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COVID-19, Arrhythmic Risk, and Inflammation

2020; Lippincott Williams & Wilkins; Volume: 142; Issue: 1 Linguagem: Inglês

10.1161/circulationaha.120.047293

1524-4539

Pietro Enea Lazzerini, Mohamed Boutjdir, Pier Leopoldo Capecchi,

COVID-19 and healthcare impacts

HomeCirculationVol. 142, No. 1COVID-19, Arrhythmic Risk, and Inflammation Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBCOVID-19, Arrhythmic Risk, and InflammationMind the Gap! Pietro Enea Lazzerini, Mohamed Boutjdir and Pier Leopoldo Capecchi Pietro Enea LazzeriniPietro Enea Lazzerini Pietro Enea Lazzerini, MD, Department of Medical Sciences, Surgery, and Neurosciences, University of Siena, Siena, Italy. Email E-mail Address: [email protected] https://orcid.org/0000-0001-6721-1214 Department of Medical Sciences, Surgery, and Neurosciences, University of Siena, Italy (P.E.L., P.L.C.). , Mohamed BoutjdirMohamed Boutjdir VA New York Harbor Healthcare System, SUNY Downstate Medical Center (M.B.). NYU School of Medicine (M.B.). and Pier Leopoldo CapecchiPier Leopoldo Capecchi Department of Medical Sciences, Surgery, and Neurosciences, University of Siena, Italy (P.E.L., P.L.C.). Originally published14 Apr 2020https://doi.org/10.1161/CIRCULATIONAHA.120.047293Circulation. 2020;142:7–9Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 14, 2020: Ahead of Print Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).1 Besides direct tissue invasion, SARS-CoV-2 can also elicit an exaggerated host immune response, frequently leading to a cytokine storm, which significantly contributes to multiorgan dysfunction.1 Indeed, high levels of circulating cytokines, particularly interleukin (IL)-6, are commonly found in patients with COVID-19, also associating with in-hospital death.1Accumulating data point to an increased cardiovascular disease morbidity and mortality in these patients.1 In particular, growing evidence suggest that COVID-19 is burdened by a higher risk of arrhythmic events, with important implications for survival.1 Heart palpitations were reported as one of the most common initial symptom of the disease (7.3%).1 In 138 hospitalized patients with COVID-19, arrhythmias represented the leading complication (19.6%) after acute distress respiratory syndrome, particularly in those admitted to intensive care unit where the prevalence rose to 44.4%.1 Specifically, malignant ventricular arrhythmias (ie, ventricular tachycardia/fibrillation) were found in 5.9% of cases.1It is currently believed that myocardial damage might represent a main driver of enhanced arrhythmic risk in these patients.1 Cardiac myocyte injury, reflected by increased troponin levels, was demonstrated in many individuals, particularly in those with severe disease. Accordingly, higher incidence of ventricular tachycardia/fibrillation was reported in patients with elevated troponin-T levels.1 Although the mechanisms of myocardial involvement are still under investigation, they probably include direct viral infection, hypoxia-induced apoptosis, and cytokine storm–related cell damage (Figure).1 However, the evidence presented that in intensive care unit patients, despite the high frequency of arrhythmias (≈50% of cases), only half showed acute cardiac injury (with median troponin-I levels falling in the normal range), which suggests that factors other than myocardial damage are also involved in enhancing the arrhythmic risk in COVID-19. In this regard, the potential role of pharmacological treatments in enhancing the susceptibility to QT-related life-threatening ventricular arrhythmias, particularly Torsades de Pointes (TdP), is increasingly recognized.1 In fact, some off-label drugs used to counteract the virus invasion and replication may promote corrected QT-interval (QTc) prolongation. This is the case of chloroquine/hydroxychloroquine, antimalarial agents blocking infection by increasing the endosomal pH required for virus/cell fusion, and lopinavir/ritonavir, protease inhibitors interfering with the virus RNA replication. Notably, in both cases, the impact on ventricular repolarization is direct, via inhibition of the hERG-K+ channel, and also indirect by increasing circulating levels of other concomitant QT-prolonging drugs.1 In fact, chloroquine and hydroxychloroquine inhibit CYP2D6 (cytochrome P450 2D6), which metabolizes several antipsychotics, antidepressants, and