Cardiac injury was defined by any abnormality observed in the cardiac biomarkers, electrocardiography, or echocardiography from the previous studies (Table 1).7)8)18)19)20) However, the definition in each study varies because there is no unified consensus of the definition in COVID-19 associated cardiac injury. Even though there was a high incidence and substantial impact of cardiac injury, it was not always possible to evaluate the whole set of cardiac injury markers (cardiac biomarkers, electrocardiography, and echocardiography) during the highly infectious virus pandemic. Most of the SARS-CoV-2 infected patients has a milder course with a complete recovery, which would not necessitate an evaluation. It is reasonable to perform those tests in patients with more serious disease course.21)

For the critical care patients, an evaluation of cardiac injury is readily feasible. Arentz et al.21) adopted a more specific definition of cardiac injury (more precisely, cardiomyopathy) in COVID-19 patients admitted to the intensive care unit (ICU). Cardiomyopathy was defined as evidence of a new-onset left ventricular systolic dysfunction on transthoracic echocardiogram when any one of following criteria is met: clinical signs of cardiogenic shock; an elevation in the creatinine kinase or troponin I level; a decrease in the central venous oxygen saturation (<70%).

In general, tests for the cardiac manifestation in COVID-19 is performed when the patient has cardiac symptoms such as chest pain or dyspnea, cardiomegaly observed on the chest X-ray or on the chest computed tomography (CT), or when the physician considered the test is necessary in such cases of unstable vital sign. Cardiac injury associated with COVID-19 is diagnosed when any one of the parameters is positive: cardiac enzyme elevation; new-onset or first detected abnormality by electrocardiography; new-onset or first detected abnormality by echocardiography. After the diagnosis of COVID-19 associated cardiac injury, investigation of the etiology, the decision for the future treatment strategy, and assessment of the prognosis need to be proceeded (Figure 2).

The incidence of cardiac injury associated with the SARS-CoV-2 infection is reported to be 7.2% in the overall patients, 2% in non-ICU patients, and 22% in ICU patients.7) In other reports, the incidence of cardiac injury reach up to 27.8–31% in accordance with the definitions and patient characteristics.8)19) The incidence of cardiomyopathy in ICU patients treated for COVID-19 was 33.3% and the mortality in the study population was 52.4%.21)

The mortality in COVID-19 has been caused mainly by respiratory failure due to severe acute pneumonia. However, a systemic inflammatory response syndrome, including a cytokine storm, and myocardial damage such as acute fulminant myocarditis with arrhythmic manifestations, can lead to sudden cardiac death.7)10)11)16) In this regard, the cardiac injury related to the SARS-CoV-2 infection is considered as an important issue. Patients with a previous history of coronary vascular disease and evidence of cardiac injury by elevated cardiac enzymes (Troponin-T levels) had a higher incidence of mortality.8)

The cardiac injury related to the SARS-CoV-2 infection can be explained by several mechanisms (Figure 3). The first mechanism is ACE2-mediated direct cardiac damage. ACE2 has been identified as a functional receptor for coronaviruses. The SARS-CoV-2 infection is triggered by binding of the spike protein of the virus to ACE2, which is highly expressed in the heart and lungs. The second one is hypoxia-induced myocardial injury. Oxidative stress, intracellular acidosis, and mitochondrial damage followed by hypoxia might result in cardiac injury. Previously, significantly lower oxygen saturation levels and a higher incidence of dyspneic symptoms was noted in the cardiac injury patients. The third is the cardiac microvascular damage caused by vessel hyperpermeability and angio-spasms under conditions of inflammation. The fourth mechanism is systemic inflammatory response syndrome, such as the cytokine storm, caused by the inadequate responses of type 1 and type 2 helper T cells, which may contribute to the myocardial injury.12) Fulminant myocarditis can be related to the immunologic response during a viral infection.22)23)24) The fifth can be explained by epicardial coronary artery occlusions due to an acute plaque rupture owing to coagulopathy with plaque instability driven by a systemic inflammatory response. The last one is stress-induced cardiomyopathy because of the severe stress during the course of the SARS-CoV-2 infection.12)16)25)26)27) The cardiac injury related to COVID-19 cannot be explained separately by each mechanism. Multiple factors affect the cardiomyocytes, epicardial coronary arteries and coronary microvasculature in a various way at each timepoint of the disease trajectory.9)10)11)12)16)28)29) Evaluation of the major mechanism of cardiac injury in COVID-19 is important to set up further therapeutic strategies.

