COVID-19 has several adverse effects on the cardiovascular system. Cardiac injury with troponin leak is associated with increased mortality in COVID-19, and its clinical and radiographic features are difficult to distinguish from those of heart failure (HF). Cardiac involvement may occur with COVID-19 even without respiratory tract signs and symptoms of infection. Viral infection has been widely described as one of the most common infectious causes of myopericardial diseases, such as, coxsackie, enterovirus, herpes simplex, cytomegalovirus, H1N1, respiratory syncytial virus, parvovirus B19, influenza, varicella, HIV, rubella, echovirus, and hepatitis B and C. The data about cardiac involvement as a complication of SARS-CoV-2 infection remain limited. There have been reported cases of myocarditis, myopericarditis (perimyocarditis), pericarditis, pericardial effusion, and cardiac tamponade in COVID-19 patients. Myocarditis results in focal or global myocardial inflammation, necrosis, and eventually LV systolic dysfunction. The prevalence of myopericardial diseases among COVID-19 patients is unclear. It has been reported that that up to 7% of COVID-19–related deaths were attributable to myocarditis. However, this was based on assumption and not on confirmatory diagnosis of myocarditis; thus, it may be an overestimate.
A significant number of patients admitted to the hospital with COVID-19 have an elevated serum troponin level, which is associated with an adverse outcome. Elevated troponin levels could result from various mechanisms or a combination of various mechanisms, such as right ventricular strain due to lung involvement and/or pulmonary emboli, a type 2 myocardial infarction due to hypoxemia or secondary to a systemic inflammatory response, or direct myocardial injury or inflammation causing myocarditis. A study was conducted on COVID-19-positive patients with elevated serum high-sensitivity troponin T (hsTnT) due to uncertain etiology and who underwent cardiac MRI. This study showed high incidence of myocarditis (13 of 29 patients) and lower incidence of pericardial effusion (2 of 29) in such patients. The results of the study also showed a diagnosis of myocarditis in 1%-2% of the total number of rRT-PCR-positive patients and pericardial effusion diagnosed in approximately 10% of patients with COVID-19 myocarditis. Another study from Germany included a cohort of 100 patients who were recently recovered from COVID-19 and showed that 60% of patients had evidence of myocardial inflammation. Of those 60%, 70% had a detectable hsTnT (>3 pg/mL), whereas 5% had an hsTnT raised above the reference range (>13.9 pg/mL). On the other hand, about 20% of patients had a pericardial effusion >1 cm. In one meta-analysis approximately 5% of patients with COVID-19 who underwent CT of the chest had a detectable pericardial effusion.
Patients with previous cardiac disease and/or a structurally abnormal heart may be at increased risk of developing COVID-19 myopericarditis and cardiac tamponade. The definite mechanism of SARS-CoV-2-induced cardiac injury is unknown, but there are a few different possible theories:
Cytokine storm due to dysregulated but exaggerated immune response, which leads to increased vascular permeability, cell apoptosis, suboptimal T-cell and antibody responses, and acute respiratory distress syndrome (ARDS). Elevated levels of inflammatory markers have been seen in COVID-19 patients and a concomitant rise in cardiac biomarkers have been reported, which supports the cytokine release syndrome hypothesis. Interleukin (IL)-6 seems to be the central mediator of the cytokine storm, in which it promotes the proinflammatory responses from T lymphocytes. This process causes T-lymphocyte activation and a further release of inflammatory cytokines, which stimulate more T lymphocytes, leading to a positive feedback loop of immune activation and eventually myocardial damage. Cardiotropism of the T lymphocytes possibly arises from interaction between heart-produced hepatocyte growth factor (HGF) and c-Met, which is an HGF receptor on naive T lymphocytes.
Hypoxia secondary to SARS-CoV-2 ARDS, which can lead to inflammation, cell injury, and subsequent cardiac damage. It causes increased intracellular calcium deposition and apoptosis.
Direct injury by viral replication. One study reported the concurrent presence of a high SARS-CoV-2 viral load in patients with fulminant myocarditis. However, autopsies of COVID-19 patients revealed mononuclear cell inflammatory infiltrates without viral inclusions.
Angiotensin-converting enzyme 2 (ACE2)-mediated direct myocardial involvement. SARS-CoV-2 enters human cells by binding its spike protein to the membrane protein ACE2. ACE2 can be found on the ciliated columnar epithelial cells of the respiratory tract, type II pneumocytes, and cardiomyocytes. Therefore, it is possible that SARS-CoV-2 infects the human heart, especially in case of HF as ACE2 is upregulated, although the presence of viral receptors does not always predict tropism.