antihistamines, whereas ritonavir inhibits CYP3A4 (cytochrome P450 3A4), actively involved in the metabolism of some macrolides, azole antifungals, antidepressants, and antihistamines (Figure). To this end, macrolides (particularly azithromycin, which is also reported to inhibit SARS-CoV-2 in vitro), as well as fluoroquinolones, are well-recognized QT-prolonging antibiotics frequently administered to these patients to prevent lung bacterial superinfections.1 The situation is further complicated by the fact that patients receiving these drugs are likely those very ill, thereby frequently presenting with other concomitant risk factors for QTc prolongation/TdP, such as preexisting cardiac diseases, electrolyte imbalances, and drugs given in the critical patient (antiemetics, proton pump inhibitors, or anesthetic agents). A simplified strategy for QTc surveillance in the clinical practice has just been released and is available at www.crediblemeds.com.Under this intricate scenario, a potentially important proarrhythmic actor has, however, to date been ignored, that is, the high-grade systemic inflammatory state characteristic of COVID-19. Indeed, strong evidence from basic and clinical studies points to inflammation as a novel and important risk factor for long QT-syndrome and TdP, primarily via direct electrophysiological effects of cytokines on the myocardium.2 It has been demonstrated that IL-6, tumor necrosis factor (TNF) α, and IL-1 can prolong ventricular action potential duration by modulating the expression or function of several cardiomyocyte ion channels, specifically K+ and Ca2+ channels (inflammatory cardiac channelopathies).3 In particular, we provided evidence that IL-6 directly inhibits hERG-K+ channel and prolongs action potential duration in ventricular myocytes.3 Besides the direct cardiac effects, systemic inflammation might additionally predispose to long QT-syndrome/TdP as a result of indirect mechanisms. First, it has been demonstrated that inflammatory cytokines can induce cardiac sympathetic system hyperactivation, via central hypothalamus-mediated (inflammatory reflex) and peripheral (left stellate ganglia activation) pathways,2 in turn representing a well-recognized trigger for life-threatening arrhythmic events in patients with long QT-syndrome. Second, IL-6 inhibits cytochrome p450, particularly CYP3A4, thereby increasing bioavailability of several medications, including QT-prolonging drugs (Figure). Accordingly, QTc prolongation was commonly observed in subjects with elevated C-reactive protein from different inflammatory conditions, also robustly correlating with IL-6 concentrations.4 We also demonstrated that in 40 unselected patients with TdP, elevated IL-6 levels were present, comparable with those observed in severe active rheumatoid arthritis, and 15 to 20 times higher than controls.4In light of the above considerations, dampening the systemic inflammatory response in COVID-19 might be crucial, not only to control lung involvement but also to reduce acute cardiovascular complications, including QT-related arrhythmic events, both possibly affecting short-term mortality. In particular, it may be pivotal to block the IL-6 pathway because data suggest a potential beneficial effect of the anti–IL-6 receptor monoclonal-antibody tocilizumab on COVID-19 survival.1 It is important to underline that in rheumatoid arthritis, where sudden cardiac death risk is increased and circulating inflammatory cytokines are associated with QTc prolongation,2 tocilizumab led to a rapid and significant QTc shortening, which correlated with both the decrease in C-reactive protein and cytokine levels.5 In addition, a recent phase-II clinical trial evaluating, for the first time, the impact of tocilizumab in nonrheumatoid arthritis subjects with an acute cardiac damage demonstrated that a single administration of tocilizumab reduced inflammatory response and myocardial injury, with no safety concerns (including infections) within the following 6 months.In conclusion, when treating COVID-19, physicians should always consider that these patients are burdened by an increased arrhythmic risk, which can significantly affect overall mortality. The extent of systemic inflammation, as reflected by circulating C-reactive protein (and IL-6) levels, should also be carefully considered to optimize the benefit/risk ratio, particularly when concomitant QT-prolonging