Coronaviruses have previously recorded two large epidemics in 2003 and 2012, respectively [
SARS-CoV-2 is an enveloped positive-sense single-stranded RNA virus. It spawns a wide spectrum of diseases affecting multiple organs. By early May 2020, the virus had already reached over 200 countries worldwide afflicting at least 4 million victims. As of February 10, 2021, there have been more than 106 million confirmed cases of COVID-19 and more than 2 million deaths around the globe [
Despite being of zoonotic origin, SARS-CoV-2 exhibits human-to-human transmission through the droplet, contact, and ocular routes. It can remain viable for 3 hours as an aerosol and for 72 hours on certain surfaces. The virus mainly invades the upper respiratory tract leading to respiratory symptoms. However, multisystem involvement is observed as well, including the cardiovascular system. Indeed, the natural history of COVID-19 proved that the cardiovascular system may act as a primary target for SARS-CoV-2 and thus may be influenced directly by the virus. Similarly, secondary sequelae of the disease provoke an indirect injury to the cardiovascular system. Therefore, it is reasonably valid that patients with underlying cardiovascular morbidities are at increased risk of experiencing severe disease and a higher mortality rate [
The virus can directly invade cells of various origins including the pulmonary, cardiac, and intestinal cells. Subsequently, tissues are injured through direct viral invasion and indirect release of cytokines and inflammatory markers. The exaggerated inflammatory response accompanied by the cytokine storm is a key player in the multiorgan involvement of the disease. Initially, most patients present with fever, dry cough, and shortness of breath. As the disease progresses, patients may develop nausea, vomiting, abdominal pain, and diarrhea [
Owed to the rapid development of events, a considerable amount of data has become available in the literature to explain the pathophysiology and clinical features of COVID-19. However, only a few reports provide a comprehensive review of the cardiovascular manifestations. Besides, when it comes to COVID-19 in the pediatrics population, the literature is scarce and limited. This is largely because children exhibit milder disease forms. In this paper, we provide a comprehensive review of the cardiovascular manifestations of COVID-19, with a special focus on the pediatric population.
The renin-angiotensin-aldosterone system (RAAS) is a complex system involved in regulating blood pressure and maintaining fluid and electrolyte balance. It can aggravate or precipitate atherosclerosis leading to myocardial hypertrophy and fibrosis [
The pathophysiology of COVID-19 is reflected by three phases. The first phase is triggered by viral penetration into the respiratory epithelium and is followed by cellular proliferation. The initial immune response is marked by the activation of monocytes and macrophages and is portrayed by mild symptoms. The next phase begins with pulmonary vasodilatation and increased vascular permeability. Leukocyte migration then ensues leading to fluid extravasation and pulmonary edema. Consequently, alveolar damage, hypoxemia, cardiac damage, and stress are precipitated. The final phase is characterized by a massive cytokine storm secondary to the exaggerated inflammatory response [
The excessive release of proinflammatory cytokines engenders a dramatically amplified immune response against the virus. Indeed, the plasma levels of interleukin-2 (IL2), interleukin-6 (IL-6), tumor necrosis factor
An Interplay between angiotensin II and SARS-CoV-2. SARS-CoV-2 cellular uptake is mediated primarily by the ACE2 receptor. Viral internalization is then followed by viral replication, assembly, and release. ACE2 is involved in converting angiotensin II (ATII) into angiotensin 1-7 (AT1-7). Unlike ATII, AT1-7 has anti-inflammatory, cardioprotective, and pulmoprotective effects with vasodilatory properties. Interestingly, SARS-CoV-2 binding to ACE2 provokes ACE2 internalization and downregulation. Consequently, this increases the circulatory levels of ATII and upregulates numerous proinflammatory, fibrotic, and vasoconstrictory pathways.
ACE2 is extensively expressed on the entire circulatory system, especially the coronary vessels. Vascular smooth muscles cells and endothelial cells present in both the arterial and venous systems express ACE2 on their surfaces. Viral entry and replication are potent triggers of an exaggerated immune response characterized by a cytokine storm and eventually by endothelial activation and dysfunction. The inflamed endothelium soon becomes dysfunctional and predisposes to a proinflammatory prothrombotic state [
The Chinese Center for Disease Control reported that <1% of the patients with COVID-19 were under the age of 10 years [
Cardiac-related clinical descriptions of pediatric patients with COVID-19.