Clinical presentation of COVID-19 myocarditis or myopericardial diseases varies and ranges from asymptomatic to cardiogenic shock. Some patients may present with relatively mild symptoms, such as fatigue and dyspnea. Others may present with chest discomfort with rest and/or exertion. Many patients deteriorate quickly and show symptoms of sinus tachycardia and acute HF with cardiogenic shock. In such severe cases, patients may present with signs of right-sided HF, which include peripheral edema, elevated jugular venous pressure, and right upper quadrant abdominal discomfort. The 12-lead ECG abnormalities observed in myocarditis might include new-onset bundle branch block, QTc interval prolongation, pseudoinfarction patterns, premature ventricular complexes and brady/tachyarrhythmias, and varying degrees of atrioventricular nodal block.
Patients with COVID-19 pericarditis may present with a variety of nonspecific signs and symptoms. The major clinical manifestations of acute pericarditis include fever, leukocytosis, chest discomfort, pericardial friction rub, 12-lead ECG changes, and possible pericardial effusion, which might lead to cardiac tamponade. These clinical manifestations sometimes precede the COVID-19 respiratory or gastrointestinal symptoms. Chest discomfort is usually sharp and pleuritic, which improves by sitting up and leaning forward. A pericardial friction rub is a superficial scratchy or squeaking sound that can be best heard with the diaphragm of the stethoscope over the left lower sternal border. The common 12-lead ECG changes in such patients include widespread concave ST segment elevation or PR segment depression. In some COVID-19 patients, pericarditis may lead to pericardial effusion or cardiac tamponade. Patients with cardiac tamponade show similar clinical presentations as seen in obstructive shock. Clinical findings commonly associated with cardiac tamponade include hypotension, sinus tachycardia, pulsus paradoxus, elevated jugular venous pressure, and muffled heart sounds. The combination of hypotension, elevated jugular venous pressure, and muffled heart sounds is known as Beck’s triad. In cardiac tamponade patients, the 12-lead ECG may show low-voltage QRS complexes with electrical alternans, the latter resulting from the pendulum phenomenon.
COVID-19–related myopericardial diseases can be suspected based on appropriate history including clinical presentation, travel history or exposure to sick contacts, and detailed physical examination and laboratory tests including COVID-19 rRT-PCR and inflammatory and cardiac markers. The 12-lead ECG and TTE findings may help further in making an appropriate diagnosis. Myocarditis is often suspected in patients presenting with chest discomfort after an influenza-like syndrome. There is usually clinical evidence suggesting an acute coronary syndrome (ACS) on 12-lead ECG or laboratory testing or with evidence of LV wall motion abnormalities without evidence of obstructive coronary artery disease as demonstrated by selective coronary angiography. Laboratory tests in myocarditis patients usually show elevated levels of lactate and other inflammatory markers, including CRP, ESR, and ferritin. These levels are usually increased in sepsis as well. It is especially important to distinguish fulminant myocarditis from sepsis because fluid resuscitation, which is a common practice in patients with sepsis, exacerbates fulminant myocarditis. Furthermore, it is advisable to test patients for baseline cardiac biomarkers, such as cardiac troponin and N-terminal pro–B-type natriuretic peptide (NT-proBNP) on hospital admission as these levels are elevated in myocarditis due to the acute myocardial injury, dysfunction, and possible ventricular dilation. In contrast, a negative troponin result cannot exclude myocarditis, particularly for atypical forms such as giant cell myocarditis or for those patients in the chronic phase. On the other hand, negative serial cardiac troponin levels are still helpful in the acute phase and make the diagnosis of acute myocarditis unlikely.
Additionally, cMRI, endomyocardial biopsy (EMB), or pericardial fluid analysis further help in confirming the diagnosis of COVID-19–related myopericardial diseases. The gold standard for the diagnosis of myocarditis is histological examination of the myocardium by EMB. However, a diagnosis of myocarditis can be made in the absence of EMB evidence, which requires an appropriate clinical syndrome along with evidence of myocardial edema, nonischemic late enhancement, and high T2 signaling on cMRI. EMB in patients with COVID-19 is not always possible due to limitations, such as critical illness, therefore, it is too unstable to transfer the patient to the cardiac catheterization laboratory or infection control measures prevent infected patients from being moved through the hospital for tests. However, tissue diagnoses of COVID-19 myocarditis, both pre- and postmortem have been reported in case series by confirming the presence of viral particles in the myocardium. Other cases of lymphocytic myocarditis in COVID-19 patients have been reported in Germany. A recent case series reported an analysis of cardiac tissue from 39 consecutive autopsies in elderly COVID-19 patients, which showed detection of SARS-CoV-2 RNA in the myocardium of 24 patients. However, there was no evidence of viral presence in cardiomyocytes and there was a lack of massive cell infiltration or evidence of cardiac necrosis; therefore, it was concluded that myocarditis was not present in those cases.