Although the true incidence is unclear, acute coronary syndrome (ACS) can occur in COVID-19 patients. The risk of ACS in SARS-CoV-2 infected patients may be increased due to an increased thrombotic tendency, evidenced by elevated D-dimer levels in the previous studies.7)18)19) In the inflammatory milieu, endothelial and smooth muscle cell activation, macrophage activation and tissue factor expression in atheromatous plaque, and platelet activation with further elaboration of inflammatory mediators can precipitate plaque rupture resulting in ACS.30) Not just a typical type 1 myocardial infarction (MI), but a type 2 MI related to the increased demand during the virus infection can develop especially in patients with underlying coronary artery disease.31) Frequently, the symptoms of an infection and the signs of non-ischemic cardiac injury can masquerade as ACS, and therefore a high index of suspicion for alternative diagnosis is mandatory by utilizing non-invasive diagnostic methods (cardiac biomarkers, electrocardiography, echocardiography, and cardiac CT).28)32) Given the risk of an infection spreading to other patients and to the healthcare providers during the transportation and procedure, adjusting the protocols for ACS treatment with increasing consideration for thrombolytics is considered in many centers during the virus pandemic.33)34)35)36)

Increased evidences has shown that COVID-19 is burdened by a higher risk of arrhythmic events, with a related risk on mortality.37) Palpitations have been reported as one of the most common initial symptoms of this disease (7.3%).37) In 138 hospitalized COVID-19 patients, arrhythmias represented the leading complication (19.6%) after acute respiratory distress syndrome, with an increased risk of up to 44.4% in those admitted to intensive care units. More serious arrhythmic complications such as ventricular tachycardia or ventricular fibrillation were found in 5.9% of cases.37)38) The risk of arrhythmias can be associated with cardiomyopathy caused by cardiac injury, or possibly related to the usage of anti-viral/anti-bacterial medications causing QT-prolongation.28)38) Physicians should keep in mind the risk of increased arrhythmic events in COVID-19 patients, which can significantly affect the overall mortality. Close monitoring for arrhythmic events and careful decision making for anti-viral/anti-bacterial medications is crucial especially in a serious disease status with a vulnerable status.

There are several reports of SARS-CoV-2 with cardiac involvement as the presentation of acute myocarditis.10)22)24)39) The pathogenesis of cardiac involvement associated with SARS-CoV-2 may reflect a process of a replication and dissemination of the virus through the blood or lymphatic system from the respiratory tract. Tavazzi et al.39) reported the myocardial localization of SARS-CoV-2 with myofibrillar lysis and inflammatory cell infiltration during the acute phase of COVID-19. The general immunologic response in viral myocarditis is as follows: first, there is the viral entry and activation of the innate immune response, which takes 1–7 days after the infection; second, there is the activation of the acquired immune response by natural killer cells, macrophages, and T-lymphocytes which takes 1–4 weeks; and lastly, there is either recovery by the clearance of the virus or disease progression by the delayed and ineffective viral clearance with chronic inflammation, which takes months to years.40)41)42)43) The extent of the local tissue damage and cytokine storm triggered by the host immune response both contribute to the severity of the myocarditis. An exaggerated inflammatory response can be extremely fatal, and immunomodulators such as corticosteroids are considered in selected cases even though the efficacy and safety is questionable.28)44) Combined with these mechanisms related to a host immune response, multiple factors are responsible for the cardiac consequence of COVID-19, such as an oxygen supply and demand imbalance (with or without coronary artery disease), increased right ventricular afterload due to respiratory acidosis, hypoxemia and positive pressure ventilation.29)39) Even though it is difficult to discriminate all the possible mechanisms related to myocarditis, accordingly the effort to identify the dominant cause is necessary for the selection of the proper target treatment.

