Ppt 19 Reviews - Los Angeles Ca 90048

The number of patients with the 2019 novel coronavirus disease (COVID-19) continues to ascension, with >1 1000000 confirmed cases worldwide.¹ Based nigh exclusively on data from Cathay, where the pandemic originated, cardiac injury appears to be a prominent characteristic of the affliction, occurring in 20% to 30% of hospitalized patients and contributing to xl% of deaths.^2–iv Scholarship on COVID-19 is chop-chop evolving: the cumulative number of PubMed citations involving both terms "COVID" and "middle" increased from none on February 20 to n=61 by April 3, 2020, while ≈2000 publications appeared with the term COVID lone in the starting time iii months of the calendar year. Many more papers are listed in nonrefereed archives (eg, medRxiv and bioRxiv).

Compared with other major viral outbreaks in contemporary history, including astringent acute respiratory syndrome (SARS) of 2002 to 2003, COVID-19 appears to take a lower case-fatality charge per unit. The symptomatic case-fatality adventure is one.4% simply increases substantially later sixty years of age. Interestingly, the relative susceptibility to symptomatic infection also increases with historic period, raising questions about underlying biology of host responses in relation to age.⁵ Despite the relatively low case-fatality run a risk, however, the basic reproduction number (a measure of transmissibility) is effectually two.0 to 2.5, suggesting that it spreads more easily.⁶ Coupled with an impressive capacity for asymptomatic manual, the SARS novel coronavirus (SARS-CoV-2) has ideal attributes for pandemic spread.^vii,8

In this review, we talk over cardiac involvement in the context of SARS-CoV-ii immunology, the speculated office of angiotensin-converting enzyme 2, and emerging therapeutic strategies, which now include cell-based approaches.

Immune Over-Reaction Kills

Acute affliction progression can exist divided into 3 singled-out phases: an early infection stage, a pulmonary phase, and a severe hyperinflammation phase (Figure 1).^9–xi In whatsoever given patient, however, there can be significant overlap among the phases. Although most cases are mild or asymptomatic (81%),¹² this paradigm of affliction progression in critically ill patients with COVID-19 is heuristically instructive in highlighting the role of inflammation and secondary organ interest. During the early on infection stage, the virus infiltrates the lung parenchyma and begins to proliferate. This stage is characterized past mild constitutional symptoms and marks the initial response by innate immunity, namely monocytes and macrophages. Collateral tissue injury and the inflammatory processes that follow—vasodilation, endothelial permeability, leukocyte recruitment—lead to further pulmonary damage, hypoxemia, and cardiovascular stress. In a subset of patients, the host inflammatory response continues to amplify (even with diminishing viral loads) and results in systemic inflammation.^11,13 This systemic toxicity, in plow, has the potential to injure afar organs. Reports of myocarditis in COVID-19 without evidence of direct viral infiltration implicate the center equally ane such target of systemic inflammation (Figure 2).¹⁴

Figure 1. — **Figure i.** **Progression of the acute illness in 2019 novel coronavirus disease (COVID-xix).** The disease progression over time is divided into iii pathological phases: an early infection phase, a pulmonary stage, and a severe hyperinflammation phase. The early infection stage is characterized past viral infiltration and replication. Lymphocytopenia is a primal laboratory finding at this stage. The disease progresses into the pulmonary phase, characterized by respiratory compromise and aberrant chest imaging. An exaggerated inflammatory response driven past the host immunity defines the hyperinflammation phase. Inflammatory markers are elevated at this phase, and secondary organ damage becomes apparent. The present schematic depicts only the astute stage of illness (cf. Effigy seven). Adapted from Siddiqi and Mehra9 and Belkaid and Rouse.¹⁰

**Figure 2.** **Proposed mechanisms of cardiac injury with clinical sequelae.** Cardiac injury can result via direct or indirect mechanisms. The direct mechanism involves viral infiltration into myocardial tissue, resulting in cardiomyocyte decease and inflammation. Indirect mechanisms include cardiac stress due to respiratory failure and hypoxemia and cardiac inflammation secondary to severe systemic hyperinflammation. Biomarkers (cardiac troponin I and brain-type natriuretic peptide), arrhythmias, myocardial infarction, and heart failure are manifestations of myocardial injury. HFpEF indicates heart failure with preserved ejection fraction; HFrEF, centre failure with reduced ejection fraction; and SARS-CoV-2, astringent acute respiratory syndrome novel coronavirus.

Within this framework of acute affliction progression, lymphocytopenia is a prominent characteristic and is associated with adverse outcomes. A college proportion of nonsurvivors and critically ill patients with COVID-19 exhibit progressive lymphocytopenia (Figure 3A). Despite macerated lymphocyte counts, even so, patients with severe disease somewhen develop higher white claret prison cell and neutrophil counts.^3,15–17 This suggests a high vulnerability of lymphocytes to viral infection and destruction. Autopsy studies from the SARS epidemic, acquired past the near identical SARS-CoV, revealed not only the capacity for direct leukocyte infection but too a relative predilection for lymphocytes. Over 50% of lymphocytes harbored viral particles by electron microscopy, and most of these were T cells (Effigy 3B). Both CD4⁺ and CD8⁺ T cells were reduced and remained low until convalescence (Figure 3C).¹⁸ Furthermore, secondary lymphoid organs contained decreased numbers of lymphocytes, suggesting that sequestration did not business relationship for lymphocytopenia. Patients infected with SARS-CoV-ii as well exhibit lower levels of T lymphocytes, with decreases in both helper and regulatory T cells.^nineteen The decrease in regulatory T cells is peculiarly notable, given their critical role in immune homeostasis and prevention of excessive inflammation later infection.^10,20–22

Figure 3. — **Effigy 3.** **Lymphocytopenia and T-cell destruction.** A, Progressive lymphocytopenia in patients with 2019 novel coronavirus illness (COVID-xix), with more profound depletion in nonsurvivors. Reproduced from Zhou et al¹⁶ with permission. Copyright ©2020, Elsevier. B, Electron microgram demonstrating viral inclusion bodies inside a circulating T lymphocyte in patients with astringent astute respiratory syndrome coronavirus (SARS-CoV) on the left. Bar, 2 µm. Insert: college power image showing a group of SARS coronavirus-like particles. Bar, 0.2 µm. On right, lymphocyte with 3 coronavirus-like particles (white arrows). Bar 0.five µm. Insert: higher power image of the membrane region showing entrance of the viral particle. Bar, 0.ane µm. Reproduced from Gu et al^xviii with permission. Copyright ©2005, The Rockefeller Academy Press. C, Lymphocyte counts for CD3⁺, CD4⁺, and CD8⁺ T cells in patients with confirmed SARS and not-SARS controls (north=15/group). Adapted from Gu et al^xviii with permission. Copyright ©2005, The Rockefeller University Printing.

Exaggerated systemic inflammation, or cytokine storm, may correlate with lymphocytopenia and is a hallmark of severe disease.²³ Systemic inflammation represents an advanced stage of the acute illness (the third stage in Figure 1), characterized by multiple organ failure and elevation of key inflammatory markers.^nine Based on clinical data, these inflammatory markers include IL (interleukin)-6, IL-two, IL-7, TNF (tumor necrosis factor)-α, IFN (interferon)-γ IP (inducible protein)-x, MCP (monocyte chemoattractant protein)-1, MIP (macrophage inflammatory protein)-1α, Chiliad-CSF (granulocyte-colony stimulating gene), CRP (C-reactive poly peptide), procalcitonin, and ferritin.^{iii,15–17,23} Following a viral infection, these cytokines actuate pathways that lead to immune prison cell differentiation, trafficking of leukocytes to sites of infection, and expansion of hematopoietic progenitor cells.²⁴ These biomarkers are non just indicators of inflammation merely likewise are associated with high mortality. In retrospective clinical series, nonsurvivors exhibited higher levels of IL-vi, ferritin (Effigy 4A) and CRP (Figure 4B).^iii,16 Although inflammation starts and propagates at the organ of initial injury (ie, lungs), the amplified inflammatory response can have deleterious bystander effects on other organs, including the heart. Consistent with this notion, biomarkers of cardiac injury and electrocardiographic abnormalities correlate with elevated inflammatory markers.^4,25 This represents an indirect mechanism of cardiac injury. There are hypotheses, however, that implicate direct myocardial injury, as well.

