTEs. One of the patients with a follow-up TTE did have an improved left ventricular ejection fraction of 60%, back to baseline. Another limitation is that atypical variants of TTS may have been missed despite our efforts to keep the search query broad for any wall motion abnormalities.

The true prevalence of TTS in patients with COVID-19 may be cofounded by missing data, atypical variants of TTS, or the presence of coexisting coronary artery disease. In our cohort, the prevalence of TTS in patients with COVID-19 was approximately 1%.