Discussion
TC, also known as stress cardiomyopathy or broken heart syndrome, was first described in Japan in 1990. It is a clinical syndrome characterised by an acute and transient LV dysfunction often related to an acute physical or emotional stressful event.1 TC has previously been described in patients with other viral infections, including influenza A2 and influenza B3 in its classic form, as well as in its variant forms.4 There are only a few reported cases of TC described in literature among patients with COVID-19.4–10 In this case series, we describe the clinical characteristics of seven patients who initially presented with COVID-19 infection and subsequently developed TC.
Diagnosis of TC is based on clinical setting, ECG abnormalities, significant elevation of N-terminal-pro-Beta natriuretic peptide (NT-pro-BNP) and echocardiogram,11–13 which was the case for all of our patients (table 1). A coronary angiogram is performed under normal circumstances. However, given active COVID-19 illness and the risk of exposure to infection of healthcare workers, we deferred coronary angiography in our patients and based the diagnosis on the above-mentioned well-established parameters.11–13
Non-coronary distribution of LV wall motion abnormities is the hallmark of TC. The most commonly encountered pattern is apical hypokinesia/akinesia/dyskinesia with basal hyperkinesis (typical variant). Less than 5% of patients develop the reverse pattern called inverted or reverse TC characterised by basal hypokinesis/akinesis with apical hyperkinesia; other rare patterns like global TC, global with apical cap sparing, midventricular and focal have also been described.12 13 In the literature review of eight described cases of COVID-19 TC (table 3), five had typical TC, one reverse variant, one median TC and one patient had unclear variant of TC. In our series of seven patients, three were typical TC and two patients had an inverted or reverse variant of TC. One of our patients (patient 2) also had RV TC in addition to typical LV TC, which represents a rare variant of biventricular TC. Ours is the first report on biventricular TC with SARS-CoV-2 infection. In addition, patient 5 in our series had a global TC variant with apical cap sparing, with complete recovery of his LV function to baseline within 2 weeks. This is the first description of global TC with SARS-CoV-2 infection.
The exact mechanism of TC is unclear; however, several hypotheses have been proposed. The most widely accepted hypothesis is related to complex systemic responses to acute, severe stress and the response of the cardiovascular system to sudden surges in endogenous or exogenously administered catecholamines. In primary TC, acute cardiac symptoms resulting from emotional or physical stress are the main reason for seeking medical attention. In contrast, secondary TC develops in patients who are hospitalised for other reasons. The intense sympathetic stimulation in these patients caused by the primary condition or its treatment results in the development of TC.12 13 Some of the commonly identified triggers for the development of secondary TC are respiratory conditions, intubation, medication use, epinephrine use, anxiety and beta-blocker withdrawal.14–17 Many of these triggers are present in patients with severe COVID-19 pneumonia. This could possibly be the explanation for a higher number of reported cases of TC with SARS-CoV-2 compared with other similar respiratory viruses.8 9
Previous observational studies have shown that patients with secondary TC are older, males are more commonly affected than females and they have higher rates of HTN, DM, dyslipidaemia, cerebrovascular disease and cardiac arrhythmia.12 14–17 The same trend was also observed in our series. A similar pattern was also seen in eight cases of TC and COVID-19 described in the literature (table 3). Furthermore, increased risk of life-threatening complications and a 10-fold higher mortality rate as compared with primary TC were also observed in these studies.14 15 Hence, early identification of patients with COVID-19 who are at higher risk for developing secondary TC is important for appropriate management and prevention of complications, and thus improved outcomes.
Certain risk factors can be identified from our series and the study of cases described in the literature that predispose patients with COVID-19 to secondary TC. These are older age, presence of HTN, DM, HLD, prior stroke, AF and psychiatric illness, hypoxia and severe COVID-19 pneumonia requiring mechanical ventilatory support. Patients with the above-mentioned risk factors should be considered for closer monitoring on the telemetry floor, and development of new tachycardia or hypotension should be further investigated with ECG and blood work for cardiac biomarkers (troponin and NT-pro-BNP). Any new ECG changes or abnormalities in cardiac biomarkers should be followed by a TTE (figure 1).
Figure 1Approach to hospitalised patients with COVID-19 pneumonia who are at risk for secondary TC. AF, atrial fibrillation; HLD, hyperlipidaemia; HTN, hypertension; RVR, rapid ventricular rate; TC, Takotsubo cardiomyopathy.