Reference | Number of cases | Country | Age | Sex | Physical exam | ECG | Echo | Elevated labs | Imaging | Treatment | Outcome |
---|---|---|---|---|---|---|---|---|---|---|---|
[ | 1 | China | 55 d | F | Tachycardia, respiratory distress, pharyngeal hyperemia, cough | NA | NA | Troponin, CK-MB, procalcitonin | Ground-glass opacities, pneumonia | IVIG, inhaled interferon alfa 1b, glutathione, Chinese lotus qingwen | Survived |
[ | 1 | China | 13 m | M | Cough, crackles | NA | Heart failure | CRP, creatinine kinase, D-dimer, IL6, interferon-gamma, | Multiple patch-like shadows, pneumonia | Virazole, oseltamivir, interferon, IVIG, steroids, oxygen therapy, mechanical ventilation | Survived |
[ | 9 | China | 11 m-10 y | 3M | Productive cough | NA | NA | CK-MB, Pro-BNP, D-dimer | Pulmonary consolidation, ground-glass opacities | Inhaled interferon, ribavirin, lopinaviritonavir | NA |
[ | 13/2135 | China | 0–18 y | 12M | NA | NA | Heart failure | NA | NA | NA | NA |
[ | 3 | USA | 6–13 y | 2M | Tachycardia, tachypnea, hypotension, systolic murmur, dyspnea | Sinus tachycardia | Depressed function, MR, flow reversal in descending aorta, pericardial effusion | Procalcitonin, D-dimer, fibrinogen, troponin, CRP, LDH | NA | IL6 inhibitor, IVIG, hydroxychloroquine | Survived |
[ | 21 | France | 3–17 y | 9M | Cough | QT prolongation, ST-segment elevation, ventricular arrhythmia | Coronary artery dilatation, myocarditis, pleural effusion, depressed ejection fraction | CRP, procalcitonin, IL6, Pro-BNP, D-dimer | Local patchy shadows, ground-glass opacities, interstitial abnormalities | IVIG, aspirin, corticosteroids, inotropes, oxygen support, mechanical ventilation | Survived |
[ | 1 | USA | 6 y | F | Syncope, respiratory distress, hypotension | Junctional rhythm | Depressed ejection function, MR | CRP, procalcitonin, Pro-BNP, D-dimer | Diffuse patchy infiltrates | Aspirin, IVIG, inotropic support, oxygen support, ECMO | Survived |
[ | 99 | USA | 0–20 y | 53M | Hypotension, cough, shortness of breath, wheezing | NA | Ventricular dysfunction, pericardial effusion, CAA | Troponin, Pro-BNP, D-dimer, CRP, fibrinogen, ferritin, ESR | Opacities, pleural effusion | Corticosteroids, IVIG, oxygen support, inotropic support, ECMO | 2/99 died |
[ | 186 | USA | 0–20 y | 115M | NA | NA | Coronary artery dilatation, CAA, depressed EF, pericardial effusion | Pro-BNP, troponin, D-dimer, fibrinogen, INR | NA | IL6 inhibitors, IL1Ra inhibitor, IVIG, corticosteroids mechanical ventilation, ECMO, vasopressor support, oxygen support | 4/186 died |
[ | 15 | USA | 3–20 y | 11M | Cough, dyspnea, chest pain, tachycardia, hypotension | Ventricular tachycardia, and ectopy, diffuse ST elevation | Depressed LV/biventricular function, coronary artery ectasia and dilatation, cardiogenic shock | Troponin, Pro-BNP, fibrinogen, CRP, D-dimer, procalcitonin, IL6, IL8, TNF alfa | Ground-glass opacities, pleural effusion | IVIG, steroids, anakinra, remdesivir, inotropic support, anticoagulation, mechanical ventilation, ECMO, intraaortic balloon pump, tocilizumab, COVID-19 convalescent plasma, | 1/15 died |
[ | 5 | France and Switzerland | 2–16 y | 18M | Respiratory distress, chest pain | Ventricular arrhythmia, nonspecific ST elevation | Cardiogenic shock, LV dysfunction and hypokinesis, coronary artery dilatation, pericardial effusion | Troponin, creatinine kinase, Pro-BNP, D-dimer, CRP, procalcitonin, IL6 | NA | Inotropic support, mechanical ventilation, ECMO, IVIG, steroids, anakinra | Survival |
[ | 4 | USA | 3–20 y | 3M | Tachycardia | Low voltage nonspecific | Myocarditis, MR, depressed LV and RV functions, pericardial effusion | CRP, ferritin, troponin, pro-BPN, D-dimer, ferritin, fibrinogen | NA | IVIG, anticoagulation, tocilizumab, convalescent plasma, mechanical ventilation, ECMO | 1/4 died |
[ | 1 | USA | 6 m | F | Tachycardia, tachypnea | NA | Normal | ESR, CRP | Opacities | Aspirin, IVIG | Survived |
[ | 156 | France | 5–11 y | 77M | NA | NA | Myocarditis | NA | NA | Mechanical ventilation, inotropic support | 1/156 died |
