LitCovid-sentences  

PMC:7534795 / 1971-123886 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T12 0-15 Sentence denotes 1 Introduction
T13 16-256 Sentence denotes The first outbreak of the novel coronaviruses was triggered by severe and acute respiratory syndrome coronavirus (SARS-CoV) in China in 2002, which was followed in 2012 by the Middle East respiratory syndrome-related coronavirus (MERS-CoV).
T14 257-484 Sentence denotes Both SARS-CoV and MERS-CoV are infectious, lethal and accounted for thousands of deaths over the past two decades (de Wit, van Doremalen, Falzarano, & Munster, 2016; Zaki, van Boheemen, Bestebroer, Osterhaus, & Fouchier, 2012).
T15 485-987 Sentence denotes The Coronavirus Study Group of the International Committee on Taxonomy of Viruses evaluated the novelty of the coronavirus responsible for the recent outbreak in 2019 (COVID-19) and formally considered it related to SARS-CoV, as they share about 79% nucleotide identity and accordingly named it as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or 2019-novel coronavirus (Coronaviridae Study Group of the International Committee on Taxonomy of, 2020; Ren et al., 2020; Zhou et al., 2020).
T16 988-1177 Sentence denotes The recent eruption of COVID-19 was first reported in Wuhan, Hubei Province, China in late December 2019 when a series of pneumonia cases of unknown cause were detected (Wang et al., 2020).
T17 1178-1274 Sentence denotes Highly contagious, COVID-19 spread rapidly throughout China and most countries across the world.
T18 1275-1553 Sentence denotes On March 11th, the spread of COVID-19 was declared by the World Health Organization as a global pandemic and by October 9, 2020, the cumulative number of diagnosed patients internationally was 36,577,872 with 1,062,677 global deaths (https://coronavirus.jhu.edu/map.html, 2020).
T19 1554-1712 Sentence denotes Coronaviruses infect both animals and humans affecting their respiratory, gastrointestinal, cardiovascular and central nervous systems (Cui, Li, & Shi, 2019).
T20 1713-1943 Sentence denotes Consistently, SARS-CoV-2 primarily targets the lungs but it can affect many other organs and systems, including the kidneys, heart, blood vessels, gastrointestinal tract and brain (Wadman, Couzin-Frankel, Kaiser, & Matacic, 2020).
T21 1944-2068 Sentence denotes Symptoms of COVID-19 are manifested as myalgia, fatigue, fever and dry cough, together with lower respiratory tract disease.
T22 2069-2292 Sentence denotes In some cases, the severe progression of the disease leads to acute lung injury (ALI), acute respiratory distress syndrome (ARDS), respiratory failure, sepsis, heart failure (HF) and sudden cardiac arrest within a few days.
T23 2293-2456 Sentence denotes Importantly, there is significant morbidity and mortality in the elderly and individuals with underlying health conditions (Chen et al., 2020; Huang et al., 2020).
T24 2457-2731 Sentence denotes Although treatment with corticosteroids, antiviral therapy and mechanical respiratory support have been employed, there is still no specific treatment for COVID-19 and therefore supportive care is of paramount importance (Huang et al., 2020; Wu & McGoogan, 2020) (Table 1 ).
T25 2732-2844 Sentence denotes Table 1 Overview of some proposed pharmacological agents with potential beneficial effects in COVID-19 patients.
T26 2845-2894 Sentence denotes Pharmacological intervention Conclusion Reference
T27 2895-3050 Sentence denotes Antioxidants including Vitamin C and E • Antioxidant effects may ameliorate cardiac injuries of critically ill COVID-19 patients (Wang, Zhang, & Bai, 2020)
T28 3051-3119 Sentence denotes Melatonin • May have preventive effect against septic cardiomyopathy
T29 3120-3253 Sentence denotes • Has benefits in myocardial infarction, cardiomyopathy, hypertensive heart diseases, and pulmonary hypertension (Zhang et al., 2020)
T30 3254-3536 Sentence denotes Anti-interleukin-6 • Tocilizumab (anti-IL-6 receptor), siltuximab (anti-IL-6), and sirukumab (anti-IL-6) are proposed as possible treatments to manage cytokine storm and elevated IL-6 levels (Akhmerov & Marban, 2020; Hendren, Drazner, Bozkurt, & Cooper Jr., 2020; Rizk et al., 2020)
T31 3537-3797 Sentence denotes Anti-TNFα • Infliximab, adalimumab, etanercept, golimumab, certolizumab as TNFα neutralizing therapies suggested as potential agents for COVID-19 hyperinflammatory state which may ameliorate organ damage including acute cardiac injury (Convertino et al., 2020)
T32 3798-4070 Sentence denotes Janus kinase (JAK) inhibitors • Ruxolitinib, tofacitinib, baricitinib are proposed to be beneficial in controlling excessive IL-6 signaling through STAT-1 and STAT-3 pathways (Alijotas-Reig et al., 2020; Convertino et al., 2020; Richardson et al., 2020; Rizk et al., 2020)
T33 4071-4317 Sentence denotes Anti-interleukin-1 • Anakinra, a modified IL-1 receptor antagonist protein, is suggested to have therapeutic potential in cytokine storm, given its effectiveness on patient survival in severe sepsis (Alijotas-Reig et al., 2020; Rizk et al., 2020)
T34 4318-4453 Sentence denotes Granulocyte-macrophage-colony stimulating factor (GM-CSF) inhibition • GM-CSF can play a pro-inflammatory role signaling to macrophages
T35 4454-4527 Sentence denotes • COVID-19 patients have been demonstrated to have elevated GM-CSF levels
T36 4528-4680 Sentence denotes • Literature proposes that targeting GM-CSF upstream of inflammatory cytokines ex. gimsilumab, may be useful to blunt cytokine storm (Rizk et al., 2020)
T37 4681-4913 Sentence denotes Statins • Anti-inflammatory properties, including reduction in cytokines, may benefit in COVID-19 hyperinflammatory states in addition to their conventional cardioprotective properties (Alijotas-Reig et al., 2020; Rizk et al., 2020)
T38 4914-5107 Sentence denotes ACEi/ARBs • Proposed that treatment with RAAS antagonists may theoretically be beneficial by upregulating ACE2 and compensating for ACE2 receptors lost due to COVID-19 (Akhmerov & Marban, 2020)
T39 5108-5273 Sentence denotes N-acetylcysteine (NAC) • Anti-oxidant and anti-inflammatory properties of NAC proposed as an adjuvant therapy for COVID-19 and secondary cardiovascular complications
T40 5274-5505 Sentence denotes • Suggested role for NAC in prevention of hypertension, atherosclerosis-associated inflammation, acute heart failure, thrombo-inflammation, and myocardial ischemia (De Flora, Balansky, & La Maestra, 2020; Guglielmetti et al., 2020)
T41 5506-5657 Sentence denotes Eicosanoids and soluble epoxide hydrolase (sEH) inhibitors • Epoxyeicosatrienoic acids (EETs) are cardioprotective, anti-inflammatory and pro-resolving
T42 5658-5803 Sentence denotes • Inhibition of their metabolizing enzyme, sEH, may be beneficial by maintaining eicosanoid levels and reducing endoplasmic reticulum (ER) stress
T43 5804-5929 Sentence denotes • Potential to limit inflammatory storm and resolve inflammation in addition to their established cardioprotective properties
T44 5930-6065 Sentence denotes • Co-treatment with sEH inhibitors and omega-3 fatty acids may provide synergistic effects (Hammock, Wang, Gilligan, & Panigrahy, 2020)
T45 6067-6111 Sentence denotes 2 COVID-19 and cardiovascular complications
T46 6112-6344 Sentence denotes The correlation between pneumonia, an inflammatory condition of lung alveoli with a compromised ability for gas exchange, and cardiovascular complications has been well established (Cilli et al., 2018; Corrales-Medina et al., 2011).
T47 6345-6627 Sentence denotes For example, patients with underlying cardiovascular disease are more likely to develop community-acquired pneumonia (Corrales-Medina et al., 2015) and about 8 to 25% of patients with community acquired pneumonia develop at least one cardiac complication during their hospital stay.
T48 6628-6782 Sentence denotes The exaggerated cardiovascular episodes after pneumonia have been associated with increased mortality (Corrales-Medina et al., 2012; Viasus et al., 2013).
T49 6783-6974 Sentence denotes In line with these observations, cardiac complications have been reported in patients with novel coronavirus infections such as tachycardia and hypotension, which are common in SARS patients.
T50 6975-7107 Sentence denotes Moreover, arrhythmia, cardiomegaly and diastolic dysfunction have been reported in SARS patients (Li et al., 2003; Yu et al., 2006).
T51 7108-7259 Sentence denotes In addition, infection with MERS-CoV was associated with acute myocarditis, myocardial edema and severe left ventricular dysfunction (Alhogbani, 2016).
T52 7260-7434 Sentence denotes In the context of COVID-19, both patients with and without underlying cardiovascular comorbidities can develop cardiovascular complications secondary to SARS-CoV-2 infection.
T53 7435-7798 Sentence denotes For example, Wang et al., reported that among 138 hospitalized patients with COVID-19 in Wuhan, China, cardiac injury, as evidenced by new ECG or echocardiographic abnormalities or elevated high-sensitivity cardiac troponin I, was present in 7.2% of all patients and 22% of patients who required intensive care unit (ICU) hospitalization (Wang, Hu, et al., 2020).
T54 7799-8141 Sentence denotes Moreover, the National Health Commission of China reported that 12% of patients infected with SARS-CoV-2 and without known cardiovascular disease (CVD) had elevated troponin levels or cardiac arrest during hospitalization, 17% had coronary heart disease and 35% of patients had hypertension (Zheng, Ma, Zhang, & Xie, 2020; Zhou et al., 2020).
T55 8142-8325 Sentence denotes However, there is accumulating evidence that COVID-19 patients with underlying CVD are at higher risk for developing severe complications (Huang et al., 2020; Wang, Hu, et al., 2020).
T56 8326-8533 Sentence denotes For instance, older patients with underlying CVD who are infected with SARS-CoV-2 are more prone to become severely ill, develop cardiac injury or require intensive care (Guo et al., 2020; Shi et al., 2020).
T57 8534-8763 Sentence denotes The death rate among patients with underlying CVD has been stated as 10.5%, which is much higher than that of the general population (Epidemiology Working Group for Ncip Epidemic Response & Prevention, 2020; Wu & McGoogan, 2020).
T58 8764-8997 Sentence denotes Furthermore, according to an epidemiological study conducted in China, 4.2% of the confirmed cases and 22.7% of mortalities have cardiovascular comorbidities (Epidemiology Working Group for Ncip Epidemic Response & Prevention, 2020).
T59 8998-9223 Sentence denotes Many COVID-19 patients suffer from persistent hypotension, myocardial injury, myocarditis, left ventricular dysfunction, arrhythmia and HF (Guan, et al., 2020; Guo et al., 2020; Inciardi et al., 2020; Zhou, Yu, et al., 2020).
T60 9224-9460 Sentence denotes Importantly, cardiac biopsy samples collected from patients with COVID-19 demonstrated increased interstitial infiltration of mononuclear inflammatory cells providing extra evidence of myocarditis in COVID-19 patients (Xu et al., 2020).
T61 9461-9752 Sentence denotes Therefore, cardiovascular damage secondary to COVID-19 is now drawing growing attention in clinical practice (Table 2 ) and the American College of Cardiology recently issued a clinical report to address the cardiovascular consequences of SARS-CoV-2 infection (Mohammad Madjid et al., 2020).
T62 9753-9822 Sentence denotes Table 2 Overview of COVID-19-associated cardiovascular complications.
T63 9823-9890 Sentence denotes COVID-19-induced cardiovascular injury Proposed mechanism of injury
T64 9891-9937 Sentence denotes • Acute myocarditis • Direct pathogen invasion
T65 9938-9963 Sentence denotes • Indirect cytokine storm
T66 9964-10013 Sentence denotes • Instability of coronary atherosclerotic plaques
T67 10014-10028 Sentence denotes • Coagulopathy
T68 10029-10039 Sentence denotes • Acute MI
T69 10040-10054 Sentence denotes • Hypertension
T70 10055-10111 Sentence denotes • Left ventricular dilation, hypertrophy and dysfunction
T71 10112-10214 Sentence denotes • Arrhythmias (long QT-syndrome, torsade de pointes) • Indirect inflammatory response (Cytokine storm)
T72 10215-10293 Sentence denotes • Worsening of heart failure • Indirect inflammatory response (Cytokine storm)
T73 10294-10355 Sentence denotes • Volume overload due to impaired sodium and water metabolism
T74 10356-10393 Sentence denotes • Disturbance of endothelial function
T75 10394-10436 Sentence denotes • Pyroptosis of cardiomyocytes • Hypoxemia
T76 10437-10475 Sentence denotes • Activation of the NLRP3 inflammasome
T77 10476-10651 Sentence denotes • Severe tachycardia, increased peripheral resistance, hypertension, increased myocardial oxygen requirements and ischemia • Pneumonia-induced increase in sympathetic activity
T78 10653-10729 Sentence denotes 3 Potential mechanisms of cardiovascular complications in COVID-19 patients
T79 10730-10924 Sentence denotes To date, there have been few reports about the pathologic features of COVID-19 and consequently the exact pathophysiological mechanisms of myocardial injury secondary to COVID-19 remain elusive.
T80 10925-11172 Sentence denotes However, direct damage by the virus, exaggerated uncontrolled inflammatory responses, instability of coronary plaques, thrombosis and hypoxia have been proposed as possible mechanisms (Guo et al., 2020; Zheng et al., 2020; Zhou, Yu, et al., 2020).
T81 11173-11315 Sentence denotes Importantly, the severity of infection, patient characteristics and host reaction all participate in the development of cardiac complications.
T82 11316-11443 Sentence denotes The main proposed mechanisms for cardiovascular deterioration in patients with COVID-19 can be summarized as follows (Fig. 1 ).
T83 11444-11523 Sentence denotes Fig. 1 Potential mechanisms of SARS-CoV-2-induced cardiovascular complications.
T84 11524-11649 Sentence denotes SARS-Cov-2 may be taken up by cardiac cells using different routes, such as via ACE2 receptors expressed on the cell surface.
T85 11650-11872 Sentence denotes Following entry, SARS-CoV-2 may exert cardiac injury by direct action and/or induction of immune responses resulting in release of pro-inflammatory cytokines (‘Cytokine storm’) such as IL, TNF-α, INF-γ, FGF, MCP1 and VEGF.
T86 11873-12111 Sentence denotes SARS-CoV-2 can trigger the innate immune response involving NLRP3 inflammasomes which lead to activation of pro-inflammatory cytokines, IL-1β and IL-18 and the inflammatory cascade (IL-6 and TNF-α) resulting in tissue damage and fibrosis.
T87 12112-12299 Sentence denotes SARS-CoV-2-induced pneumonia results in the development of hypoxemia which can impair Ca2+ homeostasis, increase ROS production and activate NLRP3 inflammasomes leading to cardiac damage.
T88 12300-12444 Sentence denotes Activation of the sympathetic nervous system in response to pneumonia leads to vasoconstriction and tachycardia compromising coronary perfusion.
T89 12445-12530 Sentence denotes This results in a mismatch of myocardial O2 demand and supply precipitating ischemia.
T90 12531-12668 Sentence denotes SARS-CoV-2 can destabilize coronary atherosclerotic plaques and mediate platelet aggregation resulting in arterial and venous thrombosis.
