COVID-19 and Cardiovascular Disease
Abstract
A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.
With the coronavirus disease 2019 (COVID-19) pandemic entering its second year, the extrapulmonary impact of the disease has become increasingly evident. For the cardiovascular system, infection with the etiologic virus, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), can manifest acutely and persist into convalescence and possibly beyond.1 Clinical outcomes are worse in patients with COVID-19 with cardiovascular disease and risk factors (eg, hypertension, diabetes, and obesity). Acute cardiac injury, inferred from elevations in cTn (cardiac troponin) levels, is reported in 8% to 62% of patients hospitalized with COVID-19 and is associated with greater disease severity, including need for mechanical ventilation, and death.2–6
SARS-CoV-2 contrasts from earlier coronavirus disease outbreaks in both its global epidemiology and cardiovascular impact.7,8 In 2002, the SARS-CoV pandemic arose in Guangdong province, China; of the 8098 people infected worldwide, 774 died, yielding a case fatality rate of 9.6%.9,10 In 2012, the Middle East Respiratory Syndrome outbreak arose from the Arabian peninsula and infected 2562 people, with a case fatality rate of ≈34.4% and cases occasionally still being reported.11 The current SARS-CoV-2 pandemic became evident in December 2019 from Wuhan, Hubei province, China. As of February 15, 2021, SARS-CoV-2 has infected over 109 million people and caused over 2.4 million deaths.12 Overall, the worldwide apparent case fatality rate is estimated to be ≈4%.13 However, case fatality rates vary by country from <0.1% to >20% and are influenced by testing strategies that define the infected population, economics, health care resources, comorbidity rates, demographics, and politics. In the United States alone, there have been over 550 000 deaths out of 30.6 million cases.12 Furthermore, detection of SARS-CoV-2 infection is based on convenience sampling, not randomized testing. There is also increasing awareness of asymptomatic, presymptomatic, and pauci-symptomatic COVID-19 illness, which can nevertheless transmit infection. Thus, reported cases of SARS-CoV-2 infection likely underestimate its true prevalence. Regardless, even as cardiovascular complications were reported in case series of SARS-CoV and Middle East Respiratory Syndrome,14 the cardiovascular impact of SARS-CoV-2 seems more prominent and correlates with COVID-19 disease severity and mortality.
This update focuses on the impact of SARS-CoV-2 on the heart and vasculature. We review SARS-CoV-2 clinical data implicating cardiovascular involvement, mechanisms underlying cardiovascular involvement, and implications for clinical management and future research directions.
SARS-CoV-2 Viral Entry and Life Cycle
SARS-CoV-2 is a betacoronavirus closely related to SARS-CoV and a number of naturally occurring bat coronaviruses.15,16 Like other coronaviruses, SARS-CoV-2 virions are decorated with trimers of the spike protein that resemble a halo or corona upon electron microscopy, for which the family was named. These spike trimers, along with other viral structural proteins, are expressed late in the viral life cycle and incorporated into budding virus in the endoplasmic reticulum-Golgi intermediate compartment. The spike protein contains a surface subunit (S1) that includes the signal sequence, an N-terminal domain, a receptor-binding domain (RBD), and the NRP1 (neuropilin-1)-binding domain (BD) (Figure 1A). The transmembrane subunit (S2) contains the fusion peptide, 2 heptad repeat domains (HR1 and HR2), a transmembrane domain, and a short cytoplasmic tail. Within the producer cell, the SARS-CoV-2 spike protein is processed by the cellular protease furin at the S1/S2 site, separating the S1 and S2 domains18 and exposing a conserved C-terminal motif, RXXROH.
Figure 1. Structural components of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) spike protein, interactions with ACE2 (angiotensin-converting enzyme 2) and host cell entry.A, Spike protein structural and functional elements. B, Interaction of the spike protein and processing resulting in viral entry to host cells. C and D, Structural and membrane topology of ACE2 and binding to SARS-CoV-2 S-protein receptor binding domain (RBD). C, ACE2 as a transmembrane protein with an N-terminal extracellular protease ectodomain and a short cytoplasmic C-terminus. Protease enzymatic activity is in the ectodomain (protease domain [PD]), containing a carboxypeptidase catalytic site. The receptor binding site for SARS-CoV-2 is more toward the N-Terminus, involving the N-terminal helix (NTH). D, X-ray crystallography of SARS-Cov-2 RBD bound to ACE2. ACE2 is in green, RBD in cyan and the CoV-2 receptor binding moiety (RBM) in red. Reproduced from Lan et al17 with permission. Copyright©2020, Springer Nature. ACE2 indicates angiotensin-converting enzyme 2; FP, fusion peptide; HR, heptad repeat domain; NRP1 BD, neuropilin-1 binding domain; NTD, N-terminal domain; SS, signal sequence; TM, transmembrane domain; and TMPRSS2, transmembrane protease serine 2.
Entry of SARS-CoV-2 Into Host Cells
The Host Cell Receptor for SARS CoV-2 Is the Biologically Critical Enzyme ACE2
In 2003, 1 month after reports that it generated angiotensin 1-7 from ANG II (angiotensin II) in the intact human LV19 and was upregulated at enzyme activity and protein levels in explanted human hearts,20 ACE2 was surprisingly identified as the receptor for SARS-CoV.21 SARS-CoV-2 also binds to ACE2. Binding of the spike protein RBD to ACE2 brings the virion into proximity with the host cell surface membrane and induces conformational changes in the RBD that initiate the process of membrane fusion.18,22
Infection of target cells (Figure 1B) is facilitated by the binding of NRP1 expressed on target cells, to the RXXROH NRP1 BD exposed by furin cleavage. Although not required for infection, NRP1 is an attachment factor that significantly enhances viral infectivity.23 Similarly, integrin α5 or α5β1 dimer, known to mediate cell binding and entry of certain viruses,24 binds to and is co-regulated with ACE2 in ventricular remodeling.25 In the Vero E6 cell model, an α5β1 dimer inhibitor prevents SARS-CoV-2 infection and reduces binding of SARS-Cov-2 to ACE2.26 Thus, α5βb1 integrin, likely through binding to α5, may also be an attachment factor or even a co-receptor for SARS-CoV-2 entry.25–27 Following attachment, SARS-CoV-2 RBD binds to the cell surface receptor ACE2. SARS-CoV-2 is subsequently taken up into target cells via endocytosis, and in the presence of low pH, the RBD undergoes dramatic structural refolding.28,29 Concomitant with binding to ACE2, in many cell types, the cellular transmembrane serine protease TMPRSS2 (transmembrane protease serine 2) cleaves the S2 transmembrane subunit at the S2’ position,28 triggering further conformational changes in the spike protein that enable the fusion peptide to insert into the cellular membrane. Cellular cathepsins can also process the S2’ position. In some cell types, such as human ventricular myocardium30 and inducible pluripotent stem cell–derived cardiomyocytes,31,32 where TMPRSS2 is expressed at very low levels, cathepsin inhibitors, rather than TMPRSS2 inhibitors, prevent SARS-CoV-2 cell entry. Thus, mechanisms involved in membrane fusion and cell entry may be cell-specific. The HR1 and HR2 domains of S2 subsequently interact within the trimers to form an energetically stable 6-helix bundle that brings the viral and cellular membranes into proximity and initiates the formation of a fusion pore, releasing viral contents into the cytosol.33,34
Several important differences exist between entry of SARS-CoV-2 and SARS-CoV. SARS-CoV-2 contains a furin cleavage site at S1/S2 that is not present in SARS-CoV; instead, cellular cathepsins mediate cleavage of S1 and S2.35,36 The furin cleavage of SARS-CoV-2 spike protein has several important consequences, including enhancing cell-cell fusion and enabling the virus to infect human lung cells.37 The SARS-CoV-2 spike protein RBD has a number of mutations that confer higher affinity for ACE2 than SARS-CoV38,39 and prevent effective cross-neutralization by antibodies targeting the RBD40–42 with some exceptions.43–47 Conversely, genetic polymorphisms in ACE2 vary across populations,48 several missense variants are predicted to disrupt ACE2 function and structure that may affect SARS-CoV-2 interactions,49 and a recently reported short isoform that lacks spike high-affinity binding sites and that is upregulated in response to IFN (interferon) stimulation may affect host resistance.50 A new, more highly transmissible strain of SARS-CoV-2 emerging from the United Kingdom (20I/501Y.V1) at the end of 2020 appears to have an even higher affinity for ACE2, via a N501Y mutation at one of the 6 key RBD contact sites.51 In South African (20H/501Y.V2) and Brazilian (20J/501Y.V3) variants, an E484K mutation has emerged that seems to confer heightened resistance to neutralization while only modestly increasing affinity for ACE2.52 Together, these factors underlying differences in cell-cell spread, viral tropism, and affinity for ACE2 may underlie the enhanced transmission of SARS-CoV-2.
Late Life Cycle of SARS-CoV-2
Following cell entry, the ≈30 kb SARS-CoV-2 genomic RNA is translated into large concatenated polypeptides corresponding to the ORF1a and ORF1b reading frames. These polypeptides contain the viral nsps (nonstructural proteins), including the nsp3 and nsp5 viral proteases that process the polypeptide chains into 15 to 16 nsp subunits. Most nsps form the viral replication and transcription complex responsible for replicating the full-length viral genome. The structural proteins, including spike, nucleocapsid, membrane, and envelope proteins, are expressed from a subgenomic promoter in a series of nested transcripts and assemble with the full-length viral RNA in the endoplasmic reticulum-Golgi intermediate compartment. Additional details on the coronavirus life cycle can be found in an excellent review.53
ACE2 and Preferential Access of SARS-CoV-2 to Human Cardiac Myocytes and Other Cardiovascular System Host Cells
Viruses use a wide range of proteins, carbohydrates, or lipids to bind to host cells and consequently enter them for viral propagation. However, ACE2 stands as the only example of a critical myocardial enzyme used by a highly pathogenic virus for cell binding and entry. SARS-CoV, SARS-CoV-2, and 2 other coronaviruses54,55 are known to use ACE2 for cell binding and entry, but no other virus families are known to utilize ACE2 as a host cell receptor. In contrast to many other highly infectious pathogenic viruses such as influenza,56 the initial binding of SARS-CoV-2 spike protein to its host cell receptor ACE2 is of very high affinity18; the SARS-CoV-2 spike protein binds to human ACE2 via its RBD with reported equilibrium constants (dissociation constants, or KDs) of 1.218 and 4.7 nmol/L.17 The ACE2-binding affinity of SARS-CoV spike protein is somewhat less, ≈30 nmol/L.17 Cell-specific expression and high-affinity binding of ACE2 to the SARS-CoV-2 spike protein RBD likely account for the relatively high incidence of cardiovascular involvement in COVID-19.
Distribution of ACE2 and Other Viral Entry Proteins in Cardiovascular Tissue and Cells
Host cell receptor binding of a virus is essential to cell invasion, and cell and tissue distribution of host receptors is a major determinant of viral tropism and its clinical manifestations. The tissue distribution of ACE2 includes the heart, lung, intestines, kidney, testis, nose, and mouth.57 While nasal and pulmonary epithelial cells are recognized as the first infected cells, after initial viral replication and circulation, many cardiac resident cells express the necessary components for uptake and replication. Based on gene expression studies, human ventricular myocardium contains all the requisite mediators of SARS-CoV-2 binding and entry. Although TMPRSS2 is minimally expressed in the heart, there is high expression of ACE2, and other proteases (eg, FURIN, NRP1, CTSB/L) known to participate in priming and membrane fusion, and integrin co-receptors appear to be ubiquitously expressed (Figure 2).25–27 More recent studies, employing single nuclei RNA sequencing,58–60 open source proteomics,61 and immunostaining,61 have confirmed ACE2 expression in cardiac myocytes and pericytes with lack of evidence for ACE2 expression in endothelial cells.30,61 Lung expression is mostly confined to type 2 alveolar cells.61 In ventricular myocardium cardiac myocytes and fibroblasts exhibit ACE2 expression, but pericytes, which support the microvasculature throughout the myocardium, appear particularly susceptible with robust expression of ACE2 (Figure 3A).60
Figure 2. Gene expression by tissue of genes encoding viral entry proteins that interact with severe acute respiratory syndrome-coronavirus 2 from GTEx. The lung and intestines express high levels of ACE2 (angiotensin-converting enzyme 2) and transmembrane protease serine 2 (TMPRSS2), whereas the heart left ventricle expresses ACE2 at high levels, but TMPRSS2 at low levels. However, CTSB and CTSL (encoding cathepsins B and L, respectively), FURIN, NRP1, and ITGA5 and ITGB1 (integrins) show expression in all tissues displayed. Obtained from the Genotype-Tissue Expression (GTEx) Portal, accessed on January 14, 2021.
Figure 3. ACE2 (angiotensin-converting enzyme 2) expression in human myocardium.A, Relative expression of ACE2, TMPRSS2, and CTSL in left ventricle by snRNASeq. B, snRNASeq showing expression of ACE2 in cell subtypes, demonstrating increases in ACE2 expression in cardiomyocytes but reduced expression in fibroblasts, pericytes, and vascular smooth muscle cells (VSMCs) in dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) ventricles. C, Effects of ACE inhibitors on ACE2 expression across cell types in HCM, showing no significant change. D and E, ACE2 expression in adult human heart from public scRNASeq databases. D, Age and (E) normal vs heart failure and male vs female stratification. A, B, and C reproduced from Tucker et al60 with permission. Copyright©2020, Wolters Kluwer Health, Inc. D and E reproduced from Liu et al62 with permission. Copyright©2020, Oxford University Press.
Functional and Structural Characterization of Human Myocardial ACE2
The renin-angiotensin system, including the balance of ACE (angiotensin-converting enzyme) and ACE2, has important physiological effects on the cardiovascular system (Figure 4). In the human heart, generation of the octapeptide ANG II from angiotensin I is mostly (85%–89%) mediated by ACE.63 In human ventricular myocardium, breakdown/hydrolysis of ANG II is primarily mediated by ACE2, leading to formation of angiotensin 1-7,19 a counter-regulatory peptide that is antihypertrophic and has other favorable biologic activities (Figure 4). Thus, ACE2 nullifies the pathological hypertrophy and other adverse effects of ANG II by both catalyzing its breakdown and generating a counter-regulatory peptide. The importance of ACE2’s enzymatic action on ANG II is highlighted by the effects of ACE2 gene inactivation, which leads to reduction of contractile function64 or pathological ventricular hypertrophy when subjected to chronic afterload stress.65 ACE2 structure has transmembrane, cytosolic, and extracellular domains, the latter containing carboxypeptidase activity (Figure 1C).66 The ACE2 amino acid composition of the catalytic domain is 42% homologous with the ACE catalytic domain, but ACE inhibitors have no effect on ACE2 activity.57
Figure 4. Renin-angiotensin system and ACE2 (angiotensin-converting enzyme 2).
The ACE2 receptor region is in the N-terminal helix region of the extracellular domain (Figure 1C). The RBD-binding moiety in ACE2 is in a region distinct from the carboxypeptidase catalytic domain (Figure 1C and 1D),66 creating the possibility of targeting this region of ACE2 to interfere with SARS-CoV-2 binding to ACE2 without reducing enzymatic activity. Given the cardiovascular protective function of ACE2 carboxypeptidase activity under normal physiological conditions, a lack of enzyme inhibition is a requisite for any ACE2-targeted therapeutic agent designed to prevent SARS-CoV-2 binding to ACE2.25
Regulation of ACE2 in LV Myocardial Remodeling
The mechanisms involved in SARS-Cov-2 cell binding and entry seem to be modified by heart muscle disorders. Given the susceptibility of those with preexisting cardiovascular conditions to severe COVID presentations, several studies examined the expression of ACE2 in (non-COVID) failing hearts.58,60,67,68 With pathological eccentric remodeling of the left ventricle (LV), ACE2 mRNA expression increases ≈2-fold and then decreases toward normal levels on reverse remodeling.25 Proteases are not regulated with remodeling, but multiple integrins are, and ITGA5 mRNA expression tracks with ACE2. More recently, single nuclei RNA sequencing studies showed that upregulation in failing hearts was specific to cardiomyocytes (Figure 3B),60 suggesting a potential mechanism for the enhanced susceptibility in patients with heart failure. The regulation of ACE2 is independent of treatment with ACE inhibitors or ARBs (Figure 3C).25,60 These and other studies,20,58,69 indicating that ACE2 upregulation is associated with pathological ventricular remodeling, may have implications for susceptibility or response to SARS-CoV-2 infection in those with cardiovascular comorbidities.25,70 Conversely, ACE2 expression in cardiac cells seems to be lower with older age and in males, compared with females (ACE2 is also X linked), (Figure 3D and 3E) both factors associated with worse disease severity.62 Whether and how these sex and age differences in ACE2 expression contribute to the sex and age differences observed in COVID-19 severity remain unclear.