Patients with SARS-CoV-2 infection related cardiac injury including myocarditis could present with acute decompensated heart failure (HF) (Figure 2). They might have HF with a reduced or preserved ejection fraction.28)

Infection is one of the major precipitating factors of acute decompensation in HF, and patients admitted with acute HF precipitated by an infection had a high 90‐day risk of death.45)46) It is necessary to exert every effort to reduce the risk of SARS-CoV-2 infections in patients with HF—social distancing, hand washing, wearing personal protective equipment, and reducing unnecessary hospital visits.4) Maintaining an optimal guideline directed medical therapy including angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) is also highly recommended since there is no sufficient evidence to discontinue these critical medications for the concern of increased viral invasion due to the increased expression of ACE2.4)47) This issue will be discussed in detail later in a separated part.

Thrombosis is a common consequence of an infection and is associated with a poor patient outcome. Many viral infections affect the pathways of hemostasis and coagulation, inducing either thrombotic or hemorrhagic complications.48) In patients with pneumonia caused by an influenza infection, the occurrence of venous thromboembolisms has been shown to be increased.49) Assessing the risk of venous thromboembolisms is essential especially in COVID-19 patients with a critical condition. Early reports from China showed a higher prothrombin time and D-dimer level on admission in ICU patients with COVID-19 as compared to non-ICU patients.19) A retrospective analysis of 183 COVID-19 patients also revealed a higher D-dimer and fibrin degradation product in non-survivals.50) Patients with COVID-19 in a critical condition would have complications such as renal failure, respiratory failure, or liver dysfunction, which can affect both venous thromboembolisms and the bleeding status.3)7) Among the patients with COVID-19 at high risk for venous thromboembolism, 44 (11%) of 407 also had a high risk of bleeding.51) Therefore, anticoagulation should be considered with a balance of the thrombotic risk and bleeding risk. When COVID-19 patients are indicated for anticoagulation therapy, the dose and duration of drug should be adjusted individually, and non-medical prophylactic measures need to be fully utilized such as mechanical compressions with elastic compression stockings or intermittent pneumatic compression.

There has been concern about using ACEi or ARB in COVID-19 patients owing to their role in altering the ACE2, which acts as a functional receptor of SARS-CoV-2.12)47) A high incidence of SARS-CoV-2 infections in patients with hypertension, heart failure, or cardiovascular disease who are common renin-angiotensin-aldosterone system (RAAS) blocker users increased the suspicion of their harmful effects.3)7)17)54) Inconsistent results of the previous animal models with respect to the effects of RAAS inhibitors on ACE2 also raised controversy.55)56)57)58)59) The beneficial effect of ACEi or ARB has been suggested by attenuating the local RAAS activation and unopposed angiotensin II accumulation caused by a continued viral infection and replication that contribute to reducing the membrane ACE2 expression.47) There is no concrete evidence or proven benefit to discontinue RAAS blockers and they are well established medications to improve outcomes in various diseases such as hypertension, myocardial infarction, chronic kidney disease, and heart failure. Furthermore, abrupt withdrawal of them in high-risk patients may result in clinical instability and adverse outcomes. Therefore, we need to maintain RAAS inhibitors in COVID-19 patients as previous guidelines recommend.

Heart transplant patients are at high risk of an infection and challenges exist regarding the maintenance of immunosuppression therapy after the infection, which can further raise the risk of graft rejection. A case study of two heart transplant patients from the Hubei province of China confirmed with the SARS-CoV-2 infection, revealed typical symptoms in these patients. One had a milder presentation, while the other required hospitalization with cessation of immunosuppression, along with treatment with methylprednisolone and intravenous immunoglobulin.60) When routine preventive measures were well adopted, the incidence of an infection in heart transplant patients can be minimized. A survey of 87 heart transplant recipients in Wuhan, China did not find a higher risk of infection with SARS-CoV-2.61) As of May 31st, there have been no confirmed heart transplant patients reported in South Korea. It is recommended to continue heart transplantations unless the risk of an infection spreading presents during the procedure. Surveillance of both the donor and recipient and related healthcare providers needs to be performed as per the individual organization's protocol and based on the up to date guideline recommendations.62)63) Even though the evidence is lacking, the current consensus for the management of heart transplant recipients who developed COVID-19 is to deliver the best supportive treatment for the viral infection and continuation of immunosuppression for mild disease. In more serious disease, reduction for anti-metabolites (mycophenolate or azathioprine) and further treatment with immunomodulators need to be considered.16)