T91 12669-12773 Sentence denotes Altogether, these SARS-CoV-2 mediated effects may be contributing to the observed cardiovascular injury.
T92 12774-13237 Sentence denotes ACE2, Angiotensin-converting enzyme-2; Ca2+, Calcium; FGF, Fibroblast growth factor; IL, Interleukin; INF, Interferon; MCP-1, Monocyte chemoattractant protein-1; NFκB, Nuclear factor kappa-light-chain enhancer activated B-cells; NLRP3, NACHT, LRR and PYD domains-containing protein 3; O2, Oxygen; ROS, Reactive oxygen species; SARS-CoV-2, Severe and acute respiratory syndrome coronavirus; TNF-α, Tumor necrosis factor-α; VEGF, Vascular endothelial growth factor.
T93 13239-13268 Sentence denotes 3.1 Direct pathogen invasion
T94 13269-13373 Sentence denotes Direct invasion of pathogens to the cardiac tissue has been confirmed in patients with severe pneumonia.
T95 13374-13587 Sentence denotes For example, Streptococcus pneumoniae was identified in the myocardium of patients with severe pneumococcal disease, leading to local inflammatory reactions and consequently cardiac injury (Xu, Shi, et al., 2020).
T96 13588-13840 Sentence denotes Oudit et al. reported SARS-CoV RNA was detected in 35% (7/20) of autopsied human heart samples obtained from SARS patients during the Toronto SARS outbreak, suggesting the likelihood of direct damage to cardiomyocytes by the virus (Oudit et al., 2009).
T97 13841-14036 Sentence denotes In the same report, a study in mice infected with the human strain of the SARS-CoV demonstrated that pulmonary infection with SARS-CoV also precipitated myocardial infection (Oudit et al., 2009).
T98 14037-14270 Sentence denotes As SARS-CoV-2 is genetically related to SARS-CoV, there is a high potential that it shares a similar mechanism and the same functional host-cell receptor, angiotensin-converting enzyme 2 (ACE2) for cell entry (Gheblawi et al., 2020).
T99 14271-14632 Sentence denotes Importantly, ACE2 is highly expressed in both the heart and the lung (Patel, Zhong, Grant, & Oudit, 2016) and evidence indicates the affinity of SARS-CoV-2 to ACE2 is approximately 10- to 20-fold higher than that for SARS-CoV which may account for both the greater pathogenicity of SARS-CoV-2 and the rapid spread (Gheblawi et al., 2020; Hoffmann et al., 2020).
T100 14633-14751 Sentence denotes Altogether, SARS-CoV-2 might directly infect the myocardial tissue leading to severe cardiac injury (Wu et al., 2020).
T101 14752-14873 Sentence denotes However, large-scale biopsy studies are still warranted to further confirm the direct myocardial infection by SARS-CoV-2.
T102 14875-14927 Sentence denotes 3.2 Indirect inflammatory response - cytokine storm
T103 14928-15040 Sentence denotes Inflammation plays an important role in the development of cardiovascular impairment in the setting of COVID-19.
T104 15041-15325 Sentence denotes Similar to SARS-CoV and MERS-CoV infection, SARS-CoV-2 infection can also trigger excessive host immune responses, leading to extensive and uncontrolled release of proinflammatory cytokines termed as cytokine storm (Restrepo & Reyes, 2018; Zumla, Hui, Azhar, Memish, & Maeurer, 2020).
T105 15326-15438 Sentence denotes Cytokines play a pivotal role in the immune response to defend against different bacterial and viral infections.
T106 15439-15719 Sentence denotes However, it has also been established that dysregulated, amplified and uncontrolled immune responses may cause immunopathology leading to systematic self-attack contributing to multiple organ damage and cardiovascular injury secondary to SARS-CoV-2 infection (Zhang et al., 2020).
T107 15720-16300 Sentence denotes A plethora of studies have shown increased amounts of cytokines, such as interleukin-6 (IL-6), IL-7, IL-8, IL-9, IL-10, IL-1β, IL-1RA, tumor necrosis factor-alpha (TNF-α), granulocyte-macrophage colony-stimulating factor, fibroblast growth factor, macrophage inflammatory protein 1 alpha, platelet-derived growth factor, monocyte chemoattractant protein and vascular endothelial growth factor in the serum of COVID-19 patients, especially in ICU patients (Chen, Zhou, et al., 2020; Conti et al., 2020; Huang et al., 2020; Wang, Hu, et al., 2020; Zhang, Zhao, Zhang, et al., 2020).
T108 16301-16420 Sentence denotes Importantly, there is a strong correlation between serum cytokine levels and mortality rates in patients with COVID-19.
T109 16421-16535 Sentence denotes The amplified and uncontrolled inflammatory response induces cellular apoptosis or necrosis of the affected cells.
T110 16536-16767 Sentence denotes This is followed by increased permeability of blood vessels leading to the accumulation of inflammatory monocytes, macrophages and neutrophils in different body organs fueling the inflammatory cascade (Channappanavar et al., 2016).
T111 16768-16936 Sentence denotes The vicious circle intensifies the situation as the cytokine storm is further stimulated and the regulation of immune response is lost resulting in severe consequences.
T112 16937-17077 Sentence denotes Collectively, this indicates the uncontrolled inflammatory response is a major factor in the adverse response observed in COVID-19 patients.
T113 17078-17241 Sentence denotes In that sense, it would seem reasonable that ameliorating the exaggerated immune response would improve the clinical outcomes in patients with COVID-19 (Table 3 ).
T114 17242-17440 Sentence denotes Table 3 Overview of the pharmacological approaches under investigation for ameliorating cytokine storm, hyperinflammatory state and the associated secondary organ complications in COVID-19 patients.
T115 17441-17547 Sentence denotes Pharmacological intervention Sample size and criteria Treatment protocol Key findings Conclusion Reference
T116 17548-17644 Sentence denotes • Tocilizumab for IL-6 cytokine release syndrome • Multicenter Randomized controlled trial (RCT)
T117 17645-17673 Sentence denotes • Severe COVID-19 infections
T118 17674-17694 Sentence denotes • 18–85 years of age
T119 17695-17716 Sentence denotes • Elevated serum IL-6
T120 17717-17757 Sentence denotes • N = 94 standard therapy + tocilizumab
T121 17758-17818 Sentence denotes • N = 94 standard therapy • 4–8 mg/kg tocilizumab i.v. once
T122 17819-17950 Sentence denotes • Additional dose if fever persists in 24 h after first dose • First phase showed normalization of fever within 24 h of tocilizumab
T123 17951-18056 Sentence denotes • Improved respiratory function, oxygenation, and pulmonary lesions • Phase 4 study completed in May 2020
T124 18057-18074 Sentence denotes • Results pending
T125 18075-18224 Sentence denotes • Tocilizumab may be a promising investigative therapy to reduce cytokine release syndrome and associated multi-organ damage (ChiCTR2000029765, 2020)
T126 18225-18323 Sentence denotes • Tocilizumab to mitigate cytokine storm and associated complications • Retrospective cohort study
T127 18324-18342 Sentence denotes • >18 years of age
T128 18343-18395 Sentence denotes • Intensive care unit (ICU) COVID-19 hospitalization
T129 18396-18444 Sentence denotes • Primary endpoint of hospital-related mortality
T130 18445-18483 Sentence denotes • N = 210 standard care + tocilizumab
T131 18484-18552 Sentence denotes • N = 420 standard care • 400 mg single dose or 8 mg/kg tocilizumab
T132 18553-18707 Sentence denotes • 88% required 1 infusion, 12% received a second infusion • Hazard ratio (HR) 0.71 for hospital related mortality (95% confidence interval (CI) 0.56–0.89)
T133 18708-18790 Sentence denotes • Treatment was more effective in patients with C-reactive protein (CRP) >15 mg/dL
T134 18791-19001 Sentence denotes • HR 0.48 (95% CI 0.30–0.77) than those with CRP <15 mg/dL HR 0.92 (95% CI 0.57–1.48) • Tocilizumab treatment is associated with a lower rate of mortality, particularly in those with enhanced inflammatory state
T135 19002-19093 Sentence denotes • Double blind RCT recently completed with results pending NCT04320615 (Biran et al., 2020)
T136 19094-19168 Sentence denotes • Tocilizumab to mitigate cytokine storm • Prospective observational study
T137 19169-19208 Sentence denotes • Severe or critical COVID-19 infection
T138 19209-19232 Sentence denotes • 25 to 88 years of age
T139 19233-19273 Sentence denotes • N = 21 tocilizumab + standard therapy
T140 19274-19333 Sentence denotes • 42.9% had CVD • 4–8 mg/kg or 400 mg tocilizumab i.v. once
T141 19334-19462 Sentence denotes • 85.7% received single dose of tocilizumab, 14.3% required second dose within 12 h of first dose • Fever normalized within 24 h
T142 19463-19496 Sentence denotes • Reduced O2 therapy requirements
T143 19497-19533 Sentence denotes • Minimal improvement in IL-6 levels
T144 19534-19562 Sentence denotes • CT lung lesion improvement
T145 19563-19631 Sentence denotes • All patients discharged • Limited sample size and no control group
T146 19632-19755 Sentence denotes • Tocilizumab treatment in severe COVID-19 cases may improve clinical symptoms in hyperinflammatory state (Xu et al., 2020)
T147 19756-19877 Sentence denotes • Intensive methylprednisolone regimen +/− tocilizumab for management of cytokine storm • Prospective observational study
T148 19878-19933 Sentence denotes • O2 sat ≤ 94% OR tachypnea, elevated CRP, high D-dimer
T149 19934-19997 Sentence denotes • Primary outcome of hospital discharge or clinical improvement
T150 19998-20042 Sentence denotes • N = 86 methylprednisolone +/− tocilizumab
T151 20043-20076 Sentence denotes • N = 86 standard care • Stage 1:
T152 20077-20150 Sentence denotes Immediate methylprednisolone 250 mg i.v. on day 1, then 80 mg on days 2–5
T153 20151-20224 Sentence denotes • Stage 2 (lack of clinical improvement or worsening respiratory status):
T154 20225-20338 Sentence denotes Add tocilizumab 8 mg/kg i.v. once between days 2–5 • Improvement in respiratory status HR 1.79 (95% CI 1.20–2.67)
T155 20339-20390 Sentence denotes • Improvement reached in a shorter time vs. control
T156 20391-20619 Sentence denotes • Reduced hospital mortality and need for mechanical ventilation • Short duration of intensive immunosuppressive therapy is associated with improved clinical outcomes in patients with hyperinflammaory state (Ramiro et al., 2020)
T157 20620-20716 Sentence denotes • Ruxolitinib treatment for elevated cytokine levels and inflammatory response • Prospective RCT
T158 20717-20762 Sentence denotes • 18 to 75 years of age with severe infection
T159 20763-20812 Sentence denotes • Primary outcome of time to clinical improvement
T160 20813-20850 Sentence denotes • N = 20 ruxolitinib + standard care
T161 20851-20915 Sentence denotes • N = 21 placebo + standard care • Ruxolitinib 5 mg twice daily
T162 20916-21020 Sentence denotes • Placebo vitamin C 100 mg twice daily • No difference in primary endpoint HR 1.669 (95% CI 0.836–3.335)
T163 21021-21077 Sentence denotes • Improvement in lung computerized tomography (CT) scans
T164 21078-21247 Sentence denotes • Significantly reduced cytokine levels and CRP by day 3 • Ruxolitinib may hasten time of chest CT scan improvement and mitigate systemic inflammation (Cao et al., 2020)
T165 21248-21353 Sentence denotes • Anakinra for targeting the cytokine inflammatory cascade through IL-1 blockade • Open label case series
T166 21354-21374 Sentence denotes • Elevated CRP N = 9
T167 21375-21422 Sentence denotes • 6/9 with CVD risk factors (diabetes, obesity)
T168 21423-21492 Sentence denotes • 3/9 with hypertension • Anakinra 100 mg every 12 h s.c. on days 1–3
T169 21493-21565 Sentence denotes • Anakinra 100 mg once daily s.c. on days 4–10 • Fever subsided by day 3
T170 21566-21606 Sentence denotes • CRP normalized in 5 patients by day 11
T171 21607-21646 Sentence denotes • Halted progression of CT lung lesions
T172 21647-21717 Sentence denotes • 100% survival • Small case series, potential for confounding factors
T173 21718-21768 Sentence denotes • Potential therapy to target inflammatory cascade
T174 21769-21865 Sentence denotes • Positive results in patients with hypertension and other CVD risk factors (Aouba et al., 2020)
T175 21866-21883 Sentence denotes • Ana-COVID study
T176 21884-21972 Sentence denotes • Anakinra for COVID-19 hyperinflammatory state • Prospective/retrospective cohort study
T177 21973-22022 Sentence denotes • Hospitalized adults with critical lung function
T178 22023-22076 Sentence denotes • Cohort with CVD (hypertension, stroke, cardiopathy)
T179 22077-22148 Sentence denotes • Primary outcome of ICU admission with mechanical ventilation or death
T180 22149-22183 Sentence denotes • N = 52 anakinra + standard care
T181 22184-22253 Sentence denotes • N = 44 standard care • Anakinra 100 mg s.c. twice daily for 3 days
T182 22254-22546 Sentence denotes • Then anakinra 100 mg s.c. once daily for 7 days • Significantly reduced need for mechanical ventilation or death HR 0.22 (0.11–0.41) • Anakinra may be associated with improved outcomes in patients with severe COVID-19 infection, including those with CVD and history of cardiovascular events
T183 22547-22617 Sentence denotes • May be due to mitigation of inflammatory cascade (Huet et al., 2020)
T184 22618-22890 Sentence denotes The innate immune system detects viral infections by using pattern recognition receptors, particularly Toll-like receptors (TLR), to recognize pathogen-associated molecular patterns of the virus including lipids, lipoproteins, proteins and nucleic acids (Li et al., 2020).
T185 22891-23206 Sentence denotes Activation of the TLR increases the expression of the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interferon (IFN) regulatory factor 3 and mitogen-activated protein kinases, which subsequently induce the expression of a myriad of inflammatory factors (Akira, 2009).
T186 23207-23481 Sentence denotes For example, the binding of SARS-CoV-2 to TLR activates the NF-κB inflammatory pathway triggering the transcription of the different components of the NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) inflammasome (Chen, Moriyama, Chang, & Ichinohe, 2019; Siu et al., 2019).
T187 23482-23804 Sentence denotes The NLRP3 inflammasome is a large multiple protein platform consisting of main 3 components, the NLRP3 scaffold, the adapter component apoptosis-associated speck-like protein carrying a caspase activation and recruitment domain and the inactive zymogen procaspase-1 (Elliott & Sutterwala, 2015; Latz, Xiao, & Stutz, 2013).
T188 23805-24122 Sentence denotes Upon activation of the NLRP3 inflammasome and once assembled, procaspase-1 is converted into the active effector protease caspase-1, which then causes cleavage and maturation of proinflammatory cytokines pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into their corresponding active forms, inflammatory IL-1β and IL-18.
T189 24123-24349 Sentence denotes This, in turn, triggers a cascade of other downstream mediators of inflammation such as TNF-α, IL-6, prostaglandins and leukotrienes which induces more tissue damage, fever, and fibrosis (Conti et al., 2020; Yue et al., 2018).
T190 24350-24593 Sentence denotes Based on the robust inflammatory response triggered by the NLRP3 inflammasome cascade, targeting the pathway has potential therapeutic value, which can reduce the detrimental consequences of uncontrolled inflammation from SARS-CoVs infections.