**Figure 4.** **Inflammatory markers in survivors and nonsurvivors with 2019 novel coronavirus disease (COVID-19).** A, Levels of IL (interleukin)-6 (**left**) and serum ferritin (**right**) in survivors (n=137) and nonsurvivors (northward=54). Reproduced from Zhou et al^sixteen with permission. Copyright ©2020, Elsevier. B, Levels of cardiac troponin, C-reactive protein, and IL-six in patients who died (north=68) and patients who were discharged (n=82). Adapted from Ruan et al³ with permission. Copyright ©2020, Springer Nature. C, Levels of high-sensitivity cardiac troponin I in survivors (n=137) and nonsurvivors (n=54). Reproduced from Zhou et al¹⁶ with permission. Copyright ©2020, Elsevier.

The Role of Angiotensin-Converting Enzyme 2 in COVID-xix

ACE (Angiotensin-converting enzyme) 2 is a carboxypeptidase that converts angiotensin II into angiotensin-(1–vii). This enzyme is homologous to ACE but serves a counterbalancing role in the renin-angiotensin-aldosterone system.^26–28 Beyond its function in cardiovascular homeostasis, ACE2 is also a functional receptor and a portal of entry for both SARS-CoV and SARS-CoV-two.^29–31 The reader is referred elsewhere for an extensive review of this crucial link in the pathogenesis and pathophysiology of COVID-nineteen.³² ACE2 is expressed in multiple tissues, including lungs, center, and kidneys.^28,33 In animal models, ACE2 expression in the heart is an essential regulator of office, with ACE2 knockout mice developing severe left ventricular dysfunction.³⁴ SARS-CoV infection appears to downregulate ACE2, which may contribute to myocardial dysfunction.³⁵ Thus, the link between SARS-CoV and ACE2 provides one theoretical mechanism for cardiac dysfunction in COVID-19: ACE2 downregulation leads to cardiac dysfunction. In add-on, the relationship betwixt viral entry and ACE2 forms the footing for the controversy surrounding the use of renin-angiotensin-aldosterone system antagonists, which increase ACE2 expression in animal studies and, therefore, can theoretically increase susceptibility to infection. But even the directionality of the effects is debated: college ACE2 levels may be protective, past providing a reservoir of receptors to offset those lost in the form of infection.^36,37 However, there is, every bit yet, no convincing, corollary information in humans relating to the virus of interest, SARS-CoV-ii.

Cardiac Involvement

Cardiac interest, at least at the level of biomarker elevations, is a prominent feature in COVID-19 and is associated with a worse prognosis.^2,3,xv–17 For example, patients with adverse outcomes, including ICU admission and mortality, had significantly higher levels of cardiac TnI (troponin I; Figure 4B and 4C).^3,16 BNP (Brain-type natriuretic peptide) levels were also elevated among ICU admissions in Washington and appeared more universal than troponin elevations.³⁸ Furthermore, amid causes of decease in a Wuhan cohort, myocardial damage and center failure contributed to forty% of deaths, either exclusively or in conjunction with respiratory failure.³ In an adapted Cox regression model, patients with elevated circulating biomarkers of cardiac injury were at significantly college gamble of death.² Surprisingly, the bloodshed take a chance associated with acute cardiac injury was more significant than age, diabetes mellitus, chronic pulmonary disease, or prior history of cardiovascular disease.^two,4 Thus, cardiac involvement is both prevalent and, apparently, prognostic in COVID-xix. Nevertheless, picayune is known regarding the incidence of genuine clinical manifestations of heart disease; biomarker elevations may simply reflect systemic illness in a big fraction of critically sick patients with COVID-xix.

The mechanisms of cardiac injury are not well established simply likely involve increased cardiac stress due to respiratory failure and hypoxemia, directly myocardial infection by SARS-CoV-2, indirect injury from the systemic inflammatory response, or a combination of all three factors (Effigy 2). Case reports of myocarditis in COVID-nineteen provide testify for cardiac inflammation but do not illuminate the mechanism. Autopsies show inflammatory infiltrates composed of macrophages and, to a lesser extent, CD4⁺ T cells.^xiv,39 These mononuclear infiltrates are associated with regions of cardiomyocyte necrosis, which, by Dallas Criteria, defines myocarditis.^40,41 Thus far, however, there are no data demonstrating the presence of SARS-CoV-2 inside myocardial tissue. Postmortem real-time polymerase chain reaction analyses of heart tissue from the SARS epidemic, all the same, detected the viral genome in 35% of patients (n=7/20) who died from SARS. Of notation, these hearts also had decreased levels of ACE2 and increased hypertrophy.³⁵ Taken together, information technology remains unclear how much of the cardiac injury is owing to direct viral infection versus indirect systemic toxicity. Furthermore, it is unclear which cell populations within the myocardium are most vulnerable to infection and systemic inflammation. ACE2 expression levels may requite a hint, but again the implications of such differences are debatable. Myocardial pericytes, which play an important function in maintaining endothelial function, express ACE2 abundantly.⁴² Dysfunction in cardiac pericytes and endothelial cells, either due to straight infection or global inflammation, can lead to disruption in the coronary microcirculation with downstream ischemic consequences, but the relationship to COVID-19 is purely conjectural.

Finally, there are bereft data to decide whether myocarditis in COVID-19 more commonly causes heart failure with preserved ejection fraction or reduced ejection fraction. Although there are isolated COVID-19 reports of depressed ventricular role, the majority of patients with simple lymphocytic myocarditis present with normal middle role.^43–46 Consistent with the possibility that eye failure with preserved ejection fraction may exist more common, a case study from Wuhan highlights the coexistence of elevated TnI and BNP in a critically ill COVID-19 patient with an echocardiographic ejection fraction of 60%.⁴⁷ Given the difficulty of performing echocardiography under strict isolation while wearing personal protective equipment, and the associated risk to staff, the verbal prevalence, and nature of cardiac dysfunction in COVID-xix may never exist fully apparent.

Other facets of cardiac involvement include blood pressure abnormalities and arrhythmias. In a Wuhan cohort, a higher proportion of critically ill patients and nonsurvivors had elevated claret pressure, which is counterintuitive in a critically ill, vasoplegic population.^3,17 Whether this hypertension is just a reaction to the illness, a predisposing factor to the illness, or a phenomenon related to potential derangements in ACE2 expression cannot be ascertained from the retrospective data. It is also important to notation that in dissimilar cohorts, including the critically ill patients in Washington Land, the patients were hypotensive and required vasopressor support, as is typical for patients with severe infectious diseases.⁴⁸ In add-on to blood pressure level abnormalities, patients can likewise develop arrhythmias, ranging from tachycardia and bradycardia to asystole. Based on epidemiological data, palpitations are present in 7.3% of patients, and a significantly college proportion of critically ill patients develop arrhythmias, although these have not all the same been characterized.^xv,49 Arrhythmias in this patient population tin arise secondary to hypoxemia, metabolic derangements, systemic inflammation, or myocarditis.