The role of pericardial fluid analysis in the diagnosis of COVID-19–related myopericardial diseases is controversial. There are case reports from Italy in which the pericardial fluid of one patient with COVID-19 tested positive for SARS-CoV-2 RNA; however, only one out of three viral genes was present, which suggested a low viral load. There are few more case reports of pericardial disease in COVID-19 patients, but in such case reports no comment has been made about whether the aspirated sample was infected or sterile. Finally, there are cases of pericardial disease in which pericardial fluid samples taken from COVID-19 patients were negative for SARS-CoV-2 (Table 7-1 and Figure 7-3).
TABLE 7-1Diagnostic Findings Suggestive of COVID-19–Related Myopericardial Diseases ||Download (.pdf) TABLE 7-1 Diagnostic Findings Suggestive of COVID-19–Related Myopericardial Diseases
Clinical presentation of chest discomfort after an influenza-like syndrome
Elevated levels of lactate
Elevated inflammatory markers, including CRP, ESR, and ferritin
Elevated levels of cardiac biomarkers, such as cardiac troponin and NT-proBNP (negative troponin result cannot exclude myocarditis, but it can suggest the presence of a chronic variant of myocarditis)
Evidence suggesting ACS on 12-lead ECG or LV wall motion abnormalities on 2D echocardiogram without evidence of obstructive coronary artery disease demonstrated by selective coronary angiography
Evidence of myocardial edema, nonischemic late enhancement, and high T2 signaling on cMRI
Pericardial fluid analysis is controversial because it may or may not show SARS-CoV-2 RNA
Gold-standard for diagnosis of myocarditis is histological examination of the myocardium by EMB, which may show the presence of viral particles in the myocardium along with massive cell infiltration or evidence of cardiac necrosis
MRI showing the pericardial thickening in pericarditis.
The best choice of pharmacological treatment for pericarditis in patients with COVID-19 needs more data and studies. NSAIDs are usually first line in all acute and recurring cases of pericarditis with no contraindications. However, a retrospective study performed in France showed that patients on NSAIDs for symptom control before hospitalization for pneumonia developed more severe forms of the disease and had longer hospitalization stays. Furthermore, worsening of symptoms in four COVID-19 patients was noted after receiving NSAIDs and this result was soon supported by the French Health Ministry. Published data have shown that ibuprofen increases the expression of ACE2 receptors. However, there is epidemiological evidence that does not allow the establishment of a causal link for the negative effect of ibuprofen in patients with COVID-19. Additionally, World Health Organization (WHO) and the American Food and Drug Administration (FDA) guidelines do not recommend interrupting the use of ibuprofen in symptomatic COVID-19 cases. Because of these controversial data and reports, the use of NSAIDs should be considered only after weighing the risk-benefit ratio in symptomatic COVID-19 patients.
Currently, colchicine has been increasingly used along with NSAIDs in treatment for acute and recurring pericarditis with excellent results; therefore, the use of colchicine should be considered in cases of COVID-19 patients with pericarditis. Regarding the use of colchicine in COVID-19 patients, at least eight studies are registered on clinicaltrials.gov for the evaluation of its effects in alleviating systemic and/or myocardial inflammation. Furthermore, two studies are already in progress: the Colchicine Coronavirus SARS-CoV-2 Trial (COLCORONA) and the ECLA PHRI COLCOVID Trial: Effects of Colchicine on Moderate/High-Risk Hospitalized COVID-19 Patients.
Corticosteroids are widely used in treatments for acute pericarditis because these drugs improve symptoms and reduce inflammatory markers. However, the COPE study showed that use of corticosteroids should be limited to cases of intolerance, contraindications, or failure of treatment with NSAIDs and colchicine due to an increased risk of recurrence. COVID-19 has been shown to have a unique pathophysiology with the state of hyperinflammation and cytokine storm; thus, the use of corticosteroids could be considered for COVID-19 pericarditis due to its anti-inflammatory properties. However, the question remains: What is the ideal dose of corticosteroids in such patients? Potential risks of treatment with corticosteroids include risk of secondary infection and delay in viral clearance. Corticosteroids can be used in COVID-19 pericarditis patients as a substitute of NSAIDs with good results; however, more data are needed to support its use and to determine the best possible dose.
The management of COVID-19 myocarditis includes the use of immunomodulatory therapy, such as corticosteroids, intravenous immunoglobulin (IVIG), plasma exchange therapy, and cytokine inhibitors (tocilizumab). Antiviral agents such as remdesivir, supportive therapy such as mechanical ventilation, and cardiocirculatory-assist devices such as intra-aortic balloon pump counterpulsation are proved useful treatment modalities in patients with myocarditis. Ideally, treatment of myocarditis in COVID-19 patients should be modified based on the clinical presentation of each patient.