T191 24594-24755 Sentence denotes Inflammation is well known to participate in various CVDs, such as atherosclerosis, coagulopathy, coronary artery disease and HF (Libby, Ridker, & Maseri, 2002).
T192 24756-24923 Sentence denotes In the majority of severe cases of COVID-19, the cytokine storm has been coupled with elevated levels of erythematosus sedimentation rate and C-reactive protein (CRP).
T193 24924-25128 Sentence denotes Subsequently, hypercoagulation and disseminated intravascular coagulation would present as thrombosis, thrombocytopenia and gangrene of the limbs (Siddiqi & Mehra, 2020; Zhang, Zhao, Zhang, et al., 2020).
T194 25129-25396 Sentence denotes The identification of key cytokines such as TNFα in patients with HF demonstrated a strong positive correlation between cytokines and the severity of left ventricular dilation/hypertrophy and left ventricular dysfunction (Dibbs et al., 2003; Janczewski et al., 2003).
T195 25397-25535 Sentence denotes Other evidence indicates increased IL-1β and IL-6 levels detected in patients with acute myocarditis and acute MI (Xu, Shi, et al., 2020).
T196 25536-25734 Sentence denotes Increased IL-6 levels have been associated with long QT-syndrome in patients with systemic inflammation, leading to higher risks for arrhythmias such as torsade de pointes (Aromolaran et al., 2018).
T197 25735-25908 Sentence denotes As well, the level of IL-6 can be used as a predictor of adverse cardiovascular events after acute coronary syndrome and chronic HF (Fanola et al., 2017; Held et al., 2017).
T198 25909-26045 Sentence denotes The serum levels of IL-8 are increased in patients with acute MI and is associated with higher mortality rates (Cavusoglu et al., 2015).
T199 26046-26327 Sentence denotes Collectively, we can conclude there is a strong correlation between elevated inflammatory markers and the adverse cardiovascular outcomes observed in patients with COVID-19 suggesting the potential role of an inflammatory storm in the development and progression of cardiac injury.
T200 26328-26559 Sentence denotes Importantly, it has been reported that populations at high risk to develop the more severe forms of cardiac complications secondary to COVID-19 are patients with advanced age, obesity, metabolic syndrome, hypertension and diabetes.
T201 26560-26786 Sentence denotes These conditions share a common feature where immune changes favour a hyperinflammatory state and compromised inflammatory resolution (Bruunsgaard & Pedersen, 2003; Goldstein, 2010; Lawrence & Gilroy, 2007; Rius et al., 2012).
T202 26787-27043 Sentence denotes Therefore, traditional cardiovascular treatment plus anti-inflammatory therapy targeting key steps and components of the cytokine storm could be hypothesized as a therapeutic strategy and management of cardiovascular impairment in severe cases of COVID-19.
T203 27044-27252 Sentence denotes As the inflammatory response in different organs share common pathways, ameliorating the systematic inflammatory response will benefit the cardiovascular system and have potential advantages for other organs.
T204 27254-27283 Sentence denotes 3.3 Miscellaneous mechanisms
T205 27284-27643 Sentence denotes Other proposed mechanisms of COVID-19–associated cardiovascular impairment include instability of coronary atherosclerotic plaques (Madjid, Vela, Khalili-Tabrizi, Casscells, & Litovsky, 2007) and increased platelet-aggregating activity (Modica, Karlsson, & Mooe, 2007) leading to excessive and uncontrolled coagulation and thrombosis (Milbrandt et al., 2009).
T206 27644-27912 Sentence denotes The systemic inflammatory response to pneumonia induces endothelial dysfunction, increases the procoagulant activity of the blood and consequently triggers inflammatory reactions within coronary atherosclerotic plaques, making them unstable and susceptible to rupture.
T207 27913-28014 Sentence denotes Together, this contributes to the formation of an occlusive thrombus over a ruptured coronary plaque.
T208 28015-28182 Sentence denotes It is documented that COVID-19 patients are prone to arterial and venous thromboembolisms due to hypoxia, excessive inflammation and diffuse intravascular coagulation.
T209 28183-28325 Sentence denotes In a Dutch study of 184 ICU patients with proven COVID-19 pneumonia, one-third of patients exhibited blood clots and thrombotic complications.
T210 28326-28518 Sentence denotes These findings, consequently, reinforced the recommendation to use antiplatelets and other pharmacological thrombosis prophylaxis drugs in all COVID-19 patients (Klok et al., 2020) (Table 4 ).
T211 28519-28667 Sentence denotes Table 4 Overview of the pharmacological interventions under investigation targeting hypercoagulability and platelet activation in COVID-19 patients.
T212 28668-28774 Sentence denotes Pharmacological intervention Sample size and criteria Treatment protocol Key findings Conclusion Reference
T213 28775-28868 Sentence denotes • Heparin anticoagulant treatment in sepsis-induced coagulopathy • Retrospective cohort study
T214 28869-28888 Sentence denotes • ≥ 18 years of age
T215 28889-28916 Sentence denotes • Severe COVID-19 infection
T216 28917-28982 Sentence denotes • Evaluation of 28-day mortality in heparin and non-heparin users
T217 28983-29033 Sentence denotes • 48.5% comorbid hypertension and/or heart disease
T218 29034-29051 Sentence denotes • N = 99 heparin
T219 29052-29277 Sentence denotes • N = 350 no heparin • Unfractionated (10, 000–15, 000 U/day) or low molecular weight heparin (40–60 mg enoxaparin/day) for 7 days or longer • No difference in 28-day mortality endpoint between heparin and non-heparin users.
T220 29278-29388 Sentence denotes • Lower 28-day mortality in patients with sepsis-induced coagulopathy (SIC) score of ≥4 in stratified analysis
T221 29389-29604 Sentence denotes • Odd Ratio (OR) 0.372 (95% CI 0.154–0.901) • Heparin may be associated with a lower 28-day mortality rate only in patients with enhanced coagulopathy risk such as SIC score of 4 or greater (Tang, Bai, et al., 2020)
T222 29605-29759 Sentence denotes • Antiplatelet and anticoagulant combination therapy for hypoxemia, respiratory failure, and cardiac adverse events • Case control, proof-of-concept study
T223 29760-29811 Sentence denotes • Adult patients with hypoxemic respiratory failure
T224 29812-29880 Sentence denotes • N = 5 ASA + clopidogrel + tirofiban + fondaparinux + standard care
T225 29881-29941 Sentence denotes • N = 5 matched controls given low molecular weight heparin
T226 29942-30012 Sentence denotes • Secondary outcome included major and minor cardiac adverse events 1.
T227 30013-30119 Sentence denotes Single dose of acetylsalicylic acid (ASA) 250 mg i.v. and single loading dose of oral clopidogrel 300 mg2.
T228 30120-30179 Sentence denotes ASA and clopidogrel continued at 75 mg orally for 30 days3.
T229 30180-30279 Sentence denotes Tirofiban 25 μg/kg as bolus i.v. injection, then 0.15 μg/kg/min continuous i.v. infusion for 48 h4.
T230 30280-30409 Sentence denotes Fondaparinux 2.5 mg/day s.c. for the duration of the hospital stay • Significant improvement in alveolar-arterial oxygen gradient
T231 30410-30463 Sentence denotes • Significant improvement in CRP and lymphocyte count
T232 30464-30597 Sentence denotes • Patients in treatment group did not experience any cardiac adverse events • Small study and not a randomized controlled trial (RCT)
T233 30598-30795 Sentence denotes • Intensive antithrombotic therapy may be useful in patients with severe respiratory distress with prothrombotic state at risk for acute cardiac events (Viecca, Radovanovic, Forleo, & Santus, 2020)
T234 30796-31024 Sentence denotes A 12-year follow-up study conducted by Wu et al. of 25 patients who recovered from SARS-CoV infection demonstrated patients were affected by various metabolic disturbances altering lipid metabolism and the cardiovascular system.
T235 31025-31207 Sentence denotes These patients suffered from hyperlipidemia, increased serum concentrations of free fatty acids, abnormal glucose metabolism and other cardiovascular abnormalities (Wu et al., 2017).
T236 31208-31448 Sentence denotes Considering the genetic similarities between SARS-CoV and SARS-CoV-2, Zhang et al. recently proposed the use of the lipid-lowering statins, which also possess anti-inflammatory properties, as a therapeutic option for patients with COVID-19.
T237 31449-31687 Sentence denotes This study reported that amongst 13,981 cases of COVID-19, in-hospital use of statins was associated with a lower risk of death and a significantly lower inflammatory response during the entire hospitalization period (Zhang et al., 2020).
T238 31688-31837 Sentence denotes Thus, suggesting the use of lipid-lowering drugs with anti-inflammatory properties can improve the cardiovascular outcomes in patients with COVID-19.
T239 31838-32003 Sentence denotes COVID-19 patients are susceptible to hypoxemia due to reduced lung performance, impaired gas exchange across the inflamed alveoli and abnormal ventilation/perfusion.
T240 32004-32111 Sentence denotes This will lead to decreased myocardial oxygen supply, myocardial ischemia and impaired calcium homeostasis.
T241 32112-32336 Sentence denotes The disturbance in calcium balance will trigger the activation of the NLRP3 inflammasome and different inflammatory components which consequently lead to the death of cardiomyocytes (Moccia et al., 2020; Zheng et al., 2020).
T242 32337-32494 Sentence denotes Additionally, the systemic response to pneumonia includes an increase in sympathetic activity causing severe tachycardia and increased peripheral resistance.
T243 32495-32699 Sentence denotes Subsequently, a rapid heart rate together with vasoconstriction may result in elevated myocardial oxygen requirements and a shortened diastolic interval, the period during which coronary perfusion occurs.
T244 32700-32924 Sentence denotes The mismatch between myocardial oxygen demand and supply can lead to cardiac ischemia and infarction, especially in the presence of pre-existing coronary artery disease (Corrales-Medina, Musher, Shachkina, & Chirinos, 2013).
T245 32925-33347 Sentence denotes Volume overload due to impaired sodium and water metabolism (Dreyfuss, Leviel, Paillard, Rahmani, & Coste, 1988), transient disturbance of endothelial function and vascular tone (Benson, Akbarian, Adler, & Abelmann, 1970; Kumar, Wallace, Ramirez, Benson, & Abelmann, 1970) and cardiac arrhythmias (Cilli et al., 2018) may also contribute to decreased left ventricular function or worsening of HF in patients with COVID-19.
T246 33348-33542 Sentence denotes Collectively, these effects can all result in the aggravation of existing CVDs and trigger severe events, such as acute coronary syndromes, thrombosis, myocardial ischemia or exacerbation of HF.
T247 33543-33739 Sentence denotes Indeed, cardiovascular protective strategies are needed for the prevention and management of severe adverse cardiovascular events to improve the prognosis of COVID-19 patients (Table 5, Table 6 ).
T248 33740-33851 Sentence denotes Table 5 Overview of proposed pharmacological approaches to attenuate COVID-19 associated cardiovascular injury.
T249 33852-33958 Sentence denotes Pharmacological intervention Sample size and criteria Treatment protocol Key findings Conclusion Reference
T250 33959-34110 Sentence denotes • Colchicine for the improvement of cardiac biomarkers, inflammation, and clinical outcomes • Prospective, open-label randomized controlled trial (RCT)
T251 34111-34147 Sentence denotes • N = 55 colchicine + standard care
T252 34148-34171 Sentence denotes • N = 50 standard care
T253 34172-34533 Sentence denotes • Primary endpoints included maximum cardiac troponin level, time for C-reactive protein (CRP) to reach 3× upper limit normal, time to deterioration by at least 2 points on clinical status scale • Colchicine 1.5 mg loading dose, 0.5 mg after 60 min, and then 0.5 mg twice daily + standard care for up to 3 weeks • No difference in cardiac troponin or CRP levels
T254 34534-34635 Sentence denotes • Clinical deterioration less common with colchicine treatment odd ratio (OR) 0.11 (95% CI 0.01–0.96)
T255 34636-34946 Sentence denotes • Abdominal pain and diarrhea significantly more common with colchicine treatment • Colchicine may not have a significant effect on cardiac or inflammatory biomarkers, however it may be useful in stabilizing patients with severe COVID-19 infection and preventing clinical deterioration (Deftereos et al., 2020)
T256 34947-35041 Sentence denotes • Statin therapy and impact on inflammation and patient prognosis • Retrospective cohort study
T257 35042-35090 Sentence denotes • Primary endpoint of 28-day all-cause mortality
T258 35091-35141 Sentence denotes • Secondary endpoint included acute cardiac injury
T259 35142-35164 Sentence denotes • N = 1219 statin use
T260 35165-35214 Sentence denotes • N = 12, 762 no statin • In-hospital statin use
T261 35215-35236 Sentence denotes • Atorvastatin 83.2%,
T262 35237-35257 Sentence denotes • Rosuvastatin 15.6%
T263 35258-35468 Sentence denotes • Dose differences between statins were converted to a daily equivalent dose of atorvastatin ranging from 18.9–20.0 mg/day • Reduced all-cause mortality with statin use hazard ratio (HR) 0.63 (95% CI 0.48–0.84)
T264 35469-35579 Sentence denotes • Patients on ACEi/ARB therapy in addition to statin did not have increased mortality compared to statin alone
T265 35580-35637 Sentence denotes • Statin therapy not associated with acute cardiac injury
T266 35638-35918 Sentence denotes • Inflammatory markers CRP, IL-6 were lower in statin treated patients while in hospital • Reduced mortality and improved prognosis associated with in-hospital statin use may be due to the anti-inflammatory and immunomodulatory effects of statins (Zhang, Qin, Cheng, et al., 2020)
T267 35919-36043 Sentence denotes • ACEi/ARB impact on mortality in COVID-19 patients with concomitant hypertension • Retrospective, multi-centre cohort study
T268 36044-36108 Sentence denotes • Patients with comorbid hypertension hospitalized with COVID-19
T269 36109-36129 Sentence denotes • Age 18 to 74 years
T270 36130-36178 Sentence denotes • Primary endpoint of 28-day all-cause mortality
T271 36179-36206 Sentence denotes • N = 188 ACEi/ARB therapy
T272 36207-36270 Sentence denotes • N = 940 no ACEi/ARB • ACEi/ARB for treatment of hypertension
T273 36271-36411 Sentence denotes • individual patient dosing regimens not specified • Risk of all-cause mortality lower in ACEi/ARB treated group HR 0.42 (95% CI 0.19–0.92).
T274 36412-36544 Sentence denotes • Use of ACEi/ARB in comparison to other anti-hypertension therapies was associated with lower mortality HR 0.30 (95% CI 0.12–0.70).
T275 36545-36682 Sentence denotes • No difference in acute cardiac injury outcome between groups • Chronic ACEi/ARB therapy may not increase mortality of COVID-19 patients
T276 36683-36793 Sentence denotes • May not have much benefit in acute heart injury due to COVID-19 inflammation (Zhang, Zhu, Cai, et al., 2020)
T277 36794-36900 Sentence denotes • Statin use impact on acute myocardial injury patient outcomes • Retrospective observational cohort study
T278 36901-36934 Sentence denotes • Patients with elevated troponin
T279 36935-36970 Sentence denotes • History of CVD in 24% of patients
T280 36971-36982 Sentence denotes • N = 3069
T281 36983-37084 Sentence denotes • Objective to characterize myocardial injury and associated outcomes • 36% of patients using statins
T282 37085-37354 Sentence denotes • Doses and regimens not specified • Statin use amongst patients with acute myocardial injury was associated with improved survival HR 0.57 (95% CI 0.47–0.69) • Statin treatment may be associated with a survival benefit in patients with CVD and elevated troponin levels
T283 37355-37463 Sentence denotes • Exact beneficial mechanism(s) associated with statins in COVID-19 remain to be studied (Lala et al., 2020)
T284 37464-37625 Sentence denotes Table 6 Summary of the ongoing trials investigating pharmacological agents targeting a cytokine storm and acute cardiac injury secondary to SARS-CoV-2 infection.