Finally, acute coronary syndromes and acute myocardial infarction (AMI) can occur in patients with COVID-19, but the incidence of such events is unclear. In principle, risk for acute coronary syndromes in afflicted patients may be increased due to heightened thrombotic proclivity, as evidenced past significantly elevated D-dimer levels.^15–17 Underlying this risk are known predisposing factors related to inflammation: endothelial and smooth muscle cell activation; macrophage activation, and tissue factor expression in atheromatous plaque; and platelet activation with further elaboration of inflammatory mediators.^l Clinical studies on prior epidemics approve these observations by showing a strong association between viral respiratory infections and AMI (incidence ratio for AMI inside 7 days of infection: 2.eight–ten.1).⁵¹ Although robust data on the scope of AMI in COVID-19 are not available yet, AMI did contribute to in-hospital bloodshed in the SARS epidemic.¹³ Given the risks incurred by transporting infected patients and subjecting them to percutaneous intervention, some centers are adjusting their acute coronary syndrome protocols and handling paradigms, with increasing consideration given to thrombolytic therapy.^52,53 Finally, the symptoms of infection and the high prevalence of nonischemic cardiac injury can masquerade as astute coronary syndromes (including electrocardiographic abnormalities, troponin elevations, and chest pain); therefore, a high index of suspicion for culling diagnosis is necessary.⁴⁶

Therapeutics

The progression of COVID-19 involves distinct but overlapping pathophysiological phases (Figure 1). Appreciation of these phases may permit informed deployment of tailored therapy. For example, immunosuppressive regimens are probable most beneficial during the hyperinflammation stage, rather than the early infection phase when intact immunity may be critical for pathogen eradication. Thus, the use of the agents discussed below must be considered in the context of disease progression, although little phase-specific distinction has been made and then far in the literature. The Table summarizes the properties of various agents under investigation for the treatment of COVID-xix.

**Table.** Therapeutic Strategies for COVID-19
Therapy	Rationale for COVID-19	Clinical Evidence in COVID-nineteen
Antimicrobials
Lopinavir-ritonavir	Inhibits SARS-CoV in vitro, improves clinical outcomes in common marmoset with MERS-CoV^54,55	No benefit in RCT⁵⁶
Remdesivir	Preclinical efficacy with SARS/MERS-CoV and SARS-CoV-two ^57–59	Case study (due north=1)^threescore
Ribavirin (± IFN)	Improves effect in rhesus macaques with MERS-CoV⁶¹; inhibits MERS-CoV in vitro⁶²	None
Favipiravir	Inhibits SARS-CoV-2 in vitro⁵⁹	RCT: improved fever simply non respiratory failure⁶³
(Hydroxy)chloroquine	Inhibits SARS-CoV-2 in vitro^59,64	Nonrandomized trial: decreased viral load, no clinical outcomes data⁶⁵
Corticosteroids	Immunosuppressive effect in inflammatory syndromes	None
Immunoglobulin/antibody-based therapies
Intravenous immunoglobulin	Established immunomodulatory effects in autoimmune and inflammatory syndromes	Case report (n=3)⁶⁶
Ambulatory plasma	Passive antibody immunity with chapters to neutralize the virus	Instance series showed improved clinical course⁶⁷
IL-6(R) monoclonal antibodies	Immunomodulation for transplantation and immune-checkpoint inhibitor side effects^68,69	Case series showed respiratory improvement⁷⁰
Jail cell-based therapies
Mesenchymal stem cells	Known immunomodulatory properties	Unmarried-arm study (northward=seven), showed improvement in symptoms, pulmonary function⁷¹
Mesenchymal stem cells	Known immunomodulatory properties	Example report (n=one)⁷²
Cardiosphere-derived cells	Known immunomodulatory and cardioprotective properties^73–79	CS cubed trial currently enrolling

Antiviral and Antimalarial Agents

Lopinavir and ritonavir are HIV protease inhibitors that demonstrated antiviral effects in vitro against SARS-CoV (Figure 5A) and decreased viral loads in nonhuman primates infected with Middle Eastward respiratory syndrome-CoV (Effigy 5B).^54,55,80 An open up-label randomized controlled trial, withal, did non show efficacy in patients with COVID-19 (Figure 5C).⁵⁶ Remdesivir, a nucleoside analogue initially adult for Ebola, was as well effective against SARS/Middle Due east respiratory syndrome-CoV in vitro and in murine and nonhuman primate models.^57,58 Importantly, remdesivir was besides able to inhibit SARS-CoV-two in vitro.⁵⁹ Thus far, all the same, the only clinical evidence of remdesivir efficacy in COVID-nineteen is a instance report.^threescore Ribavirin showed like therapeutic potential in a preclinical study with Eye East respiratory syndrome-CoV-infected rhesus macaques, just these findings have not been translated to COVID-19.⁶¹ Finally, favipiravir was recently tested in an open-label randomized trial and showed faster resolution of fever and cough but similar rates of respiratory failure compared to the control group receiving umifenovir.⁶³ These latter findings take not undergone peer-review yet, and the study pattern has many deficiencies. Another agent that has garnered attention in the media is hydroxychloroquine. Both chloroquine and hydroxychloroquine showed inhibitory furnishings against SARS-CoV-ii in vitro.^59,64 Hydroxychloroquine (with or without adjunctive azithromycin) has as well been claimed to be effective in patients with COVID-xix, merely this study had several major shortcomings.⁶⁵Figure 5D shows a timeline of the work bachelor to appointment on antimalarials and COVID-19. Although more recent trials involving hydroxychloroquine improved in design and execution, the testify for efficacy remains tentative; further evaluation will be necessary to justify the routine use of hydroxychloroquine in COVID-19.⁸¹ Finally, serine protease inhibitors that target viral entry also stand for a potential therapy. SARS-CoV-2 gains entry into the cell through a process that requires priming of the Due south protein by the host serine protease TMPRSS2, which can be inhibited by a clinically available serine protease inhibitor.⁸² Hereafter clinical trials volition provide answers nearly the feasibility and efficacy of this and other treatments in COVID-19.

It is important to notation that the antiviral and antimalarial agents above have potential cardiac toxicities, including conduction abnormalities and long-QT syndrome, necessitating careful electrocardiographic monitoring.⁸⁵ Therefore, the off-label use of these agents, while rampant in the real-earth, must be carefully considered in the context of demonstrated take a chance but uncertain do good.

Immunoglobulins and Anti-IL6 Antibodies

The rationale behind immunoglobulin utilise relies on 2 mechanisms: viral neutralization and immunomodulation. One intriguing awarding of the former mechanism is the use of convalescent serum or plasma. In this application, serum is collected from patients who recover from illness, screened for viral-neutralizing antibodies, and administered in a prophylactic or therapeutic manner.⁸⁶ This passive antibody therapy is believed to neutralize the SARS-CoV-ii virus, thereby attenuating disease severity, but will likely accept the greatest effect if administered early on.^86,87 A recent case series showed that transfusion of convalescent plasma into critically sick patients with COVID-19 improved clinical outcomes, but these findings volition crave validation in prospective clinical trials.⁶⁷ Unlike convalescent plasma, intravenous allowed globulin therapy relies on polyclonal antibodies from a pool of healthy donors. Intravenous immune globulin has pleiotropic effects that culminate in suppression of inflammation, and, therefore, this therapy can potentially alleviate illness severity in the hyperinflammation phase. Case reports support this hypothesis, but more robust evidence is needed to confirm these findings.⁶⁶ Likewise, there is good reason to wonder if patients with COVID-nineteen with cytokine storm may do good from monoclonal antibodies targeting IL-vi or IL-six receptor, which accept been successful in attenuating the sequelae of inflammation in transplant patients, simply very limited clinical data support this conjecture.^68,70

Corticosteroids

Corticosteroid use was common during the SARS and Eye E respiratory syndrome epidemics and continues today with COVID-19 on an advertizing hoc basis, despite lack of clinical bear witness of efficacy. In astringent cases of the affliction, characterized past hyperinflammation, there is a theoretical rationale for corticosteroid use. Additionally, corticosteroid use was associated with a lower incidence of myocardial infarction among patients hospitalized for pneumonia.⁸⁸ This ascertainment harkens back to the discussed relationship betwixt inflammation and thrombotic proclivity. Randomized trials, meta-analyses, and case-command studies from prior viral epidemics, withal, demonstrated no survival benefit.⁸⁹