risk factors including QT-prolonging medications are present. The administration of anti–IL-6 targeted therapies (tocilizumab, sarilumab) to patients with COVID-19, particularly those severely ill, might represent a very useful "2 birds with 1 stone" approach, not only promoting the recovery from multi-organ dysfunction but also mitigating the associated high arrhythmic risk.Download figureDownload PowerPointFigure. Putative mechanisms underlying ventricular arrhythmic risk in patients with coronavirus disease 2019 (COVID-19). Acute cardiac damage and antiviral therapies are currently considered the main drivers of the enhanced arrhythmic risk observed in patients with COVID-19. Myocardial injury might be the result of direct viral invasion of the heart, as well as an indirect consequence of the severe lung involvement (hypoxia-mediated cardiomyocyte damage). Concomitant pharmacological treatments, including some off-label drugs used to counteract the virus invasion/replication such as antimalarials (chloroquine/hydroxychloroquine), protease inhibitors (lopinavir/ritonavir), and macrolides (azithromycin) can prolong corrected QT-interval (QTc) and, possibly, increase the risk of Torsades de Pointes. Under this scenario, the abnormal systemic immune-inflammatory response elicited by the virus (not infrequently a real cytokine storm) might further and critically enhance the propensity to develop arrhythmic events, including malignant ventricular arrhythmias. In fact, besides participating in myocardial injury, inflammatory cytokines, particularly IL-6 (interleukin 6), can promote QTc prolongation both directly by modulating cardiomyocyte's ion channels, and indirectly by increasing bioavailability of concomitant QT-prolonging drugs (via CYP450 [cytochrome P450]-3A4 inhibition). In addition, as a result of a direct stimulation of autonomic nervous system, inflammatory cytokines can induce cardiac sympathetic system hyperactivation, also increasing the electric instability of the heart. SARS-COV-2 indicates severe acute respiratory syndrome coronavirus-2.Sources of FundingThis work was funded by Ministero dell'Istruzione, dell'Università e della Ricerca 2017XZMBYX.DisclosuresPietro Enea Lazzerini received a grant (minor funding) from Roche Italia S.p.A. in 2018. The other authors report no conflicts.Footnotes*Drs Boutjdir and Capecchi contributed equally.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circPietro Enea Lazzerini, MD, Department of Medical Sciences, Surgery, and Neurosciences, University of Siena, Siena, Italy. Email lazzerini7@unisi.itReferences1. Driggin E, Madhavan MV, Bikdeli B, Chuich T, Laracy J, Biondi-Zoccai G, Brown TS, Der Nigoghossian C, Zidar DA, Haythe J, et al. Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic.J Am Coll Cardiol. 2020; 75:2352–2371. doi: 10.1016/j.jacc.2020.03.031CrossrefMedlineGoogle Scholar2. Lazzerini PE, Capecchi PL, Laghi-Pasini F. Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis.Eur Heart J. 2017; 38:1717–1727. doi: 10.1093/eurheartj/ehw208MedlineGoogle Scholar3. Lazzerini PE, Laghi-Pasini F, Boutjdir M, Capecchi PL. Cardioimmunology of arrhythmias: the role of autoimmune and inflammatory cardiac channelopathies.Nat Rev Immunol. 2019; 19:63–64. doi: 10.1038/s41577-018-0098-zCrossrefMedlineGoogle Scholar4. Lazzerini PE, Laghi-Pasini F, Bertolozzi I, Morozzi G, Lorenzini S, Simpatico A, Selvi E, Bacarelli MR, Finizola F, Vanni F, et al. Systemic inflammation as a novel QT-prolonging risk factor in patients with Torsades de Pointes.Heart. 2017; 103:1821–1829. doi: 10.1136/heartjnl-2016-311079CrossrefMedlineGoogle Scholar5. Lazzerini PE, Acampa M, Capecchi PL, Fineschi I, Selvi E, Moscadelli V, Zimbone S, Gentile D, Galeazzi M, Laghi-Pasini F. Antiarrhythmic potential of anticytokine therapy in rheumatoid arthritis: tocilizumab reduces corrected QT interval by controlling systemic inflammation.Arthritis Care Res (Hoboken). 2015; 67:332–339. doi: 10.1002/acr.22455CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited By Yu L, Liu Y and Feng Y (2024) Cardiac arrhythmia in COVID‐19 patients, Annals of Noninvasive Electrocardiology, 10.1111/anec.13105, 29:2, Online publication date: 1-Mar-2024. Mani S and Garcia M (2024) COVID-19 and the Cardiovascular System Textbook of SARS-CoV-2 and COVID-19, 10.1016/B978-0-323-87539-4.00006-3, (137-158), . 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