T285 37626-37708 Sentence denotes Pharmacological intervention Sample size and criteria Treatment protocol Reference
T286 37709-37725 Sentence denotes • TACTIC-E Trial
T287 37726-37780 Sentence denotes • Immunomodulatory agents • Multi-arm randomized trial
T288 37781-37830 Sentence denotes • Pre-intensive care unit (ICU) COVID-19 patients
T289 37831-37912 Sentence denotes • Immunomodulatory drug EDP1815 vs. dapagliflozin + ambrisentan vs. standard care
T290 37913-38049 Sentence denotes • Primary outcome includes need for cardiovascular organ support • EDP1815 as 2 capsules twice daily (1.6 × 1011 cells) for up to 7 days
T291 38050-38121 Sentence denotes • Dapagliflozin 10 mg + ambrisentan 5 mg once daily (NCT04393246, 2020)
T292 38122-38275 Sentence denotes • High dose IV Vitamin C to ameliorate cytokine storm and associated organ dysfunction • Prospective placebo controlled randomized controlled trial (RCT)
T293 38276-38286 Sentence denotes • N = 308
T294 38287-38332 Sentence denotes • High dose i.v. vitamin C (HIVC) vs. placebo
T295 38333-38530 Sentence denotes • Primary outcome of ventilator-free days • 12 g/50 ml vitamin C infusion 12 ml/h twice daily for 7 days vs. 50 ml sterile water for injection infused at 12 ml/h (Liu, Zhu, Zhang, Li, & Peng, 2020)
T296 38531-38585 Sentence denotes • TOC-COVID Trial • Prospective placebo controlled RCT
T297 38586-38628 Sentence denotes • N = 100 tocilizumab + standard treatment
T298 38629-38668 Sentence denotes • N = 100 placebo + standard treatment
T299 38669-38774 Sentence denotes • Primary outcome of ventilation-free days • Tocilizumab 8 mg/kg single i.v. dose (Rilinger et al., 2020)
T300 38775-38791 Sentence denotes • TACTIC-R Trial
T301 38792-38862 Sentence denotes • Immunomodulatory agents • Randomized parallel 3-arm open label trial
T302 38863-38885 Sentence denotes • N = 125 Baricitinib
T303 38886-38908 Sentence denotes • N = 125 Ravulizumab
T304 38909-38935 Sentence denotes • N = 125 standard of care
T305 38936-39050 Sentence denotes • Primary outcome includes need for cardiovascular organ support • Baricitinib 4 mg orally once daily on days 1–14
T306 39051-39126 Sentence denotes • Ravulizumab single i.v. weight-based dose regimen (Kulkarni et al., 2020)
T307 39127-39143 Sentence denotes • CytoResc Trial
T308 39144-39230 Sentence denotes • Cytokine storm in hyperinflammation and shock • Prospective, open-label, pilot study
T309 39231-39306 Sentence denotes • ‘CytoSorb’ polystyrene-based hemoadsorber to adsorb circulating cytokines
T310 39307-39330 Sentence denotes • N = 40–50 ‘CytoSorb’
T311 39331-39356 Sentence denotes • N = 40–50 standard care
T312 39357-39511 Sentence denotes • Primary outcome is time to resolution of vasoplegic shock • ‘CytoSorb’ therapy administered via a shaldon catheter for 3–7 days (Stockmann et al., 2020)
T313 39512-39566 Sentence denotes • MelCOVID Trial • Double blind placebo controlled RCT
T314 39567-39590 Sentence denotes • ICU COVID-19 patients
T315 39591-39628 Sentence denotes • N = 12 melatonin + standard of care
T316 39629-39669 Sentence denotes • N = 6 placebo control + standard care
T317 39670-39773 Sentence denotes • Secondary outcome includes CRP, IL-6 levels • Melatonin 5 mg/kg/day i.v. divided every 6 h for 7 days
T318 39774-39868 Sentence denotes • Placebo dose of 5 mg/kg/day i.v. divided every 6 h for 7 days (Rodriguez-Rubio et al., 2020)
T319 39869-39958 Sentence denotes • Siltuximab for patients diagnosed with severe respiratory complications due to COVID-19
T320 39959-40042 Sentence denotes • Anti-IL-6 mitigation of cytokine storm • Observational retrospective cohort study
T321 40043-40113 Sentence denotes • Cohort A: continuous positive airway pressure followed by siltuximab
T322 40114-40159 Sentence denotes • Cohort B: intubation followed by siltuximab
T323 40160-40240 Sentence denotes • Control group receiving continuous positive airway pressure or intubation only
T324 40241-40251 Sentence denotes • N = 220
T325 40252-40347 Sentence denotes • Primary outcome of mortality over 30 days • Detailed siltuximab dosing regimen not specified.
T326 40348-40403 Sentence denotes • Treatment procedure was based on clinicians judgement
T327 40404-40434 Sentence denotes • Study completed May 8, 2020.
T328 40435-40470 Sentence denotes Results pending (NCT04322188, 2020)
T329 40471-40486 Sentence denotes • COV-AID Trial
T330 40487-40564 Sentence denotes • Use of anti-interleukin agents for cytokine storm • Phase 3 prospective RCT
T331 40565-40604 Sentence denotes • Patients with signs of cytokine storm
T332 40605-40649 Sentence denotes • N = 38 Anakinra alone (anti-IL-1 receptor)
T333 40650-40688 Sentence denotes • N = 76 Siltuximab alone (anti-IL-6)
T334 40689-40720 Sentence denotes • N = 38 Anakinra + siltuximab
T335 40721-40768 Sentence denotes • N = 76 Tocilizumab alone (anti-IL-6 receptor)
T336 40769-40800 Sentence denotes • N = 38 Anakinra + tocilizumab
T337 40801-40829 Sentence denotes • N = 76 standard care alone
T338 40830-40920 Sentence denotes • Primary outcome as time to clinical improvement • Anakinra 100 mg s.c. daily for 28 days
T339 40921-40963 Sentence denotes • Siltuximab single i.v. infusion 11 mg/kg
T340 40964-41037 Sentence denotes • Tocilizumab single i.v. infusion 8 mg/kg max 800 mg (Maes et al., 2020)
T341 41038-41086 Sentence denotes • Sarilumab for hospitalized COVID-19 infections
T342 41087-41128 Sentence denotes • Cytokine storm syndrome • Phase 2/3 RCT
T343 41129-41139 Sentence denotes • Phase 2:
T344 41140-41217 Sentence denotes Sarilumab in hospitalized patients regardless of disease severity vs. placebo
T345 41218-41303 Sentence denotes • Primary outcome of % change in CRP in patients with serum IL-6 > upper limit normal
T346 41304-41323 Sentence denotes • Phase 3 Cohort 1:
T347 41324-41413 Sentence denotes Sarilumab in hospitalized critical infection receiving mechanical ventilation vs. placebo
T348 41414-41425 Sentence denotes • Cohort 2:
T349 41426-41506 Sentence denotes Sarilumab in hospitalized infection receiving mechanical ventilation vs. placebo
T350 41507-41518 Sentence denotes • N = 1912
T351 41519-41605 Sentence denotes • Primary outcome of at least 1 point improvement on 7 point clinical scale • Phase 2:
T352 41606-41629 Sentence denotes Low dose sarilumab i.v.
T353 41630-41640 Sentence denotes • Phase 2:
T354 41641-41664 Sentence denotes Mid-dose sarilumab i.v.
T355 41665-41684 Sentence denotes • Phase 3 Cohort 1:
T356 41685-41708 Sentence denotes Low dose sarilumab i.v.
T357 41709-41728 Sentence denotes • Phase 3 Cohort 1:
T358 41729-41752 Sentence denotes Mid-dose sarilumab i.v.
T359 41753-41772 Sentence denotes • Phase 3 Cohort 2:
T360 41773-41797 Sentence denotes High dose sarilumab i.v.
T361 41798-41867 Sentence denotes • Placebo given to match sarilumab administration (NCT04315298, 2020)
T362 41868-41889 Sentence denotes • CORIMUNO-SARI Trial
T363 41890-41944 Sentence denotes • Sarilumab to mitigate enhanced IL-6 signalling • RCT
T364 41945-41995 Sentence denotes • Moderate, severe, or critical COVID-19 pneumonia
T365 41996-42028 Sentence denotes • Sarilumab vs. standard of care
T366 42029-42117 Sentence denotes • N = 239 • Sarilumab 400 mg single i.v. infusion over 1 h on day 1 (NCT04324073, 2020)
T367 42118-42197 Sentence denotes • Barcitinib for hospitalized COVID-19 patients • Non-randomized clinical trial
T368 42198-42260 Sentence denotes • Any adult patient hospitalized with moderate/severe COVID-19
T369 42261-42313 Sentence denotes • Barcitinib + standard care vs. standard care alone
T370 42314-42427 Sentence denotes • Primary outcome of clinical status after 15 days • Barcitinib 2 mg orally daily for 10 days (NCT04321993, 2020)
T371 42428-42477 Sentence denotes • RUXCOVID Trial • Phase 3 placebo-controlled RCT
T372 42478-42517 Sentence denotes • Patients age ≥ 12 with cytokine storm
T373 42518-42575 Sentence denotes • Ruxolitinib + standard care vs. placebo + standard care
T374 42576-42610 Sentence denotes • N = 402 randomized in 2:1 ratio
T375 42611-42681 Sentence denotes • treatment: placebo • Ruxolitinib 5 mg orally twice daily for 14 days
T376 42682-42735 Sentence denotes • May extend treatment to 28 days (NCT04362137, 2020)
T377 42736-42804 Sentence denotes • Losartan (ARB) in patients hospitalized for COVID-19 • Phase 2 RCT
T378 42805-42843 Sentence denotes • Losartan vs. placebo + standard care
T379 42844-42854 Sentence denotes • N = 200
T380 42855-42979 Sentence denotes • Secondary outcome includes cardiovascular organ failure/dysfunction • Losartan 50 mg orally once daily (NCT04312009, 2020)
T381 42980-43065 Sentence denotes • Losartan (ARB) in patients not requiring hospitalization for COVID-19 • Phase 2 RCT
T382 43066-43104 Sentence denotes • Losartan vs. placebo + standard care
T383 43105-43115 Sentence denotes • N = 500
T384 43116-43253 Sentence denotes • Primary outcome of patients admitted to hospital within 15 days of randomization • Losartan 25 mg orally once daily (NCT04311177, 2020)
T385 43254-43365 Sentence denotes • Eicosapentaenoic acid (EPA) free fatty acid for hospitalized COVID-19 patients • Phase 3 interventional trial
T386 43366-43430 Sentence denotes • Treatment with EPA gastro-resistant capsules vs. standard care
T387 43431-43456 Sentence denotes • 28-day treatment period
T388 43457-43575 Sentence denotes • Primary outcome of time to treatment failure i.e. need for additional therapy, intubation, transfer to ICU, or death
T389 43576-43753 Sentence denotes • Secondary outcome includes reduction of IL-6 levels • Eicosapentaenoic acid free fatty acid (EPA-FFA) 1 g gastro-resistant capsules twice daily (2 g total) (NCT04335032, 2020)
T390 43754-43771 Sentence denotes • COLCORONA Trial
T391 43772-43892 Sentence denotes • Colchicine and inflammatory cytokine storm • Phase 3 multi-centre placebo-controlled randomized controlled trial (RCT)
T392 43893-43916 Sentence denotes • Age 40 years or older
T393 43917-44058 Sentence denotes • Patients must have at least one high-risk factor i.e. uncontrolled hypertension, HF, coronary artery disease (CAD), diabetes, obesity, etc.
T394 44059-44083 Sentence denotes • Colchicine vs. placebo
T395 44084-44102 Sentence denotes • 30-day treatment
T396 44103-44114 Sentence denotes • N = 6000
T397 44115-44266 Sentence denotes • Primary composite endpoint of need for hospitalization or death • Colchicine 0.5 mg orally twice daily for 3 days, then 0.5 mg once daily for 27 days
T398 44267-44333 Sentence denotes • Placebo will match colchicine administration (NCT04322682, 2020)
T399 44335-44416 Sentence denotes 4 Adverse cardiovascular effects of the proposed empirical/supportive treatments
T400 44417-44599 Sentence denotes Currently, there is no approved vaccination or effective drug for protecting against or treating COVID-19; only symptomatic therapy and empirical/supportive treatments are available.
T401 44600-44750 Sentence denotes Many of the mortalities related to COVID-19 have been primarily attributed to original patient comorbidities instead of pneumonia (Wang et al., 2020).
T402 44751-44894 Sentence denotes This highlights the importance of focusing on pre-existing comorbidities of COVID-19 patients, particularly those of the cardiovascular system.
T403 44895-45055 Sentence denotes Attention to therapies with cardiovascular side effects being proposed and applied to patients with COVID-19, especially those with underlying CVD is important.
T404 45056-45201 Sentence denotes Notably, many of the therapies proposed to ameliorate the poor prognosis of COVID-19 patients are associated with cardiovascular adverse effects.
T405 45202-45481 Sentence denotes For example, treatment of patients with COVID-19 with non-steroidal anti-inflammatory drugs, glucocorticoids and anti-viral agents, such as ribavirin, lopinavir/ritonavir, INF-α and the antibiotic azithromycin, could further increase the cardiovascular risk of COVID-19 patients.
T406 45482-45766 Sentence denotes Excessive use of non-steroidal anti-inflammatory drugs and glucocorticoids is associated with deleterious effects on the cardiovascular system increasing the risk of events including, ischemia, MI, arrhythmias and HF (England, Thiele, Anderson, & Mikuls, 2018; Roubille et al., 2015).
T407 45767-46121 Sentence denotes Although corticosteroids are sometimes prescribed for the treatment of patients with severe SARS-CoV infection for the possible relief of inflammation (Wong et al., 2004), recent evidence suggests corticosteroids may exacerbate lung injury associated with SARS-CoV-2 due to delayed viral clearance (Mehta, et al., 2020; Russell, Millar, & Baillie, 2020).
T408 46122-46373 Sentence denotes The antiviral agents lopinavir and ritonavir have been tested in a randomized controlled, open-label trial in hospitalized adult patients with COVID-19 and concluded that no benefit was observed with lopinavir–ritonavir treatment beyond standard care.
T409 46374-46587 Sentence denotes Moreover, about 14% of lopinavir–ritonavir recipients were unable to complete the full 14-day course of administration due primarily to the adverse events including the risks of QT prolongation (Cao et al., 2020).
T410 46588-46887 Sentence denotes It is important to highlight that the adverse effects of these antivirals involve altering the cardiac electrical conduction system causing QTc and/or PR interval prolongation, which can lead to atrioventricular block and torsade de pointes arrhythmias increasing the risk of MI (Worm et al., 2010).