Cell-Based Therapies

In the field of middle disease, clinical studies with prison cell therapy began nearly ii decades agone and take involved skeletal myoblasts, bone marrow mononuclear cells, mesenchymal stalk cells (MSCs), mesenchymal precursor cells, CD34⁺ cells, cardiopoietic cells, and cardiosphere-derived cells (CDCs). While such trials have been generally disappointing in achieving myocardial regeneration, extensive preclinical studies, and some clinical findings, support the notion that cell therapy can attenuate inflammation, which may be attractive in COVID-19.⁹⁰

MSCs are somatic progenitor cells that possess immunomodulatory properties.⁹¹ Two recent studies investigated the furnishings of MSCs in COVID-xix. The outset report enrolled 7 patients and demonstrated improvements in pulmonary function and peripheral lymphocyte counts after MSC infusion. Of note, the bulk of patients (vi/7) were not critically sick, and with a small control group (n=3) information technology is difficult to conclude whether clinical improvement was office of the natural class or treatment effect.⁷¹ The second study is a case written report involving a 65-twelvemonth-old female who received umbilical string MSCs⁷² superimposed on other therapies, which included corticosteroids, lopinavir-ritonavir, IFN-α, oseltamivir, immunoglobulin, and thymosin α1. Thus, little decision can exist drawn near the efficacy of MSCs in this report. Boosted studies are needed to further appraise the efficacy of MSCs.

CDCs are stromal progenitor cells that can be isolated from human heart tissue through well-specified civilisation techniques (Figure 6A).⁹² CDCs have been tested in >200 patients in clinical trials for myocardial infarction, center failure with reduced and preserved ejection fraction, Duchenne muscular dystrophy, and pulmonary hypertension (Effigy 6B), besides as hypoplastic left ventricle. The trials that take reported results all revealed disease-modifying bioactivity, albeit to variable degrees.⁹⁰ CDCs exert their furnishings in a paracrine fashion past secreting exosomes, which have anti-inflammatory and immunomodulatory properties.⁹³ Inside the framework of SARS-CoV-2 pathogenesis, multiple pathways known to be CDC-sensitive may serve as therapeutic targets; Effigy 6C shows that these targets include proinflammatory pathways (TNF-α, IFN- γ, IL-1β, and IL-6) and anti-inflammatory pathways (regulatory T cells and IL-x) that have been explored in animate being models of myocardial ischemia, myocarditis, muscular dystrophy, center failure with preserved ejection fraction, nonischemic dilated cardiomyopathy, and pulmonary hypertension.^73–79 The salutary effects in these models, along with the immunomodulatory properties of CDCs, motivated the (CS)3 trial (CdcS for Cytokine Tempest in Covid Syndrome),³ which has already enrolled several confirmed patients with COVID-xix who are critically sick and show signs of lymphocytopenia and cytokine storm. Among exploratory outcomes are mortality, length of stay in intensive care, duration of ventilatory support, and indices of cardiac and immune function. This trial, and studies exploring other jail cell types, will hopefully provide further insight into the potential utility of cell-based therapies for COVID-19.

Long-Term Sequelae of SARS-CoV-ii Infection

Cardiovascular complications are possible even afterwards recovery from disease. Figure vii depicts schematically the concept that, once the acute stage of disease has resolved, longer-term complications may ascend in the convalescent and chronic phases of disease, long after viral clearance has been accomplished. COVID-19 is a nascent pandemic and, therefore, long-term sequelae are unknown, but in that location are reports of complications which occur soon subsequently resolution of the acute symptoms. A instance report from Italy describes fulminant myocarditis in a ambulatory patient 1 week afterward her respiratory symptoms resolved.⁴⁶ This suggests that background inflammation can persist and evolve silently, manifesting later on in an insidious style. Fifty-fifty subsequently apparently complete recovery, still, at that place may be chronic sequelae. The previous SARS epidemic is instructive considering sufficient time has elapsed for long-term follow-upwardly. A substantial proportion of survivors from the epidemic adult avascular necrosis, pulmonary fibrosis, and dyslipidemia.^94–96 The latter manifestations are particularly important as they represent cardiovascular risk factors. In improver, hospitalization for pneumonia has been associated with increased brusque- and long-term hazard for cardiovascular disease, and this is especially true if there are cardiac complications during the alphabetize hospitalization.^97,98 Thus, cardiac interest may persist long after resolution of the acute illness. Much remains to be learned here. In this continuously changing field, this review was comprehensive as of April 3, 2020, but the discussion will continue to evolve with the rapid, daily accumulation of new knowledge—an inspiring and immensely humbling prospect.

**Figure 7.** **Long-term sequelae of 2019 novel coronavirus disease (COVID-19).** After resolution of the astute disease (cf. Figure 1), prior infection with severe acute respiratory syndrome novel coronavirus (SARS-CoV-ii) may result in persistent manifestation of disease. The schematic depicts the concept of progression over time divided into 3 phases: acute phase, convalescent, and chronic. The times on the 10-axis are approximate. Assuming clearance of the SARS-CoV-2 virus in the astute phase, host response probable shapes the manifestations of affliction in the convalescent and chronic phases. Disease manifestations remain somewhat conjectural; those listed hither are described in case reports, or in the long-term aftereffects of SARS-CoV or Eye East respiratory syndrome (MERS)-CoV infection.

Conclusions

The COVID-xix pandemic has motivated an explosion of new research, which is already providing fundamental insights into the pathogenesis of the disease. Notwithstanding, many questions remain unanswered. Lymphocytopenia, hyperinflammation, and cardiac interest are all prominent features of the affliction and have prognostic value, but the mechanistic links among these phenomena are ill-defined. Similarly, despite the rapidly growing number of clinical trials, no definitive therapies (other than supportive care) are available at this fourth dimension. New therapeutic paradigms, however, are beginning to emerge, and with rigorous investigation will ultimately advance our understanding and treatment of the illness. Even afterward COVID-nineteen has become a distant memory, the lessons learned during this uncertain time will probable inform the cess and therapeutics of other syndromes of hyperinflammation affecting the heart and vasculature.

Nonstandard Abbreviations and Acronyms

ACE	angiotensin-converting enzyme
AMI	acute myocardial infarction
BNP	brain-type natriuretic peptide
CDCs	cardiosphere-derived cells
COVID-19	2019 novel coronavirus illness
CRP	C-reactive protein
(CS)3	CdcS for Cytokine Storm in Covid Syndrome
G-CSF	granulocyte-colony stimulating factor
IFN	interferon
IL	interleukin
IP	inducible protein
MCP	monocyte chemoattractant protein
MIP	macrophage inflammatory poly peptide
MSCs	mesenchymal stem cells
SARS	severe astute respiratory syndrome
SARS-CoV	severe acute respiratory syndrome coronavirus
SARS-CoV-2	severe acute respiratory syndrome novel coronavirus
TNF	tumor necrosis gene
TnI	troponin I

Acknowledgments

We give thanks all other members of the Marbán laboratory for their dedication, resilience and creativity in responding to the COVID-19 crisis. The icons in Figure 1 and schematics in Effigy 2 and Figure 5D were created with BioRender.com.

Sources of Funding

A. Akhmerov was supported by the National Institutes of Wellness (NIH) T32 HL116273-07. Full general lab back up was provided past grants from the NIH, US Section of Defence, and California Institute for Regenerative Medicine. East. Marbán holds the Mark South. Siegel Family Distinguished Chair of the Cedars-Sinai Medical Centre.

Disclosures

East. Marbán owns founder's equity in Capricor Therapeutics. E. Marbán's spouse is employed by Capricor and owns equity in the company. The other author reports no conflicts.

Footnotes

For Sources of Funding and Disclosures, run across page 1453.