The next sections explore cardiovascular manifestations of the potential direct and indirect myocardial effects of SARS-CoV-2 infection. Myocardial and/or vascular injury have been postulated to occur via direct viral infection as well as indirectly, from immune responses to viral infection.
Direct Myocardial Effects
Clinical Evidence for Acute Myocardial Injury
Acute Clinical Cardiovascular Manifestations
Among hospitalized patients with COVID-19, evidence of acute cardiac compromise is common and includes acute heart failure (3%–33%),71–73 cardiogenic shock (9%–17%),74 myocardial ischemia or infarction (0.9%–11%),71 ventricular dysfunction (left ventricular [10%–41%], right ventricular [33%–47%], biventricular [3%–15%]),75–78 stress cardiomyopathy (2%–5.6%),75,77 arrhythmias (9%–17%),71,72,74,79 venous thromboembolism (23%–27%),73 and arterial thrombosis secondary to viral-mediated coagulopathy.80
Preexisting cardiovascular disease (coronary heart disease, heart failure, cerebrovascular disease), cardiovascular risk factors (eg, male sex, older age, hypertension, diabetes), and other comorbidities (eg, chronic obstructive pulmonary disease, chronic renal failure, and cancer) predispose patients with COVID-19 to more severe disease and mortality. Racial and ethnic disparities in COVID-19 outcomes are also evident. In a meta-analysis, Black, Asian, and Hispanic individuals had a higher risk of COVID-19 infection compared with White individuals; more severe disease, marked by need for intensive therapy units and death, was associated with Asian cohorts.81 Other studies have highlighted health disparities in the United States with higher mortality rates in Black82,83 and Latinx populations,82,83 and in predominantly Black compared with White populated counties.83,84 In an analysis of the American Heart Association, COVID-19 Cardiovascular Disease Registry of 7868 patients hospitalized with COVID-19, 33% were Hispanic, 25.5% non-Hispanic Black, 6.3% Asian, and 35.2% non-Hispanic White; in-hospital mortality and major adverse cardiovascular events (death, myocardial infarction, stroke, heart failure) did not differ by race or ethnicity after adjustment, although Black and Hispanic patients had a larger burden of mortality due to their higher proportions of hospitalizations.85 Asian patients had the highest cardiorespiratory severity score.85
Biomarker Evidence for Cardiac Injury
Biomarker evidence of cardiac injury is strongly associated with worse COVID-19 outcomes. Elevation of cardiac biomarkers, such as NT-proBNP, cTn, or d-dimer,4,6,86,87 predict poor clinical outcomes. In hospitalized patients with COVID-19, the prevalence of elevated hs-TnT (high-sensitivity troponin-T) is 20% to 30%.5,88 Inferred from such elevated cTn levels, acute myocardial injury reportedly ranges from 8% to 62% overall,2,3 with worse disease severity associated with a higher prevalence of elevated levels. Elevated cTn levels were rare in COVID-19 survivors with an uncomplicated course (1%–20%), common in severely ill patients (46%–100%), and nearly universal in the critically ill (ie, requiring intensive care or mechanical ventilation) and nonsurvivors.2,4,5 Among 2736 hospitalized patients with COVID-19 in New York City, even small elevations of cTn I (>0.03–0.09 ng/mL) were associated with higher mortality.89 Furthermore, the greater the cTn elevation, the higher the mortality risk.5,89 Compared with those without cTnI elevation, patients with COVID-19 with cTn elevation have higher risks of acute respiratory distress syndrome (58%–59% versus 12%–15%),4,5 need for mechanical ventilation (22%–60% vs 4%–10%),4,5 malignant arrhythmias (17% versus 2% VT/VF),4 and death (51%–95% versus 5%–27%).4,5 cTn and NT-proBNP levels increase during hospitalization in nonsurvivors but not among survivors.4,6
Imaging Evidence for Myocardial Injury
Biomarker evidence of myocardial injury with associated echocardiographic abnormalities correlate with higher risk of in-hospital mortality. Echocardiographic abnormalities commonly reported in hospitalized patients with COVID-19 include right ventricular (RV) dysfunction (26.3%), LV wall motion abnormalities (23.7%), global LV dysfunction (18.4%), grade II or III diastolic dysfunction (13.2%), and pericardial effusion (7.2%).3
Abnormalities suggesting injury on cardiac magnetic resonance imaging (CMR) have also been reported commonly. CMR findings include T1 mapping abnormalities (suggesting diffuse myocardial changes such as diffuse fibrosis and/or edema); T2, short tau inversion recovery, or T2 mapping abnormalities (more specific for myocardial inflammation, as occurs in acute myocarditis); late gadolinium enhancement (LGE, suggestive of acute myocardial injury and/or myocardial fibrosis); or pericardial involvement—all of which can indicate cardiac pathologies associated with COVID-19. In a systematic review comprising 199 patients from 34 acute or postrecovery CMR studies in patients with COVID-19,90 CMR diagnoses included myocarditis in 40.2%, myopericarditis in 1.5%, Takotsubo in 1.5%, ischemia in 2.5%, and dual ischemic and nonischemic changes in 2.0%. Regional wall motion abnormalities were reported in 13/32 (40.6%), edema (on T2 or short tau inversion recovery) in 46/90 (51.1%), LGE in 85/199 (42.7%), and T1 and T2 mapping abnormalities in 109/150 (73%) and 91/144 (63%), respectively. Additionally, perfusion and extracellular volume mapping abnormalities were described in 18/21 (85%) and 21/40 (52%) patients, respectively. Pericardial involvement included pericardial effusion (43/175; 24%) and pericardial LGE (22/100; 22%). In summary, the most common CMR diagnosis was myocarditis, and imaging findings included evidence of diffuse myocardial edema, and myocardial fibrosis. However, it is important to note the majority of findings reported were mild increases in T1 and T2 times, and the clinical significance of isolated T1/T2 abnormalities related to COVID-19 still remains unknown.
Postrecovery Cardiac Involvement
The potential for long-term cardiac sequelae of COVID-19-associated myocardial injury has been highlighted by CMR studies in recovered patients (Online Table I) with evidence of myocardial fibrosis or myocarditis reported in 9% to 78% of patients recovered from acute COVID-19. Among 100 post-COVID-19 patients who underwent CMR 2 to 3 months after the diagnosis, Puntmann et al1 reported cardiac involvement in 78% with evidence of ongoing inflammation in 60%. On the day of imaging, 71% had elevated hs-TnT. Cardiac symptoms were common and included atypical chest pain (17%), palpitations (20%), and dyspnea and exhaustion (36%). Recovered patients had lower left ventricular (LV) ejection fraction and higher LV volumes compared with risk factor–matched controls. In 3 patients with severe CMR findings, endomyocardial biopsy revealed active lymphocytic infiltration but without detectable viral genome.
CMR findings were also reported in 26 patients who had recovered from COVID-19 but with cardiac symptoms after discharge, including chest pain, palpitations, or chest distress.91 Abnormal CMRs with increased T2 signal and/or positive LGE were found in 15 (58%), including myocardial edema in 14 (54%), and 8 (31%) with LGE. Compared with 20 healthy controls of similar age and sex, T1, T2, and extracellular volume values were significantly elevated in the recovered patients with positive CMR findings. Only one of the abnormal CMR patients had impaired LVEF (45%) with reduced contractility of the segments with edema. Abnormal right ventricular functional parameters, including ejection fraction, cardiac output, cardiac index, stroke volume, and stroke volume/BSA were also found in patients with abnormal CMRs compared with healthy controls.
Studies in competitive collegiate athletes report a 27% to 46% prevalence of LGE.92,93 In 26 competitive college athletes (mean age, 19.5 years),92 CMR revealed evidence of myocarditis in 4 (15%) and LGE in 12 (46%); 8 (31%) had LGE without T2 elevation, suggesting prior myocardial injury. None had required hospitalization or received COVID-19 antiviral therapy. Twelve had only mild symptoms (sore throat, shortness of breath, myalgias, fever), and the others were asymptomatic. The study lacked a control group for comparison, used CMR criteria derived from symptomatic rather than asymptomatic patients, and included 2 (8%) with LGE at the RV insertion site that has been considered a nonspecific finding in athletes. Nevertheless, abnormalities were not detected by other measures (there were no diagnostic changes on ECG, all had normal ventricular function and volumes by transthoracic echo and CMR, all had normal cTnI). Another study of 59 collegiate athletes reported CMR findings in 16 (27%), of whom 13 (22%) had nonpathological punctate inferoseptal RV insertion abnormalities; 2 (3%) met criteria for myocarditis, 1 (2%) had other myocardial abnormalities, and 1 (2%) had pericarditis.93 Mild increases in T1, T2, or extracellular volume were seen in 39% of COVID-19+ athletes, compared with 13% of 60 athletic controls and 8% of 27 healthy controls. A third study of 145 competitive student athletes with CMRs a median of 15 days after diagnosis reported that only 2 (1.4%) met criteria for myocarditis, 2 (1.4%) had LGE without T2 abnormality, 1 had pericardial enhancement, and 38 (26.2%) had LGE at the RV insertion site.94 Excluding nonspecific RV insertion site LGE, the prevalence of LGE abnormalities in athletes in these studies ranged from 2.8% to 38% with 1.4% to 15% meeting criteria for myocarditis (Online Table I).
Such CMR findings of myocarditis and myocardial fibrosis raise concerns regarding potential long-term cardiac sequelae, including increased risk for heart failure and arrhythmias based on prior experience with myocarditis. The presence of LGE related to myocarditis often implies myocardial necrosis in addition to myocardial edema and has previously been associated with adverse outcomes in multiple non-COVID related myocarditis CMR studies.95,96 This risk has been shown to be further modulated by LV dysfunction (LVEF<50%)97 and persistent T2 elevation or myocardial edema.98 The significant prevalence of abnormal LGE (12%) in the Puntmann et al,1 control group highlights the need to expand our understanding of subclinical myocardial injury in the general population and athletes. At this time, the actual risk of complications in patients with abnormal CMR findings remains undefined. Moreover, whether isolated elevations in T1/T2 times are due to capillaritis, microthombi, or endothelial dysfunction secondary to a systemic inflammatory response, or histologically defined myocarditis remains undiscerned.
Post-Acute COVID-19 Syndrome
Post-acute sequelae of SARS-CoV-2 infection, often termed postacute COVID syndrome, or long-COVID, can occur in recovering patients. Among 143 patients seen as outpatients after COVID-19 infection, only 12.6% were asymptomatic.22 Symptoms included fatigue (53.1%), dyspnea (43.4%), joint pain (27.3%), and chest pain (21.7%); 44.1% reported worsened quality of life. Among 1733 discharged patients with COVID-19 followed up a median of 6 months after symptom onset, the most common symptoms were fatigue or muscle weakness (63%), sleep difficulties (26%), and anxiety or depression (23%).99 Greater illness severity during hospitalization was associated with more impaired pulmonary diffusion capacities and abnormal chest imaging.99 What remains unclear are the contributions of post-COVID cardiac involvement and acute COVID myocardial injury to the symptoms of postacute COVID-19 syndrome.
Mechanisms of Direct Cardiac Injury
Analyses of prior coronavirus outbreaks and COVID-19 data suggest several potential mechanisms of COVID-19 myocardial injury (Figure 5). Acutely, SARS-CoV-2 may directly infect and damage cardiac cells, triggering severe cellular and organ-wide pathology and dysfunction, although fulminant myocarditis is relatively uncommon in COVID-19. A rabbit coronavirus model of myocarditis and heart failure was established over 25 years ago and demonstrated direct viral infection of the heart,100 presaging the effects of SARS-CoV-2 on the human myocardium.
Figure 5. Approximate time course of immune response and cardiovascular effects. ACE2 indicates angiotensin-converting enzyme 2.
Evidence of Direct Cardiac Viral Infection From Cardiac Autopsies and Endomyocardial Biopsies
Cardiac autopsies have shown cardiomegaly, RV dilation, evidence of RV strain (19%), lymphocytic myocarditis (14%–40%), focal pericarditis (19%), endocardial thrombosis (14%) or endothelitis, and small vessel thrombosis (19%).101–104 Cardiac tropism of SARS-CoV-2 was initially established by quantitative RT-PCR detection of viral RNA in postmortem hearts of patients with COVID-19 and subsequently in endomyocardial biopsies of patients with suspected myocarditis.105–107 Whether the detected viral RNA reflected infected cardiac cells or circulating viral particles remained in question until more recently. Cardiac cellular tropism of SARS-CoV-2 has now been proven by in situ labeling of SARS-CoV-2 RNA and by electron microscopy detection of virus-like particles within cardiomyocytes,108 interstitial cells,105,107 and endothelial cells102,108,109 of postmortem hearts. Putative SARS-CoV-2 viral particles have also been detected by electron microscopy on endomyocardial biopsy.110 Autopsies in patients with acute myocarditis have recently demonstrated evidence of viral infection, processing, and replication within cardiomyocytes.31 The preponderance of evidence suggests that SARS-CoV-2 can readily infect human cardiac myocytes31,110 and can be detected in myocytes on autopsy or by endomyocardial biopsy in patients with31,110 and without111 clinical evidence of cardiac involvement.
Despite reports of SARS-CoV-2 in some hearts with histologically proven myocarditis,31 viral RNA has been undetectable in other COVID-19 myocarditis cases or did not correlate with sites of myocarditis.102,105,112,113 Furthermore, acute myocarditis as defined by Dallas criteria has rarely been detected in COVID-19 nonsurvivors. Of 277 hearts across 22 COVID-19 autopsy studies, only 20 cases of myocarditis (7.2%) were reported.114 The actual prevalence of COVID-19 myocarditis was likely lower, as several cases were reportedly functionally insignificant. In contrast to the low prevalence of myocarditis, interstitial macrophage infiltration without cardiomyocyte degeneration was common in a multicenter COVID-19 autopsy series (18 of 21 cases, 86%).101
Other more common histological findings reported by COVID-19 autopsy series include perivascular and myocardial inflammatory infiltrates, endocardial and small vessel thrombosis, endotheliitis, and myocyte degeneration.101–104 Whether direct SARS-CoV-2 cytotoxicity underlies these more common cardiac histopathologies remains unclear. Few autopsy series assessed SARS-CoV-2 viral load in the heart. One study of 39 postmortem hearts detected SARS-CoV-2 by qRT-PCR in 24 (61.5%) cases, with 16 hearts exhibiting a high viral load (>1000 genomic copies per µg of total RNA).105 Although the high viral load hearts had a proinflammatory transcriptomic profile, no immune cell infiltrates were found. Whether the heterogeneity of COVID-19 cardiac histopathology signifies distinct endophenotypes of COVID-19 myocardial injury or a continuum of one pathological process remains to be determined. Also unknown is how either SARS-CoV-2 viral load or patient immunopathology relates to these diverse cardiac pathological findings in COVID-19.