T411 46888-47164 Sentence denotes Further, the use of these protease inhibitors can lead to metabolic disturbances such as hyperglycemia, hyperlipidemia and lipodystrophy, which may also contribute to adverse cardiovascular outcomes (Hill, Sawyer, & Gazzard, 2009; Tsiodras, Mantzoros, Hammer, & Samore, 2000).
T412 47165-47322 Sentence denotes Recently, IFN-α2b was used in an uncontrolled exploratory study including 77 hospitalized adults with confirmed COVID-19 in Wuhan, China (Zhou et al., 2020).
T413 47323-47544 Sentence denotes The trial showed that treatment with IFN-α2b markedly decreased the duration of detectable virus in the upper respiratory tract and also reduced the interval of the elevated inflammatory markers IL-6 and CRP in the blood.
T414 47545-47788 Sentence denotes However, treatment with IFN-α has been associated with hypertension, hypertriglyceridemia and direct cardiotoxicities, including arrhythmias, MI and cardiomyopathy, which could exacerbate underlying cardiac dysfunction (Page 2nd et al., 2016).
T415 47789-48161 Sentence denotes An open-label randomized trial has been conducted to test the efficacy of IFN beta-1b, lopinavir–ritonavir and ribavirin for treating patients admitted to hospital with COVID-19 and concluded early triple antiviral therapy was effective in alleviating symptoms and shortening the duration of hospital stay in patients with mild to moderate infections (Hung, et al., 2020).
T416 48162-48380 Sentence denotes However, it is worth noting ribavirin has a US boxed warning issued for hemolytic anemia associated with use that may worsen underlying cardiac disease and lead to fatal and non-fatal MI (Durante-Mangoni et al., 2011).
T417 48381-48666 Sentence denotes Numerous recent studies proposed the use of hydroxychloroquine and azithromycin as a treatment of COVID-19 in open-label non-randomized clinical trials, however, no positive results were produced (Arshad et al., 2020; Cavalcanti, et al., 2020; Gautret et al., 2020; Tang et al., 2020).
T418 48667-48971 Sentence denotes Well known adverse effects associated with azithromycin or hydroxychloroquine include development of severe QT prolongation (Gibson et al., 2017), which worsened when azithromycin is combined with hydroxychloroquine to treat COVID-19 patients (Choi, Lim, Chung, Choi, & Yoon, 2018; Mercuro et al., 2020).
T419 48972-49160 Sentence denotes Currently, there are multiple in vitro experiments and preclinical studies being performed around the world to test novel COVID-19 therapies, which are quickly moving into clinical trials.
T420 49161-49310 Sentence denotes Importantly, the early efficacy results have been limited to small-scale clinical studies in which the safety profiles have not been well-identified.
T421 49311-49435 Sentence denotes The safety profiles will be critical for COVID-19 patients with underlying comorbidities such as cardiovascular dysfunction.
T422 49436-49597 Sentence denotes Therefore, as there is a need for rapid clinical translation and a wide use of novel therapies for COVID-19, continued attention to safety profiles is important.
T423 49598-49749 Sentence denotes The rapid spread of COVID-19 globally continues to impact susceptible populations, like elderly patients and individuals with underlying comorbidities.
T424 49750-49999 Sentence denotes While underlying cardiovascular issues are impacted by COVID-19 infection, many existing and novel therapeutic strategies have direct adverse cardiovascular effects, highlighting the importance for consideration in new drug research and development.
T425 50001-50051 Sentence denotes 5 Overview of the n-3 polyunsaturated fatty acids
T426 50052-50188 Sentence denotes The long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) are essential fatty acids obtained from both dietary and non-dietary sources.
T427 50189-50247 Sentence denotes The simplest n-3 PUFA is α-linolenic acid (ALA, 18:3 n-3).
T428 50248-50370 Sentence denotes Once inside the body, ALA can be converted through a series of elongation and desaturation reactions into other n-3 PUFAs.
T429 50371-50626 Sentence denotes For instance, ALA is metabolized into eicosapentaenoic acid (EPA, C20:5n-3) which can be further metabolized into docosahexaenoic acid (DHA, C22:6n-3), the two most abundant n-3 PUFAs in mammalian tissues (Wiktorowska-Owczarek, Berezinska, & Nowak, 2015).
T430 50627-50732 Sentence denotes Mammals lack the necessary enzymes (delta-12 and delta-15 desaturase) required to synthesize ALA de novo.
T431 50733-50922 Sentence denotes As such, these fatty acids are described as “essential” and must be obtained from the diet such as fish, other marine sources, plants or supplements (Burdge & Calder, 2015; Sprecher, 1981).
T432 50923-51024 Sentence denotes Conversely, linoleic acid (LA, 18:2 n-6) is considered the primary source of the essential n-6 PUFAs.
T433 51025-51159 Sentence denotes LA can be further metabolized into arachidonic acid (AA, 20:4n-6) by the same series of elongase and delta-4,-5,-6 desaturase enzymes.
T434 51160-51504 Sentence denotes As n-3 PUFAs can compete for the same metabolic pathways with n-6 PUFAs, n-3 PUFAs supplementation may reduce the synthesis of n-6 PUFA-derived metabolites, thus, altering the metabolite profile and impacting numerous signaling pathways within the body, including the immune system, leading to disparate effects (Arterburn, Hall, & Oken, 2006).
T435 51506-51602 Sentence denotes 6 Role of n-3 polyunsaturated fatty acids in patients with respiratory infections and/or sepsis
T436 51603-51916 Sentence denotes A plethora of human and animal studies have investigated the beneficial effects of EPA and DHA in patients with ALI and ARDS which are common characteristics observed in severe SARS-CoV-2 patients (Messina et al., 2020; Nelson et al., 2003; Shirai, Yoshida, Matsumaru, Toyoda, & Ogura, 2015; Singer et al., 2006).
T437 51917-52132 Sentence denotes Mancuso et al. demonstrated Long-Evans rats fed enteral diets containing fish oil as a source of n-3 PUFAs for 21 days were subjected to acute inflammation caused by an intravenous injection of Salmonella endotoxin.
T438 52133-52363 Sentence denotes N-3 PUFA fed rats had a lower severity of pulmonary microvascular protein permeability and decreased pulmonary neutrophil accumulation compared to rats fed the n-6 PUFA enriched diet (Mancuso et al., 1997a; Mancuso et al., 1997b).
T439 52364-52647 Sentence denotes Furthermore, stimulated alveolar macrophages had lower concentrations of AA-derived metabolites, such as thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) suggesting a beneficial effect of n-3 PUFAs over n-6 PUFAs in attenuation of ALI (Mancuso et al., 1997a; Mancuso et al., 1997b).
T440 52648-52936 Sentence denotes Saedisomeolia et al. demonstrated in Calu-3 epithelial cells infected with Rhinovirus RV-43 and RV-1B that pre-incubating with DHA significantly reduced the release of IL-6 and IFN-γ-inducible protein, suppressing RV-induced inflammation (Saedisomeolia, Wood, Garg, Gibson, & Wark, 2009).
T441 52937-53202 Sentence denotes Collectively, these studies demonstrate that the anti-inflammatory properties of n-3 PUFAs play a pivotal role in attenuating the uncontrolled immune response in the lungs secondary to bacterial or viral infections which could be helpful in the setting of COVID-19.
T442 53203-53319 Sentence denotes Clinical evidence from trials assessing the role of n-3 PUFAs in ameliorating ALI, ARDS and sepsis has been limited.
T443 53320-53556 Sentence denotes Pontes-Arruda et al. investigated the effect of a diet enriched with EPA, γ-linolenic acid and antioxidants in patients with severe sepsis or septic shock who required mechanical ventilation (Pontes-Arruda, Aragao, & Albuquerque, 2006).
T444 53557-53726 Sentence denotes The data suggested the diet contributed to improved ICU and hospital clinical outcomes and was associated with lower mortality rates when compared to the control groups.
T445 53727-54041 Sentence denotes Meta-analysis reported a significant reduction in ventilator-free days, organ failures, length of stay in ICU, mortality rates as well as relevant improvements in oxygenation and clinical outcomes of ventilated patients with ALI/ARDS given EPA and γ-linolenic acid (Pontes-Arruda, Demichele, Seth, & Singer, 2008).
T446 54042-54262 Sentence denotes The efficacy and safety of a diet supplemented with a high-dose EPA and DHA (9 g/d added to 1 g/d ascorbic acid, 400UI/12 h α-tocopherol and 100 μg/d selenium) was assessed in patients with early-stage sepsis for 7 days.
T447 54263-54480 Sentence denotes The investigators found patients had lower levels of CRP, IL-6 and procalcitonin, as well as less need for mechanical ventilation and reduced development of severe sepsis (Hosny, Nahas, Ali, Elshafei, & Khaled, 2013).
T448 54481-54745 Sentence denotes Evidence for beneficial effects of n-3 PUFA-containing diets in patients with severe ARDS demonstrated similar outcomes such as reduced duration of mechanical ventilation, shorter ICU length and improved oxygenation (Langlois, D'Aragon, Hardy, & Manzanares, 2019).
T449 54746-55098 Sentence denotes These effects are highlighted in a recent systematic review with a meta-analysis demonstrated critically ill patients receiving parenteral nutrition therapy enriched with fish oil lipid emulsion had reduced risk for infection and sepsis (40% and 56%, respectively) as well a reduction of hospital and ICU stay by about two days (Pradelli et al., 2020).
T450 55099-55251 Sentence denotes Together, these studies demonstrate n-3 PUFA supplementation has favorable results in terms of multiple inflammatory, respiratory and clinical outcomes.
T451 55252-55536 Sentence denotes Recently, Bristrian proposed the use of parenteral supplementation of fish-oil emulsions, containing substantial amounts of EPA and DHA (4–6 g/d), to treat patients with severe SARS-CoV-2, in order to inhibit cytokine secretion and mitigate the inflammatory response (Bistrian, 2020).
T452 55537-55926 Sentence denotes In agreement with this idea, Torrinhas et al. suggested the immune modulatory properties of n-3 PUFAs will provide important and beneficial effects to improve clinical outcomes of COVID-19 particularly in hospitalized high-risk populations with severe underlying conditions including the elderly, obese, hypertensive, oncologic and diabetic patients (Torrinhas, Calder, & Waitzberg, 2020).
T453 55927-56195 Sentence denotes Furthermore, they suggested n-3 PUFAs could provide additional benefits by attenuating the aggravated inflammatory state observed with pre-existing health conditions which might have a role in triggering detrimental outcomes associated with severe COVID-19 phenotypes.
T454 56196-56380 Sentence denotes Currently, there is an open-label, randomized control study to investigate the effect of n-3 PUFAs in hospitalized subjects with confirmed SARS-CoV-2 (NCT04335032) (NCT04335032, 2020).
T455 56381-56523 Sentence denotes The study comprises 240 participants, with one group receiving standard care, the other additionally being provided 2 g daily of EPA capsules.
T456 56524-56793 Sentence denotes Interventions will be carried out between 28 and 90 days and the efficacy of EPA in the treatment of the disease, oxygen saturation, levels of pro-inflammatory IL-6, mortality rate, ICU stays, hospitalization days and need for mechanical ventilation will be determined.
T457 56794-57035 Sentence denotes While the results from this study are not available, the evidence suggests oral or intravenous administration of bioactive lipids could potentially reduce the severity and/or enhance the recovery of those infected with COVID-19 (Das, 2020a).
T458 57036-57086 Sentence denotes However, further research is undoubtedly required.
T459 57088-57149 Sentence denotes 7 Cardiovascular benefits of n-3 polyunsaturated fatty acids
T460 57150-57459 Sentence denotes N-3 PUFAs and many of the their endogenously generated metabolites act as bioactive lipid molecules with a wide array of properties against numerous disorders including CVD (Lordan, Redfern, Tsoupras, & Zabetakis, 2020; Lordan, Tsoupras, & Zabetakis, 2017; Moro, Nagahashi, Ramanathan, Takabe, & Wakai, 2016).
T461 57460-57743 Sentence denotes Numerous studies have suggested higher consumption of n-3 PUFAs lowers the number of mortalities related to CVD (Darwesh, Sosnowski, Lee, Keshavarz-Bahaghighat, & Seubert, 2019; Kris-Etherton, Harris, Appel, & Nutrition, 2003; Lee, O'Keefe, Lavie, & Harris, 2009; Mozaffarian, 2007).
T462 57744-58010 Sentence denotes For instance, Mozaffarian et al. demonstrated higher plasma levels of n-3 PUFA biomarkers in a U.S. adults cohort study was associated with lower total mortality attributable with fewer cardiovascular compared to non-cardiovascular deaths (Mozaffarian et al., 2013).
T463 58011-58373 Sentence denotes Currently, the intake of n-3 PUFAs is still recommended by the American Heart Association to prevent clinical CVD episodes in individuals with predominant coronary heart disease, such as a recent MI, to reduce death rates as well as individuals with prevalent HF to reduce hospitalizations and number of mortalities (Sacks et al., 2017; Siscovick, et al., 2017).
T464 58374-58519 Sentence denotes The cardiovascular benefits of n-3 PUFAs could be attributed to their pleiotropic effects on the different elements of the cardiovascular system.
T465 58520-58807 Sentence denotes Evidence suggests a higher intake of n-3 PUFAs has a beneficial effect on lipid profiles by replacing saturated fatty acids and lowering triglyceride levels, thereby stabilizing atherosclerotic plaques and reducing the incidence of thrombus formation (Plutzky, 1999; Thies et al., 2003).
T466 58808-59274 Sentence denotes Furthermore, n-3 PUFAs can enrich cell membranes and alter the lipid raft structure and function leading to improved organelle and cellular function (Din et al., 2008), autonomic tone (Abuissa, O'Keefe Jr., Harris, & Lavie, 2005; O'Keefe Jr., Abuissa, Sastre, Steinhaus, & Harris, 2006), elevated arrhythmic thresholds (Anand, Alkadri, Lavie, & Milani, 2008) and ameliorating hypertension (Geleijnse, Giltay, Grobbee, Donders, & Kok, 2002; O'Keefe Jr. et al., 2006).
T467 59275-59487 Sentence denotes Importantly, several experimental, clinical and epidemiological studies hypothesize that the cardioprotective effects of n-3 PUFAs and their metabolites are attributed mainly to their immunomodulatory properties.
T468 59488-59710 Sentence denotes Notably, emerging evidence demonstrates the ability of n-3 PUFAs to reduce circulating levels of inflammatory chemokines, cytokines, and the pro-inflammatory metabolites derived from n-6 PUFAs (Calder, 2013, Calder, 2017).
T469 59712-59792 Sentence denotes 8 Potential cardioprotective mechanisms of n-3 PUFAs in the setting of COVID-19
T470 59793-59953 Sentence denotes Based on several clinical reports, COVID-19 patients with severe ALI/ARDS may also suffer from increased risk of sepsis and cardiac arrest (Huang et al., 2020).
T471 59954-60162 Sentence denotes Accumulating reports have indicated that n-3 PUFAs could improve resolution of inflammation, sepsis survival and precondition the heart against septic cardiomyopathy (Korner et al., 2018; Leger et al., 2019).
T472 60163-60419 Sentence denotes In this review, we propose that n-3 PUFAs can protect against and ameliorate cardiovascular complications associated with COVID-19 mainly due to their immunomodulatory features, antioxidant potential as well as their ability to maintain tissue homeostasis.
T473 60420-60676 Sentence denotes This section will highlight the cardioprotective mechanisms of n-3 PUFAs and their metabolites hypothesizing how n-3 PUFAs might have a supportive adjuvant utility in treating and protecting against cardiac complications associated with COVID-19 (Fig. 2 ).