Patients with secondary TC are more likely to experience cardiogenic shock, respiratory failure requiring mechanical ventilatory support and coagulation disorder.14–18 In our case series, all patients were diagnosed with TC around the time of intubation. It is difficult to ascertain if the deterioration of respiratory status was secondary to TC complicating COVID-19 or, more likely, TC was caused by worsening of COVID-19 pneumonia. Previous studies on secondary TC indicate that males have a higher rate of complications and in-hospital mortality.16 17. However, in our case series of seven patients with COVID-19 complicated by TC, death was observed in two out of four males and two out of three females. Furthermore, complications and mortality rates in secondary TC was found to be higher in older patients (>70 years), lower blood pressure (<110 mm Hg), lower EF (<45%), presence of RV involvement and mitral regurgitation.12 19 20 Three out of four patients who died in our series had EF less than 45% and older (>70 years). All four patients who died in our series had mitral regurgitation, RV involvement and required more than one pressor for the management of their hypotension (table 2). From the literature review of cases, the person who died was also older, required ionotropic support and had EF <40%.
There are no randomised controlled trials or guidelines on the management of patients with secondary TC. Management of these patients is generally supportive. However, after careful review of patients from our series and of published available cases of secondary TC complicating COVID-19, we propose dividing these patients into two groups (figure 2):
Figure 2Proposed approach to patients with features of TC on TTE. EF, ejection fraction; MR, magnetic resonance; RV, right ventricle; TC, Takotsubo cardiomyopathy; TTE, transthoracic echocardiogram.
Those who are at high risk for complications, as indicated by their advanced age (>70 years), comorbidities (HTN, DM, HLD, previous stroke and psychiatric illness), severe COVID-19 pneumonia, requirement for mechanical ventilation, hypotension, lower EF (<45%), presence of moderate-severe mitral regurgitation and RV involvement.
Lower risk group: those who do not have above-mentioned high-risk features.
Lower risk groups can be managed with supportive care. However, higher risk groups may require more aggressive treatment with mechanical circulatory support devices for the management of cardiogenic shock,12 rather than traditional approach with inotropes and vasopressors which can worsen TC leading to poor outcome.12 19 21 22 Patients who belonged to high-risk group in our series of seven patients from echocardiographic features had a 100% mortality rate (table 2).
We recognised three patterns of outcome of patients with COVID-19 pneumonia complicated by secondary TC:
In-hospital death secondary to low output state likely due to TC complicating COVID-19. This was observed in four out of seven patients in our series.
Recovery of LV function, with death due to multiorgan failure secondary to COVID-19 disease. This was observed in one patient in our series.
Recovery with or without sequelae: two patients recovered with sequelae and one without.
SARS-CoV-2 is now known to affect the myocardium. Studies from Wuhan, China, indicate that patients who develop cardiac injury manifested by elevation of high-sensitivity troponin I (TnI) levels have higher overall mortality, with rates as high as 59.6%.23 24 However, not all patients who have elevation in their cardiac biomarkers have viral myocarditis, but it can be due to the development of secondary TC. The exact role of SARS-CoV-2 in TC development has yet to be determined. Possible mechanisms could be an interaction of viral spike protein with ACE2 receptors in the heart, procoagulant state created by the virus, direct myocardial damage, endothelial injury and microvascular dysfunction. Further research is required to determine the role of viral interaction with cardiac ACE2 receptors and the development of cardiomyopathy in patients with COVID-19. Nevertheless, the diagnosis of COVID-19 and the state of being in a pandemic itself produces a huge emotional stress in patients, which predisposes them to develop TC.
We believe that the development of TC in patients with COVID-19 is multifactorial in nature and starts from being in a pandemic state, the stress associated with a COVID-19 diagnosis, hypoxia secondary to COVID-19 pneumonia and intense inflammatory state caused by the virus with a release of the cytokine storm. These characteristics along with the presence of predisposing factors, such as DM, intubation and use of vasopressors could trigger TC in patients with COVID-19.
To the best of our knowledge, this is the largest series of COVID-19-associated TC cases described in the literature. A literature review of the available cases suggested a higher rate of recovery of cardiac function and lower mortality rate than in our series. This is mainly attributable to the severity of cases in our cohort. However, more studies are required to understand the role of SARS-CoV-2 in the development of TC.
Limitations
The inability to completely rule out coronary artery disease was a limitation in our case series. However, three of our patients had echocardiograms documenting the recovery of cardiac function, and one had had a recent cardiac catheterisation with no evidence of epicardial coronary artery disease.
The proposed algorithms are based on our literature review of studies on secondary TC and not validated for secondary TC in patients with COVID-19 pneumonia. This is meant to serve just as a guide for clinicians.