Defining Cardiac Cell Targets of SARS-CoV-2
As above, single-cell and single nuclei RNA sequencing studies have demonstrated expression of ACE2 in pericytes, cardiomyocytes, and fibroblasts, with cardiomyocyte-specific upregulation of ACE2 in failing hearts (Figure 3B).60,115 The presence of severe microvascular injury in postmortem analyses supports a role for pericytes, which show high ACE2 expression in single nuclei RNA sequencing studies, but whether the microvascular injury involves direct infection or indirect inflammatory mechanisms is unclear. Several groups have utilized human inducible pluripotent stem cell–derived cardiomyocytes, living tissue slices, and engineered heart tissue to model SARS-CoV2 infection,31,116–118 demonstrating ACE2 expression and direct cardiomyocyte susceptibility to SARS-CoV-2 infection. Infection produced cytotoxic effects110,118 and activated innate immune responses, including IFN signaling, apoptosis, reactive oxygen stress, and antiviral clearance pathways, as well as inhibition of metabolic pathways and suppression of ACE2 expression.110,118 Such models are also useful in studying mechanisms of viral infection and drug effects. For example, ACE2 antibody was demonstrated to blunt infection in cardiomyocytes,118 and infection of inducible pluripotent stem cell–derived cardiomyocytes was dependent on ACE2 and cathepsins and blocked by remdesivir.110
Indirect Myocardial Effects
Mechanisms of Indirect Cardiovascular Injury
While the direct cardiovascular manifestations of COVID19 detailed above stem from unique aspects of SARS-CoV2 virology and may be specific to coronaviruses, indirect pathological mechanisms have been reported, including hypoxia-induced myocardial injury due to hypoxic respiratory failure and hypoxemia, small vessel ischemia due to microvascular injury and thrombosis, or acute RV failure due to pulmonary embolism or in situ pulmonary artery thrombosis. Cardiac injury may also stem from a dysfunctional immune response. Canonical features of the normal immune response after viral exposure are reviewed in Figure 5 and below. Hypo- and hyper-immune responses may contribute to severity of COVID-19 disease. Systemic inflammatory responses or cytokine storm may lead to cell death and multiorgan dysfunction, and late autoimmune phenomena have been postulated to contribute to autonomic dysfunction.
The remarkable variety of symptoms, clinical severity, and manifestations after SARS-CoV2 exposure underscores our limited understanding of the heterogeneity of immune dysfunction in COVID-19. A deeper understanding of the pathways that account for immune success or failure in COVID19 would inform our understanding of the mechanisms that account for cardiovascular disease in more generalizable settings.
Normal Immune Mechanisms of Host Protection After Viral Exposure
The innate immune system provides the first-line host defense that senses viral infection, kills virus-infected cells to minimize viral replication, induces inflammation, and enhances adaptive immunity (Figure 5). The adaptive immune response, comprised of T cell and B cell (antibody) responses, ultimately neutralizes viral particles, clears the virus, and establishes long term immunity.
Innate Immune Activation
Innate immune signaling is rapidly induced by pathogen-associated molecular pattern and damage-associated molecular pattern molecules, which signal through pattern recognition receptors. Examples of pattern recognition receptors include membrane-bound receptors (eg, TLRs [toll-like receptors]) and cytoplasmic receptors (eg, NLRs [NOD-like receptors]). Activation of these pathways induces type I interferon (IFNβ and multiple IFNα species), proinflammatory cytokines (eg, TNF [tumor necrosis factor]), and chemokines (which enhance recruitment of leukocytes). Type I IFN signals through IFNαβ receptors, increasing class I major histocompatibility complex expression and antigen presentation to CD8+ T cells, which kill virus-infected cells. Type I IFN also enhances killing of infected cells by natural killer cells and inhibits mRNA translation, a critical control point in the lifecycle of RNA viruses. A parallel mechanism for local control of viral infection and cytokine activation is the assembly of inflammasomes, a set of multimeric cytoplasmic signaling complexes. For example, NLRP3 inflammasome mediates activation of caspase-1, which cleaves pro-IL-1β and pro-IL-18 into active proinflammatory cytokines that can synergistically activate NF-κB to augment IL-6 and TNF expression. Inflammasomes can also cause apoptosis or pyroptosis, a proinflammatory/lytic cell death.
Adaptive Immune Responses
Immature dendritic cells resident at sites of infection (eg, the lung) sense danger signals, which induce a maturation process that results in enhanced major histocompatibility complex molecule expression and antigen presentation, accompanied by migration to lymph nodes. In the lymph node, antigens presented by class I and class II major histocompatibility complex molecules activate naive CD8+ and CD4+ T cells, respectively. CD8+ T cells contribute as cytolytic effector cells, killing virus-infected cells, while CD4+ T cells are helpers to promote B cell/antibody responses or effector cells that migrate to sites of infection to provide host defense, including production of cytokines. Thus, inflammatory mechanisms result from both innate and adaptive immune responses.
Dysregulation of Inflammatory or Immune Responses
Hyperinflammation
Since levels of certain proinflammatory cytokines correlate with markers of cardiac injury, adverse cardiovascular events and mortality, proinflammatory cytokines may mediate local and systemic pathology in COVID-19. Seen in chimeric antigen receptor T cell therapy, cytokine release syndrome can cause cardiopulmonary collapse, including vasoplegic shock, transient LV dysfunction, and fulminant lymphocytic myocarditis. Cytokine release syndrome in this setting is often responsive to IL-6 interruption.32 Inflammasome activation may also contribute to a hyperinflammatory milieu, and the attendant lytic cell death may contribute to tissue injury and thrombosis. Although the early observational and anecdotal experience with anticytokine therapy was promising,119 randomized trials suggest the benefit of tocilizumab for the prevention of mechanical ventilation or death may be modest.120–122
Failure of Adequate Type I Interferon Responses
Patients with severe COVID had lower type I IFN levels despite higher viral loads123 and were also more likely to have a hyperinflammatory profile characterized by higher IL-6 and TNF plasma levels and elevated expression of NF-κB-related genes.123 Consistent with this, plasmacytoid dendritic cells are reduced during acute illness (compared with convalescence and/or controls), especially in those with a severe course.124 Impaired dendritic cell function also corresponds with delayed T cell responses in SARS-CoV-2.124 Deficient-type I IFN activation may also be due to autoantibodies that neutralize the ligand and/or receptor,125 but the mechanisms accounting for a potential failure of type I IFN production are unknown.126 The extent to which the activity of specific cytokines (eg, IL-6, IL-1β, TNF) is a marker or mediator of disease severity and whether these pathways account for cardiovascular impairment is a crucial knowledge gap and may have relevance to cardiovascular resilience in the face of non-COVID critical illnesses.
Adaptive Immune Dysfunction and Myocarditis
Lymphopenia at presentation is strongly prognostic of mortality in COVID-196; patients with a fatal course had protracted lymphopenia and tended to have steep increases in D-dimer and cTn levels in association with elevated inflammatory cytokines. Lymphopenia in COVID-19 predominantly reflects T cell depletion, whereas B cell numbers are preserved.127 Naive T cells tend to be diminished in the elderly, a finding associated with a poor prognosis.128 Greater disease severity is also associated with lower levels of circulating spike-specific TfH cells and lower numbers of CD8+ IFNg+ T cells, whereas T17 cells were not generally detected. More recent reports suggest T cell function may indeed be critical to host protection and long term immunity. In those recovered from COVID-19, T cell responses appear to correlate with neutralizing antibody titers, suggesting that productive adaptive responses to SARS-CoV-2 leading to both T and B cell immunity are possible.129 T cells responsive to SARS-CoV-2 have been identified from peripheral blood and persist at least 6 months after infection.130 SARS-CoV also induced durable T cell memory, identifiable in many at least 4 years after infection.131 Interestingly, recent studies suggest that preexisting protection against SARS-CoV-2 may be derived from memory T cell immunity to common coronaviruses.128,132
Whether aberrant T cell responses contribute to cardiovascular manifestations has not been determined. Although effector/memory T cell activation can induce prothrombotic activation of monocytes and contribute to thrombotic risk,133 whether T cells are direct contributors to other manifestations of cardiovascular injury in the setting of COVID-19 is less clear. For example, COVID-19 autopsy series have only rarely identified lymphocytic myocarditis. T regulatory cells have been implicated in myocardial fibrosis, but whether expansion of these cells during or after infection contribute to myocardial to myocardial fibrosis has not been established.
Potential Role of Antibody-Dependent Enhancement/Injury
In addition to protective neutralizing activity, antibodies can recruit complement, provide an ACE2-independent route to infection via Fc receptor interactions,134 or have cross-specificity to self antigens, functions with pathological consequences (ie, antibody-dependent enhancement). These humoral effects have been previously shown to play a role in autoimmune cardiomyopathies or non-COVID viral myocarditis.135,136 To date, there has not been convincing evidence of antibody-dependent enhancement in SARS-CoV-2 infection or therapies. Instead, concern derives from observations that severe COVID-19 is paradoxically associated with higher SARS-CoV-2-specific antibody titers compared with those with minimal symptoms or an asymptomatic course, although differences in viral load may be an alternate explanation.137,138 Nevertheless, continued vigilance and scrutiny of clinical datasets is warranted, especially as we enter into the vaccination era of COVID-19.139
Systemic immune dysfunction causes widespread endothelial injury even in tissues that are not directly infected by the virus. The presence of a systemic abnormality in immune responses in patients with COVID-19 is well documented, but these immune-related insults may not depend on local viral infection. Strikingly, Lee et al showed significant microvascular injury and fibrinogen leakage in the brain tissue of patients with COVID-19, but no evidence of virus was detected in the tissues.71 It is likely that a humoral factor may be eliciting vessel damage, and further studies will be needed to uncover the mechanisms of this phenomenon.
Vascular Thrombosis and Platelet Activation
Thrombosis in venous and arterial circulatory beds has been a prominent feature of SARS-CoV-2 infection.140,141 Viral inflammation and degranulation of endothelial cells was demonstrated by scanning electron microscopy. Inflammation of vascular endothelial cells (endotheliitis) leads to degranulation and exocytosis of Weibel Palade Bodies (WPBs) containing von Willebrand Factor, which promotes recruitment of platelets, as well as platelet-to-platelet aggregates through the glycoprotein 1b receptor.142 Platelet activation remains a common final step in thrombus formation.
Indirect Activation of Platelets and Interaction With the Innate Immune System
Disruption of the subendothelial barrier promotes tissue factor release, activating the extrinsic coagulation cascade, culminating in prothrombin to thrombin conversion. Thrombin stimulates 2 G-protein-coupled receptors on the surface of the human platelet belonging to the proteinase-activated receptor (PAR) pathway, PAR1 and PAR4.143 Platelet PAR1 and PAR4 activation leads to exocytosis and secretion of alpha granules, dense granules, and WPBs.144 Platelet serotonin release likely impacts the endothelium, causing endothelium- and nonendothelium-dependent changes in vascular tone and inflammation. The cause of thrombus formation in COVID-19 likely involves coordinated activation between several pathways of thrombosis and the innate immune system (thrombo-inflammation or immunothrombosis). Early in the pandemic, leukocyte count was the only reported independent predictor of thrombosis.141 Both platelet and endothelial cells activate and recruit circulating leukocytes. Several investigators have now demonstrated in patients with COVID-19 that activated neutrophils release de-condensed chromatin into the extracellular milieu in a mesh-like, prothrombotic network, called neutrophil extracellular traps.145–147
Direct Platelet Reprogramming
The platelet phenotype is hyper-reactive in patients with COVID-19, at least in part from a divergent circulating platelet phenotype.148–150 A coordinated SARS-CoV-2 receptor access module through surface ACE2 and TMPRSS2 is clear in multiple cells, and demonstrated in platelets from patients with COVID-19 through immunologic techniques permitting direct and indirect visualization.150–152 Interestingly, one group did not convincingly demonstrate ACE2 protein on the surface of platelets following a leukocyte CD45-depletion step.148 CD45 is present on the surface of platelets in health and disease153 and so could have diminished the signal required to detect ACE2. Other SARS-CoV-2 receptors have been demonstrated in various cells, including the HDL (high-density lipoprotein) scavenger receptor BI and CD147. These receptors were previously reported to be expressed on the surface of platelets, with a post-receptor signal transduction pathway that increases platelet reactivity and promotes thrombosis.154–158 Importantly, in situ end organ thrombosis, especially in the lung and heart, is a signature of SARS-CoV-2, and the oxygen-reduced microvasculature is a region where platelets are especially reactive.159,160
Autoimmune Phenomena and Adaptive Immune Dysfunction in COVID-19-Associated Vascular Thrombosis
Immunologic dysfunction is an important contributor to the vascular complications that arise in patients with COVID-19, and thrombotic arterial and venous occlusions are a major cause of end-organ damage.161 Abnormal coagulation characteristics associate with severity of COVID19 disease162,170 and high-plasma D-dimer concentration is a risk factor for death.163,164 Implicating adaptive immune system dysfunction, antiplatelet, antiphospholipid, and antiendothelial cell autoantibodies have been demonstrated in patients with SARS-CoV-2.165–168 Prothrombotic autoantibodies targeting phospholipids and phospholipid binding proteins (aPL antibodies) were found in 52% of 172 hospitalized patients with COVID-19169 and included anticardiolipin IgG, IgM, and IgA; anti-B2 glycoprotein I IgG, IgM, and IgA; and antiphosphatidylserine/prothrombin (aPS/PT) IgG and IgM. Antiphospholipid antibodies also activated neutrophils and initiated neutrophil extracellular trap extrusion, consistent with the proposed immunothrombosis mechanism in COVID19.170 Early case reports indicated thrombocytopenia in some patients with COVID-19 may be caused by easier haptenization of platelet antigens, including the cytokine CLCL4, also known as PF4 (platelet factor 4), as evidenced by circulating anti-PF4 antibodies165,171 and earlier observations in which light transmission aggregometry functional assays with the additional of heparin to donor platelets mixed with serum from patients with COVID-19 promoted platelet activations.165 These observations present a true treatment dilemma, given the propensity of patients with COVID-19 to form thrombi, and the need for anticoagulation. Curiously, several patients with COVID-19, meeting clinical diagnostic criteria for heparin-induced thrombocytopenia, subsequently tested positive for anti-PF4 antibodies, but in heparin-induced platelet aggregation assays were negative using the heparin-induced thrombocytopenia confirmatory test platelet serotonin release assay.172,173 Most recently, it was revealed that circulating blood IgG in patients with COVID-19 promotes a procoagulant phenotype and thrombocytopenia through platelet apoptosis by stimulating platelet Fc gamma receptor IIA.174 Overall, a pattern of autoantibody production in COVID-19 that simultaneously activates neutrophils and promotes thrombosis seems clear and may account for the morbidity and mortality benefit shown in the CoDEX and Recovery trials, respectively, when patients were randomized to immune suppression with dexamethasone.175,176
Renin-Angiotensin System Dysfunction
ACE2 has a robust physiological role in regulating angiotensin II, bradykinin activity, and protection against pulmonary capillary leakage and heart failure. However, ACE2 is critical for SARS-CoV-2 cell entry, and since treatment with ACEI/ARBs might increase ACE2 expression, early concerns centered on whether these medications may increase the risk of SARS-CoV-2 infection. However, large observational studies reported that these medications, when prescribed chronically for CVD antecedent to COVID-19 testing, are not associated with greater infectivity.177 Some reports suggest abrogation of the RAS may be associated with protection from severe COVID-19.178 ACEI/ARB-associated protection against COVID-19 is plausible since SARS-CoV-2 engagement and internalization via ACE2 may cause ACE2 shedding or depletion179 that may promote unregulated angiotensin II and/or bradykinin activity. Indeed, ANG II levels appear to be elevated in patients with severe COVID-19,180,181 and infusion of human recombinant soluble ACE2 may be sufficient to suppress these levels which was attended by marked reductions in inflammatory indices.182 Thus, ACE2 is a critical gateway for SARS-COV2 binding and entry, but its functional disruption may lead to further disruption of cardiopulmonary homeostasis during COVID-19.
The impact of SARS-CoV-2 infection on myocardial ACE2 expression is unclear. Lung expression of ACE2 is reduced in a murine system with SARS-Co-V spike protein administration,183 either because of cell internalization of spike-ACE2 and/or membrane shedding after cleavage by proteases. ACE2 downregulation was associated with an increase in lung tissue ANG II levels.183 Thus, in COVID-19, ANG II levels may also be increased,181 due to ACE2 downregulation and reduced enzyme activity. Theoretically, these predicted increases in ANG II levels could be countered by delivering maximal doses of ACE inhibitors and AT1 receptor blockers. However, in the absence of supporting evidence, such an approach is unwarranted and needs to be studied. Myocardial ACE2 expression during and after SARS-CoV-2 infection is currently under investigation.
Translating to Therapies for SARS-CoV-2
Based on growing knowledge of the life cycle of SARS-CoV-2 and its interactions with host cells, it is useful to define preventive or therapeutic strategies on the basis of the time sequence of pathogenic events: prevention upon exposure, inhibition of viral proliferation, and attenuation of exuberant host inflammatory response. Within the latter 2 categories are included 3 specific subclasses of therapies: biologics, new small-molecule therapeutics, and repurposed or repositioned approved therapeutics. Last, organ (system)-specific therapies should also be considered for individuals with complicated infections that lead to specific pathologies, such as a prothrombotic state, stroke syndromes, or acute kidney injury, the treatment of which at the current time is not specific for SARS-CoV-2.
