Cardiovascular impact of COVID-19 with a focus on children: A systematic review

Table 2 Hypothesized pathophysiological mechanisms for cardiac injury in coronavirus disease-2019

Mechanism	Explanation
COVID-19–related myocarditis	SARS-CoV-2 may directly cause myocardial damage by entering cardiomyocytes using the ACE2 receptor, a human cell receptor with a strong binding affinity to the virus spike protein of SARS-CoV-2 (highly expressed in the heart). The virus is also capable of active CD8+ T lymphocytes migrate to the cardiomyocytes and cause myocardial inflammation through cell-mediated cytotoxicity. There is evidence demonstrating that SARS-CoV-2 infects the myocardial tissue.
Deregulated immune response & cytokine storm	SARS-CoV-2 infection may lead to deregulated immune response with higher neutrophil-lymphocyte-ratio, lower levels of both T helper and T suppressor cells, and higher expression of pro-inflammatory cytokines (IFN-γ, TNF, IL-1, IL-6 and IL-18), which are released into the circulation. This cytokine storm syndrome has a role in cardiovascular system injury, causing multi-system inflammation and multi-organ failure with direct cardiotoxicity and rapid onset of severe cardiac dysfunction, hemodynamically instability and vascular leakage with peripheral and pulmonary edema.
Oxygen supply and demand imbalance	Myocardial injury may result from the imbalance between oxygen supply and demand due to a severe acute respiratory distress syndrome and systemic hypotension with myocardial hypo-perfusion in association with increased cardio metabolic demand in the myocardial tissue. This can result in myocytes hypoxia and necrosis.
Thromboembolic events	The systemic inflammation secondary to the cytokine storm also causes endothelial dysfunction and increases the procoagulant activity of the blood, which can further contribute to the formation of multi-organ micro thrombi and also occlusive thrombi over a ruptured coronary plaque.
Cardiotoxicity of drugs used against SARS-CoV-2	Off-label drugs available for COVID-19 treatment can produce myocardial dysfunction, severe systemic hypotension, QT prolongation with ventricular arrhythmia and AV block
Deleterious effects of inotropes and mechanical ventilation	Mechanical ventilation in critically ill children is another possible cause of cardiovascular adverse effects, such as a decrease in cardiac output due to decreased venous return to the right heart, right ventricular dysfunction, and impaired left ventricular elastics. Increased right ventricular after-load due to the pulmonary infection can be worsened by mechanical ventilation with high PEEP, leading to right ventricular failure and subsequent myocardial injury. Inotropes can provoke an increased cardio metabolic demand during an hypoxemic condition,
Pre-existing Heart diseases	Patients with pre-existing heart diseases have increased morbidity and mortality related to viral infection It is reasonable to assume that patients with underlying heart diseases with low cardiopulmonary reserve are susceptible to cardiac injury, and once such patients are infected with COVID-19, myocardial ischemia or infarction, and left ventricular systolic dysfunction or ventricular arrhythmia are more likely to occur, ultimately leading to a sudden deterioration.

ACE2: Angiotensin-converting enzyme 2; COVID-19: Coronavirus disease-2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; IFN: Interferon; TNF: Tumor necrosis factor; IL: Interleukin.