Reverse Takotsubo Syndrome Triggered by COVID-19–Associated Cytokine Storm: Unveiling a Novel Pattern of Myocardial Dysfunction in SARS-CoV-2 Infection

Introduction

Takotsubo cardiomyopathy (TTC), also known as stress-induced cardiomyopathy, is characterized by transient and reversible systolic dysfunction of the left ventricle. The classic form typically presents with apical akinesia or hypokinesia and compensatory basal hyperkinesia, giving the heart a shape reminiscent of a Japanese “takotsubo” pot [1].

Reverse takotsubo cardiomyopathy (rTTC) is a less common variant that displays the opposite pattern – basal akinesia or hypokinesia with apical hyperkinesia [2]. Although its pathophysiology remains incompletely understood, differential β-adrenergic receptor distribution in the myocardium may play a central role. Epinephrine and norepinephrine initially activate β2-adrenergic receptors via the Gs pathway, increasing cAMP and enhancing calcium influx and myocardial contractility. However, excessive stimulation can lead to Gs-to-Gi switching, resulting in reduced basal contractility while sparing or enhancing apical function. The proposed mechanisms include differential β-adrenergic receptor distribution, catecholamine surge, microvascular dysfunction, and regional sympathetic hyperactivity [2].

Unlike classic TTC, which is often triggered by emotional or physical stress, rTTC has been more commonly associated with neurological conditions such as stroke, epilepsy, or subarachnoid hemorrhage, and is more prevalent among younger women, suggesting a possible hormonal or genetic predisposition [3]. While both TTC and rTTC can mimic acute coronary syndrome, they are typically distinguished by the absence of significant coronary artery obstruction on angiography [3].

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, primarily affects the respiratory system but is increasingly recognized for its cardiovascular complications. These include myocarditis, thromboembolic events, heart failure, and stress cardiomyopathy, particularly in the context of severe inflammatory response [4]. The emergence of variants such as omicron (B.1.1.529) has further complicated and broadened the clinical spectrum, with cases of fulminant myocarditis and ventricular dysfunction reported in unvaccinated patients infected with subvariant BA.2. Recent reports have described TTC and rTTC in patients with COVID-19, often associated with systemic inflammation, direct viral injury, hypoxia, ACE2 receptor dysregulation, and cytokine storm [5].

This case report aims to contribute to the growing understanding of rTTC in COVID-19 by highlighting a unique temporal correlation between cytokine storm and cardiac dysfunction, thereby reinforcing the diagnostic value of echocardiography in this setting.

We report the case of a 48-year-old woman with no prior cardiovascular disease who developed rTTC triggered by a hyperinflammatory response associated with COVID-19 caused by the omicron variant.

Case Report

We present the case of a 48-year-old Hispanic woman who developed rTTC in the context of COVID-19 due to the omicron variant. Her medical history included morbid obesity (BMI: 44.2 kg/m2), hypertension, and rheumatoid arthritis. She had no prior cardiovascular disease and had completed a 4-dose COVID-19 vaccination schedule with ChAdOx1-S (AstraZeneca), with her last dose administered 2 months before admission.

She presented to the emergency department in early January 2023 with acute-onset chest pain, fever, fatigue, and dry cough. On examination, she was febrile (39.8°C), tachycardic (130 bpm), tachypneic (24 breaths/min), and mildly hypotensive (106/68 mmHg), with oxygen saturation of 96% on room air. Clinical findings included bilateral pulmonary crepitations, anterior thoracic erythema, and signs of dehydration. Initial blood tests showed lymphopenia (900 cells/μL) and markedly elevated ferritin levels (5421 ng/mL on Day 1), which peaked at 14 707 ng/mL on Day 4. Chest computed tomography (CT) revealed bilateral ground-glass opacities and left basal consolidation, consistent with COVID-19 pneumonia (Figure 1). SARS-CoV-2 infection was confirmed by RT-PCR.