T474 60677-61675 Sentence denotes Fig. 2 Potential cardioprotective mechanisms of n-3 PUFAs in the setting of COVID-19. (A) N-3 PUFAs ameliorate uncontrolled immune responses and exert anti-inflammatory effects via several mechanisms. (B) N-3 PUFAs attenuate the vicious cycle/interaction of mitochondrial dysfunction and aggravated immune response. (C) N-3 PUFAs have the capability to attenuate viral infections via both direct effects on membrane integrity and indirect mechanisms through activating the humoral response to decrease overall viral load. (D) N-3 PUFAs have the ability to regulate the RAAS system in the favor of the vasodilatory, the anti-inflammatory and the cardioprotective ACE2/Ang (1–7) effectors. (E) N-3 PUFAs enhance antioxidant capacity and attenuate oxidative stress in the tissue. (F) N-3 PUFAs ameliorate coagulopathy by exerting anti-thrombotic effects. (G) The triglyceride-lowering effect of n-3 PUFAs may play a key role in blunting the exaggerated inflammation observed in patients with COVID-19.
T475 61676-61935 Sentence denotes ACE, Angiotensin-converting enzyme; Ang, Angiotensin; CRP, C-reactive protein; IL, Interleukin; mtDNA, Mitochondrial DNA; PUFA, Poly unsaturated fatty acid; ROS, Reactive oxygen species; TGs, Triglycerides; TNF-α, Tumor necrosis factor alpha; TX, Thromboxane.
T476 61937-61987 Sentence denotes 8.1 The anti-inflammatory properties of n-3 PUFAs
T477 61988-62179 Sentence denotes As mentioned earlier, an exacerbated immune system response and uncontrolled inflammation are fundamental mechanisms in the development of cardiovascular impairment in patients with COVID-19.
T478 62180-62445 Sentence denotes Accordingly, a plethora of experimental studies and clinical trials demonstrate that targeting different inflammatory components may be considered promising strategies to control cardiovascular impairment during the acute and remission phases of COVID-19 (Fig. 3 ).
T479 62446-62964 Sentence denotes Fig. 3 A summary of the anti-inflammatory mechanisms of n-3 PUFAs. (A) N-3 PUFAs can regulate expression of inflammatory cytokines, chemokines and adhesion molecules, inhibit NLRP3 inflammasomes, activate anti-inflammatory transcription factors (PPARα/γ) and activate GPR120 receptors which inhibit TLR4-mediated activation of NF-κB. (B) N-3 PUFAs are metabolized by COX/5-LOX into 5-series LTs which exert anti-inflammatory effects. (C) N-3 PUFAs can replace n-6 PUFAs, such as AA, altering the inflammatory response.
T480 62965-63271 Sentence denotes N-3 PUFA will alter cell membrane composition, fluidity and mediated signaling. (D) N-3 PUFAs, DHA and EPA, are metabolized by CYP epoxygenases into bioactive epoxylipids with anti-inflammatory properties. (E) N-3 PUFAs are metabolized by COX/LOX into SPMs which act as potent anti-inflammatory modulators.
T481 63272-63964 Sentence denotes AA, Arachidonic acid; CCL, Chemokine ligand; COX, Cyclooxygenase; CYP, Cytochrome P450; DHA, Docosahexaenoic acid; EDP, Epoxydocosapentaenoic acid; EEQ, Epoxyeicosatetraenoic acid; EPA, Eicosapentaenoic acid; GRP, G-protein coupled receptor; IL, Interleukin; LOX, Lipoxygenase; LT, Leukotriene; PUFA, Poly unsaturated fatty acid; NFκB, Nuclear factor kappa-light-chain enhancer activated B-cells; NLRP3, NACHT, LRR and PYD domains-containing protein 3; PLA2, Phospholipase A2; PMN, Polymorphonuclear neutrophils; PPAR, Peroxisome proliferator-activated receptor; ROS, Reactive oxygen species; SPMs, Specialized pro-resolving mediators; TLR, Toll like receptor; TNF-α, Tumor necrosis factor-α.
T482 63966-64091 Sentence denotes 8.1.1 N-3 PUFAs regulate the expression of several proinflammatory innate immune components and modulate macrophage response
T483 64092-64338 Sentence denotes A ‘cytokine storm’ and activation of the central innate immune pathway linking the NLRP3 inflammasome, IL-1β, TNF-α and IL-6 response is a primary cause of excessive inflammation reported in COVID-19 that negatively impacts cardiovascular system.
T484 64339-64488 Sentence denotes Therefore, targeting the different components is a promising approach to ameliorate cardiac complications secondary to COVID-19 (Huang et al., 2020).
T485 64489-64794 Sentence denotes While there is no direct clinical evidence related to the use of n-3 PUFAs in COVID-19 patients, the application of n-3 PUFAs in several inflammatory settings, including cardiovascular disorders, has been demonstrated to ameliorate detrimental immune reactions by several mechanisms (Rogero et al., 2020).
T486 64795-65013 Sentence denotes The anti-inflammatory effect of n-3 PUFAs seems to be consistent across several previous clinical findings (Calder, Carr, Gombart, & Eggersdorfer, 2020; Fritsche, 2006; Kiecolt-Glaser et al., 2012; Vedin et al., 2008).
T487 65014-65451 Sentence denotes Intriguingly, Tan et al. recently demonstrated in a randomized controlled study that high-dose n-3 PUFA supplementation (1.5 g/day EPA and 1.0 g/day DHA) markedly reduces plasma levels of IL-6, IL-1β and TNF-α after 4 weeks of therapy in middle or late-aged patients with chronic venous leg ulcers suggesting n-3 PUFAs as an effective low-risk dietary intervention to modulate inflammation (Tan, Sullenbarger, Prakash, & McDaniel, 2018).
T488 65452-65592 Sentence denotes This study indicates that n-3 PUFAs could have direct modulatory effects on the main components of the cytokine storm IL-6, IL-1β and TNF-α.
T489 65593-65981 Sentence denotes N-3 PUFAs can modulate the transcription and expression of inflammatory genes including cytokines, chemokines and adhesion molecules in cardiomyocytes, fibroblasts, endothelial cells, monocytes and macrophages (Collie-Duguid & Wahle, 1996; De Caterina, Cybulsky, Clinton, Gimbrone, & Libby, 1994; Hughes, Southon, & Pinder, 1996; Miles, Wallace, & Calder, 2000; Sanderson & Calder, 1998).
T490 65982-66370 Sentence denotes This is primarily achieved through the regulation of key transcription factors, such as inhibiting NF-κB (Kumar, Takada, Boriek, & Aggarwal, 2004; Lo, Chiu, Fu, Lo, & Helton, 1999; Novak, Babcock, Jho, Helton, & Espat, 2003; Zhao, Joshi-Barve, Barve, & Chen, 2004) or activating peroxisome proliferator-activated receptors-α/γ (PPARα/γ) (Gani & Sylte, 2008; Zapata-Gonzalez et al., 2008).
T491 66371-66666 Sentence denotes Activation of PPARα/γ can directly interfere with the activation of NF-κB and prevent its shuttling to the nucleus reducing the inflammatory burst (Matsumoto et al., 2008; Mishra, Chaudhary, & Sethi, 2004; Poynter & Daynes, 1998; Ricote, Huang, Welch, & Glass, 1999; Vanden Berghe et al., 2003).
T492 66667-66932 Sentence denotes Interestingly, direct activation of PPAR, using PPAR agonists, was proposed as a therapeutic target for blunting and regulating cytokine storm in COVID-19 patients suggesting n-3 PUFAs could have a promising effect (Ciavarella, Motta, Valente, & Pasquinelli, 2020).
T493 66933-67128 Sentence denotes Another important immunomodulatory mechanism induced by n-3 PUFAs involves activation of G protein-coupled receptor 120 (GPR120), which mediates strong and wide-ranging anti-inflammatory effects.
T494 67129-67312 Sentence denotes Research from Oh et al. indicates n-3 PUFAs stimulate GPR120 in both monocytic RAW 264.7 cells and primary intraperitoneal macrophages inhibiting TLR4-mediated inflammatory responses.
T495 67313-67420 Sentence denotes Knockdown of GPR120 attenuates the protective effects attributed to n-3 PUFA consumption (Oh et al., 2010).
T496 67421-67549 Sentence denotes These studies together provide evidence that n-3 PUFAs mediate anti-inflammatory effects through different mechanistic pathways.
T497 67550-67709 Sentence denotes Cardiac macrophages are primarily derived and replenished from inflammatory monocytes in response to an infection with resident macrophages also having a role.
T498 67710-67846 Sentence denotes Briefly, macrophages will differentiate into classical M1 inflammatory cells to clean cellular and matrix debris (Epelman et al., 2014).
T499 67847-68081 Sentence denotes Subsequently, M1 macrophages may undergo polarization and transformation to the alternatively activated or reparatory M2 stage which secrete IL-10 to promote resolution and contribute to wound healing and tissue repair (Murray, 2017).
T500 68082-68380 Sentence denotes Controlling the migration and the polarization of macrophages to the myocardium in the context of COVID-19 is a tentative approach to limit cardiac injury (Frantz & Nahrendorf, 2014; Fujiu, Wang, & Nagai, 2014; Leblond et al., 2015; van Amerongen, Harmsen, van Rooijen, Petersen, & van Luyn, 2007).
T501 68381-68524 Sentence denotes In COVID-19, an excessive cardiac recruitment and accumulation of pro-inflammatory M1 macrophages potentially aggravates cardiovascular injury.
T502 68525-68723 Sentence denotes Notably, as M1 macrophages secrete a large variety of chemokines and cytokines such as TNF-α and IL-1β to recruit and activate other immune cells from both the innate and the adaptive immune system.
T503 68724-68955 Sentence denotes The effect will impede the reparative phase mediated by M2 macrophages and thus aggravates adverse cardiac remodeling (Dewald et al., 2005; Gordon, Pluddemann, & Martinez Estrada, 2014; Murray & Wynn, 2011; ter Horst et al., 2015).
T504 68956-69248 Sentence denotes Interestingly, evidence demonstrates n-3 PUFAs and/or their biologically active metabolites have the ability to blunt the expression, production and release of IL-1β, TNF-α, and IL-6 by M1 macrophages (Allam-Ndoul, Guenard, Barbier, & Vohl, 2017; Liu et al., 2014; Mildenberger et al., 2017).
T505 69249-69544 Sentence denotes Schoeniger et al., showed n-3 PUFAs have the ability to down-regulate inflammatory processes and reduce the production and secretion of pro-inflammatory cytokines from RAW 264.7 macrophages infected with microorganisms, R. equi and P. aeruginosa (Schoeniger, Adolph, Fuhrmann, & Schumann, 2011).
T506 69545-69792 Sentence denotes Moreover, the inhibitory effects of EPA and DHA on the pro-inflammatory NLRP3 inflammasome pathway has also been well-documented in macrophage cell lines as well as in primary human and mouse macrophages (Iverson et al., 2018; Kumar et al., 2016).
T507 69793-69972 Sentence denotes Kumar et al., investigated the effects of 15-lipoxygenase (LOX) metabolites of ALA on lipopolysaccharide (LPS) -induced inflammation in RAW 264.7 cells and peritoneal macrophages.
T508 69973-70149 Sentence denotes The findings revealed the anti-inflammatory effects of these metabolites involve inactivation of the NLRP3 inflammasome complex through the PPAR-γ pathway (Kumar et al., 2016).
T509 70150-70477 Sentence denotes N-3 PUFAs can increase the phagocytic capacity of macrophages, which has been shown through the engulfment of zymosan particles (Chang, Lee, Kim, & Surh, 2015), Pseudomonas aeruginosa, Rhodococcus equi (Adolph, Fuhrmann, & Schumann, 2012), E.coli (Davidson, Kerr, Guy, & Rotondo, 1998) and apoptotic cells (Chang et al., 2015).
T510 70478-70804 Sentence denotes It has been suggested the increase in phagocytic capacity of macrophages upon n-3 PUFA treatment could be attributed to changes in the cellular membrane composition and structure caused by the incorporation of the n-3 PUFAs (Hellwing, Tigistu-Sahle, Fuhrmann, Kakela, & Schumann, 2018; Schoeniger, Fuhrmann, & Schumann, 2016).
T511 70805-71044 Sentence denotes Importantly, n-3 PUFAs have been found to promote M2 polarization in macrophage cell lines and primary mouse macrophages enhancing resolution of inflammation and tissue repair after infection (Chang et al., 2015; Ohue-Kitano et al., 2018).
T512 71045-71304 Sentence denotes Collectively, the modulatory properties of n-3 PUFAs on the immune system could impart a promising beneficial effect on the cardiovascular system in the context of COVID-19, an effect which needs further exploration and confirmation in larger clinical trials.
T513 71306-71392 Sentence denotes 8.1.2 Shifting to the anti-inflammatory COX- and LOX-derived metabolites of n-3 PUFAs
T514 71393-71660 Sentence denotes Accumulating literature demonstrates potent immunomodulatory properties of metabolites generated from n-3 PUFAs and consequently their impact on cardiovascular health (Jamieson, Endo, Darwesh, Samokhvalov, & Seubert, 2017; Schunck, Konkel, Fischer, & Weylandt, 2018).
T515 71661-71875 Sentence denotes The metabolism of n-3 and n-6 PUFAs is closely interconnected as parent compounds compete for the same metabolic enzymes but result in the production of a wide array of either pro- or anti-inflammatory metabolites.
T516 71876-72152 Sentence denotes For example, cyclooxygenase (COX) converts the n-6 PUFA arachidonic acid (AA) to the 2-series of prostaglandins (PGs) and the 2-series of thromboxanes (TX), while lipoxygenase (LOX) enzymes metabolize AA to the 4-series leukotrienes (LTs) and the hydroxyicosatetraenoic acids.
T517 72153-72365 Sentence denotes These lipid mediators are considered pro-inflammatory and are involved in various pathological processes including cardiovascular disorders (Innes & Calder, 2018; Kalinski, 2012; Lewis, Austen, & Soberman, 1990).
T518 72366-72502 Sentence denotes The synthesis and production of PGE2 occurs in several cells, including dendritic cells, macrophages, fibroblasts and endothelial cells.
T519 72503-72769 Sentence denotes PGE2 not only mediates vasodilation, endothelial permeability and increase of pain (Ricciotti & FitzGerald, 2011) but also contributes to the tissue influx of neutrophils, mast cells and macrophages and can affect the differentiation of these cells (Kalinski, 2012).
T520 72770-73109 Sentence denotes N-3 PUFAs can also act as a substrate for COX and 5-LOX enzymes resulting in production of the 3-series of PGs and TxAs as well as 5-series LTs, which are a set of less inflammatory or even anti-inflammatory metabolites in comparison to the metabolite family derived from AA (Corey, Shih, & Cashman, 1983; Lee et al., 1984; Surette, 2008).
T521 73110-73308 Sentence denotes These eicosanoids are responsible for producing several physiological responses related to inflammation, and their imbalance has been observed in several diseases (Calder, 2006; Falck et al., 2011).
T522 73309-73576 Sentence denotes For example, the production of PGE2 and LTB4 by human inflammatory cells was significantly decreased in a diet rich in fish oil (Caughey, Mantzioris, Gibson, Cleland, & James, 1996; Lee et al., 1985; Prescott, 1984; von Schacky, Kiefl, Jendraschak, & Kaminski, 1993).