Correspondence to: Eduardo Marbán, Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S San Vicente Blvd, AHSP A3600, Los Angeles, CA 90048. Email eduardo. [email protected] org

References

1. World Wellness System. Coronavirus illness 2019 (COVID-19): state of affairs reports.Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/. Accessed Apr 3, 2020.Google Scholar
2. Shi Due south, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, et al. . Association of cardiac injury with mortality in hospitalized patients with COVID-nineteen in Wuhan, People's republic of china [published online March 25, 2020]. JAMA Cardiol . 2020. doi: ten.1001/jamacardio.2020.0950. https://jamanetwork.com/journals/jamacardiology/fullarticle/2763524.CrossrefMedlineGoogle Scholar
3. Ruan Q, Yang K, Wang W, Jiang Fifty, Song J. Clinical predictors of mortality due to COVID-19 based on an assay of data of 150 patients from Wuhan, China [published online March iii, 2020]. Intensive Care Med . 2020. doi: 10.1007/s00134-020-05991-x. https://world wide web.ncbi.nlm.nih.gov/pmc/articles/PMC7080116/.Google Scholar
four. Guo T, Fan Y, Chen M, Wu 10, Zhang L, He T, Wang H, Wan J, Wang X, Lu Z. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-xix) [published online March 27, 2020]. JAMA Cardiol . 2020. doi: ten.1001/jamacardio.2020.1017. https://jamanetwork.com/journals/jamacardiology/fullarticle/2763845.CrossrefGoogle Scholar
5. Wu JT, Leung K, Bushman One thousand, Kishore North, Niehus R, de Salazar PM, Cowling BJ, Lipsitch M, Leung GM. Estimating clinical severity of COVID-19 from the manual dynamics in Wuhan, People's republic of china. Nat Med . 2020; 26(4):506–510.CrossrefMedlineGoogle Scholar
6. Callaway E, Cyranoski D, Mallapaty S, Stoye East, Tollefson J. The coronavirus pandemic in five powerful charts. Nature . 2020; 579:482–483. doi: 10.1038/d41586-020-00758-iiCrossrefMedlineGoogle Scholar
7. Bai Y, Yao Fifty, Wei T, Tian F, Jin DY, Chen L, Wang Chiliad. Presumed asymptomatic carrier transmission of COVID-19 [published online February 21, 2020]. JAMA . 2020. doi: 10.1001/jama.2020.2565. https://jamanetwork.com/journals/jama/fullarticle/2762028.CrossrefMedlineGoogle Scholar
viii. Rothe C, Schunk Thousand, Sothmann P, Bretzel G, Froeschl G, Wallrauch C, Zimmer T, Thiel V, Janke C, Guggemos W, et al. . Transmission of 2019-nCoV infection from an asymptomatic contact in Germany. Northward Engl J Med . 2020; 382:970–971. doi: x.1056/NEJMc2001468CrossrefMedlineGoogle Scholar
ix. Siddiqi HK, Mehra MR. Covid-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal [published online March 20, 2020]. J Heart Lung Transplant . 2020. doi: ten.1016/j.healun.2020.03.012. https://world wide web.sciencedirect.com/science/article/pii/S105324982031473X?via%3Dihub.CrossrefGoogle Scholar
ten. Belkaid Y, Rouse BT. Natural regulatory T cells in communicable diseases. Nat Immunol . 2005; half dozen:353–360. doi: x.1038/ni1181CrossrefMedlineGoogle Scholar
xi. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol . 2017; 39:529–539. doi: x.1007/s00281-017-0629-xCrossrefMedlineGoogle Scholar
12. Wu Z, McGoogan JM. Characteristics of and of import lessons from the coronavirus affliction 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the chinese heart for disease control and prevention [published online Feb 24, 2020]. JAMA . 2020. doi: 10.1001/jama.2020.2648. https://jamanetwork.com/journals/jama/fullarticle/2762130.CrossrefGoogle Scholar
13. Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, Law KI, Tang BS, Hon TY, Chan CS, et al. ; HKU/UCH SARS Study Grouping. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective written report. Lancet . 2003; 361:1767–1772. doi: 10.1016/s0140-6736(03)13412-vCrossrefMedlineGoogle Scholar
14. Yao XH, Li TY, He ZC, Ping YF, Liu HW, Yu SC, Mou HM, Wang LH, Zhang HR, Fu WJ, et al. . [A pathological report of three COVID-nineteen cases past minimally invasive autopsies]. Zhonghua Bing Li Xue Za Zhi . 2020; 49:E009. doi: 10.3760/cma.j.cn112151-20200312-00193MedlineGoogle Scholar
fifteen. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, et al. . Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China [published online February 7, 2020]. JAMA . 2020. doi: 10.1001/jama.2020.1585. https://jamanetwork.com/journals/jama/fullarticle/2761044.CrossrefGoogle Scholar
16. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu 10, et al. . Clinical form and run a risk factors for mortality of developed inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet . 2020; 395:1054–1062. doi: 10.1016/S0140-6736(20)30566-threeCrossrefMedlineGoogle Scholar
17. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan 1000, Xu J, Gu X, et al. . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet . 2020; 395:497–506. doi: 10.1016/S0140-6736(xx)30183-5CrossrefMedlineGoogle Scholar
xviii. Gu J, Gong E, Zhang B, Zheng J, Gao Z, Zhong Y, Zou W, Zhan J, Wang South, Xie Z, et al. . Multiple organ infection and the pathogenesis of SARS. J Exp Med . 2005; 202:415–424. doi: 10.1084/jem.20050828CrossrefMedlineGoogle Scholar
19. Qin C, Zhou L, Hu Z, Zhang S, Yang Southward, Tao Y, Xie C, Ma K, Shang G, Wang W, et al. . Dysregulation of immune response in patients with COVID-xix in Wuhan, China. Clin Infect Dis . 2020; pii:ciaa248. doi: 10.1093/cid/ciaa248CrossrefGoogle Scholar
20. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell . 2008; 133:775–787. doi: x.1016/j.jail cell.2008.05.009CrossrefMedlineGoogle Scholar
21. Hori S, Carvalho TL, Demengeot J. CD25+CD4+ regulatory T cells suppress CD4+ T cell-mediated pulmonary hyperinflammation driven by Pneumocystis carinii in immunodeficient mice. Eur J Immunol . 2002; 32:1282–1291. doi: 10.1002/1521-4141(200205)32:v<1282::AID-IMMU1282>three.0.CO;2-#CrossrefMedlineGoogle Scholar
22. Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe flu and development of immunomodulatory therapy. Jail cell Mol Immunol . 2016; 13:3–ten. doi: ten.1038/cmi.2015.74CrossrefMedlineGoogle Scholar
23. Mehta P, McAuley DF, Brown Yard, Sanchez E, Tattersall RS, Manson JJ; HLH Beyond Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet . 2020; 395:1033–1034. doi: x.1016/S0140-6736(xx)30628-0CrossrefMedlineGoogle Scholar
24. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev . 2012; 76:xvi–32. doi: 10.1128/MMBR.05015-11CrossrefMedlineGoogle Scholar
25. Ma KL, Liu ZH, Cao CF, Liu MK, Liao J, Zou JB, Kong LX, Wan KQ, Zhang J, Wang QB, et al. . COVID-19 myocarditis and severity factors: an adult cohort study [published online March 23, 2020]. medRxiv . 2020. https://www.medrxiv.org/content/10.1101/2020.03.19.20034124v1.Google Scholar
26. Turner AJ, Hiscox JA, Hooper NM. ACE2: from vasopeptidase to SARS virus receptor. Trends Pharmacol Sci . 2004; 25:291–294. doi: 10.1016/j.tips.2004.04.001CrossrefMedlineGoogle Scholar
