key: cord-0795090-ww2vq3n4 authors: Hendren, Nicholas S.; Grodin, Justin L.; Drazner, Mark H. title: Unique Patterns of Cardiovascular Involvement in COVID-19 date: 2020-05-14 journal: J Card Fail DOI: 10.1016/j.cardfail.2020.05.006 sha: d9e92b16d3728d89e5d58c499a970eaba56facad doc_id: 795090 cord_uid: ww2vq3n4 nan ACovCS, Acute COVID-19 Cardiovascular Syndrome initially thought to be a disease largely characterized by respiratory disease and a fever, subsequent data have highlighted this clinical scope was too narrow. Indeed, the majority of individuals infected with SARS-CoV-2 may be asymptomatic, while others present with a variety of symptoms including cardiac, neurological, and hypercoagulable complications 1-4 . We recently have termed the broad spectrum of cardiovascular and thromboembolic complications the acute COVID-19 cardiovascular syndrome (ACovCS) 3 . These cardiac complications include acute coronary syndrome with obstructive coronary artery disease (CAD), acute myocardial injury with non-obstructive CAD, heart failure, cardiogenic shock, myocarditis, arrythmias, pericardial effusions, and cardiac tamponade, as well as thromboembolic complications such as stroke, pulmonary embolism, and deep vein thrombosis 3 . Recently, cardiac presentations of COVID-19 in the absence of significant pulmonary involvement have been described in case reports or case series (see Table 1 ). However, to our knowledge, a framework describing the variable presentations of cardiac involvement in COVID-19 within the broader spectrum of symptomatic SARS-CoV-2 infection has not been previously proposed. We attempt to fill this void by highlighting two patterns of cardiac presentations: the more common phenotype with cardiac involvement superimposed on top of the typical pulmonary predominate symptoms ("mixed pulmonary and cardiac"), or as an isolated or predominate cardiac presentation ("predominate cardiac"). Unquestionably there are patients where the distinctions between these patterns is blurred (e.g., a patient with STEMI who has mild pulmonary infiltrates); however, we believe this classification provides a useful framework for future research and therapeutic endeavors. A contrast of the characteristics of the mixed pulmonary and cardiac versus predominate cardiac patterns is shown in Figure 1 . First, the prevalence of mixed cardiopulmonary disease as assessed by elevated cardiac troponin levels, is variable, but occurs in 10-25% of patients hospitalized with COVID-19 3, 4 . In contrast, the cardiac predominate phenotype appears to be much less common, likely well <5% of patients hospitalized with COVID-19 5, 6 . Fever is a common manifestation of COVID-19 when there is typical pulmonary involvement but may be absent in the predominate cardiac phenotype. Both presentations can have elevated inflammatory and elevated cardiac biomarkers (e.g. cardiac troponin and natriuretic peptides); however, in the mixed presentations, the troponin is less likely to be severely elevated upon admission but can rise considerably during the hospitalization. In contrast, the troponin level with an isolated cardiac presentation can be absent or markedly elevated depending on the presentation (e.g., when presenting with a ST-elevation myocardial infarction or myocarditis). ACovCS with cardiac predominate disease may be more apparent at hospital presentation relative to mixed cardiopulmonary disease because the predominate cardiac manifestations (e.g. chest pain due to a myocardial infarction) often results in symptoms which lead patients to seek emergent care. In contrast, ACovCS superimposed on pulmonary disease is unpredictable and can occur at any time during hospital admission. Indeed, reports now suggest that this late complication can be seen in critically ill patients perhaps even after apparent respiratory stabilization 7 . Furthermore, in the minority of patients with COVID-19 who develop shock, patients with cardiac predominate disease would be anticipated to develop cardiogenic rather than distributive shock. In short, these two patterns of ACovCS presentation can be distinguished from each other by their associated clinical characteristics. We anticipate that future research will better characterize the differences in the disease course and outcomes between these two groups. Just as there is variability in cardiac presentations of COVID-19, SARS-CoV-2 infection overall has a wide spectrum of disease penetrance with many patients displaying few to no symptoms, while an unfortunate minority develop severe life limiting disease. The basis of such disease variability, including why the cardiac system is involved in only a minority of patients, is entirely unknown at this juncture but there are some putative risk factors to consider (see Figure 2 ). SARS-CoV-2 is the seventh coronavirus known to infect humans and strongly binds to the Angiotensin-Converting Enzyme 2 (ACE2) receptor which is expressed by pericytes and cardiomyocytes 8 . Further analysis has determined that the receptor binding domain on the SARS-CoV-2 spike protein, the host ACE2 receptor and host cell transmembrane serine protease 2 (TMPRSS2) are all essential for host cell infection 3, 8 . In addition, the host cell ADAM metallopeptidase domain 17 (ADAM17) participates in ACE2 receptor cleavage from the cell membrane leading to release into the circulation 9 . Cleaved ACE2 has the potential to influence clotting cascades and feedback to the renin-angiotensin system which may impact vascular, cardiac and renal pathophysiology 4 . As such, it is reasonable to speculate that genetic variations within the host, whether that be the ACE2 receptor, TMPRSS2, or ADAM17, may influence variability of presentation clinical presentations, the prevalence of ACovCS and COVID-19 clinical outcomes. Whether such genetic differences contribute to the disparities in COVID-19 outcomes between races is unknown. Finally, rare genetic mutations that lead to familial cardiomyopathy may predispose a subset of patients to developing fulminant myocarditis in the setting of a COVID-19 infection, a so-called "two-hit hypothesis". Support for this possibility comes from prior observations in children of an association of certain genetic mutations with an increased risk for developing acquired myocarditis in the setting of acute viral infections 10 . Whether or not a two-hit hypothesis contributes to the rarely described cases of biopsy-proven fulminant COVID-19 myocarditis is also unknown. Other factors which may influence the variable presentation of COVID-19 include mutations in the circulating SARS-CoV-2 virus though it remains uncertain whether such observations explain the regional differences in the outcomes of COVID-19. Likewise, antecedent patient characteristics including age, race, gender, and comorbid health conditions, particularly diabetes, chronic lung disease, and cardiovascular diseases such as hypertension, CAD, heart failure may impact disease severity and penetrance not only through baseline risk but also potentially through differential ACE2 tissue expression. Additionally, the powerful influences of lower socioeconomic status and unfavorable environmental factors likely contribute to racial COVID-19 health disparities 11 . Other factors that may influence disease variability in the overall population include a history of smoking, e-cigarette use, illicit drug use, the route of infection (inhaled versus direct mucosal contact), viral inoculation dose, healthcare delivery systems, and host immune status among others. Urgent investigation is needed to understand the basis of this variability of disease progression, including those that predispose to cardiac involvement. We suspect that gaining such knowledge may also provide insights into the pathophysiology and progression of cardiomyopathy and heart failure that extends beyond COVID-19. COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features COVID-19 Antibody Seroprevalence Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome Elevated Troponin in Patients With Coronavirus Disease 2019: Possible Mechanisms Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. 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