There are three mechanisms that lead to cardiac involvement in the setting of COVID-19: (1) direct injury caused by direct viral entry to myocardial cells, (2) hypoxia-induced myocardial ischemia, and (3) heightened exaggerated inflammatory response characterized by endothelial overactivation and microvascular thrombi [
In a similar manner, the inflammatory markers correlate with electrocardiographic abnormalities and cardiac injury [
Oudit et al. performed autopsies on patients with confirmed SARS infection. He reported that 35% of these patients had the virus’s genome embedded in the DNA of the myocardial cells. The same subset of patients had a more aggressive course during their illness as compared to patients without cardiac involvement [
Type I myocardial injury is defined by the acute elevation in cardiac troponin levels with or without evidence of myocardial ischemia on an electrocardiogram. The presence of acute myocardial injury among COVID-19 patients was identified as a significant factor associated with a 3.4-increased risk of death. Similarly, it is estimated that one-third to one-fifth of hospitalized patients with COVID-19 will have evidence of acute myocardial injury. Additionally, the presence of myocardial injury is also associated with a higher need for mechanical ventilation [
Myocardial infarction, under the umbrella of acute myocardial injury, is caused by the dislodgement of an atherosclerotic plaque in individuals with atherosclerosis. Viral products can predispose to plaque displacement by binding to and activating immune receptors on cells present within the plaque. This cascade of infection and inflammation causes coronary endothelial dysfunction and thrombosis [
Type II MI emanates from an imbalance in myocardial oxygen demand and supply. In the setting of COVID-19, type II MI may arise from several contributory factors: (1) the presence of an atherosclerotic plaque that predisposes to gradual reduction in blood flow, (2) a dysfunctional endothelium, (3) elevated levels of ATII, (4) hypertension and vasoconstriction, and (5) hypoxemia [
The incidence of myocardial ischemia in the general COVID-19 population ranges between 7% and 40%, which reflects the heterogeneity of the studied population [
Heart failure and myocardial damage contributed to approximately 40% of the deaths of SARS-CoV-2-positive patients. This mortality risk is significantly higher than the one associated with older age and prior medical diseases [
In adults, injury to the myocardium and subsequent troponin elevation was reported in up to 12% of SARS-CoV-2-infected patients [
In addition to the increased mortality risk, elevated troponin levels also correlate with a worse clinical picture (higher need for mechanical ventilation), as well as higher levels of other biomarkers such as IL-6, CRP, and D-dimer [
Patients commonly present with tachycardia, which later leads to impaired diastolic filling and subsequent systolic and diastolic dysfunction. Eventually, mortality increases when patients present with hypotension and heart failure. A large cohort study reported that up to 7% of patients with SARS-CoV-2 had an element of left ventricular diastolic dysfunction with ensuing low cardiac output. On the other hand, in this same cohort, left ventricular systolic dysfunction was reported in more >50% of patients [
In one of the largest cohort studies in China limited to the pediatric population, 13 out of the 2135 patients who tested positive for SARS-CoV-2 had cardiac involvement [
Myocarditis is defined as inflammation in the myocardium of the heart. Once present, it can cause dysfunction in the cardiac muscle, disruption in the electrical system, and reduction in cardiac contractility. The incidence is currently unknown in patients with COVID-19, as the evidence in the literature is limited to case reports [
In a large pediatric cohort study, myocarditis was noted in 71% of the admitted patients [
There are different types of arrhythmias described in the setting COVID-19 infection. The long list includes but not limited to sinus tachycardia, atrial arrhythmia, first-degree atrioventricular block, nonsustained ventricular tachycardia and fibrillation, premature atrial and ventricular beats, and incomplete right bundle branch blocks [