27. Bernstein KE. Two ACEs and a centre. Nature . 2002; 417:799–802. doi: 10.1038/417799aCrossrefMedlineGoogle Scholar
28. Donoghue K, Hsieh F, Baronas E, Godbout K, Gosselin K, Stagliano North, Donovan K, Woolf B, Robison K, Jeyaseelan R, et al. . A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-ix. Circ Res . 2000; 87:E1–E9. doi: 10.1161/01.res.87.5.e1LinkGoogle Scholar
29. Li West, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran Chiliad, Sullivan JL, Luzuriaga Thousand, Greenough TC, et al. . Angiotensin-converting enzyme two is a functional receptor for the SARS coronavirus. Nature . 2003; 426:450–454. doi: x.1038/nature02145CrossrefMedlineGoogle Scholar
30. Zhou P, Yang Xl, Wang XG, Hu B, Zhang 50, Zhang West, Si Hour, Zhu Y, Li B, Huang CL, et al. . A pneumonia outbreak associated with a new coronavirus of likely bat origin. Nature . 2020; 579:270–273. doi: 10.1038/s41586-020-2012-7CrossrefMedlineGoogle Scholar
31. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-ii and other lineage B betacoronaviruses. Nat Microbiol . 2020; 5:562–569. doi: 10.1038/s41564-020-0688-yCrossrefMedlineGoogle Scholar
32. Gheblawia Yard, Wang K, Viveirosa A, Nguyen Q, Zhongd J, Turnere AJ, Raizada MK, Grant MB, Oudita GY. Angiotensin converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: jubilant the 20th ceremony of the discovery of ACE2 [published online April viii, 2020]. Circ Res . 2020. doi: 10.1161/CIRCRESAHA.120.317015. https://world wide web.ahajournals.org/doi/abs/10.1161/CIRCRESAHA.120.317015.LinkGoogle Scholar
33. Zou X, Chen Yard, Zou J, Han P, Hao J, Han Z. Single-prison cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential adventure of different homo organs vulnerable to 2019-nCoV infection [published online March 12, 2020]. Front Med . 2020. doi: ten.1007/s11684-020-0754-0. https://link.springer.com/article/10.1007/s11684-020-0754-0.CrossrefMedlineGoogle Scholar
34. Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, da Costa J, Zhang L, Pei Y, et al. . Angiotensin-converting enzyme 2 is an essential regulator of centre function. Nature . 2002; 417:822–828. doi: x.1038/nature00786CrossrefMedlineGoogle Scholar
35. Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM, Butany J. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest . 2009; 39:618–625. doi: ten.1111/j.1365-2362.2009.02153.xCrossrefMedlineGoogle Scholar
36. Vaduganathan Grand, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone organization inhibitors in patients with Covid-19. Northward Engl J Med . 2020; 382:1653–1659. doi: 10.1056/NEJMsr2005760CrossrefMedlineGoogle Scholar
37. Monteil 5, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, Leopoldi A, Garreta E, Hurtado del Pozo C, Prosper F, et al. . Inhibition of SARS-CoV-2 infections in engineered homo tissues using clinical-grade soluble human ACE2 [publised online April 2020]. Prison cell . 2020. doi: x.1016/j.cell.2020.04.004. https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00739.pdf.CrossrefMedlineGoogle Scholar
38. Arentz Thou, Yim E, Klaff Fifty, Lokhandwala S, Riedo FX, Chong M, Lee M. Characteristics and outcomes of 21 critically sick patients with COVID-19 in Washington Country [published online March 19, 2020]. JAMA . 2020. doi: 10.1001/jama.2020.4326. https://jamanetwork.com/journals/jama/fullarticle/2763485.CrossrefMedlineGoogle Scholar
39. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, et al. . Pathological findings of COVID-19 associated with astute respiratory distress syndrome. Lancet Respir Med . 2020; 8:420–422. doi: 10.1016/S2213-2600(20)30076-XCrossrefMedlineGoogle Scholar
40. Aretz HT. Myocarditis: the Dallas criteria. Hum Pathol . 1987; 18:619–624. doi: 10.1016/s0046-8177(87)80363-5CrossrefMedlineGoogle Scholar
41. Fung G, Luo H, Qiu Y, Yang D, McManus B. Myocarditis. Circ Res . 2016; 118:496–514. doi: 10.1161/CIRCRESAHA.115.306573LinkGoogle Scholar
42. Chen 50, Li X, Chen Thou, Feng Y, Xiong C. The ACE2 expression in human eye indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2 [published online March 30, 2020]. Cardiovasc Res . 2020. doi: 10.1093/cvr/cvaa078. https://bookish.oup.com/cardiovascres/article/doi/10.1093/cvr/cvaa078/5813131.CrossrefGoogle Scholar
43. Hu H, Ma F, Wei Ten, Fang Y. Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin [published online March xvi, 2020]. Eur Centre J . 2020. doi: 10.1093/eurheartj/ehaa190. https://academic.oup.com/eurheartj/commodity/doi/x.1093/eurheartj/ehaa190/5807656.CrossrefGoogle Scholar
44. Ammirati East, Cipriani M, Moro C, Raineri C, Pini D, Sormani P, Mantovani R, Varrenti 1000, Pedrotti P, Conca C, et al. ; Registro Lombardo delle Miocarditi. Clinical presentation and issue in a gimmicky cohort of patients with astute myocarditis: multicenter lombardy registry. Apportionment . 2018; 138:1088–1099. doi: 10.1161/CIRCULATIONAHA.118.035319LinkGoogle Scholar
45. Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, Wang Z, Li J, Li J, Feng C, et al. . Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci People's republic of china Life Sci . 2020; 63:364–374. doi: x.1007/s11427-020-1643-eightCrossrefMedlineGoogle Scholar
46. Inciardi RM, Lupi L, Zaccone Thousand, Italia 50, Raffo Grand, Tomasoni D, Cani DS, Cerini M, Farina D, Gavazzi E, et al. . Cardiac interest in a patient with coronavirus affliction 2019 (COVID-19) [published online March 27, 2020]. JAMA Cardiol . 2020. doi: 10.1001/jamacardio.2020.1096. https://jamanetwork.com/journals/jamacardiology/fullarticle/2763843.CrossrefMedlineGoogle Scholar
47. American College of Cardiology. ACC-CCA Webinar: COVID-19 Severe Case Direction.Bachelor at: https://www.acc.org//~/media/Non-Clinical/Files-PDFs-Excel-MS-Word-etc/Latest%20in%20Cardiology/COVID19-Hub/w2-19march2020.zip. Accessed March 19, 2020.Google Scholar
48. Bhatraju PK, Ghassemieh BJ, Nichols One thousand, Kim R, Jerome KR, Nalla AK, Greninger AL, Pipavath S, Wurfel MM, Evans Fifty, et al. . Covid-19 in critically ill patients in the Seattle region - case series [published online March thirty, 2020]. N Engl J Med . 2020. doi: 10.1056/NEJMoa2004500. https://world wide web.nejm.org/doi/full/x.1056/NEJMoa2004500?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%xx%200pubmed.CrossrefMedlineGoogle Scholar
49. Liu Thou, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, Xiao W, Wang YN, Zhong MH, Li CH, et al. . Clinical characteristics of novel coronavirus cases in 3rd hospitals in Hubei province [published online Feb 7, 2020]. Chin Med J (Engl) . 2020. doi: 10.1097/CM9.0000000000000744. https://journals.lww.com/cmj/Abstract/9000/Clinical_characteristics_of_novel_coronavirus.99408.aspx.Google Scholar
50. Libby P, Simon DI. Inflammation and thrombosis: the clot thickens. Circulation . 2001; 103:1718–1720. doi: 10.1161/01.cir.103.13.1718CrossrefMedlineGoogle Scholar