By Day 4, cardiac biomarkers showed elevated troponin T (28 ng/L), increased N-terminal B-type natriuretic peptide (NT-proBNP) (1582 pg/mL), and elevated alanine aminotransferase (ALT; 178 U/L), while troponin I remained normal. Transthoracic echocardiography demonstrated basal hypokinesia of the inferior and inferolateral walls, with preserved apical contractility – hallmarks of rTTC (Figure 2). The left ventricular ejection fraction (LVEF) was moderately reduced (45%), global longitudinal strain was −14%, and grade I diastolic dysfunction was noted. Electrocardiogram (ECG) revealed sinus tachycardia, left anterior fascicular block, and non-specific ST-T changes in inferior leads. These features were consistent with the clinical and imaging distinctions between classical and reverse takotsubo cardiomyopathy (Table 1).

Given the non-specific ECG findings, preserved apical contractility, absence of ischemic ECG changes, and modest troponin T elevation, the diagnosis of rTTC was favored over myocardial infarction (low pre-test probability in a 48-year-old woman with atypical ECG and preserved apex). Coronary angiography was deferred due to low pre-test probability and rapid echocardiographic improvement.

The inflammatory phase (Days 1–3) was marked by high-grade fever, systemic inflammation, and respiratory symptoms. She received paracetamol (1 g every 8 hours), ritonavir (100 mg twice daily), supplemental oxygen, and prophylactic fondaparinux (2.5 mg daily, subcutaneously). On Day 4 (cardiac involvement phase), given the peak of inflammatory markers (ferritin: 14 707 ng/mL; C-reactive protein [CRP]: 95 mg/L) and echocardiographic findings of rTTC, cardioprotective and anti-inflammatory therapy was initiated with colchicine (0.5 mg daily) and spironolactone (25 mg daily).

In the subsequent days (Days 5–6), during the inflammatory peak, the patient remained tachycardic, and ventricular dysfunction persisted. Ferritin and CRP remained elevated. Colchicine and spironolactone therapy was continued.

During the resolution phase (Days 7–10), clinical improvement was observed with reduction of systemic inflammation, and echocardiography showed improved LVEF to 55%. On Days 11–12, she was clinically stable and afebrile, and functional recovery was evident. Laboratory tests showed a reduction in ferritin (1210 ng/mL) and NT-proBNP (106 pg/mL). She was discharged with outpatient follow-up and maintenance colchicine therapy. A detailed summary of the patient’s clinical evolution and interventions is provided in Table 2.

At her 6-month follow-up visit, a transthoracic echocardiogram showed full recovery of left ventricular systolic function (LVEF: 63% by Simpson’s method). Mild concentric remodeling of the left ventricle and grade I diastolic dysfunction persisted, however. The left atrium was within normal limits (volume: 33 mL/m2). Right ventricular function was preserved (tricuspid annular plane systolic excursion: 23 mm), with an estimated pulmonary artery systolic pressure of 16 mmHg. There were no valvular abnormalities or pericardial effusion. Advanced right heart and atrial function parameters that had not been evaluated during the acute hospitalization were included in this comprehensive follow-up evaluation. The evolution of her echocardiographic parameters is detailed in Table 3.

At her 12-month follow-up visit, a 12-lead ECG (identical to that performed as part of her preoperative assessment) showed sinus rhythm at 73 bpm, normal axis (−20°), and no ischemic or conduction abnormalities. QTc was 434 ms, within the normal range for women (≤450 ms). The patient remained asymptomatic and was cleared for elective surgery. No evidence of long-term cardiac sequelae was found.

Discussion

Reverse takotsubo cardiomyopathy is an emerging but uncommon cardiac complication associated with COVID-19. It is believed to arise from a complex interplay of endothelial dysfunction, systemic inflammation, and catecholaminergic surge, especially under cytokine storm conditions [6].

SARS-CoV-2 utilizes its spike (S) protein to bind to the ACE2 receptor for host cell entry, a process enhanced by TMPRSS2 and furin proteases [7]. ACE2 is highly expressed in cardiomyocytes and plays a protective role by counteracting the renin–angiotensin system. However, ACE2 downregulation during infection leads to elevated angiotensin II, promoting vasoconstriction, inflammation, and myocardial injury [8].