Preventive Therapies
Vaccination is the cornerstone of prevention against SARS-CoV-2 infection. The World Health Organization reported that as of September, 2020, there were 36 vaccine candidates in clinical trials and 146 other candidates currently in preclinical evaluation.184 By any measure, the rapidity of vaccine candidate development and initial clinical trial implementation is an amazing accomplishment, given that this virus has only been recognized for ≈1 year. The vaccines currently in clinical trials comprise 5 different subclasses: inactivated virion-based vaccines, RNA vaccines, DNA vaccines, nonreplicating and replicating viral vector-based vaccines, and recombinant protein subunit-based vaccines. Among these candidates, almost all require a second dose of vaccine after the initial dose, usually at 2, 3, or 4 weeks, for optimal protection.
The benefits and risks of these different types of vaccine have been extensively reviewed184 and will only be briefly summarized here. Inactivated and live attenuated vaccines have been the mainstays of vaccinology since its inception. While these can be readily produced and stably express antigenic epitopes that are in the appropriate conformation, the expression of a highly antigenic but pathogenically less important antigen may skew the immune response. In addition, these vaccines are more difficult to produce owing to the requirement for Biosafety Level 3 facilities. Both DNA and (m)RNA vaccines, by contrast, can be rapidly produced, requiring only conventional nucleic acid synthesis, and their ability to generate specific viral proteins that can be processed by antigen-presenting cells (in the skin—dendritic cells) into a variety of potentially immunogenic conformations is a clear advantage over conventional vaccines. Chemical instability of mRNA is a limiting feature that requires special storage or modification with stabilizing vehicles in their preparation. Although mRNA vaccines are novel, recent phase 1 and 2/3 randomized trials have reported ≈95% efficacy with very low incidence of serious adverse events and efficacy demonstrated across race, ethnic, and age groups.185,186 With limited experience thus far using these nucleic acid-based vaccines, however, their precise adverse event rates, vaccine efficacy among different populations with differing risks of infectious complications, long-term safety, and durability of protection remain to be determined. Viral vector-based vaccines involve the use of a carrier virus (adenovirus, poxvirus) engineered to carry an immunogenically relevant protein from the virus of interest. The advantage to these vaccines is that they can infect antigen-presenting cells directly, and they tend to be chemically and biologically stable. These vaccines can induce an anamnestic response in an immune system previously exposed to these common carrier viruses. Last, vaccines that incorporate specific recombinant proteins of interest (such as the spike protein) can stimulate an effective immune response. As the protein is not exposed to the immune system in its complex biological context, however, its protection may be limited, or the immune response relatively unbalanced.
Therapeutic Approaches Directed at ACE2 and Other Entry Proteins
An obvious therapeutic approach to treating any viral infection including SARS-CoV-2 is to prevent virus-host cell receptor binding.187 This could be achieved by targeting the spike protein (as antibodies do in the course of the immune response) or by targeting of the ACE2 domains that interact with the spike protein. Use of the latter approach must avoid loss of ACE2 physiological function. Use of decoy soluble ACE2 receptors might be a way to circumvent this problem, and such an agent is currently in clinical trials.188 Other approaches include administering an antibody that blocks RBD-ACE2 binding without affecting enzyme activity, or administering an ACE2 enzyme activity agonist, such diminazene,189 as blockade is attempted.
Inhibition of SARS-CoV-2 viral entry into host cells in the (upper) airway has been recently achieved using a lipid-conjugated peptide derived from the spike protein’s C-terminal heptad repeat domain. In preclinical studies, this lipopeptide has been shown to inhibit cell-cell fusion mediated by the spike protein, block infection in cultured cells, and inhibit the spread of virus in human airway epithelial cells.190 Similarly, other entry inhibitors have been identified from generic screens of approved drugs (vide infra), including clemastine, amiodarone, trimeprazine, busitinib, toremifene, flupenthixol, and azelastine, likely via histamine receptor antagonism.191 Last, owing to the now established role of the integrin α5β1 as a ligand for the spike protein and for ACE2, efforts to interrupt those interactions represent another strategy for inhibiting viral entry. To this end, the integrin-binding peptide, ATN-161, has recently been shown to inhibit these critical interactions in early infection.26
Drug Development Strategies
In general, 2 broad strategies can identify potential pharmacotherapies for SARS-CoV-2: target-based drug development and unbiased drug screening. In the former, a detailed understanding of the SARS-CoV-2 life cycle and its molecular determinants is essential, with considerable knowledge gleaned from experiments and by analogy with previous SARS-CoV studies. Each segment of SARS-CoV-2 life cycle of SARS-CoV-2 is a potential therapeutic target: host cell attachment, membrane fusion, uncoating, RNA translation, replication, structural protein assembly, and virion constitution, and exocytosis. Specific targets have been identified for some of these steps, including the following: viral entry—spike protein (neutralizing antibodies, SARS-CoV-2-HR2-derived decoy peptides, peptide fusion inhibitor EK1), ACE2 (human recombinant soluble ACE2—APN01), TMPRSS2 (camostat, mafamostat, bromohexine, rubitecan, loprazolam), CD147 (meplazumab, metuximab, metuzumab), integrin α5β1 (ATN-161), adaptor-related protein complex 2 or AAK1 (baricitinib), membrane lipids (umifenovir), and specific neutralizing antibodies; and viral replication—3CL protease (lopinavir/ritonavir, darunavir), and RNA-dependent RNA-polymerase (remdesivir, favipiravir, ribavirin).192 Some are novel therapies specific to SARS-CoV-2 (eg, APN01) while others are repositioned drugs previously approved for other purposes (eg, ribavirin). Importantly, some treatments target viral proteins (eg, camostat) while others target host proteins (ATN-161). An additional therapeutic strategy has been to focus on the impaired innate immune response early in the infection or on the exuberant immune response observed in some patients later in the course of infection, leading to serious, systemic complications such as a prothrombotic state. Targets considered in these domains and potential treatments include: interferons β1a and β1b; IL-6 receptor (tocilizumab, sarilumab, situximab); IL-1 receptor/IL-1β (anakinra, canakinumab); less specific immunosuppressive therapies (dexamethasone); and ongoing clinical trials of immunomodulatory antibodies.193
While this conventional strategy is a time-honored approach, it suffers from excessive reliance on a single target, and inadequate assessment of off-target effects. The most specific drugs are promiscuous, a fact that has been increasingly documented in comprehensive databases such as DrugBank. This promiscuity and the complex interactions among (protein) targets provide a rationale for a molecular network-based strategy for drug repurposing, including for SARS-CoV-2.
One approach for a repurposing strategy can begin with the comprehensive protein-protein interaction network. Previous work analyzed this interactome to assess where proteins that govern specific disease phenotypes are located and showed that these disease-specific proteins cluster in different subnetworks or modules throughout the interactome.194 These disease modules can be used to guide drug repurposing by identifying the proximity of the target of a drug approved for a different disease to the disease module of interest. This approach has successfully identified repurposable drugs for coronary heart disease,195 malignancies,196 and cardiovascular calcification.197
In the case of SARS-CoV-2, the interactions of viral proteins with human host proteins add complexity within the interactome. To address this issue, Loscalzo and colleagues mapped the 332 human proteins that Gordon et al169 showed bound to 26 (of 29) SARS-CoV-2 proteins to the protein interactome and demonstrated that they agglomerate as a cluster or disease module.198 Based on the COVID-related proteins expressed in the lung (214 of 332, or 64%), 3 analytical strategies to identify potential drug targets for consideration were applied: a network proximity strategy, a network diffusion strategy, and an artificial intelligence–based neural network strategy, to rank-order a list of 6340 FDA-approved drugs. The 3 different methods provided complementary ranking information, leading to the development of a combined or aggregated ranking algorithm, which gave the best predictive accuracy. Curation of the top 10% of the rank list yielded 74 candidate drugs that were next tested in a high-throughput assay to identify those drugs that are viricidal with no or minimal (host cell) cytotoxicity where from the 74 screened compounds, 28% were shown to be effective.198 Among the drugs identified were azelastine, folic acid, auranofin, fluvastatin, ivermectin, and aminolevulinic acid, to highlight but a few. This strategy is depicted in Figure 6. Other network medicine–based strategies for drug repurposing for SARS-CoV-2 that include tissue-specific transcriptomics have also been recently published, demonstrating a potential role for melatonin.199
Figure 6. Network-based drug repurposing paradigm for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2).A, Network-based drug discovery strategy for SARS-CoV-2 in which the viral proteome is depicted overlapping with the human protein interactome, which, in turn, is shown overlapping with the drug-target protein interactome. B, Network-based proximity strategy for drug repurposing in which the proximity of a drug target for another disease to the disease module of interest serves as the basis for pursuing repositioning of that drug. C, The covidome, or the subnetwork or disease module in the protein interactome, is used as the basis for identifying drug targets for drug repurposing, which is evaluated through 3 complementary methods—network proximity, network diffusion, and AI prioritization, leading to a ranking algorithm that yields repurposable drugs for experimental analysis.
The benefit of drug repurposing is that prior drug approval obviates, or at least limits, the need for preclinical animal studies. These compounds have already been used in humans, and their toxicity is well known. Presumably, they can be used directly and safely in patients with SARS-CoV-2 infection. This approach, however, presumes that there is no unique interaction between this novel infection and the repurposed drug that could lead to an unpredictable toxicity. For this reason, understanding the biology implicit in the network architecture of the COVID interactome can provide some guidance in considering potential toxicities that warrant study before human trials.
Translating to Strategies for Management of Patients After COVID-19 Infection
Implications of CMR Findings After Recovery From COVID-19 Acute Infection
CMR findings have highlighted uncertainties in the evaluation and management of patients recovering from COVID-19. Despite normal ECG and echocardiographic findings, normal levels of myocardial biomarkers, and minimal or no symptoms, myocardial findings on CMR may still be present. Nevertheless, the clinical significance of CMR abnormalities, which in most of the reported studies were mild, remains unknown.
Moreover, the pathophysiologic mechanisms of late inflammatory changes and the long-term impact of myocarditis or myocardial fibrosis implicated by CMR on heart failure200,201 or arrhythmic risk202 remain uncertain. Longitudinal studies are needed to determine the natural history and clinical significance of the described CMR findings in patients with COVID-19-induced myocarditis, as LGE and myocardial edema can be dynamic.98 In addition to including matched healthy controls in MRI studies, matched patients with recent non-COVID-19 viral infections would help elucidate the presence of potential differential prevalence of myocarditis related to viral etiology.
Prolonged Exertional Intolerance and Dysautonomia
There is increasing evidence of long COVID-19 symptoms beyond the period of acute infection with prolonged exertional intolerance becoming a frequent finding in not only competitive athletes and active individuals, but many young and older survivors of COVID-19. Common symptoms associated with myocarditis and post-COVID syndrome include chest pain, dyspnea, and palpitations. Besides concerns over CMR findings of cardiac injury, COVID-19-related small fiber neuropathy and dysautonomia are now being reported in individual cases.203–205 COVID-19-related postural orthostatic tachycardia syndrome has also been identified. Relative cardiac deconditioning during a period of exercise and training restriction is a confounder when trying to delineate the cause for exertional intolerance.
Evaluation Post-COVID-19
For investigation of COVID-19-mediated cardiac involvement or dysautonomia in patients with postacute-COVID-19 symptoms or for cardiac risk assessment for return to exercise or sports participation, an algorithm and suggested evaluation for acute and chronic assessment of cardiac involvement are presented in Online Table II. There remains uncertainty as to the yield of noninvasive testing. Serum biomarkers suggestive of myocardial damage are typically elevated in acute myocarditis, although 3 studies reported normal troponin levels post-COVID-19, despite abnormal CMRs.91,92,206 Noninvasive testing, including the ECG and echocardiogram, may provide additional signs suggestive of COVID-19-mediated cardiac involvement. However, a post-COVID-19 CMR study of collegiate athletes noted no definitive ECG or echocardiographic abnormalities.92 Nevertheless, a recent expert consensus statement on screening for potential cardiac involvement in competitive athletes recovering from COVID-19 recommends a targeted approach based on the presence and nature of symptoms with a combination of ECG, biomarkers, and echocardiography for athletes with prolonged or more than mild symptoms.207 A similar targeted approach could be considered for nonathletes with such symptoms, as well.
Implications on Return to Exercise or Sports Participation After COVID-19 Infection
The potential for heightened risk of sudden cardiac death in post-COVID myocardial fibrosis or inflammation is of concern for athletes or active individuals returning to exercise. The wide range of LGE prevalence post-COVID-19 has produced controversy over routine versus targeted use of CMR. Risk stratification with noninvasive biomarkers, ECG, or echocardiography may be insensitive for detection of CMR abnormalities. Conversely, ECG changes considered abnormal in nonathletes may represent normal variants in athletes.208
According to the American College of Cardiology Sports and Exercise Cardiology Section, athletes who have recovered from COVID-19 may return to sports participation based on biomarker and noninvasive cardiac imaging, including an ECG and echocardiogram.209 Athletes are advised to restrict exercise for 10 to 14 days with gradual escalation in exercise intensity. Cardiovascular risk assessment is recommended for mild symptoms lasting longer than 10 days; for moderate or severe symptoms, including hospitalization, advanced cardiac testing is dependent upon symptoms and abnormal findings in baseline testing.210 Patients with COVID-19 myocarditis are advised to follow published return-to-play guidelines for competitive athletes with myocarditis.211 Whether these recommendations will be adequate remains to be determined.
Uncertainty of Long-Term Consequences, Gaps, and Future Needs
The potential for long-term evolution into chronic myocardial disease/cardiomyopathy and other cardiovascular complications, including heart failure, chronic sinus tachycardia, autonomic dysfunction, and arrhythmias, awaits further definition and may have significant implications. Additionally, studies are needed to determine if therapeutic interventions to mitigate the inflammatory response can also limit the extent of intermediate to long-term myocardial injury related to COVID-19. Evaluation of postacute COVID-19 syndrome (long-COVID-19) and recommendations for long-term surveillance, monitoring, and return to exercise or sports participation remain areas in need of further study.
Concluding Remarks
The COVID-19 pandemic has produced devastating effects worldwide with loss of health, life, and livelihoods, particularly in people of color, the underserved, the vulnerable elderly, and those with prior cardiovascular disease. Further understanding of the basic viral-host interactions mediating the varied responses to infection are yet needed to improve prevention and treatment strategies, including those for the long-term cardiovascular effects of the infection. Preventive vaccines offer hope that the pandemic may wane over the next year, and their rapid, successful development within less than a year coupled with the increasing identification of effective treatments are a testament to the massive commitment and tireless efforts of the scientific community, front-line caregivers, and health care leadership. Lessons learned in our response to COVID-19 will hopefully prepare us for future pandemics.
Nonstandard Abbreviations and Acronyms
| ACE | angiotensin-converting enzyme |
| ANG II | angiotensin II |
| CMR | cardiac magnetic resonance imaging |
| COVID-19 | coronavirus disease 2019 |
| cTn | cardiac troponin |
| HDL | high-density lipoprotein |
| hs-TnT | high-sensitivity troponin-T |
| IFN | interferon |
| LGE | late gadolinium enhancement |
| LV | left ventricle |
| NLR | NOD-like receptor |
| NRP1 BD | neuropilin-1 binding domain |
| NRP-1 | neuropilin-1 |
| nsp | nonstructural protein |
| PAR | proteinase-activated receptor |
| PF4 | platelet factor 4 |
| RBD | receptor binding domain |
| RV | right ventricle |
| SARS-CoV-2 | severe acute respiratory syndrome-coronavirus 2 |
| TLR | toll-like receptor |
| TMPRSS2 | transmembrane protease serine 2 |
| TNF | tumor necrosis factor |
| WPB | Weibel Palade Body |
Sources of Funding
M.K. Chung received funding from 810959 AHA Covid-19 Rapid Response Research Coordinating Center grant, 814633 AHA Covid-19 Rapid Response Research grant, NIH/NHLBI R01HL111314. D.A. Zidar received funding from Veterans Affairs COVID-19 Rapid Response Pilot and HIH/NCI UO1CA260513-01. J. Loscalzo received funding from NIH/NHLBI R01HL155107, NIH/NHLBI R01HL55096, NIH/NHLBI U54 HL119145, NIH/NIGMS U01 HG007690, and AHA grant D700382. N.R. Tucker received funding from K01-HL140187. S.J. Cameron received funding from grants NHLBI K08HL128856 and LRPHL120200.