51. Kwong JC, Schwartz KL, Campitelli MA, Chung H, Crowcroft NS, Karnauchow T, Katz Thousand, Ko DT, McGeer AJ, McNally D, et al. . Acute myocardial infarction after laboratory-confirmed flu infection. N Engl J Med . 2018; 378:345–353. doi: 10.1056/NEJMoa1702090CrossrefMedlineGoogle Scholar
52. Zeng J, Huang J, Pan L. How to balance acute myocardial infarction and COVID-19: the protocols from Sichuan Provincial People'southward Hospital [published online March eleven, 2020]. Intensive Intendance Med . 2020. doi: 10.1007/s00134-020-05993-nine. https://link.springer.com/article/10.1007%2Fs00134-020-05993-9.CrossrefGoogle Scholar
53. Welt FGP, Shah PB, Aronow Hd, Bortnick AE, Henry TD, Sherwood MW, Immature MN, Davidson LJ, Kadavath South, Mahmud E, et al. . Catheterization laboratory considerations during the coronavirus (COVID-19) pandemic: from ACC'south Interventional Council and SCAI [published online March sixteen, 2020]. J Am Coll Cardiol . 2020. doi: 10.1016/j.jacc.2020.03.021. https://www.sciencedirect.com/science/commodity/pii/S0735109720345666?via%3Dihub.CrossrefGoogle Scholar
54. Chan JF, Yao Y, Yeung ML, Deng W, Bao L, Jia L, Li F, Xiao C, Gao H, Yu P, et al. . Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis . 2015; 212:1904–1913. doi: 10.1093/infdis/jiv392CrossrefMedlineGoogle Scholar
55. Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, Kao RY, Poon LL, Wong CL, Guan Y, et al. ; HKU/UCH SARS Written report Grouping. Function of lopinavir/ritonavir in the handling of SARS: initial virological and clinical findings. Thorax . 2004; 59:252–256. doi: 10.1136/thorax.2003.012658CrossrefMedlineGoogle Scholar
56. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan Fifty, Song B, Cai Y, Wei Thousand, et al. . A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19 [published online March 18, 2020]. N Engl J Med . 2020. doi: 10.1056/NEJMoa2001282CrossrefGoogle Scholar
57. de Wit E, Feldmann F, Cronin J, Jordan R, Okumura A, Thomas T, Scott D, Cihlar T, Feldmann H. Prophylactic and therapeutic remdesivir (GS-5734) handling in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U Due south A . 2020; 117:6771–6776. doi: 10.1073/pnas.1922083117CrossrefMedlineGoogle Scholar
58. Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Instance JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, et al. . Broad-spectrum antiviral gs-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med . 2017; ix:eaal3653. doi: 10.1126/scitranslmed.aal3653CrossrefMedlineGoogle Scholar
59. Wang M, Cao R, Zhang L, Yang 10, Liu J, Xu Yard, Shi Z, Hu Z, Zhong W, Xiao Thousand. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res . 2020; 30:269–271. doi: 10.1038/s41422-020-0282-0CrossrefMedlineGoogle Scholar
60. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, Spitters C, Ericson Yard, Wilkerson S, Tural A, et al. ; Washington Country 2019-nCoV Case Investigation Team. Start case of 2019 novel coronavirus in the United States. N Engl J Med . 2020; 382:929–936. doi: 10.1056/NEJMoa2001191CrossrefMedlineGoogle Scholar
61. Falzarano D, de Wit Due east, Rasmussen AL, Feldmann F, Okumura A, Scott DP, Brining D, Bushmaker T, Martellaro C, Baseler L, et al. . Handling with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med . 2013; nineteen:1313–1317. doi: 10.1038/nm.3362CrossrefMedlineGoogle Scholar
62. Falzarano D, de Wit Due east, Martellaro C, Callison J, Munster VJ, Feldmann H. Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. Sci Rep . 2013; 3:1686. doi: 10.1038/srep01686CrossrefMedlineGoogle Scholar
63. Chen C, Huang J, Cheng Z, Zhang Y, Cheng Z, Wu J, Chen Due south, Zhang Y, Chen B, Lu M, et al. . Favipiravir versus arbidol for COVID-19: a randomized clinical trial [published online Apr viii, 2020]. medRxiv . 2020. doi: 10.1101/2020.03.17.20037432. https://www.medrxiv.org/content/10.1101/2020.03.17.20037432v1.total.pdf.Google Scholar
64. Yao X, Ye F, Zhang G, Cui C, Huang B, Niu P, Liu X, Zhao Fifty, Dong Eastward, Vocal C, et al. . In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe astute respiratory syndrome coronavirus two (SARS-CoV-2) [published online March ix, 2020]. Clin Infect Dis . 2020. doi: 10.1093/cid/ciaa237. https://academic.oup.com/cid/article/doi/x.1093/cid/ciaa237/5801998.CrossrefGoogle Scholar
65. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe K, Doudier B, Courjon J, Giordanengo V, Vieira VE, et al. . Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents . 2020:105949. doi: 10.1016/j.ijantimicag.2020.105949CrossrefMedlineGoogle Scholar
66. Cao W, Liu Ten, Bai T, Fan H, Hong K, Song H, Han Y, Lin Fifty, Ruan L, Li T. High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019. Open Forum Infect Dis . 2020; 7:ofaa102. doi: ten.1093/ofid/ofaa102. https://academic.oup.com/ofid/article/7/iii/ofaa102/5810740.CrossrefMedlineGoogle Scholar
67. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, et al. . Treatment of v critically ill patients with covid-19 with convalescent plasma [published online March 27, 2020]. JAMA . 2020. doi: 10.1001/jama.2020.4783. https://jamanetwork.com/journals/jama/fullarticle/2763983.CrossrefGoogle Scholar
68. Choi J, Aubert O, Vo A, Loupy A, Haas G, Puliyanda D, Kim I, Louie S, Kang A, Peng A, et al. . Cess of tocilizumab (anti-interleukin-6 receptor monoclonal) equally a potential treatment for chronic antibiotic-mediated rejection and transplant glomerulopathy in HLA-sensitized renal allograft recipients. Am J Transplant . 2017; 17:2381–2389. doi: 10.1111/ajt.14228CrossrefMedlineGoogle Scholar
69. Stroud CR, Hegde A, Cherry-red C, Naqash AR, Sharma Due north, Addepalli S, Cherukuri S, Parent T, Hardin J, Walker P. Tocilizumab for the management of allowed mediated agin events secondary to PD-1 occludent. J Oncol Pharm Pract . 2019; 25:551–557. doi: 10.1177/1078155217745144CrossrefMedlineGoogle Scholar
70. Xu Ten, Han Grand, Li T, Zhao H, Wang GQ. Effective treatment of astringent COVID-19 patients with tocilizumab [published online]. ChinaXiv . 2020. doi. 10.12074/202003.00026Google Scholar
71. Leng Z, Zhu R, Hou Due west, Feng Y, Yang Y, Han Q, Shan G, Meng F, Du D, Wang S, et al. . Transplantation of ACE2- mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis . 2020; 11:216–228. doi: x.14336/Advertizing.2020.0228. http://www.aginganddisease.org/EN/10.14336/AD.2020.0228.CrossrefMedlineGoogle Scholar
72. Liang B, Chen J, Li T, et al. . Clinical remission of a critically ill COVID-xix patient treated by homo umbilical string mesenchymal stem cells [published online]. ChinaXiv . 2020. doi: x.12074/202002.00084Google Scholar
73. de Couto G, Liu W, Tseliou E, Dominicus B, Makkar N, Kanazawa H, Arditi M, Marbán E. Macrophages mediate cardioprotective cellular postconditioning in astute myocardial infarction. J Clin Invest . 2015; 125:3147–3162. doi: x.1172/JCI81321CrossrefMedlineGoogle Scholar