T523 73577-73884 Sentence denotes Therefore, the metabolism of n-3 PUFAs by COX and LOX enzymes not only reduce the AA-derived pro-inflammatory metabolites but also alter the metabolic profile towards more biologically active anti-inflammatory mediators (Goldman, Pickett, & Goetzl, 1983; Lee et al., 1984; Lee, Mencia-Huerta, et al., 1984).
T524 73885-74054 Sentence denotes This may represent one of the central anti-inflammatory and consequently cardioprotective mechanisms of n-3 PUFAs against cardiac complications associated with COVID-19.
T525 74056-74157 Sentence denotes 8.1.3 Anti-inflammatory features of the n-3 PUFAs-derived specialized pro-resolving mediators (SPMs)
T526 74158-74506 Sentence denotes Metabolism of n-3 PUFAs also generates another group of highly specialized pro-resolving mediators (SPMs) which include resolvins ‘resolution phase interaction products’ produced from both EPA (E-series, RvE1-2) and DHA (D-series, RvD1-6) as well as protectins and maresins produced from DHA (Serhan et al., 2002; Serhan, Chiang, & Van Dyke, 2008).
T527 74507-74706 Sentence denotes Both the COX and LOX pathways are involved in the synthesis of these metabolites with distinct epimers being produced in the presence and absence of aspirin (Mas, Croft, Zahra, Barden, & Mori, 2012).
T528 74707-75049 Sentence denotes SPMs possess potent anti-inflammatory and inflammation resolving properties which is essential to terminate ongoing inflammatory processes, accelerate the cleaning process and aid in tissue regeneration and wound healing allowing tissue homeostasis to return (Serhan et al., 2000; Serhan et al., 2002; Spite et al., 2009; Titos et al., 2011).
T529 75050-75161 Sentence denotes Several mechanistic pathways contribute to the anti-inflammatory effects of resolvins, protectins and maresins.
T530 75162-75420 Sentence denotes This includes preventing the migration of neutrophils and monocytes across epithelial cells and promoting clearance of polymorphonuclear (PMNs) leukocytes, apoptotic cells and debris from the site of inflammation (Campbell et al., 2007; Serhan et al., 2002).
T531 75421-75676 Sentence denotes Krishnamoorthy et al. showed resolvins inhibit tissue migration of neutrophils by lowering the expression of surface adhesion receptors on neutrophils, such as CD11b or CD18, and reducing the production of the chemokine IL-8 (Krishnamoorthy et al., 2010).
T532 75677-75946 Sentence denotes Additionally, the partial agonist/antagonist activity of RvE1 toward LTB4 receptors on PMNs will inhibit NF-κB activation, abolish pro-inflammatory cytokine production and reduce PMN leukocyte infiltration (Arita et al., 2007; Serhan et al., 2002; Serhan et al., 2008).
T533 75947-76220 Sentence denotes Resolvins can blunt reactive oxygen species (ROS) production from neutrophils, induce neutrophil apoptosis and clearance by macrophages, as well contribute to inhibiting chemokine signaling (Ariel et al., 2006; Schwab, Chiang, Arita, & Serhan, 2007; Serhan & Chiang, 2004).
T534 76221-76525 Sentence denotes Furthermore, Morin et al. demonstrated a diet enriched with DHA and monoglycerides can significantly increase the levels of RvD2 and RvD3, which correlate with reduced levels of proinflammatory mediators CRP, IL-6, TNF-α, and IL-1β in a rat model of hypertension (Morin, Rousseau, Blier, & Fortin, 2015).
T535 76526-76627 Sentence denotes Additionally, there is growing evidence for a role of SPMs in regulating the humoral immune response.
T536 76628-76953 Sentence denotes A study conducted by Ramon et al., showed 17-hydroxydocosahexaenoic acid (17-HDHA), the precursor of the D-series SPMs (RvD1, 17R-RvD1, RvD2), can reduce IL-6 secretion in human B cells, increase B cell antibody production and promote B cell differentiation to an antibody secreting cell (Ramon, Gao, Serhan, & Phipps, 2012).
T537 76954-77157 Sentence denotes These new findings highlight the potential applications of SPMs as non-toxic, supportive adjuvants and as anti-inflammatory therapeutic molecules particularly during infection as in the case of COVID-19.
T538 77158-77252 Sentence denotes Resolvins, protectins and maresins play a pivotal role regulating the function of macrophages.
T539 77253-77430 Sentence denotes Sulciner et al. demonstrates RvD1, RvD2 or RvE1 can inhibit debris-stimulated cancer progression by enhancing clearance of debris via macrophage phagocytosis in multiple tumors.
T540 77431-77666 Sentence denotes These resolvins suppressed the release of the proinflammatory cytokines/chemokines, including TNFα, IL-6, IL-8, chemokine ligand 4, and chemokine ligand 5, by human macrophages cocultured with tumor cell debris (Sulciner et al., 2018).
T541 77667-77854 Sentence denotes Maresins are conjugates of sulfides synthetized by macrophages, which are also participants in acute inflammation resolution and seem to promote tissue regeneration (Serhan et al., 2009).
T542 77855-78077 Sentence denotes Maresin-1 biosynthesis involves an active intermediate (13S,14S-epoxi-DHA) that stimulates macrophage conversion from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotype (Dalli, Ramon, Norris, Colas, & Serhan, 2015).
T543 78078-78505 Sentence denotes It is noteworthy that M2 macrophages secrete resolvins, protectins and maresins to dampen inflammation and restore homeostasis (Bouchery & Harris, 2017; Ramon et al., 2016) and at the same time augment phagocytic capacity of macrophages and other cells to remove debris from the site(s) of infection and injury and enhance microbial clearance (Dalli et al., 2013; Norris et al., 2018; Poorani, Bhatt, Dwarakanath, & Das, 2016).
T544 78506-78713 Sentence denotes The role of resolvins in the resolution of inflammation has been demonstrated in several animal models of ALI and ARDS (Gao et al., 2017; Uddin & Levy, 2011; Wang, Yan, Hao, & Jin, 2018; Zhang et al., 2019).
T545 78714-79078 Sentence denotes These studies carried out using rat and mouse models infected with the E.coli endotoxin, LPS, suggested the pro-resolving effects of these molecules could be attributed, for example, to the suppression of neutrophil infiltration due to reduced expression and release of pro-inflammatory cytokines from alveolar macrophages (Uddin & Levy, 2011; Zhang et al., 2019).
T546 79079-79298 Sentence denotes Further, it has been demonstrated protectins may reduce the replication of influenza (Morita et al., 2013) and potentially affect the inflammatory manifestations of respiratory viral diseases (Russell & Schwarze, 2014).
T547 79299-79503 Sentence denotes Importantly, pro-inflammatory cytokines, TNF-α and IL-6, will inhibit the activities of desaturases, which are essential for the generation of AA, EPA and DHA from their precursors LA and ALA (Das, 2013).
T548 79504-79776 Sentence denotes Hence, in instances where there is a substantial degree of inflammation due to high levels of IL-6 and TNF-α, such as following COVID-19 infection, a deficiency of EPA and DHA and subsequent decreased generation of resolvins, protectins and maresins can occur (Das, 2018).
T549 79777-80015 Sentence denotes Thus, administration of PUFAs and/or their metabolites, resolvins, protectins and maresins can suppress inappropriate production of IL-6 and TNF-α to resolve inflammation, enhance recovery and limit cytokine storm (Das, 2019) in COVID-19.
T550 80016-80193 Sentence denotes Together, the studies imply administration of n-3 PUFA may enhance recovery from infections and further, if present in adequate amounts, may modulate the response to infections.
T551 80195-80263 Sentence denotes 8.1.4 Role of CYP-mediated metabolites in ameliorating inflammation
T552 80264-80680 Sentence denotes CYP2J and CYP2C isoforms, the constitutively expressed cytochrome P450 (CYP) epoxygenases found in the cardiovascular system, metabolize EPA into 5 regioisomeric epoxyeicosatetraenoic acids (5,6-, 8,9-, 11,12-, 14,15-, 17,18-EEQ) and DHA into 6 regioisomeric epoxydocosapentaenoic acids (4,5-, 7,8-, 10,11-, 13,14-, 16,17-, 19,20-EDP) (Arnold et al., 2010; Konkel & Schunck, 2011; Westphal, Konkel, & Schunck, 2015).
T553 80681-80894 Sentence denotes Recent evidence suggests that 17,18-EEQ and 19,20-EDP mediate several anti-inflammatory effects of n-3 PUFAs in various models of tissue injury (Arnold et al., 2010; Ulu et al., 2014; Wang, Chai, Lu, & Lee, 2011).
T554 80895-81229 Sentence denotes For example, Fang et al. demonstrated a n-3 PUFA-rich diet attenuates MI injury in mice by producing a protective eicosanoid pattern, which results in shifting the metabolite profile to a more anti-inflammatory state by increasing the levels of the 19,20-EDP and 17,18-EEQ and decreasing the pro-inflammatory PGE2 (Fang et al., 2018).
T555 81230-81417 Sentence denotes The cardioprotective effects of n-3 PUFAs are also attributed to their ability to attenuate the NLRP3 inflammasome complex cascade (Darwesh, Jamieson, Wang, Samokhvalov, & Seubert, 2019).
T556 81418-81533 Sentence denotes Importantly, the anti-inflammatory features of CYP-derived epoxy metabolites have been reported in numerous models.
T557 81534-81853 Sentence denotes For example, in TNFα-induced retinal vascular inflammation, Capozzi et al. demonstrated 19,20-EDP can ameliorate vascular adhesion molecule and intracellular adhesion molecule expression and reduce leukocyte adherence to human retinal microvascular endothelial cell monolayers (Capozzi, Hammer, McCollum, & Penn, 2016).
T558 81854-82087 Sentence denotes Additionally, evidence demonstrates intraperitoneal infusions of 17,18-EEQ and 19,20-EDP protect against allergic intestinal inflammation and kidney fibrosis in corresponding mouse models (Kunisawa et al., 2015; Sharma et al., 2016).
T559 82088-82352 Sentence denotes 17,18-EEQ was able to inhibit TNFα-induced inflammation in human lung tissue obtained from patients undergoing surgery for lung carcinoma via inhibition of NF-κB and activation of the transcription factor PPAR-γ (Morin, Sirois, Echave, Albadine, & Rousseau, 2010).
T560 82353-82471 Sentence denotes The anti-inflammatory properties of DHA epoxides were also well demonstrated using animal models of inflammatory pain.
T561 82472-82717 Sentence denotes For example, Morisseau et al. demonstrated that direct injection of the DHA epoxides, EDPs, together with the pro-inflammatory carrageenan into the paw or spinal cord of male Sprague-Dawley rats resulted in significant antihyperalgesic activity.
T562 82718-82946 Sentence denotes Surprisingly, both the parent free fatty acid DHA and the corresponding diols were inactive, supporting the hypothesis that the epoxylipids mediate many of the beneficial effects of the parent compounds (Morisseau et al., 2010).
T563 82947-83086 Sentence denotes The bacterial endotoxin, LPS, has a marked role in triggering inflammatory injury which can result in several cardiovascular complications.
T564 83087-83364 Sentence denotes In a study using HL-1 cardiac cells, 19,20-EDP protected against LPS-stimulated inflammatory injury by activating the histone deacetylase Sirtuin-1 inhibiting the activation the pro-inflammatory transcription factor NF-κB (Samokhvalov, Jamieson, Vriend, Quan, & Seubert, 2015).
T565 83365-83571 Sentence denotes The accumulating evidence suggests the anti-inflammatory properties of CYP-epoxygenase metabolites of n-3 PUFAs have a substantial role in activating protective responses in models of cardiovascular injury.
T566 83572-83722 Sentence denotes However, further investigation is required to elucidate whether the protective properties limit cardiovascular injury secondary to COVID-19 infection.
T567 83724-83814 Sentence denotes 8.1.5 N-3 PUFAs alter cell membrane structure and function - modulation of the lipid raft
T568 83815-84055 Sentence denotes Within a cell, n-3 PUFAs can be found incorporated into phospholipid membranes where elevating levels will replace existing n-6 PUFAs thereby altering the composition and properties of lipid rafts (Lordan et al., 2017; Lordan et al., 2020).
T569 84056-84230 Sentence denotes The increased incorporation of n-3 PUFAs into membrane bilayers can have a role in mediating immunomodulatory effects by altering membrane composition, fluidity and function.
T570 84231-84423 Sentence denotes These changes will impact membrane-mediated signaling, protein trafficking, generation of bioactive lipids, cytokine secretion and gene activation in both innate and adaptive immune responses.
T571 84424-84634 Sentence denotes For example, a change in fluidity can interfere with the dimerization and expression of the TLR4 subunits, blocking the downstream inflammatory reaction (Ciesielska & Kwiatkowska, 2015; Takashima et al., 2016).
T572 84635-85000 Sentence denotes Evidence of these effects by n-3 PUFAs have been demonstrated to impact the maturation of dendritic cells, macrophage function and T and B cell polarization/activation (Katagiri, Kiyokawa, & Fujimoto, 2001; Kim et al., 2010; McMurray, Bonilla, & Chapkin, 2011; Rockett, Salameh, Carraway, Morrison, & Shaikh, 2010; Shaikh and Edidin, 2006, Shaikh and Edidin, 2008).
T573 85001-85246 Sentence denotes Interestingly, DHA appears to be better than EPA in replacing n-6 PUFAs and cholesterol in plasma membranes of aortic endothelial cells enhancing the fluidity of the phospholipid membrane (Hashimoto, Hossain, Yamasaki, Yazawa, & Masumura, 1999).
T574 85247-85381 Sentence denotes In most cell types, AA is the predominant n-6 PUFA in membrane phospholipids (Yaqoob, Pala, Cortina-Borja, Newsholme, & Calder, 2000).
T575 85382-85521 Sentence denotes Inflammatory immune cells such as monocytes, neutrophils, macrophages and lymphocytes often contain a large amount of AA in their membrane.
T576 85522-85605 Sentence denotes The high membrane AA composition is important during normal inflammatory responses.
T577 85606-85873 Sentence denotes Under stress conditions activation of phospholipase A2 liberates AA from the cell membrane leading to metabolism and production of many pro-inflammatory metabolites (Ford, Hazen, Saffitz, & Gross, 1991; Hazen, Ford, & Gross, 1991; Leslie, 2015; Mancuso et al., 2003).
T578 85874-86240 Sentence denotes Supplementation with n-3 PUFAs leads to the substitution of AA with EPA and DHA in the cell membrane which can alter immune cell reaction in response to stress stimuli by shifting the metabolic profile to less proinflammatory or even anti-inflammatory metabolite predominance (Brouard & Pascaud, 1990; Faber et al., 2011; Gibney & Hunter, 1993; Grando et al., 2009).
T579 86241-86441 Sentence denotes Therefore, increasing n-3 PUFAs, such as EPA and DHA, in the phospholipids has a potential benefit of ameliorating detrimental effects during uncontrolled inflammatory responses (Lordan et al., 2020).
T580 86443-86548 Sentence denotes 8.2 N-3 PUFAs have the potential to ameliorate mitochondrial dysfunction in the pathogenesis of COVID-19
T581 86549-86849 Sentence denotes Under normal physiological conditions, it is essential for all body organs and physiological systems, particularly the cardiovascular system, to maintain a large number of functional mitochondria to provide energy, as well as preserve and regulate different cellular functions (Murphy, et al., 2016).
