key: cord-0756692-qh5kdjbk authors: Siripanthong, Bhurint; Asatryan, Babken; Hanff, Thomas C.; Chatha, Salman R.; Khanji, Mohammed Y.; Ricci, Fabrizio; Muser, Daniele; Ferrari, Victor A.; Nazarian, Saman; Santangeli, Pasquale; Deo, Rajat; Cooper, Leslie T.; Mohiddin, Saidi A.; Chahal, C. Anwar A. title: The Pathogenesis and Long-Term Consequences of COVID-19 Cardiac Injury: State-of-the-Art Review date: 2022-02-09 journal: JACC Basic Transl Sci DOI: 10.1016/j.jacbts.2021.10.011 sha: 7e344e5acb5ae3497d77a82a4ec0c7104bd67bfb doc_id: 756692 cord_uid: qh5kdjbk 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. indicate an ischemic cause of the myocardial injury, it cannot be assumed that the elevated cardiac enzymes result from myocardial inflammation. 15 Additional investigations are therefore required to ascertain the existence of myocardial injury. Cardiovascular magnetic resonance (CMR) imaging has been used to assess cardiac involvement in recovered patients with COVID-19. 16 Angiotensin-converting enzyme 2 acts as a docking site for SARS-CoV-2 to gain cell entry. 23 In an in vitro study using human induced pluripotent stem cell- direct detection of SARS-CoV-2 in the heart is rare but reported; 27 among these highly selected cases, localization of SARS-CoV-2 has been confined principally to interstitial cells or macrophages, rather than the cardiomyocytes. 18, 28 An alternative proposal is that SARS-CoV-2 infects the endothelial cells, which in turn mediates cellular injury to the tissues supplied by the affected vascu- 13 and the incidence of alveolar capillary microthrombi was significantly higher than following H1N1 influenza. 12 Microthrombi have also been iden- patients. 36 Elevated interleukin-6, which was found to be one of the predictors of more rapid COVID-19 deterioration, may partly explain the acute and long-term consequences of COVID-19, including myocardial inflammation, as it is known to be a mediator of the prothrombotic state, platelet function, and antibody production. 37 Other interleukins may also be involved in acute heart failure and myocarditis. For instance, intense NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome Long-Term Consequences of COVID-19 Cardiac Injury -2 0 2 1 : --- 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 ¼ tissue factor; TNF-a ¼ tumor necrosis factor-a; other abbreviations as in Figure 1 . formation in the heart is observed in myocarditis, producing the proinflammatory cytokine interleukin-1 which exacerbates the myocardial injury. 38 Figure 2 shows the proposed molecular mechanism for the indirect and indirect myocardial injury due to SARS- One patient had a stroke several days after being discharged in stable condition following a myocarditis episode. 65 Other milder complications include reduced exercise tolerance and persistent reduction in systolic ejection fraction. 66, 67 A full summary of the 77 case reports can be found in Supplemental Table 1 . POST-COVID-19 SYNDROME. There is a distinct lack of data on the long-term sequelae and prognosis In a US study of 26 competitive athletes recovering from COVID-19, 4 male athletes (15%) had CMR findings suggestive of myocarditis on the basis of the Lake Louise criteria. 75 (early) or myocardial edema, embolism, and interstitial fibrosis with heart failure with preserved ejection fraction (HFpEF) (late). Abbreviations as in Figure 1 . Long-Term Consequences of COVID-19 Cardiac Injury -2 0 2 1 : --- COVID-19 pandemic live update Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China Follow-up of adults with noncritical COVID-19 two months after symptom onset for the Gemelli Against COVID-19 Post-Acute Care Study Group. 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