COVID-19 has been strongly linked to hyperinflammatory states such as cytokine release syndrome, characterized by elevated interleukin-6 (IL-6), ferritin, CRP, and cardiac biomarkers [9]. IL-6 induces endothelial activation and vascular hyperpermeability, triggering multi-organ dysfunction. This environment may compromise coronary microcirculation, leading to reversible myocardial dysfunction as seen in rTTC [10]. Additionally, acute stress and elevated catecholamines contribute to myocardial stunning and left ventricular contractile abnormalities. It has been suggested that rTTC may result from regional sympathetic hyperactivity or differential β-adrenergic receptor expression, predominantly affecting basal segments of the heart [11]. In our patient, these factors likely contributed to the development of basal hypokinesia with preserved apical motion.

Clinically, rTTC mimics acute coronary syndrome, presenting with chest pain and ECG abnormalities. Elevated troponin and NT-proBNP levels, though nonspecific, raise suspicion. Cardiac MRI and echocardiography are crucial for differential diagnosis, with the latter revealing the characteristic basal dysfunction seen in rTTC [12]. Although cardiac MRI was not performed in this patient, the rapid normalization of ventricular function, and biomarker decline, argue against irreversible necrosis, supporting reversible myocardial stunning due to rTTC [13].

In the setting of COVID-19, interpreting cardiac biomarkers is challenging due to inflammatory overlap. High NT-proBNP/troponin ratios may support TTC, though caution is advised, especially when troponin T >6 ng/mL or troponin I >15 ng/mL, as myocardial infarction becomes more likely [14].

Our case illustrates a clear temporal correlation between the inflammatory surge and myocardial dysfunction. Ferritin and CRP peaked during the cardiac involvement phase and gradually normalized with supportive and anti-inflammatory therapy. The patient experienced complete recovery of ventricular function by 6 months and remained asymptomatic at 1-year follow-up.

The severity of illness despite full vaccination may have been modulated by comorbidities – morbid obesity (BMI 44.2 kg/m2), hypertension, and rheumatoid arthritis – which are associated with heightened inflammatory responses and adverse COVID-19 outcomes [8,13]. This context likely amplified the hyperinflammatory milieu that precipitated the transient basal dysfunction observed in this case.

Similar to the case reported by Faqihi et al [10], our patient exhibited peak ferritin levels concurrent with left ventricle dysfunction and responded well to anti-inflammatory therapy. However, unlike most published cases, our patient was fully vaccinated, making this report uniquely informative.

Colchicine, with known ability to inhibit IL-1 and IL-6 pathways, has shown benefit in COVID-19 inflammatory control. Spironolactone may confer myocardial protection by mitigating aldosterone-mediated fibrosis, contributing to ventricular recovery in this case [15]. These therapeutic choices may have contributed to the favorable outcome observed.

This case emphasizes the need to consider rTTC in COVID-19 patients presenting with unexplained cardiac symptoms and disproportionate biomarker elevation. Early echocardiography is vital for diagnosis, especially when invasive testing is not feasible. Cardiac MRI may aid in excluding other pathologies if available [16]. Further studies are warranted to assess the utility of anti-inflammatory agents such as colchicine in rTTC, and to explore long-term outcomes in vaccinated patients with COVID-19–related cardiac events.

Conclusions

This case highlights the practical recognition and management of rTTC in the setting of COVID-19, underscoring the need to consider rTTC in patients presenting with unexplained cardiac symptoms and modest or disproportionate biomarker elevation. Early echocardiography is vital for diagnosis, especially when invasive testing is not feasible. Cardiac MRI may aid in excluding other pathologies if available [16]. The temporal coupling of inflammatory peaks with basal dysfunction, together with full functional recovery, supports a transient, inflammation-mediated mechanism consistent with rTTC.