Disclosures J. Loscalzo is scientific co-founder of Scipher Medicine, Inc, a company that focuses on utilizing network medicine approaches to understanding disease mechanisms and identifying therapeutic targets. The other authors report no conflicts.
Footnotes
References
- 1.
Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J, Shchendrygina A, Escher F, Vasa-Nicotera M, Zeiher AM, . Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from Coronavirus Disease 2019 (COVID-19).JAMA Cardiol. 2020; 5:1265–1273. doi: 10.1001/jamacardio.2020.3557CrossrefMedlineGoogle Scholar - 2.
Sandoval Y, Januzzi JL, Jaffe AS . Cardiac troponin for assessment of myocardial injury in COVID-19: JACC review topic of the week.J Am Coll Cardiol. 2020; 76:1244–1258. doi: 10.1016/j.jacc.2020.06.068CrossrefMedlineGoogle Scholar - 3.
Giustino G, Croft LB, Stefanini GG, Bragato R, Silbiger JJ, Vicenzi M, Danilov T, Kukar N, Shaban N, Kini A, . Characterization of myocardial injury in patients With COVID-19.J Am Coll Cardiol. 2020; 76:2043–2055. doi: 10.1016/j.jacc.2020.08.069CrossrefMedlineGoogle Scholar - 4.
Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, Wang H, Wan J, Wang X, Lu Z . Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5:811–818.CrossrefMedlineGoogle Scholar - 5.
Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, . Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.JAMA Cardiol. 2020; 5:802–810. doi: 10.1001/jamacardio.2020.0950CrossrefMedlineGoogle Scholar - 6.
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, . Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395:1054–1062. doi: 10.1016/S0140-6736(20)30566-3CrossrefMedlineGoogle Scholar - 7.
Song Z, Xu Y, Bao L, Zhang L, Yu P, Qu Y, Zhu H, Zhao W, Han Y, Qin C . From SARS to MERS, thrusting coronaviruses into the spotlight.Viruses. 2019; 11:59.CrossrefGoogle Scholar - 8.
Xiong TY, Redwood S, Prendergast B, Chen M . Coronaviruses and the cardiovascular system: acute and long-term implications.Eur Heart J. 2020; 41:1798–1800. doi: 10.1093/eurheartj/ehaa231CrossrefMedlineGoogle Scholar - 9. https://www.cdc.gov/sars/about/fs-sars.html. Accessed December 13, 2020.Google Scholar
- 10. https://www.who.int/publications/m/item/summary-of-probable-sars-cases-with-onset-of-illness-from-1-november-2002-to-31-july-2003. Accessed December 13, 2020.Google Scholar
- 11. World Health Organization. Middle East Respiratory Syndrome.2020. http://www.emro.who.int/health-topics/mers-cov/mers-outbreaks.html. Accessed December 13, 2020.Google Scholar
- 12. https://coronavirus.jhu.edu/map.html. Accessed April 2, 2021.Google Scholar
- 13.
Sorci G, Faivre B, Morand S . Explaining among-country variation in COVID-19 case fatality rate.Sci Rep. 2020; 10:18909. doi: 10.1038/s41598-020-75848-2CrossrefMedlineGoogle Scholar - 14.
Anupama BK, Chaudhuri D . A review of acute myocardial injury in coronavirus disease 2019.Cureus. 2020; 12:e8426.MedlineGoogle Scholar - 15.
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, . A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579:270–273. doi: 10.1038/s41586-020-2012-7CrossrefMedlineGoogle Scholar - 16.
Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, Hu Y, Tao ZW, Tian JH, Pei YY, . A new coronavirus associated with human respiratory disease in China.Nature. 2020; 579:265–269. doi: 10.1038/s41586-020-2008-3CrossrefMedlineGoogle Scholar - 17.
Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, Zhang Q, Shi X, Wang Q, Zhang L, . Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.Nature. 2020; 581:215–220. doi: 10.1038/s41586-020-2180-5CrossrefMedlineGoogle Scholar - 18.
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D . Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein.Cell. 2020; 181:281.e6–292.e6. doi: 10.1016/j.cell.2020.02.058CrossrefGoogle Scholar - 19.
Zisman LS, Meixell GE, Bristow MR, Canver CC . Angiotensin-(1-7) formation in the intact human heart: in vivo dependence on angiotensin II as substrate.Circulation. 2003; 108:1679–1681. doi: 10.1161/01.CIR.0000094733.61689.D4LinkGoogle Scholar - 20.
Zisman LS, Keller RS, Weaver B, Lin Q, Speth R, Bristow MR, Canver CC . Increased angiotensin-(1-7)-forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme Homologue ACE2.Circulation. 2003; 108:1707–1712. doi: 10.1161/01.CIR.0000094734.67990.99LinkGoogle Scholar - 21.
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, . Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.Nature. 2003; 426:450–454. doi: 10.1038/nature02145CrossrefMedlineGoogle Scholar - 22.
Carfì A, Bernabei R, Landi F ; Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients after acute COVID-19.JAMA. 2020; 324:603–605. doi: 10.1001/jama.2020.12603CrossrefMedlineGoogle Scholar - 23.
Daly JL, Simonetti B, Klein K, Chen KE, Williamson MK, Antón-Plágaro C, Shoemark DK, Simón-Gracia L, Bauer M, Hollandi R, . Neuropilin-1 is a host factor for SARS-CoV-2 infection.Science. 2020; 370:861–865. doi: 10.1126/science.abd3072CrossrefMedlineGoogle Scholar - 24.
Maginnis MS . Virus-receptor interactions: the key to cellular invasion.J Mol Biol. 2018; 430:2590–2611. doi: 10.1016/j.jmb.2018.06.024CrossrefMedlineGoogle Scholar - 25.
Bristow MR, Zisman LS, Altman NL, Gilbert EM, Lowes BD, Minobe WA, Slavov D, Schwisow JA, Rodriguez EM, Carroll IA, . Dynamic regulation of SARS-Cov-2 binding and cell entry mechanisms in remodeled human ventricular myocardium.JACC Basic Transl Sci. 2020; 5:871–883. doi: 10.1016/j.jacbts.2020.06.007CrossrefMedlineGoogle Scholar - 26.
Beddingfield BJ, Iwanaga N, Chapagain PP, Zheng W, Roy CJ, Hu TY, Kolls JK, Bix GJ . The integrin binding peptide, ATN-161, as a novel therapy for SARS-CoV-2 infection.JACC Basic Transl Sci. 2020; 6:1–8.MedlineGoogle Scholar - 27.
Lin HB, Liu PP . COVID-19 and the heart: ACE2 level and the company it keeps hold the key.JACC Basic Transl Sci. 2020; 5:884–887. doi: 10.1016/j.jacbts.2020.07.005CrossrefMedlineGoogle Scholar - 28.
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, . SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181:271.e8–280.e8. doi: 10.1016/j.cell.2020.02.052CrossrefGoogle Scholar - 29.
Zhou T, Tsybovsky Y, Gorman J, Rapp M, Cerutti G, Chuang GY, Katsamba PS, Sampson JM, Schön A, Bimela J, . Cryo-EM structures of SARS-CoV-2 Spike without and with ACE2 reveal a pH-dependent switch to mediate endosomal positioning of receptor-binding domains.Cell Host Microbe. 2020; 28:867.e5–879.e5. doi: 10.1016/j.chom.2020.11.004CrossrefGoogle Scholar - 30.
McCracken IR, Saginc G, He L, Huseynov A, Daniels A, Fletcher S, Peghaire C, Kalna V, Andaloussi-Mae M, Muhl L, . Lack of evidence of Angiotensin-Converting Enzyme 2 expression and replicative infection by SARSCoV-2 in human endothelial cells.Circulation. 2021; 143:865–868.LinkGoogle Scholar - 31.
Bailey AL, Dmytrenko O, Greenberg L, Bredemeyer AL, Ma P, Liu J, Penna V, Lai L, Winkler ES, Sviben S, . SARS-CoV-2 infects human engineered heart tissues and models COVID-19 myocarditis [published online February 26, 2021].JACC Basic Transl Sci. doi: 10.1016/j.jacbts.2021.01.002Google Scholar - 32.
Fitzgerald JC, Weiss SL, Maude SL, Barrett DM, Lacey SF, Melenhorst JJ, Shaw P, Berg RA, June CH, Porter DL, . Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia.Crit Care Med. 2017; 45:e124–e131. doi: 10.1097/CCM.0000000000002053CrossrefMedlineGoogle Scholar - 33.
Liu S, Xiao G, Chen Y, He Y, Niu J, Escalante CR, Xiong H, Farmar J, Debnath AK, Tien P, . Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors.Lancet. 2004; 363:938–947. doi: 10.1016/S0140-6736(04)15788-7CrossrefMedlineGoogle Scholar - 34.
Bosch BJ, Martina BE, Van Der Zee R, Lepault J, Haijema BJ, Versluis C, Heck AJ, De Groot R, Osterhaus AD, Rottier PJ . Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides.Proc Natl Acad Sci USA. 2004; 101:8455–8460. doi: 10.1073/pnas.0400576101CrossrefMedlineGoogle Scholar - 35.
Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bates P . Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry.Proc Natl Acad Sci USA. 2005; 102:11876–11881. doi: 10.1073/pnas.0505577102CrossrefMedlineGoogle Scholar - 36.
Huang IC, Bosch BJ, Li F, Li W, Lee KH, Ghiran S, Vasilieva N, Dermody TS, Harrison SC, Dormitzer PR, . SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells.J Biol Chem. 2006; 281:3198–3203. doi: 10.1074/jbc.M508381200CrossrefMedlineGoogle Scholar - 37.
Hoffmann M, Kleine-Weber H, Pöhlmann S . A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells.Mol Cell. 2020; 78:779–784.e5. doi: 10.1016/j.molcel.2020.04.022CrossrefMedlineGoogle Scholar - 38.
Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, Geng Q, Auerbach A, Li F . Structural basis of receptor recognition by SARS-CoV-2.Nature. 2020; 581:221–224. doi: 10.1038/s41586-020-2179-yCrossrefMedlineGoogle Scholar - 39.
Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, Lu G, Qiao C, Hu Y, Yuen KY, . Structural and functional basis of SARS-CoV-2 entry by using human ACE2.Cell. 2020; 181:894 e9–904 e9.CrossrefGoogle Scholar - 40.
Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L, Guo R, Chen T, Hu J, . Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV.Nat Commun. 2020; 11:1620. doi: 10.1038/s41467-020-15562-9CrossrefMedlineGoogle Scholar - 41.
Ju B, Zhang Q, Ge J, Wang R, Sun J, Ge X, Yu J, Shan S, Zhou B, Song S, . Human neutralizing antibodies elicited by SARS-CoV-2 infection.Nature. 2020; 584:115–119. doi: 10.1038/s41586-020-2380-zCrossrefMedlineGoogle Scholar - 42.
Lv H, Wu NC, Tsang OT, Yuan M, Perera RAPM, Leung WS, So RTY, Chan JMC, Yip GK, Chik TSH, . Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections.Cell Rep. 2020; 31:107725. doi: 10.1016/j.celrep.2020.107725CrossrefGoogle Scholar - 43.
Yuan M, Wu NC, Zhu X, Lee CD, So RTY, Lv H, Mok CKP, Wilson IA . A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV.Science. 2020; 368:630–633. doi: 10.1126/science.abb7269CrossrefMedlineGoogle Scholar - 44.
Wang C, Li W, Drabek D, Okba NMA, van Haperen R, Osterhaus ADME, van Kuppeveld FJM, Haagmans BL, Grosveld F, Bosch BJ . A human monoclonal antibody blocking SARS-CoV-2 infection.Nat Commun. 2020; 11:2251. doi: 10.1038/s41467-020-16256-yCrossrefMedlineGoogle Scholar - 45.
Pinto D, Park YJ, Beltramello M, Walls AC, Tortorici MA, Bianchi S, Jaconi S, Culap K, Zatta F, De Marco A, . Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody.Nature. 2020; 583:290–295. doi: 10.1038/s41586-020-2349-yCrossrefMedlineGoogle Scholar - 46.
Zhou D, Duyvesteyn HME, Chen CP, Huang CG, Chen TH, Shih SR, Lin YC, Cheng CY, Cheng SH, Huang YC, . Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient.Nat Struct Mol Biol. 2020; 27:950–958. doi: 10.1038/s41594-020-0480-yCrossrefMedlineGoogle Scholar - 47.
Wec AZ, Wrapp D, Herbert AS, Maurer DP, Haslwanter D, Sakharkar M, Jangra RK, Dieterle ME, Lilov A, Huang D, . Broad neutralization of SARS-related viruses by human monoclonal antibodies.Science. 2020; 369:731–736. doi: 10.1126/science.abc7424CrossrefMedlineGoogle Scholar - 48.
Hou Y, Zhao J, Martin W, Kallianpur A, Chung MK, Jehi L, Sharifi N, Erzurum S, Eng C, Cheng F . New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis.BMC Med. 2020; 18:216. doi: 10.1186/s12916-020-01673-zCrossrefMedlineGoogle Scholar - 49.
Guo X, Chen Z, Xia Y, Lin W, Li H . Investigation of the genetic variation in ACE2 on the structural recognition by the novel coronavirus (SARS-CoV-2).J Transl Med. 2020; 18:321. doi: 10.1186/s12967-020-02486-7CrossrefMedlineGoogle Scholar - 50.
Blume C, Jackson CL, Spalluto CM, Legebeke J, Nazlamova L, Conforti F, Perotin JM, Frank M, Butler J, Crispin M, . A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection.Nat Genet. 2021; 53:205–214. doi: 10.1038/s41588-020-00759-xCrossrefMedlineGoogle Scholar - 51.
Leung K, Shum MH, Leung GM, Lam TT, Wu JT . Early transmissibility assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom, October to November 2020.Euro Surveill. 2021; 26:2002106.CrossrefGoogle Scholar - 52.
Greaney AJ, Loes AN, Crawford KHD, Starr TN, Malone KD, Chu HY, Bloom JD . Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies.Cell Host Microbe. 2021; 29:463.e6–476.e6. doi: 10.1016/j.chom.2021.02.003Google Scholar - 53.
V’kovski P, Kratzel A, Steiner S, Stalder H, Thiel V . Coronavirus biology and replication: implications for SARS-CoV-2.Nat Rev Microbiol. 2021; 19:155–170. doi: 10.1038/s41579-020-00468-6CrossrefMedlineGoogle Scholar - 54.
Hofmann H, Pyrc K, van der Hoek L, Geier M, Berkhout B, Pöhlmann S . Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry.Proc Natl Acad Sci USA. 2005; 102:7988–7993. doi: 10.1073/pnas.0409465102CrossrefMedlineGoogle Scholar - 55.
Ge XY, Li JL, Yang XL, Chmura AA, Zhu G, Epstein JH, Mazet JK, Hu B, Zhang W, Peng C, . Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor.Nature. 2013; 503:535–538. doi: 10.1038/nature12711CrossrefMedlineGoogle Scholar - 56.
Dimitrov DS . Virus entry: molecular mechanisms and biomedical applications.Nat Rev Microbiol. 2004; 2:109–122. doi: 10.1038/nrmicro817CrossrefMedlineGoogle Scholar - 57.
Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, . A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.Circ Res. 2000; 87:E1–E9. doi: 10.1161/01.res.87.5.e1LinkGoogle Scholar - 58.
Chen L, Li X, Chen M, Feng Y, Xiong C . The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2.Cardiovasc Res. 2020; 116:1097–1100. doi: 10.1093/cvr/cvaa078CrossrefMedlineGoogle Scholar - 59.
Nicin L, Abplanalp WT, Mellentin H, Kattih B, Tombor L, John D, Schmitto JD, Heineke J, Emrich F, Arsalan M, . Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts.Eur Heart J. 2020; 41:1804–1806. doi: 10.1093/eurheartj/ehaa311CrossrefMedlineGoogle Scholar - 60.
Tucker NR, Chaffin M, Bedi KC, Papangeli I, Akkad AD, Arduini A, Hayat S, Eraslan G, Muus C, Bhattacharyya RP, ; Human Cell Atlas Lung Biological Network; Human Cell Atlas Lung Biological Network Consortium Members. Myocyte-specific upregulation of ACE2 in cardiovascular disease: implications for SARS-CoV-2-mediated myocarditis.Circulation. 2020; 142:708–710. doi: 10.1161/CIRCULATIONAHA.120.047911LinkGoogle Scholar - 61.