74. Lauden L, Boukouaci Due west, Borlado LR, López IP, Sepúlveda P, Tamouza R, Charron D, Al-Daccak R. Allogenicity of human cardiac stem/progenitor cells orchestrated by programmed death ligand 1. Circ Res . 2013; 112:451–464. doi: x.1161/CIRCRESAHA.112.276501.LinkGoogle Scholar
75. Gallet R, de Couto Thousand, Simsolo E, Valle J, Sun B, Liu W, Tseliou Due east, Zile MR, Marbán East. Cardiosphere-derived cells reverse center failure with preserved ejection fraction (HFpEF) in rats by decreasing fibrosis and inflammation. JACC Basic Transl Sci . 2016; i:14–28. doi: ten.1016/j.jacbts.2016.01.003CrossrefMedlineGoogle Scholar
76. Nana-Leventaki E, Nana M, Poulianitis Northward, Sampaziotis D, Perrea D, Sanoudou D, Rontogianni D, Malliaras K. Cardiosphere-derived cells benumb inflammation, preserve systolic role, and forbid agin remodeling in rat hearts with experimental autoimmune myocarditis. J Cardiovasc Pharmacol Ther . 2019; 24:seventy–77. doi: 10.1177/1074248418784287CrossrefMedlineGoogle Scholar
77. Middleton RC, Fournier Chiliad, Xu Ten, Marbán East, Lewis MI. Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension. PLoS One . 2017; 12:e0183557. doi: 10.1371/journal.pone.0183557CrossrefMedlineGoogle Scholar
78. Rogers RG, Fournier One thousand, Sanchez Fifty, Ibrahim AG, Aminzadeh MA, Lewis MI, Marban E. Illness-modifying bioactivity of intravenous cardiosphere-derived cells and exosomes in mdx mice. JCI Insight . 2019; 4:130202. doi: 10.1172/jci.insight.130202CrossrefMedlineGoogle Scholar
79. Aminzadeh MA, Tseliou E, Sunday B, Cheng K, Malliaras K, Makkar RR, Marbán Due east. Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse model of non-ischaemic dilated cardiomyopathy. Eur Middle J . 2015; 36:751–762. doi: x.1093/eurheartj/ehu196CrossrefMedlineGoogle Scholar
eighty. Li Grand, De Clercq Eastward. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov . 2020; 19:149–150. doi: 10.1038/d41573-020-00016-0CrossrefMedlineGoogle Scholar
81. Chen Z, Hu J, Zhang Z, Jiang Due south, Han Due south, Yan D, Zhuang R, Hu B, Zhang Z. Efficacy of hydroxychloroquine in patients with COVID-nineteen: results of a randomized clinical trial [published online April 10, 2020]. medRxiv . 2020. doi: 10.1101/2020.03.22.20040758Google Scholar
82. Hoffmann Chiliad, Kleine-Weber H, Schroeder South, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler Thou, Wu NH, Nitsche A, et al. . SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked past a clinically proven protease inhibitor [published online March 4, 2020]. Prison cell . 2020; pii:S0092-8674(twenty)30229-4. doi: 10.1016/j.jail cell.2020.02.052Google Scholar
83. Chen J, Liu D, Liu L, et al. . A airplane pilot study of hydroxychloroquine in handling of patients with common coronavirus disease-19 (COVID-nineteen) [published online]. J Zhejiang Univ (Med Sci) . 2020. doi: 10.3785/j.issn.1008-9292.2020.03.03Google Scholar
84. Fondation Méditerranée Infection. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a 6-day follow up: an observational report.Available at: https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf. Accessed Apr 2, 2020.Google Scholar
85. Malaria Policy Advisory Committee Coming together. The cardiotoxicity of antimalarials.Available at: https://www.who.int/malaria/mpac/mpac-mar2017-erg-cardiotoxicity-report-session2.pdf. Accessed March 22, 2017.Google Scholar
86. Casadevall A, Pirofski LA. The convalescent sera pick for containing COVID-19. J Clin Invest . 2020; 130:1545–1548. doi: 10.1172/JCI138003CrossrefMedlineGoogle Scholar
87. Chen 50, Xiong J, Bao L, Shi Y. Convalescent plasma every bit a potential therapy for COVID-19. Lancet Infect Dis . 2020; twenty:398–400. doi: 10.1016/S1473-3099(20)30141-9CrossrefMedlineGoogle Scholar
88. Cangemi R, Falcone M, Taliani K, Calvieri C, Tiseo M, Romiti GF, Bertazzoni G, Farcomeni A, Violi F; SIXTUS Written report Group. Corticosteroid use and incident myocardial infarction in adults hospitalized for community-acquired pneumonia. Ann Am Thorac Soc . 2019; xvi:91–98. doi: 10.1513/AnnalsATS.201806-419OCCrossrefMedlineGoogle Scholar
89. Russell CD, Millar JE, Baillie JK. Clinical evidence does not back up corticosteroid handling for 2019-nCoV lung injury. Lancet . 2020; 395:473–475. doi: 10.1016/S0140-6736(20)30317-2CrossrefMedlineGoogle Scholar
90. Marbán E. A mechanistic roadmap for the clinical awarding of cardiac cell therapies. Nat Biomed Eng . 2018; 2:353–361. doi: 10.1038/s41551-018-0216-zCrossrefMedlineGoogle Scholar
91. Wang LT, Ting CH, Yen ML, Liu KJ, Sytwu HK, Wu KK, Yen BL. Human mesenchymal stalk cells (MSCs) for handling towards allowed- and inflammation-mediated diseases: review of current clinical trials. J Biomed Sci . 2016; 23:76. doi: 10.1186/s12929-016-0289-5CrossrefMedlineGoogle Scholar
92. Smith RR, Barile L, Cho HC, Leppo MK, Hare JM, Messina E, Giacomello A, Abraham MR, Marbán Due east. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation . 2007; 115:896–908. doi: 10.1161/CIRCULATIONAHA.106.655209LinkGoogle Scholar
93. Ibrahim AG, Cheng One thousand, Marbán Eastward. Exosomes as critical agents of cardiac regeneration triggered past cell therapy. Stem Jail cell Reports . 2014; two:606–619. doi: 10.1016/j.stemcr.2014.04.006CrossrefMedlineGoogle Scholar
94. Wu Q, Zhou L, Sun X, Yan Z, Hu C, Wu J, Xu 50, Li X, Liu H, Yin P, et al. . Contradistinct lipid metabolism in recovered sars patients twelve years subsequently infection. Sci Rep . 2017; 7:9110. doi: 10.1038/s41598-017-09536-zCrossrefMedlineGoogle Scholar
95. Hong N, Du XK. Avascular necrosis of os in severe acute respiratory syndrome. Clin Radiol . 2004; 59:602–608. doi: 10.1016/j.crad.2003.12.008CrossrefMedlineGoogle Scholar
96. Antonio GE, Wong KT, Hui DS, Wu A, Lee Northward, Yuen EH, Leung CB, Rainer Th, Cameron P, Chung SS, et al. . Thin-section CT in patients with severe acute respiratory syndrome post-obit hospital discharge: preliminary experience. Radiology . 2003; 228:810–815. doi: 10.1148/radiol.2283030726CrossrefMedlineGoogle Scholar
97. Corrales-Medina VF, Alvarez KN, Weissfeld LA, Angus DC, Chirinos JA, Chang CC, Newman A, Loehr Fifty, Folsom AR, Elkind MS, et al. . Association between hospitalization for pneumonia and subsequent take chances of cardiovascular disease. JAMA . 2015; 313:264–274. doi: 10.1001/jama.2014.18229CrossrefMedlineGoogle Scholar
98. Cangemi R, Calvieri C, Falcone Yard, Bucci T, Bertazzoni G, Scarpellini MG, Barillà F, Taliani One thousand, Violi F; SIXTUS Written report Grouping. Relation of cardiac complications in the early phase of community-acquired pneumonia to long-term mortality and cardiovascular events. Am J Cardiol . 2015; 116:647–651. doi: 10.1016/j.amjcard.2015.05.028CrossrefMedlineGoogle Scholar

weltysude1980.blogspot.com

Source: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.120.317055