Introduction
Injuries of the myocardium, which includes acute myocardial inflammation, are well-documented complications of acute coronavirus disease 2019 (COVID-19). According to a 2020 review, approximately 5-25% of patients hospitalized with COVID-19 had evidence of myocardial injury. There are still many questions which remain unanswered regarding the descriptions of cardiac involvement and underlying mechanisms of heart injury. Additionally, the risk of thromboembolic complications is increased up to 90 days post discharge after COVID-19 infection. Several mechanisms including severe inflammation, myocardial stunning, catecholaminergic and ischemic mechanisms, and emotional stress can lead to Takotsubo cardiomyopathy (TCM) as a form of acute heart failure. The present report describes a case of massive post COVID-19 pulmonary embolism (PE) and Takotsubo cardiomyopathy presenting as myocardial infarction with non-obstructive coronary arteries (MINOCA) in the same patient two weeks after the PE event.
Case report
We present the case of a 56-year-old woman hospitalized at Cardiology Clinic due to severe dyspnea, palpitation, and weakness. She was physically active and without previous cardiovascular disease. She also denied other comorbidities or risk factors. The symptoms started three hours before the presentation. As to medical history, she only reported hospitalization due to COVID-19 infection two months before, presenting with mild pneumonia and stable clinical course. She was discharged with aspirin therapy. The patient denied any provocable PE risk factor (no history of injury, no surgical treatment, bed rest over 72h, no cancer history, no history of contraceptives or hormone therapy, no signs of DVT or previous PE/DVT). Her BMI was 26. On physical examination, she was afebrile and tachypneic, with a respiratory rate of 23 cycles/min. She was hemodynamically unstable, with a blood pressure of 90/55 mmHg, heart rate of 120 bpm, cold periphery, and disturbed cognition. There were no signs of fluid overload or DVT. The electrocardiogram showed sinus rhythm with a heart rate of 120 bpm and the presence of right bundle branch block. Due to the assessed high probability of PE (Wells score >4), urgent echocardiography (Figure 1) was performed aiming to evaluate the causes of the patient’s symptoms. The examination showed signs of pulmonary artery hypertension (PAH) with severe tricuspid regurgitation (Vmax 56 mmHg), dilated and incompressible vena cava (23 mm), severely dilated right ventricle, D-shaped left ventricle, hypokinesia of the mid-right ventricle (RV) free wall compared to the apex (McConnel’s sign) with reduced RV function – TAPSE 16, and shortened pulmonary accelerated time (AT 58 msec) (60/60 sign). Left ventricular function was normal. Those parameters showed indirect signs of possible PE. The patient was hospitalized, and heparin therapy was started. Computed tomography (CT) angiography of the thorax was performed, which revealed pulmonary embolism in the bilateral main pulmonary artery (MPA) involving the right MPA and involvement of a few segmental arteries (Figure 2). Ultrasound of the bilateral lower extremity was normal. D-dimer values were 35562 μg/mL. The patient’s laboratory results and CRP were within normal values. High-sensitivity troponin I (Hs-cTn I) was increased, with a value of 74 ng/L, and the NT-proBNP value was 1421 pg/mL. Other laboratory findings were within normal ranges, with preserved renal function for the patient’s age. Calculated glomerular filtration rate was 78 mL/min/1.73 m2. Based on the hemodynamic profile, echocardiography findings of RV dysfunction, sPESI score >1, and elevated troponin levels, the patient was initially assessed as a high risk for early mortality. Gas analyses were within normal limits, with slightly decreased pCO2 levels (pH 7.41, pCO2 26 mmHg, pO2 74mmHg, HCO3 16.5 mmol/l, S02 95%, lactate 1.5 mmol/l).
Due to high clinical risk, the patient was treated with fibrinolytic therapy (Actilyse 100 mg infusion for two hours) with significant clinical improvement after three hours. BP normalized to 120/75 mmHg, HR 90 bpm, SO2 95% on room air. Further management used unfractionated heparin 25.000 IE daily over three days. After that period, the patient was placed on rivaroxaban treatment 15 mg bid. Control echocardiography 7 days after admission showed significant reduction of RV size, reduced tricuspid regurgitation, negative McConnel’s sign, and no thrombotic formations in the right atrium and vena cava. Pre-discharge D-dimers values were 1987 μg/L. The patient was discharged after 10 days, clinically stabilized on oral anticoagulation with rivaroxaban 15 mg bid for 21 days and 20 mg od for the next six months.