Hikmet F, Méar L, Edvinsson Å, Micke P, Uhlén M, Lindskog C . The protein expression profile of ACE2 in human tissues.Mol Syst Biol. 2020; 16:e9610. doi: 10.15252/msb.20209610CrossrefMedlineGoogle Scholar - 62.
Liu H, Gai S, Wang X, Zeng J, Sun C, Zhao Y, Zheng Z . Single-cell analysis of SARS-CoV-2 receptor ACE2 and spike protein priming expression of proteases in the human heart.Cardiovasc Res. 2020; 116:1733–1741. doi: 10.1093/cvr/cvaa191CrossrefMedlineGoogle Scholar - 63.
Zisman LS, Abraham WT, Meixell GE, Vamvakias BN, Quaife RA, Lowes BD, Roden RL, Peacock SJ, Groves BM, Raynolds MV . Angiotensin II formation in the intact human heart. Predominance of the angiotensin-converting enzyme pathway.J Clin Invest. 1995; 96:1490–1498. doi: 10.1172/JCI118186CrossrefMedlineGoogle Scholar - 64.
Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, da Costa J, Zhang L, Pei Y, . Angiotensin-converting enzyme 2 is an essential regulator of heart function.Nature. 2002; 417:822–828. doi: 10.1038/nature00786CrossrefMedlineGoogle Scholar - 65.
Yamamoto K, Ohishi M, Katsuya T, Ito N, Ikushima M, Kaibe M, Tatara Y, Shiota A, Sugano S, Takeda S, . Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II.Hypertension. 2006; 47:718–726. doi: 10.1161/01.HYP.0000205833.89478.5bLinkGoogle Scholar - 66.
Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, . ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis.J Biol Chem. 2004; 279:17996–18007. doi: 10.1074/jbc.M311191200CrossrefMedlineGoogle Scholar - 67.
Guo J, Wei X, Li Q, Li L, Yang Z, Shi Y, Qin Y, Zhang X, Wang X, Zhi X, . Single-cell RNA analysis on ACE2 expression provides insights into SARS-CoV-2 potential entry into the bloodstream and heart injury.J Cell Physiol. 2020; 235:9884–9894. doi: 10.1002/jcp.29802CrossrefMedlineGoogle Scholar - 68.
Bos JM, Hebl VB, Oberg AL, Sun Z, Herman DS, Teekakirikul P, Seidman JG, Seidman CE, Dos Remedios CG, Maleszewski JJ, . Marked up-regulation of ACE2 in harts of patients with obstructive hypertrophic cardiomyopathy: implications for SARS-CoV-2-mediated COVID-19.Mayo Clin Proc. 2020; 95:1354–1368. doi: 10.1016/j.mayocp.2020.04.028CrossrefMedlineGoogle Scholar - 69.
Goulter AB, Goddard MJ, Allen JC, Clark KL . ACE2 gene expression is up-regulated in the human failing heart.BMC Med. 2004; 2:19. doi: 10.1186/1741-7015-2-19CrossrefMedlineGoogle Scholar - 70.
Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS . Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target.Intensive Care Med. 2020; 46:586–590. doi: 10.1007/s00134-020-05985-9CrossrefMedlineGoogle Scholar - 71.
Argenziano MG, Bruce SL, Slater CL, Tiao JR, Baldwin MR, Barr RG, Chang BP, Chau KH, Choi JJ, Gavin N, . Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.BMJ. 2020; 369:m1996. doi: 10.1136/bmj.m1996CrossrefMedlineGoogle Scholar - 72.
Zeng JH, Wu WB, Qu JX, Wang Y, Dong CF, Luo YF, Zhou D, Feng WX, Feng C . Cardiac manifestations of COVID-19 in Shenzhen, China.Infection. 2020; 48:861–870. doi: 10.1007/s15010-020-01473-wCrossrefMedlineGoogle Scholar - 73.
Kang Y, Chen T, Mui D, Ferrari V, Jagasia D, Scherrer-Crosbie M, Chen Y, Han Y . Cardiovascular manifestations and treatment considerations in COVID-19.Heart. 2020; 106:1132–1141. doi: 10.1136/heartjnl-2020-317056CrossrefMedlineGoogle Scholar - 74.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, . Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; 323:1061–1069. doi: 10.1001/jama.2020.1585CrossrefMedlineGoogle Scholar - 75.
Dweck MR, Bularga A, Hahn RT, Bing R, Lee KK, Chapman AR, White A, Salvo GD, Sade LE, Pearce K, . Global evaluation of echocardiography in patients with COVID-19.Eur Heart J Cardiovasc Imaging. 2020; 21:949–958. doi: 10.1093/ehjci/jeaa178CrossrefMedlineGoogle Scholar - 76.
Szekely Y, Lichter Y, Taieb P, Banai A, Hochstadt A, Merdler I, Gal Oz A, Rothschild E, Baruch G, Peri Y, . Spectrum of cardiac manifestations in COVID-19: a systematic echocardiographic study.Circulation. 2020; 142:342–353. doi: 10.1161/CIRCULATIONAHA.120.047971LinkGoogle Scholar - 77.
Jain SS, Liu Q, Raikhelkar J, Fried J, Elias P, Poterucha TJ, DeFilippis EM, Rosenblum H, Wang EY, Redfors B, . Indications for and findings on transthoracic echocardiography in COVID-19.J Am Soc Echocardiogr. 2020; 33:1278–1284. doi: 10.1016/j.echo.2020.06.009CrossrefMedlineGoogle Scholar - 78.
Mahmoud-Elsayed HM, Moody WE, Bradlow WM, Khan-Kheil AM, Senior J, Hudsmith LE, Steeds RP . Echocardiographic findings in patients with COVID-19 pneumonia.Can J Cardiol. 2020; 36:1203–1207. doi: 10.1016/j.cjca.2020.05.030CrossrefMedlineGoogle Scholar - 79.
Abrams MP, Wan EY, Waase MP, Morrow JP, Dizon JM, Yarmohammadi H, Berman JP, Rubin GA, Kushnir A, Poterucha TJ, . Clinical and cardiac characteristics of COVID-19 mortalities in a diverse New York City Cohort.J Cardiovasc Electrophysiol. 2020; 31:3086–3096. doi: 10.1111/jce.14772CrossrefMedlineGoogle Scholar - 80.
Lippi G, Sanchis-Gomar F, Favaloro EJ, Lavie CJ, Henry BM . Coronavirus disease 2019-associated coagulopathy.Mayo Clin Proc. 2021; 96:203–217. doi: 10.1016/j.mayocp.2020.10.031CrossrefMedlineGoogle Scholar - 81.
Sze S, Pan D, Nevill CR, Gray LJ, Martin CA, Nazareth J, Minhas JS, Divall P, Khunti K, Abrams KR, . Ethnicity and clinical outcomes in COVID-19: a systematic review and meta-analysis.EClinicalMedicine. 2020; 29:100630. doi: 10.1016/j.eclinm.2020.100630CrossrefMedlineGoogle Scholar - 82.
Gross CP, Essien UR, Pasha S, Gross JR, Wang SY, Nunez-Smith M . Racial and ethnic disparities in population-level Covid-19 mortality.J Gen Intern Med. 2020; 35:3097–3099. doi: 10.1007/s11606-020-06081-wCrossrefMedlineGoogle Scholar - 83.
Yancy CW . COVID-19 and African Americans.JAMA. 2020; 323:1891–1892. doi: 10.1001/jama.2020.6548CrossrefMedlineGoogle Scholar - 84.
Scannell CA, Oronce CIA, Tsugawa Y . Association between county-level racial and ethnic characteristics and COVID-19 cases and deaths in the USA.J Gen Intern Med. 2020; 35:3126–3128. doi: 10.1007/s11606-020-06083-8CrossrefMedlineGoogle Scholar - 85.
Rodriguez F, Solomon N, de Lemos JA, Das SR, Morrow DA, Bradley SM, Elkind MSV, Williams Iv JH, Holmes D, Matsouaka RA, . Racial and ethnic differences in presentation and outcomes for patients hospitalized with COVID-19: findings from the American Heart Association’s COVID-19 Cardiovascular Disease Registry [published November 17, 2020].Circulation. doi: 10.1161/CIRCULATIONAHA.120.052278. https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.052278.Google Scholar - 86.
Tang N, Li D, Wang X, Sun Z . Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost. 2020; 18:844–847. doi: 10.1111/jth.14768CrossrefMedlineGoogle Scholar - 87.
Roberts KA, Colley L, Agbaedeng TA, Ellison-Hughes GM, Ross MD . Vascular manifestations of COVID-19 - thromboembolism and microvascular dysfunction.Front Cardiovasc Med. 2020; 7:598400. doi: 10.3389/fcvm.2020.598400CrossrefMedlineGoogle Scholar - 88.
Smilowitz NR, Jethani N, Chen J, Aphinyanaphongs Y, Zhang R, Dogra S, Alviar CL, Keller N, Razzouk L, Quinones-Camacho A, . Myocardial injury in adults hospitalized with COVID-19.Circulation. 2020; 142:2393–2395. doi: 10.1161/CIRCULATIONAHA.120.050434LinkGoogle Scholar - 89.
Lala A, Johnson KW, Januzzi JL, Russak AJ, Paranjpe I, Richter F, Zhao S, Somani S, Van Vleck T, Vaid A, ; Mount Sinai COVID Informatics Center. Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection.J Am Coll Cardiol. 2020; 76:533–546. doi: 10.1016/j.jacc.2020.06.007CrossrefMedlineGoogle Scholar - 90.
Ojha V, Verma M, Pandey NN, Mani A, Malhi AS, Kumar S, Jagia P, Roy A, Sharma S . Cardiac magnetic resonance imaging in coronavirus disease 2019 (COVID-19): a systematic review of cardiac magnetic resonance imaging findings in 199 patients.J Thorac Imaging. 2020; 36:73–83.CrossrefGoogle Scholar - 91.
Huang L, Zhao P, Tang D, Zhu T, Han R, Zhan C, Liu W, Zeng H, Tao Q, Xia L . Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging.JACC Cardiovasc Imaging. 2020; 13:2330–2339. doi: 10.1016/j.jcmg.2020.05.004CrossrefMedlineGoogle Scholar - 92.
Rajpal S, Tong MS, Borchers J, Zareba KM, Obarski TP, Simonetti OP, Daniels CJ . Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection.JAMA Cardiol. 2021; 6:116–118. doi: 10.1001/jamacardio.2020.4916MedlineGoogle Scholar - 93.
Clark DE, Parikh A, Dendy JM, Diamond AB, George-Durrett K, Fish FA, Slaughter JC, Fitch W, Hughes SG, Soslow JH . COVID-19 myocardial pathology evaluation in athletes with cardiac magnetic resonance (COMPETE CMR).Circulation. 2021; 143:609–612. doi: 10.1161/CIRCULATIONAHA.120.052573LinkGoogle Scholar - 94.
Starekova J, Bluemke DA, Bradham WS, Eckhardt LL, Grist TM, Kusmirek JE, Purtell CS, Schiebler ML, Reeder SB . Evaluation for myocarditis in competitive student athletes recovering from coronavirus disease 2019 with cardiac magnetic resonance imaging [published online January 14, 2021].JAMA Cardiol. doi: 10.1001/jamacardio.2020.7444. https://jamanetwork.com/journals/jamacardiology/fullarticle/2775372.Google Scholar - 95.
Spieker M, Haberkorn S, Gastl M, Behm P, Katsianos S, Horn P, Jacoby C, Schnackenburg B, Reinecke P, Kelm M, . Abnormal T2 mapping cardiovascular magnetic resonance correlates with adverse clinical outcome in patients with suspected acute myocarditis.J Cardiovasc Magn Reson. 2017; 19:38. doi: 10.1186/s12968-017-0350-xCrossrefMedlineGoogle Scholar - 96.
Gräni C, Eichhorn C, Bière L, Murthy VL, Agarwal V, Kaneko K, Cuddy S, Aghayev A, Steigner M, Blankstein R, . Prognostic value of cardiac magnetic resonance tissue characterization in risk stratifying patients with suspected myocarditis.J Am Coll Cardiol. 2017; 70:1964–1976. doi: 10.1016/j.jacc.2017.08.050CrossrefMedlineGoogle Scholar - 97.
Ammirati E, Cipriani M, Moro C, Raineri C, Pini D, Sormani P, Mantovani R, Varrenti M, Pedrotti P, Conca C, ; Registro Lombardo delle Miocarditi. Clinical presentation and outcome in a contemporary cohort of patients with acute myocarditis: multicenter lombardy registry.Circulation. 2018; 138:1088–1099. doi: 10.1161/CIRCULATIONAHA.118.035319LinkGoogle Scholar - 98.
Aquaro GD, Ghebru Habtemicael Y, Camastra G, Monti L, Dellegrottaglie S, Moro C, Lanzillo C, Scatteia A, Di Roma M, Pontone G, ; “Cardiac Magnetic Resonance” Working Group of the Italian Society of Cardiology. Prognostic value of repeating cardiac magnetic resonance in patients with acute myocarditis.J Am Coll Cardiol. 2019; 74:2439–2448. doi: 10.1016/j.jacc.2019.08.1061CrossrefMedlineGoogle Scholar - 99.
Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, Kang L, Guo L, Liu M, Zhou X, . 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.Lancet. 2021; 397:220–232.CrossrefMedlineGoogle Scholar - 100.
Edwards S, Small JD, Geratz JD, Alexander LK, Baric RS . An experimental model for myocarditis and congestive heart failure after rabbit coronavirus infection.J Infect Dis. 1992; 165:134–140. doi: 10.1093/infdis/165.1.134CrossrefMedlineGoogle Scholar - 101.
Basso C, Leone O, Rizzo S, De Gaspari M, van der Wal AC, Aubry MC, Bois MC, Lin PT, Maleszewski JJ, Stone JR . Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.Eur Heart J. 2020; 41:3827–3835. doi: 10.1093/eurheartj/ehaa664CrossrefMedlineGoogle Scholar - 102.
Fox SE, Li G, Akmatbekov A, Harbert JL, Lameira FS, Brown JQ, Vander Heide RS . Unexpected features of cardiac pathology in COVID-19 infection.Circulation. 2020; 142:1123–1125. doi: 10.1161/CIRCULATIONAHA.120.049465LinkGoogle Scholar - 103.
Fox SE, Lameira FS, Rinker EB, Vander Heide RS . Cardiac endotheliitis and multisystem inflammatory syndrome after COVID-19.Ann Intern Med. 2020; 173:1025–1027. doi: 10.7326/L20-0882CrossrefMedlineGoogle Scholar - 104.
Schaller T, Hirschbühl K, Burkhardt K, Braun G, Trepel M, Märkl B, Claus R . Postmortem examination of patients with COVID-19.JAMA. 2020; 323:2518–2520. doi: 10.1001/jama.2020.8907CrossrefMedlineGoogle Scholar - 105.
Lindner D, Fitzek A, Bräuninger H, Aleshcheva G, Edler C, Meissner K, Scherschel K, Kirchhof P, Escher F, Schultheiss HP, . Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases.JAMA Cardiol. 2020; 5:1281–1285. doi: 10.1001/jamacardio.2020.3551CrossrefMedlineGoogle Scholar - 106.
Escher F, Pietsch H, Aleshcheva G, Bock T, Baumeier C, Elsaesser A, Wenzel P, Hamm C, Westenfeld R, Schultheiss M, . Detection of viral SARS-CoV-2 genomes and histopathological changes in endomyocardial biopsies.ESC Heart Fail. 2020; 7:2440–2447. doi: 10.1002/ehf2.12805CrossrefMedlineGoogle Scholar - 107.
Tavazzi G, Pellegrini C, Maurelli M, Belliato M, Sciutti F, Bottazzi A, Sepe PA, Resasco T, Camporotondo R, Bruno R, . Myocardial localization of coronavirus in COVID-19 cardiogenic shock.Eur J Heart Fail. 2020; 22:911–915. doi: 10.1002/ejhf.1828CrossrefMedlineGoogle Scholar - 108.