The severe systemic inflammation in COVID-19 can precipitate cardiotoxicity and lead to cardiovascular dysfunction. Patients with sepsis-induced cardiomyopathy tend to have elevated circulating levels of inflammatory markers such as IL-6 and TNF-
In April 2020, the National Health Services in the United Kingdom reported the first case of MIS-C. At the time, it was a new combination of atypical Kawasaki disease and toxic shock syndrome under the umbrella of severe COVID-19. Later, the WHO and the United States Center for Disease Control and Prevention set criteria for diagnosis with overlapping features [
Patients who develop MIS-C amidst their SARS-CoV-2 infection are usually older than patients who develop Kawasaki disease alone with the median age being 9 years in the former. The presentation tends to begin around 4–6 weeks after contracting the virus, and they are usually PCR-negative. They commonly report fever and a spectrum of respiratory symptoms ranging from cough to dyspnea. 70% of patients with MIS-C also report gastrointestinal symptoms such as abdominal pain and diarrhea. Other signs and symptoms that are related to the Kawasaki-like features are rash, fissured lips, and conjunctivitis [
Clinical and laboratory manifestations of MIS-C. The most common and prominent features in patients with MIS-C include persistent fever, mucocutaneous manifestations, gastrointestinal symptoms, organ dysfunction, and significantly elevated inflammatory markers. The multiorgan effect of the SARS-CoV-2 is summarized in this figure.
While most patients are managed with inotropic support, a large cohort study revealed that around a third of the pediatric patients presenting with MIS-C required extracorporeal membrane oxygenation [
Patients with MIS-C may develop coronary artery abnormalities such as dilatations and aneurysms. Reports have demonstrated an array of descriptions ranging from small aneurysms to giant ones. While it has been hypothesized that a mechanism similar to that observed in Kawasaki disease occurs with MIS-C, the true pathophysiology behind coronary artery abnormalities has not been elucidated yet [
In addition to coronary artery abnormalities, the second most common cardiac abnormality in MIS-C is arrhythmia. First-degree heart block is the most common presentation of arrhythmia. It has been commonly reported in children presenting with LV dysfunction. Electrocardiogram reveals QT prolongation, ST-segment changes, or T-wave abnormalities [
Cardiac transplant patients are a vulnerable population whose immunosuppressed state poses a risk of severe forms of COVID-19 infection. Despite their scarcity, reported cases and series on transplant recipients with COVID-19 show a heterogeneous clinical spectrum ranging from mild presentations to more severe forms [
Cardiovascular involvement incurs significant prognostic value to patients diagnosed with COVID-19. Multidisciplinary teams with cardiology services are essential for managing all complications in patients suffering from COVID-19, as well as in patients with underlying cardiac diseases who are prone to severe and critical COVID-19. Ultimately, we argue that allocating sufficient resources for timely diagnosis and management of cardiac complications is crucial in reducing morbidity and mortality secondary to cardiovascular sequelae. In addition, performing a thorough evaluation with an electrocardiogram, echocardiography, and basic cardiac workup is essential for timely diagnosis and treatment.
Coronary artery aneurysm
C-reactive protein
Days
Extracorporeal membrane oxygenation
Ejection fraction
Erythrocyte sedimentation rate
Females
Interleukin-1 Receptor antagonist
Interleukin-6
Interleukin-8
International normalized ratio
Intravenous immunoglobulin
Lactate dehydrogenase
Left ventricle
Males
Mitral regurgitation
Not applicable
B-type natriuretic peptide
Right ventricle
Tumor necrosis factor alfa
The United States of America.
Data are available upon request.
The authors have no conflicts of interest to declare.
Tania Abi Nassif and Ghina Fakhri contributed equally to this manuscript.