Two weeks after the discharge, the patient was once again hospitalized with chest pain and ECG signs (Figure 3) of ST segment elevation myocardial infarction and hs-troponin I 650 ng/L. Coronary angiography was performed (Figure 4), which showed normal coronary arteries, and LV ventriculography showed apical ballooning. Echocardiography (Figure 5) showed new wall motion abnormalities with apical and apicoseptal akinesia, with a left ventricular ejection fraction of 49%. RV function was normalized, with no signs of pulmonary hypertension. The patient also reported severe stress in the preceding weeks due to worsening of her young daughter health, who was severely paralyzed. We classified the patient as possible Takotsubo cardiomyopathy as a cause of MINOCA. The patient was clinically stable. She was discharged with prescription of heart failure therapy (ACE inhibitor, beta blocker, spironolactone, rivaroxaban, statin) after 5 days. Control echocardiography after three weeks (Figure 6) revealed normal LV function, without any regional wall motion abnormalities, and EF of 61%. The patient was asymptomatic, with normalized D-dimer values. This finding enabled us to confirm our diagnosis of Takotsubo cardiomyopathy with severe psychological stress and previous high-risk PE after COVID-19 infection.
Discussion
The COVID-19 outbreak was a major global health challenge. Early reports suggest incidences of DVT and PE of up to 30% in patients with COVID-19 infection (1). It is estimated that approximately 50% of these patients have elevated D-dimer levels during disease progression, which is closely associated with the risk of increased thrombosis and poor prognosis of the disease (2-5). Elevated D-dimers, elevated CRP, and neutrophils rising over time are risk factors for pulmonary embolism in COVID-19 patients, although D-dimers should always be analyzed together with clinical presentation and PE risk. Scientific data showed increased odds of in-hospital death associated with D-dimer values >1 μg/mL (3,5). Severe forms of the disease have been correlated with multiorgan involvement, supporting to the recommendations for therapeutic anticoagulation in patients with COVID-19 with increased PE risk, several risk factors and comorbidities, and elevated D-dimer levels (4). Recent literature suggests that the risk of thromboembolic complications in hospitalized patients with COVID-19 remains elevated up to 90 days after discharge. Echocardiography imaging of RV function in patients with PE is also an important imaging prognostic parameter. It enables rapid bedside guidance for suspected PE diagnosis, assessment the causes of clinical deterioration in the patient, risk stratification, and treatment. The proposed mechanisms for COVID-19-induced thrombosis include cytokine-mediated diffuse microvascular damage, a disease-specific hypercoagulable state, hypoxia, immobilization, diffuse intravascular coagulation and, in some cases, reactive thrombocytosis (6). The risk of thrombosis and PE can further be increased by obesity, advanced age, and hospitalization-related immobilization. In the present case, the patient had elevated C-reactive protein and D-dimer levels with no other risk factors for pulmonary embolism, thereby indicating a COVID-19-related hypercoagulable state as a possible cause of PE.
The use of empiric prophylactic anticoagulation in hospitalized patients with COVID has been recommended based on expert opinions and scientific guidelines (1,7). The true incidence of PE/DVT in patients receiving pharmacological thromboprophylaxis remains uncertain. Fibrinolytic therapy is lifesaving for management of PE in patients with cardiogenic shock. Our patient represents a case of successful treatment of massive PE leading to cardiogenic shock. The stress stemming from the patient’s personal life accompanied by the stress induced by the worsened health of the patient’s child and recent hospitalization for COVID-19 infection may have led to development of Takotsubo cardiomyopathy soon after the PE episode in our patient. The patient exhibited fast recovery of LV function. TCM is a form of reversible stress-induced cardiomyopathy, occurring mainly in postmenopausal women and characterized by a transient hypokinesis of the LV apex and midventricular myocardium associated with emotional or physical stress. According to literature data, patients with TCM accounted for approximately 2% of all the patients with suspected acute coronary syndrome, and it is a one of the causes of MINOCA (8,9). TCM has a good prognosis, with LV function reversing within several weeks or months. There are however some reports of TCM-induced complications, including heart failure, ventricular rupture, LV apical thrombosis, and malignant arrythmias (9). This syndrome is assumed to be caused by catecholamine toxicity, coronary spasm, coronary microvascular dysfunction, inflammation, and electrophysiological abnormalities.
The use of beta-blockers and ACE inhibitors is recommended in patients with TCM and left ventricular dysfunction and is associated with improved survival. Antiplatelet therapy is not routinely recommended and may be associated with increased mortality.
Conclusions
Hospitalized patients after COVID-19 infection are at increased risk of thromboembolic complications. Fibrinolytic therapy is a lifesaving treatment in patients with massive PE and hemodynamic instability. Psychological and physical stress, inflammation, and hypoxia can trigger myocardial injury in the form of Takotsubo cardiomyopathy as a cause of MINOCA. Awareness of the causes of these complications can lead to better patient management.