Dolhnikoff M, Ferreira Ferranti J, de Almeida Monteiro RA, Duarte-Neto AN, Soares Gomes-Gouvêa M, Viu Degaspare N, Figueiredo Delgado A, Montanari Fiorita C, Nunes Leal G, Rodrigues RM, . SARS-CoV-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome.Lancet Child Adolesc Health. 2020; 4:790–794. doi: 10.1016/S2352-4642(20)30257-1CrossrefMedlineGoogle Scholar - 109.
Kaneko N, Satta S, Komuro Y, Muthukrishnan SD, Kakarla V, Guo L, An J, Elahi F, Kornblum HI, Liebeskind DS, . Flow-mediated susceptibility and molecular response of cerebral endothelia to SARS-CoV-2 infection.Stroke. 2021; 52:260–270. doi: 10.1161/STROKEAHA.120.032764LinkGoogle Scholar - 110.
Bojkova D, Wagner JUG, Shumliakivska M, Aslan GS, Saleem U, Hansen A, Luxán G, Günther S, Pham MD, Krishnan J, . SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes.Cardiovasc Res. 2020; 116:2207–2215. doi: 10.1093/cvr/cvaa267CrossrefMedlineGoogle Scholar - 111.
Bulfamante GP, Perrucci GL, Falleni M, Sommariva E, Tosi D, Martinelli C, Songia P, Poggio P, Carugo S, Pompilio G . Evidence of SARS-CoV-2 transcriptional activity in cardiomyocytes of COVID-19 patients without clinical signs of cardiac involvement.Biomedicines. 2020; 8:626.CrossrefGoogle Scholar - 112.
Dorward DA, Russell CD, Um IH, Elshani M, Armstrong SD, Penrice-Randal R, Millar T, Lerpiniere CEB, Tagliavini G, Hartley CS, . Tissue-specific immunopathology in fatal COVID-19.Am J Respir Crit Care Med. 2021; 203:192–201. doi: 10.1164/rccm.202008-3265OCCrossrefMedlineGoogle Scholar - 113.
Fox SE, Akmatbekov A, Harbert JL, Li G, Quincy Brown J, Vander Heide RS . Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.Lancet Respir Med. 2020; 8:681–686. doi: 10.1016/S2213-2600(20)30243-5CrossrefMedlineGoogle Scholar - 114.
Halushka MK, Vander Heide RS . Myocarditis is rare in COVID-19 autopsies: cardiovascular findings across 277 postmortem examinations.Cardiovasc Pathol. 2021; 50:107300. doi: 10.1016/j.carpath.2020.107300CrossrefMedlineGoogle Scholar - 115.
Ma S, Sun S, Li J, Fan Y, Qu J, Sun L, Wang S, Zhang Y, Yang S, Liu Z, . Single-cell transcriptomic atlas of primate cardiopulmonary aging.Cell Res. 2021; 31:415–432. doi: 10.1038/s41422-020-00412-6CrossrefMedlineGoogle Scholar - 116.
Yiangou L, Davis RP, Mummery CL . Using cardiovascular cells from human pluripotent stem cells for COVID-19 research: why the heart fails.Stem Cell Reports. 2021; 16:385–397. doi: 10.1016/j.stemcr.2020.11.003CrossrefMedlineGoogle Scholar - 117.
Kwon Y, Nukala SB, Srivastava S, Miyamoto H, Ismail NI, Jousma J, Rehman J, Ong SB, Lee WH, Ong SG . Detection of viral RNA fragments in human iPSC cardiomyocytes following treatment with extracellular vesicles from SARS-CoV-2 coding sequence overexpressing lung epithelial cells.Stem Cell Res Ther. 2020; 11:514. doi: 10.1186/s13287-020-02033-7CrossrefMedlineGoogle Scholar - 118.
Sharma A, Garcia G, Wang Y, Plummer JT, Morizono K, Arumugaswami V, Svendsen CN . Human iPSC-derived cardiomyocytes are susceptible to SARS-CoV-2 infection.Cell Rep Med. 2020; 1:100052. doi: 10.1016/j.xcrm.2020.100052CrossrefMedlineGoogle Scholar - 119.
Guaraldi G, Meschiari M, Cozzi-Lepri A, Milic J, Tonelli R, Menozzi M, Franceschini E, Cuomo G, Orlando G, Borghi V, . Tocilizumab in patients with severe COVID-19: a retrospective cohort study.Lancet Rheumatol. 2020; 2:e474–e484. doi: 10.1016/S2665-9913(20)30173-9CrossrefMedlineGoogle Scholar - 120.
Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, Horick NK, Healy BC, Shah R, Bensaci AM, ; BACC Bay Tocilizumab Trial Investigators. Efficacy of tocilizumab in patients hospitalized with Covid-19.N Engl J Med. 2020; 383:2333–2344. doi: 10.1056/NEJMoa2028836CrossrefMedlineGoogle Scholar - 121.
Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, Criner GJ, Kaplan-Lewis E, Baden R, Pandit L, . Tocilizumab in patients hospitalized with Covid-19 pneumonia.N Engl J Med. 2021; 384:20–30. doi: 10.1056/NEJMoa2030340CrossrefMedlineGoogle Scholar - 122.
Hermine O, Mariette X, Tharaux PL, Resche-Rigon M, Porcher R, Ravaud P ; CORIMUNO-19 Collaborative Group. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial.JAMA Intern Med. 2021; 181:32–40. doi: 10.1001/jamainternmed.2020.6820CrossrefMedlineGoogle Scholar - 123.
Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, Péré H, Charbit B, Bondet V, Chenevier-Gobeaux C, . Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.Science. 2020; 369:718–724. doi: 10.1126/science.abc6027CrossrefMedlineGoogle Scholar - 124.
Zhou R, To KK, Wong YC, Liu L, Zhou B, Li X, Huang H, Mo Y, Luk TY, Lau TT, . Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses.Immunity. 2020; 53:864.e5–877.e5. doi: 10.1016/j.immuni.2020.07.026CrossrefGoogle Scholar - 125.
Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann H-H, Zhang Y, Dorgham K, Philippot Q, Rosain J, Béziat V, . Autoantibodies against type I IFNs in patients with life-threatening COVID-19.Science. 2020; 370:eabd4585.CrossrefMedlineGoogle Scholar - 126.
Campana P, Parisi V, Leosco D, Bencivenga D, Della Ragione F, Borriello A . Dendritic cells and SARS-CoV-2 infection: still an unclarified connection.Cells. 2020; 9:2046.CrossrefGoogle Scholar - 127.
Yang L, Gou J, Gao J, Huang L, Zhu Z, Ji S, Liu H, Xing L, Yao M, Zhang Y . Immune characteristics of severe and critical COVID-19 patients.Signal Transduct Target Ther. 2020; 5:179. doi: 10.1038/s41392-020-00296-3CrossrefMedlineGoogle Scholar - 128.
Rydyznski Moderbacher C, Ramirez SI, Dan JM, Grifoni A, Hastie KM, Weiskopf D, Belanger S, Abbott RK, Kim C, Choi J, . Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity.Cell. 2020; 183:996–1012.e19. doi: 10.1016/j.cell.2020.09.038CrossrefMedlineGoogle Scholar - 129.
Grifoni A, Weiskopf D, Ramirez SI, Mateus J, Dan JM, Moderbacher CR, Rawlings SA, Sutherland A, Premkumar L, Jadi RS, . Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals.Cell. 2020; 181:1489–1501.e15. doi: 10.1016/j.cell.2020.05.015CrossrefMedlineGoogle Scholar - 130.
Breton G, Mendoza P, Hagglof T, Oliveira TY, Schaefer-Babajew D, Gaebler C, Turroja M, Hurley A, Caskey M, Nussenzweig MC . Persistent Cellular Immunity to SARS-CoV-2 Infection.bioRxiv. Preprint posted online December 9, 2020. doi: 10.1101/2020.12.08.416636Google Scholar - 131.
Fan YY, Huang ZT, Li L, Wu MH, Yu T, Koup RA, Bailer RT, Wu CY . Characterization of SARS-CoV-specific memory T cells from recovered individuals 4 years after infection.Arch Virol. 2009; 154:1093–1099. doi: 10.1007/s00705-009-0409-6CrossrefMedlineGoogle Scholar - 132.
Sette A, Crotty S . Pre-existing immunity to SARS-CoV-2: the knowns and unknowns.Nat Rev Immunol. 2020; 20:457–458. doi: 10.1038/s41577-020-0389-zCrossrefMedlineGoogle Scholar - 133.
Freeman ML, Panigrahi S, Chen B, Juchnowski S, Sieg SF, Lederman MM, Funderburg NT, Zidar DA . CD8+ T-cell-derived tumor necrosis factor can induce tissue factor expression on monocytes.J Infect Dis. 2019; 220:73–77. doi: 10.1093/infdis/jiz051CrossrefMedlineGoogle Scholar - 134.
Jaume M, Yip MS, Cheung CY, Leung HL, Li PH, Kien F, Dutry I, Callendret B, Escriou N, Altmeyer R, . Anti-severe acute respiratory syndrome coronavirus spike antibodies trigger infection of human immune cells via a pH- and cysteine protease-independent FcγR pathway.J Virol. 2011; 85:10582–10597. doi: 10.1128/JVI.00671-11CrossrefMedlineGoogle Scholar - 135.
Cunningham MW, Antone SM, Gulizia JM, McManus BM, Fischetti VA, Gauntt CJ . Cytotoxic and viral neutralizing antibodies crossreact with streptococcal M protein, enteroviruses, and human cardiac myosin.Proc Natl Acad Sci USA. 1992; 89:1320–1324. doi: 10.1073/pnas.89.4.1320CrossrefMedlineGoogle Scholar - 136.
Alvarez FL, Neu N, Rose NR, Craig SW, Beisel KW . Heart-specific autoantibodies induced by Coxsackievirus B3: identification of heart autoantigens.Clin Immunol Immunopathol. 1987; 43:129–139. doi: 10.1016/0090-1229(87)90164-4CrossrefMedlineGoogle Scholar - 137.
Long QX, Tang XJ, Shi QL, Li Q, Deng HJ, Yuan J, Hu JL, Xu W, Zhang Y, Lv FJ, . Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections.Nat Med. 2020; 26:1200–1204. doi: 10.1038/s41591-020-0965-6CrossrefMedlineGoogle Scholar - 138.
Zohar T, Alter G . Dissecting antibody-mediated protection against SARS-CoV-2.Nature reviews Immunolog. 2020; 20:392–394.CrossrefMedlineGoogle Scholar - 139.
Arvin AM, Fink K, Schmid MA, Cathcart A, Spreafico R, Havenar-Daughton C, Lanzavecchia A, Corti D, Virgin HW . A perspective on potential antibody-dependent enhancement of SARS-CoV-2.Nature. 2020; 584:353–363. doi: 10.1038/s41586-020-2538-8CrossrefMedlineGoogle Scholar - 140.
Bilaloglu S, Aphinyanaphongs Y, Jones S, Iturrate E, Hochman J, Berger JS . Thrombosis in hospitalized patients with COVID-19 in a New York city health system.JAMA. 2020; 324:799–801. doi: 10.1001/jama.2020.13372CrossrefMedlineGoogle Scholar - 141.
Elbadawi A, Elgendy IY, Sahai A, Bhandari R, McCarthy M, Gomes M, Bishop GJ, Bartholomew JR, Kapadia S, Cameron SJ . Incidence and outcomes of thrombotic events in symptomatic patients with COVID-19.Arterioscler Thromb Vasc Biol. 2020; 41:545–547.MedlineGoogle Scholar - 142.
Denorme F, Vanhoorelbeke K, De Meyer SF . von Willebrand factor and platelet glycoprotein Ib: a thromboinflammatory axis in stroke.Front Immunol. 2019; 10:2884. doi: 10.3389/fimmu.2019.02884CrossrefMedlineGoogle Scholar - 143.
Soo Kim B, Auerbach DA, Sadhra H, Godwin M, Bhandari R, Ling FS, Mohan A, Yule DI, Wagner L, Rich DQ, . Sex-specific platelet activation through protease-activated receptors reverses in myocardial infarction.Arterioscler Thromb Vasc Biol. 2021; 41:390–400.LinkGoogle Scholar - 144.
Ntelis K, Bogdanos D, Dimitroulas T, Sakkas L, Daoussis D . Platelets in systemic sclerosis: the missing link connecting vasculopathy, autoimmunity, and fibrosis?Curr Rheumatol Rep. 2019; 21:15. doi: 10.1007/s11926-019-0815-zCrossrefMedlineGoogle Scholar - 145.
Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison JA, Blair C, Weber A, Barnes BJ, Egeblad M, . Neutrophil extracellular traps in COVID-19.JCI Insight. 2020; 5:e138999.MedlineGoogle Scholar - 146.
Wang J, Li Q, Yin Y, Zhang Y, Cao Y, Lin X, Huang L, Hoffmann D, Lu M, Qiu Y . Excessive neutrophils and neutrophil extracellular traps in COVID-19.Front Immunol. 2020; 11:2063. doi: 10.3389/fimmu.2020.02063CrossrefMedlineGoogle Scholar - 147.
Veras FP, Pontelli MC, Silva CM, Toller-Kawahisa JE, de Lima M, Nascimento DC, Schneider AH, Caetite D, Tavares LA, Paiva IM, . SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology.J Exp Med. 2020; 217:e20201129.CrossrefMedlineGoogle Scholar - 148.
Manne BK, Denorme F, Middleton EA, Portier I, Rowley JW, Stubben C, Petrey AC, Tolley ND, Guo L, Cody M, . Platelet gene expression and function in patients with COVID-19.Blood. 2020; 136:1317–1329. doi: 10.1182/blood.2020007214CrossrefMedlineGoogle Scholar - 149.
Zaid Y, Puhm F, Allaeys I, Naya A, Oudghiri M, Khalki L, Limami Y, Zaid N, Sadki K, Ben El Haj R, . Platelets can associate with SARS-Cov-2 RNA and are hyperactivated in COVID-19.Circ Res. 2020; 127:1404–1418.LinkGoogle Scholar - 150.
Zhang S, Liu Y, Wang X, Yang L, Li H, Wang Y, Liu M, Zhao X, Xie Y, Yang Y, . SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19.J Hematol Oncol. 2020; 13:120. doi: 10.1186/s13045-020-00954-7CrossrefMedlineGoogle Scholar - 151.
Sungnak W, Huang N, Bécavin C, Berg M, Queen R, Litvinukova M, Talavera-López C, Maatz H, Reichart D, Sampaziotis F, ; HCA Lung Biological Network. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes.Nat Med. 2020; 26:681–687. doi: 10.1038/s41591-020-0868-6CrossrefMedlineGoogle Scholar - 152.
Saheb Sharif-Askari N, Saheb Sharif-Askari F, Alabed M, Temsah MH, Al Heialy S, Hamid Q, Halwani R . Airways expression of SARS-CoV-2 receptor, ACE2, and TMPRSS2 is lower in children than adults and increases with smoking and COPD.Mol Ther Methods Clin Dev. 2020; 18:1–6. doi: 10.1016/j.omtm.2020.05.013CrossrefMedlineGoogle Scholar - 153.
Schmidt RA, Morrell CN, Ling FS, Simlote P, Fernandez G, Rich DQ, Adler D, Gervase J, Cameron SJ . The platelet phenotype in patients with ST-segment elevation myocardial infarction is different from non-ST-segment elevation myocardial infarction.Transl Res. 2018; 195:1–12. doi: 10.1016/j.trsl.2017.11.006CrossrefMedlineGoogle Scholar - 154.
Wei C, Wan L, Yan Q, Wang X, Zhang J, Yang X, Zhang Y, Fan C, Li D, Deng Y, . HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry.Nat Metab. 2020; 2:1391–1400.CrossrefMedlineGoogle Scholar - 155.
Ma Y, Ashraf MZ, Podrez EA . Scavenger receptor BI modulates platelet reactivity and thrombosis in dyslipidemia.Blood. 2010; 116:1932–1941. doi: 10.1182/blood-2010-02-268508CrossrefMedlineGoogle Scholar - 156.
Zimman A, Podrez EA . Regulation of platelet function by class B scavenger receptors in hyperlipidemia.Arterioscler Thromb Vasc Biol. 2010; 30:2350–2356. doi: 10.1161/ATVBAHA.110.207498LinkGoogle Scholar - 157.
