The Pathogenesis and Long-Term Consequences of COVID-19 Cardiac Injury

Abstract

The mechanisms of coronavirus disease-2019 (COVID-19)-related myocardial injury comprise both direct viral invasion and indirect (hypercoagulability and immune-mediated) cellular injuries. Some patients with COVID-19 cardiac involvement have poor clinical outcomes, with preliminary data suggesting long-term structural and functional changes. These include persistent myocardial fibrosis, edema, and intraventricular thrombi with embolic events, while functionally, the left ventricle is enlarged, with a reduced ejection fraction and new-onset arrhythmias reported in a number of patients. Myocarditis post-COVID-19 vaccination is rare but more common among young male patients. Larger studies, including prospective data from biobanks, will be useful in expanding these early findings and determining their validity.

Keywords: CMR, cardiovascular magnetic resonance; COVID-19; COVID-19, coronavirus disease-2019; CT, Computerized Tomography; LGE, late gadolinium enhancement; MI, myocardial infarction; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; athlete; cardiovascular magnetic resonance imaging; inflammation; myocardial injury; myocarditis; sudden cardiac death; troponin.

Graphical abstract

Figure 1

Summary of the Proposed Mechanisms for Myocardial Cell Injury by SARS-CoV-2 Infection Direct injury might be caused by cell entry via the angiotensin-converting enzyme 2 (ACE2) protein expressed naturally on cardiomyocytes or endothelial cell damage (endotheliitis) due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Indirect damage might be brought on by the hypercoagulability state of coronavirus disease-2019 (COVID-19), which engenders microthrombus formation, disrupting cardiac capillary flow or by means of T lymphocyte–mediated cytotoxicity as part of the phenomenon called cytokine storm. ∗Since April 2021, there have been case reports of myocarditis and pericarditis following COVID-19 vaccination across all vaccine types, especially in young male subjects. The mechanism remains unknown. IL = interleukin.

Figure 2

Acute Cardiac Injury in Coronavirus Disease 2019 In the acute setting, both direct (viral) and indirect (immune-mediated) damage to the myocardial and other heart tissues can give rise to perimyocarditis or myocarditis. Moreover, endothelial tissue injury, by means of endotheliitis and microthrombus formation, leads to type 2 myocardial infarction. TF = tissue factor; TNF= tumor necrosis factor; other abbreviations as in Figure 1.

Figure 3

Timeline of the Immune Response to COVID-19 The diagram shows the proposed immunologic reaction to SARS-CoV-2 infection, in which the proinflammatory response predominates in the acute phase, which could culminate in acute respiratory response syndrome (ARDS), multisystem inflammatory syndrome (MIS), or systemic inflammatory response syndrome (SIRS). Should there be no counterbalancing anti-inflammatory response, these syndromes could lead to multiorgan failure (MOF) or multiorgan dysfunction (MOD) and/or death. With adequate counteracting anti-inflammatory cytokines produced, the body is in the immune-suppressed phase, a process called compensatory anti-inflammatory response syndrome (CARS). With prolonged immune suppression, persistent infection can occur (ie, in the form of persistent inflammation, immunosuppression, and catabolism syndrome [PICS] or persistent post-COVID-19 syndrome [PPCS]). Abbreviations as in Figure 1.

Figure 4

Chronic Consequences of COVID-19 Infection on the Heart Most patients with cardiac involvement do fully recover, either with or without scarring (as evident in some follow-up studies). Some patients with persistent infection can develop post-COVID-19 syndrome. The cardiac presentation of this includes pericardial effusion, perimyocarditis (early) or myocardial edema, embolism, and interstitial fibrosis with heart failure with preserved ejection fraction (HFpEF) (late). Abbreviations as in Figure 1.

Central Illustration

Long-Term Consequences of Coronavirus Disease-2019–Related Myocarditis Affecting the Structure and Function of the Heart Some persistent structural abnormalities, including on T1 and T2 sequences on cardiovascular magnetic resonance, were noted in asymptomatic patients, indicating fibrosis and myocardial edema. Ongoing myocardial inflammation as shown by late gadolinium enhancement was also observed in recovered patients. A number of patients with healed myocarditis also showed reduced left ventricular (LV) ejection fraction and increased LV volume long after the episode. Functionally, in a small number of patients, new-onset arrhythmias, including atrial fibrillation and complete heart block, occurred. Concerns regarding myocardial fitness remain to be addressed, especially in young adult athletes considering return to play.