Radzikowska U, Ding M, Tan G, Zhakparov D, Peng Y, Wawrzyniak P, Wang M, Li S, Morita H, Altunbulakli C, . Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors.Allergy. 2020; 75:2829–2845. doi: 10.1111/all.14429CrossrefMedlineGoogle Scholar - 158.
Schmidt R, Bültmann A, Fischel S, Gillitzer A, Cullen P, Walch A, Jost P, Ungerer M, Tolley ND, Lindemann S, . Extracellular matrix metalloproteinase inducer (CD147) is a novel receptor on platelets, activates platelets, and augments nuclear factor kappaB-dependent inflammation in monocytes.Circ Res. 2008; 102:302–309. doi: 10.1161/CIRCRESAHA.107.157990LinkGoogle Scholar - 159.
Cameron SJ, Mix DS, Ture SK, Schmidt RA, Mohan A, Pariser D, Stoner MC, Shah P, Chen L, Zhang H, . Hypoxia and ischemia promote a maladaptive platelet phenotype.Arterioscler Thromb Vasc Biol. 2018; 38:1594–1606. doi: 10.1161/ATVBAHA.118.311186LinkGoogle Scholar - 160.
Mandal AKJ, Kho J, Ioannou A, Van den Abbeele K, Missouris CG . Covid-19 and in situ pulmonary artery thrombosis.Respir Med. 2021; 176:106176. doi: 10.1016/j.rmed.2020.106176CrossrefMedlineGoogle Scholar - 161.
Driggin E, Madhavan MV, Bikdeli B, Chuich T, Laracy J, Bondi-Zoccai G, Brown TS, Nigoghossian C, Zidar DA, Haythe J, . 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.CrossrefMedlineGoogle Scholar - 162.
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, ; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; 382:1708–1720. doi: 10.1056/NEJMoa2002032CrossrefMedlineGoogle Scholar - 163.
Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, Wen F, Huang X, Ning G, Wang W . Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations.Cell Discov. 2020; 6:11. doi: 10.1038/s41421-020-0147-1CrossrefMedlineGoogle Scholar - 164.
Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q . Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.Science. 2020; 367:1444–1448. doi: 10.1126/science.abb2762CrossrefMedlineGoogle Scholar - 165.
Tran M, Sheth C, Bhandari R, Cameron SJ, Hornacek D . SARS-CoV-2 and pulmonary embolism: who stole the platelets?Thromb J. 2020; 18:16. doi: 10.1186/s12959-020-00229-8CrossrefMedlineGoogle Scholar - 166.
Cai Z, Greene MI, Zhu Z, Zhang H . Structural features and PF4 functions that occur in heparin-induced thrombocytopenia (HIT) complicated by COVID-19.Antibodies (Basel). 2020; 9:52.CrossrefGoogle Scholar - 167.
Borghi MO, Beltagy A, Garrafa E, Curreli D, Cecchini G, Bodio C, Grossi C, Blengino S, Tincani A, Franceschini F, . Anti-phospholipid antibodies in COVID-19 are different from those detectable in the anti-phospholipid syndrome.Front Immunol. 2020; 11:584241. doi: 10.3389/fimmu.2020.584241CrossrefMedlineGoogle Scholar - 168.
Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, Chen H, Ding X, Zhao H, Zhang H, . Coagulopathy and antiphospholipid antibodies in patients with Covid-19.N Engl J Med. 2020; 382:e38. doi: 10.1056/NEJMc2007575CrossrefMedlineGoogle Scholar - 169.
Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O’Meara MJ, Rezelj VV, Guo JZ, Swaney DL, . A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.Nature. 2020; 583:459–468. doi: 10.1038/s41586-020-2286-9CrossrefMedlineGoogle Scholar - 170.
Zuo Y, Estes SK, Ali RA, Gandhi AA, Yalavarthi S, Shi H, Sule G, Gockman K, Madison JA, Zuo M, . Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19.Sci Transl Med. 2020; 12:eabd3876.CrossrefMedlineGoogle Scholar - 171.
Dragonetti D, Guarini G, Pizzuti M . Detection of anti-heparin-PF4 complex antibodies in COVID-19 patients on heparin therapy.Blood Transfus. 2020; 18:328. doi: 10.2450/2020.0164-20MedlineGoogle Scholar - 172.
Riker RR, May TL, Fraser GL, Gagnon DJ, Bandara M, Zemrak WR, Seder DB . Heparin-induced thrombocytopenia with thrombosis in COVID-19 adult respiratory distress syndrome.Res Pract Thromb Haemost. 2020; 4:936–941. doi: 10.1002/rth2.12390CrossrefMedlineGoogle Scholar - 173.
Lingamaneni P, Gonakoti S, Moturi K, Vohra I, Zia M . Heparin-induced thrombocytopenia in COVID-19.J Investig Med High Impact Case Rep. 2020; 8:2324709620944091. doi: 10.1177/2324709620944091CrossrefGoogle Scholar - 174.
Althaus K, Marini I, Zlamal J, Pelzl L, Singh A, Häberle H, Mehrländer M, Hammer S, Schulze H, Bitzer M, . Antibody-induced procoagulant platelets in severe COVID-19 infection.Blood. 2021; 137:1061–1071. doi: 10.1182/blood.2020008762CrossrefMedlineGoogle Scholar - 175.
Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, Avezum A, Lopes RD, Bueno FR, Silva MVAO, ; COALITION COVID-19 Brazil III Investigators. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial.JAMA. 2020; 324:1307–1316. doi: 10.1001/jama.2020.17021CrossrefMedlineGoogle Scholar - 176.
Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, ; RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 - preliminary report.N Engl J Med. 2020; 384:693–704. doi: 10.1056/NEJMoa2021436MedlineGoogle Scholar - 177.
Mehta N, Kalra A, Nowacki AS, Anjewierden S, Han Z, Bhat P, Carmona-Rubio AE, Jacob M, Procop GW, Harrington S, . Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5:1020–1026. doi: 10.1001/jamacardio.2020.1855CrossrefMedlineGoogle Scholar - 178.
Chung MK, Karnik S, Saef J, Bergmann C, Barnard J, Lederman MM, Tilton J, Cheng F, Harding CV, Young JB, . SARS-CoV-2 and ACE2: the biology and clinical data settling the ARB and ACEI controversy.EBioMedicine. 2020; 58:102907. doi: 10.1016/j.ebiom.2020.102907CrossrefMedlineGoogle Scholar - 179.
Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD . Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382:1653–1659. doi: 10.1056/NEJMsr2005760CrossrefMedlineGoogle Scholar - 180.
Wu Z, Hu R, Zhang C, Ren W, Yu A, Zhou X . Elevation of plasma angiotensin II level is a potential pathogenesis for the critically ill COVID-19 patients.Crit Care. 2020; 24:290. doi: 10.1186/s13054-020-03015-0CrossrefMedlineGoogle Scholar - 181.
Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, Wang Z, Li J, Li J, Feng C, . Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.Sci China Life Sci. 2020; 63:364–374. doi: 10.1007/s11427-020-1643-8CrossrefMedlineGoogle Scholar - 182.
Zoufaly A, Poglitsch M, Aberle JH, Hoepler W, Seitz T, Traugott M, Grieb A, Pawelka E, Laferl H, Wenisch C, . Human recombinant soluble ACE2 in severe COVID-19.Lancet Respir Med. 2020; 8:1154–1158. doi: 10.1016/S2213-2600(20)30418-5CrossrefMedlineGoogle Scholar - 183.
Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, . A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.Nat Med. 2005; 11:875–879. doi: 10.1038/nm1267CrossrefMedlineGoogle Scholar - 184.
Dong Y, Dai T, Wei Y, Zhang L, Zheng M, Zhou F . A systematic review of SARS-CoV-2 vaccine candidates.Signal Transduct Target Ther. 2020; 5:237. doi: 10.1038/s41392-020-00352-yCrossrefMedlineGoogle Scholar - 185.
Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, Perez JL, Pérez Marc G, Moreira ED, Zerbini C, ; C4591001 Clinical Trial Group. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.N Engl J Med. 2020; 383:2603–2615. doi: 10.1056/NEJMoa2034577CrossrefMedlineGoogle Scholar - 186.
Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, ; COVE Study Group. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384:403–416. doi: 10.1056/NEJMoa2035389CrossrefMedlineGoogle Scholar - 187.
Marsh M, Helenius A . Virus entry: open sesame.Cell. 2006; 124:729–740. doi: 10.1016/j.cell.2006.02.007CrossrefMedlineGoogle Scholar - 188.
Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, Leopoldi A, Garreta E, Hurtado Del Pozo C, Prosper F, . Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.Cell. 2020; 181:905–913.e7. doi: 10.1016/j.cell.2020.04.004CrossrefMedlineGoogle Scholar - 189.
Qaradakhi T, Gadanec LK, McSweeney KR, Tacey A, Apostolopoulos V, Levinger I, Rimarova K, Egom EE, Rodrigo L, Kruzliak P, . The potential actions of angiotensin-converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases.Clin Exp Pharmacol Physiol. 2020; 47:751–758. doi: 10.1111/1440-1681.13251CrossrefMedlineGoogle Scholar - 190.
Outlaw VK, Bovier FT, Mears MC, Cajimat MN, Zhu Y, Lin MJ, Addetia A, Lieberman NAP, Peddu V, Xie X, . Inhibition of Coronavirus Entry In Vitro and Ex Vivo by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain.mBio. 2020; 11:e01935–20.CrossrefMedlineGoogle Scholar - 191.
Yang L, Pei RJ, Li H, Ma XN, Zhou Y, Zhu FH, He PL, Tang W, Zhang YC, Xiong J, . Identification of SARS-CoV-2 entry inhibitors among already approved drugs [published online October 28, 2020].Acta Pharmacol Sin. doi: 10.1038/s41401-020-00556-6Google Scholar - 192.
Dong X, Tian Z, Shen C, Zhao C . An overview of potential therapeutic agents to treat COVID-19.Biosci Trends. 2020; 14:318–327. doi: 10.5582/bst.2020.03345CrossrefMedlineGoogle Scholar - 193.
Hussen J, Kandeel M, Hemida MG, Al-Mubarak AIA . Antibody-based immunotherapeutic strategies for COVID-19.Pathogens. 2020; 9:917.CrossrefGoogle Scholar - 194.
Menche J, Sharma A, Kitsak M, Ghiassian SD, Vidal M, Loscalzo J, Barabási AL . Disease networks. Uncovering disease-disease relationships through the incomplete interactome.Science. 2015; 347:1257601. doi: 10.1126/science.1257601CrossrefMedlineGoogle Scholar - 195.
Cheng F, Desai RJ, Handy DE, Wang R, Schneeweiss S, Barabási AL, Loscalzo J . Network-based approach to prediction and population-based validation of in silico drug repurposing.Nat Commun. 2018; 9:2691. doi: 10.1038/s41467-018-05116-5CrossrefMedlineGoogle Scholar - 196.
Cheng F, Lu W, Liu C, Fang J, Hou Y, Handy DE, Wang R, Zhao Y, Yang Y, Huang J, . A genome-wide positioning systems network algorithm for in silico drug repurposing.Nat Commun. 2019; 10:3476. doi: 10.1038/s41467-019-10744-6CrossrefMedlineGoogle Scholar - 197.
Song JS, Wang RS, Leopold JA, Loscalzo J . Network determinants of cardiovascular calcification and repositioned drug treatments.FASEB J. 2020; 34:11087–11100. doi: 10.1096/fj.202001062RCrossrefMedlineGoogle Scholar - 198.
Gysi DM, Do Valle I, Zitnik M, Ameli A, Gan X, Varol O, Sanchez H, Baron RM, Ghiassian D, Loscalzo J, . Network medicine framework for identifying drug repurposing opportunities for COVID-19.ArXiv. Preprint posted online April 15 2020.Google Scholar - 199.
Zhou Y, Hou Y, Shen J, Mehra R, Kallianpur A, Culver DA, Gack MU, Farha S, Zein J, Comhair S, . A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19.PLoS Biol. 2020; 18:e3000970. doi: 10.1371/journal.pbio.3000970CrossrefMedlineGoogle Scholar - 200.
Yancy CW, Fonarow GC . Coronavirus disease 2019 (COVID-19) and the heart-is heart failure the next chapter?JAMA Cardiol. 2020; 5:1216–1217. doi: 10.1001/jamacardio.2020.3575CrossrefMedlineGoogle Scholar - 201.
Shchedrygina A, Nagel E, Puntmann VO, Valbuena-Lopez S . COVID-19 myocarditis and prospective heart failure burden.Expert Rev Cardiovasc Ther. 2020; 19:5–14.CrossrefMedlineGoogle Scholar - 202.
Kochi AN, Tagliari AP, Forleo GB, Fassini GM, Tondo C . Cardiac and arrhythmic complications in patients with COVID-19.J Cardiovasc Electrophysiol. 2020; 31:1003–1008. doi: 10.1111/jce.14479CrossrefMedlineGoogle Scholar - 203.
Goldstein DS . The possible association between COVID-19 and postural orthostatic tachycardia syndrome.Heart rhythm. 2021; 18:508–509. doi: 10.1016/j.hrthm.2020.12.007CrossrefMedlineGoogle Scholar - 204.
Miglis MG, Prieto T, Shaik R, Muppidi S, Sinn DI, Jaradeh S . A case report of postural tachycardia syndrome after COVID-19.Clin Auton Res. 2020; 30:449–451. doi: 10.1007/s10286-020-00727-9CrossrefMedlineGoogle Scholar - 205.
Kanjwal K, Jamal S, Kichloo A, Grubb BP . New-onset postural orthostatic tachycardia syndrome following coronavirus disease 2019 infection.J Innov Card Rhythm Manag. 2020; 11:4302–4304. doi: 10.19102/icrm.2020.111102CrossrefMedlineGoogle Scholar - 206.
Clark DE, Parikh A, Dendy JM, Diamond AB, George-Durrett K, Fish FA, Fitch W, Hughes SG, Soslow JH . COVID-19 myocardial pathology evaluated through scrEening cardiac magnetic resonance (COMPETE CMR).medRxiv. Preprint posted online September 2, 2020. doi: 10.1101/2020.08.31.20185140Google Scholar - 207.
Phelan D, Kim JH, Elliott MD, Wasfy MM, Cremer P, Johri AM, Emery MS, Sengupta PP, Sharma S, Martinez MW, . Screening of potential cardiac involvement in competitive athletes recovering from COVID-19: an expert consensus statement.JACC Cardiovasc Imaging. 2020; 13:2635–2652. doi: 10.1016/j.jcmg.2020.10.005CrossrefMedlineGoogle Scholar - 208.
Sharma S, Drezner JA, Baggish A, Papadakis M, Wilson MG, Prutkin JM, La Gerche A, Ackerman MJ, Borjesson M, Salerno JC, . International recommendations for electrocardiographic interpretation in athletes.J Am Coll Cardiol. 2017; 69:1057–1075. doi: 10.1016/j.jacc.2017.01.015CrossrefMedlineGoogle Scholar - 209.
Phelan D, Kim JH, Chung EH . A game plan for the resumption of sport and exercise after coronavirus disease 2019 (COVID-19) infection.JAMA Cardiol. 2020; 5:1085–1086. doi: 10.1001/jamacardio.2020.2136CrossrefMedlineGoogle Scholar - 210.
Kim JH, Levine BD, Phelan D, Emery MS, Martinez MW, Chung EH, Thompson PD, Baggish AL . Coronavirus disease 2019 and the athletic heart: emerging perspectives on pathology, risks, and return to play.JAMA Cardiol. 2020;6:219–227.Google Scholar - 211.
Maron BJ, Udelson JE, Bonow RO, Nishimura RA, Ackerman MJ, Estes NA, Cooper LT, Link MS, Maron MS ; American Heart Association Electrocardiography and Arrhythmias Committee of Council on Clinical Cardiology, Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and American College of Cardiology. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: task force 3: hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and other cardiomyopathies, and myocarditis: a Scientific Statement From the American Heart Association and American College of Cardiology.Circulation. 2015; 132:e273–e280. doi: 10.1161/CIR.0000000000000239LinkGoogle Scholar - 212.
Knight DS, Kotecha T, Razvi Y, Chacko L, Brown JT, Jeetley PS, Goldring J, Jacobs M, Lamb LE, Negus R, . COVID-19: myocardial injury in survivors.Circulation. 2020; 142:1120–1122. doi: 10.1161/CIRCULATIONAHA.120.049252LinkGoogle Scholar
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