T582 86850-87210 Sentence denotes Maintaining a healthy pool of mitochondria depends upon a delicate balance between the formation of newly generated mitochondria termed as “mitochondrial biogenesis”, to meet the increased energy demand, and the efficient elimination of irreversibly damaged mitochondria through mitophagy (Bayeva, Gheorghiade, & Ardehali, 2013; Meyers, Basha, & Koenig, 2013).
T583 87211-87522 Sentence denotes Mitochondrial damage, decreased biogenesis and impaired mitophagy has been implicated in several pathologies including diabetes, CVDs, aging, as well as viral and bacterial infections (Cho, Kim, & Jo, 2020; Kim, Ahn, Syed, & Siddiqui, 2018; Rovira-Llopis et al., 2017; Srivastava, 2017; Wu, Zhang, & Ren, 2019).
T584 87523-87869 Sentence denotes While the intrinsic mechanism(s) involved in the pathogenesis of cardiovascular insult secondary to COVID-19 are not fully understood, altered mitochondrial homeostasis could be a major contributing factor (Grivennikova, Kareyeva, & Vinogradov, 2010; Melser, Lavie, & Benard, 2015; Murphy, et al., 2016; Saleh, Peyssonnaux, Singh, & Edeas, 2020).
T585 87870-88071 Sentence denotes Notably, symptoms such as sleep and appetite disturbance, loss of energy, fatigue and muscle weakness, observed in COVID-19 patients, are cardinal signs of mitochondrial distress (Filler et al., 2014).
T586 88072-88196 Sentence denotes Recent studies identified a level of interaction or interplay between mitochondria and innate immune inflammatory responses.
T587 88197-88396 Sentence denotes Mitochondrial dysfunction is considered both a trigger and target of uncontrolled inflammatory responses (Gurung, Lukens, & Kanneganti, 2015; Mohanty, Tiwari-Pandey, & Pandey, 2019; Yu et al., 2014).
T588 88397-88724 Sentence denotes As such, this implicates the potential role of impaired mitochondrial homeostasis in the aggravation of cardiovascular injury secondary to COVID-19 (Darwesh, Jamieson, et al., 2019; Darwesh, Keshavarz-Bahaghighat, Jamieson, & Seubert, 2019; Keshavarz-Bahaghighat, Darwesh, Sosnowski, & Seubert, 2020; Samokhvalov et al., 2018).
T589 88725-88859 Sentence denotes Inflammatory mediators are well documented to trigger several intracellular cascades that alter mitochondrial metabolism and function.
T590 88860-89152 Sentence denotes For example, the pro-inflammatory cytokines TNF-α, IL-1β and IL-6, found in the serum from COVID-19 patients, can impede mitochondrial oxidative phosphorylation, inhibit ATP production and mitochondrial ROS production exacerbating injury (Jo, Kim, Shin, & Sasakawa, 2016; Naik & Dixit, 2011).
T591 89153-89410 Sentence denotes Furthermore, IFN-γ and IL-6 can increase mitochondrial ROS production and directly affect the activity of the electron transport chain, which may cause mitochondrial membrane permeabilization, altered mitochondrial dynamics and cell death (Li et al., 2013).
T592 89411-89547 Sentence denotes Conversely, direct mitochondrial damage was found to aggravate the production of proinflammatory cytokines and worsen disease prognosis.
T593 89548-89736 Sentence denotes Briefly, the pathological changes observed in patients infected with SARS-CoV-2 such as pneumonia, hypoxia and impaired calcium homeostasis can indirectly induce mitochondrial dysfunction.
T594 89737-90018 Sentence denotes Moreover, a very recent study conducted by Singh et al. interestingly showed both RNA and RNA transcripts of SARS-CoV-2 can directly target and localize to mitochondria hijacking the host cell's mitochondrial function to viral advantage (Singh, Chaubey, Chen, & Suravajhala, 2020).
T595 90019-90165 Sentence denotes Subsequently, SARS-CoV-2 will manipulate the host cell's mitochondrial function to evade removal and facilitate virus replication and progression.
T596 90166-90691 Sentence denotes These effects lead to the release of mitochondrial DNA and ROS in the cytosol (Herst, Rowe, Carson, & Berridge, 2017; Kozlov, Lancaster Jr., Meszaros, & Weidinger, 2017; Mittal, Siddiqui, Tran, Reddy, & Malik, 2014; Starkov, 2008; Twig & Shirihai, 2011; West et al., 2015), which drives the activation and release of central pro-inflammatory cytokines such as NLRP3 inflammasomes, IL-1β and IL-6 (Jo et al., 2016; Naik & Dixit, 2011; Nakahira et al., 2011; West et al., 2015), the hallmark cytokines of the COVID-19 severity.
T597 90692-90830 Sentence denotes Thus, highlighting a vicious cycle of mitochondrial damage and inflammation that has a critical role in aggravating cardiovascular injury.
T598 90831-90954 Sentence denotes Accordingly, mitochondria are considered a strategic therapeutic target to improve the outcomes in the context of COVID-19.
T599 90955-91198 Sentence denotes Numerous studies have demonstrated cardioprotective properties of n-3 PUFA, and their epoxylipid metabolites, involve an ability to preserve a healthy mitochondrial pool and attenuate exaggerated inflammatory responses under stress conditions.
T600 91199-91484 Sentence denotes For example, n-3 PUFAs could impart a cardioprotective effect via enriching mitochondrial membrane phospholipid composition, which enhances mitochondrial function promoting efficient ATP generation (Duda, O'Shea, & Stanley, 2009; Samokhvalov, Jamieson, Fedotov, Endo, & Seubert, 2016).
T601 91485-91749 Sentence denotes In a mouse model of ischemia reperfusion injury, both DHA and its epoxy metabolite, 19,20-EDP, were able to improve postischemic functional recovery by preserving mitochondrial function and attenuating NLRP3 inflammasome response (Darwesh, Jamieson, et al., 2019).
T602 91750-92035 Sentence denotes Moreover, recent data indicates a synthetic EDP analogue imparts cardioprotective effects against ischemia reperfusion injury via preservation of mitochondrial homeostasis and anti-oxidant defenses, which blunted a detrimental innate NLRP3 inflammasome response (Darwesh et al., 2020).
T603 92036-92228 Sentence denotes Earlier data demonstrated 19,20-EDP protected HL-1 cardiac cells from the bacterial endotoxin, LPS, cell injury by preserving mitochondrial biogenesis and integrity (Samokhvalov et al., 2015).
T604 92229-92439 Sentence denotes These data suggest n-3 PUFAs and their metabolites provide beneficial protective responses in models of cardiovascular injury via maintaining mitochondrial quality and ameliorating detrimental immune responses.
T605 92440-92544 Sentence denotes However, further research is required to investigate the proposed hypothesis in the context of COVID-19.
T606 92546-92609 Sentence denotes 8.3 Direct and indirect effects of n-3 PUFAs on the viral load
T607 92610-92888 Sentence denotes Although EPA and DHA have been widely used to ameliorate chronic inflammatory diseases their effect on viral infections remains limited (Das, 2018; Husson et al., 2016; Ingram, Eaton, Erdos, Tedder, & Vreeland, 1982; Juers, Rogers, McCurdy, & Cook, 1976; Territo & Golde, 1979).
T608 92889-93268 Sentence denotes Some evidence indicates EPA, DHA and other dietary unsaturated fatty acids can inactivate viruses by directly causing leakage or lysis of the viral envelopes, which will disrupt the membrane integrity or activate the humoral immune system to produce antibodies against these pathogens (Das, 2018, Das, 2020a; Hilmarsson, Larusson, & Thormar, 2006; Kohn, Gitelman, & Inbar, 1980).
T609 93269-93496 Sentence denotes Morita et al. demonstrated n-3 PUFA-derived lipid mediator, protectin D1, exhibits antiviral activity, markedly attenuates influenza A virus replication and improves survival in severe influenza infection in male C57Bl/6J mice.
T610 93497-93672 Sentence denotes This study highlighted the importance of the endogenous protectin D1 as an innate suppressor of influenza virus replication attenuating lethal infection (Morita et al., 2013).
T611 93673-93820 Sentence denotes In another study, Ramon et al. evaluated the ability of 17-HDHA, a SPM derived from DHA, for improving the immune response to H1N1 influenza virus.
T612 93821-94097 Sentence denotes The results showed 17-HDHA was able to enhance the humoral immunity against viruses by increasing the number of antibody-secreting cells and the levels of H1N1 antibodies, which resulted in greater protection against live H1N1 influenza infection in mice (Ramon et al., 2014).
T613 94098-94529 Sentence denotes More recently, Braz-De-Melo highlighted the beneficial effects of n-3 PUFAs against viral infections by showing that DHA pre-treatment to neuroblastoma SH-SY5Y cells infected with Zika virus increased their viability and proliferation, restored mitochondrial function, reduced viral load and triggered an anti-inflammatory response identifying n-3 PUFAs as useful therapeutic tools in combating viruses (Braz-De-Melo et al., 2019).
T614 94530-94732 Sentence denotes Additionally, Yan et al. has shown that EPA and DHA can inhibit the replication of both enterovirus A71 and coxsackievirus A16 the most common causes of hand, foot, and mouth disease (Yan et al., 2019).
T615 94733-94961 Sentence denotes Collectively, we can conclude that n-3 PUFAs have the capability to attenuate viral infections via both direct effects on membrane integrity and indirect mechanisms activating the humoral response to decrease overall viral load.
T616 94962-95138 Sentence denotes In contrast, the immunosuppressive effects of EPA and DHA supplementation can decrease the immune response against viral infections and thus compromising removal from the body.
T617 95139-95318 Sentence denotes C57BL/6J mice supplemented with fish oil and infected with H1N1 influenza virus showed a 40% higher mortality rate and 70% higher viral load compared to the corresponding control.
T618 95319-95519 Sentence denotes Moreover, the treated mice had markedly reduced numbers of CD8+ T lymphocytes and reduced mRNA expression of inflammatory mediators IL-6 and TNF-α (Schwerbrock, Karlsson, Shi, Sheridan, & Beck, 2009).
T619 95520-95780 Sentence denotes Similarly, BALB/c mice fed a high-fat diet rich in EPA and DHA had reduced levels of IFN-γ, serum immunoglobulin G and lung immunoglobulin A-specific antibodies following infection with the influenza virus, indicating a virus-specific lung T cell cytotoxicity.
T620 95781-95910 Sentence denotes These results suggested supplementation with a diet rich in EPA and DHA could impair immune response by delaying virus clearance.
T621 95911-96240 Sentence denotes However, differences noticed during the course of infection did not affect the ultimate outcome as n-3 PUFA-fed mice were finally able to clear the virus and returned to pre-infection food consumption and body weight similar to the control group (Byleveld, Pang, Clancy, & Roberts, 1999; Byleveld, Pang, Clancy, & Roberts, 2000).
T622 96241-96429 Sentence denotes Importantly, other factors contribute to these opposite results, for example, an initial weight loss is typically observed when mice are supplemented with fish oil (Byleveld et al., 1999).
T623 96430-96594 Sentence denotes In addition, thoroughly controlled animal studies have not been conducted with the SARS-CoV-2 virus and significant variations between viruses should be considered.
T624 96595-96746 Sentence denotes Therefore, further research is needed to understand the role of EPA and DHA in the immune response related specifically to SARS-CoV-2 viral infections.
T625 96748-96852 Sentence denotes 8.4 Role of n-3 PUFAs in modulating the renin-angiotensin aldosterone system in the setting of COVID-19
T626 96853-96997 Sentence denotes The renin-angiotensin aldosterone system (RAAS) is a key regulator of vascular function modulating natriuresis, blood volume and blood pressure.
T627 96998-97135 Sentence denotes Briefly, angiotensin I (Ang I) is metabolized by angiotensin-converting enzyme (ACE) to form the vasoconstrictor angiotensin II (Ang II).
T628 97136-97459 Sentence denotes Accumulation, prolonged and excessive binding of Ang II to the angiotensin 1 receptor in the heart and blood vessels mediates several effects which include vasoconstriction, hypertension, cardiac hypertrophy, increased ROS production and adverse fibrosis (Fyhrquist, Metsarinne, & Tikkanen, 1995; Perazella & Setaro, 2003).
T629 97460-97681 Sentence denotes Earlier literature demonstrated Ang II may act as a proinflammatory cytokine potentially having a significant role in cardiac remodeling (Gibbons, Pratt, & Dzau, 1992; Griendling, Minieri, Ollerenshaw, & Alexander, 1994).
T630 97682-98047 Sentence denotes Conversely, the master regulator ACE2, a type 1 integral membrane glycoprotein expressed in most tissues including the lungs, kidneys, heart and vascular endothelium layers, can metabolize Ang II to produce the vasodilator angiotensin (Ang 1–7) which protects the cardiovascular system against the actions of Ang II (Das, 2018; Kumar & Das, 1997; Yan et al., 2020).
T631 98048-98417 Sentence denotes Beside its vasodilatory properties, Ang-(1–7) promotes resolution of inflammation by decreasing TNF-α, IL-6, vascular adhesion molecule, monocyte chemoattractant protein-1 and macrophage infiltration enhancing the survival of cardiomyocytes and endothelial cells during severe immune responses (Simoes e Silva, Silveira, Ferreira, & Teixeira, 2013; Zhang et al., 2015).
T632 98418-98636 Sentence denotes Accordingly, several clinical and experimental studies reported dysregulation of RAAS due to increased Ang II and decreased ACE2 can lead to detrimental inflammatory responses and worsening of cardiovascular disorders.
T633 98637-98949 Sentence denotes Therefore, maintaining the activity of ACE2 is essential in preserving the balance of the RAAS and effects on vasoconstriction, sodium retention and fibrosis and may elicit protective effects against hypertension, HF, MI and other CVDs (Crackower et al., 2002; Patel et al., 2016; Wang, Gheblawi, & Oudit, 2020).
T634 98950-99061 Sentence denotes Recent evidence has demonstrated SARS-CoV-2 uses ACE2 as an internalization receptor to enter the target cells.
T635 99062-99283 Sentence denotes The spike (S) glycoprotein of SARS-CoV-2 recognizes and interacts with its target ACE2 receptor on the host cell surface, mediating viral entry during the infection cycle (Letko, Marzi, & Munster, 2020; Yan et al., 2020).
T636 99284-99392 Sentence denotes Excessive binding of spike protein to ACE2 leads to downregulation of the ACE2 receptor (Jung et al., 2020).
T637 99393-99540 Sentence denotes This finding is consistent with reports in the animal models infected with SARS-CoV (Crackower et al., 2002; Imai et al., 2005; Kuba et al., 2005).
T638 99541-99736 Sentence denotes The reduction in ACE2 levels leads to excessive pro-inflammatory responses adversely affecting both lung and cardiovascular systems (Crackower et al., 2002; Imai et al., 2005; Kuba et al., 2005).
T639 99737-99964 Sentence denotes These detrimental effects can be explained as the partial decrease in ACE2 function leads to dominant angiotensin II effects, including augmented cytokine storm, inflammation, vasoconstriction and susceptibility for thrombosis.
T640 99965-100162 Sentence denotes These effects further increase the cardiovascular burden by worsening hypertension, HF and other cardiovascular disorders in predisposed patients (Liu, Blet, Smyth, & Li, 2020; Oudit et al., 2009).
T641 100163-100278 Sentence denotes Importantly, the accumulation of Ang II was positively associated to viral load and lung injury (Liu et al., 2020).
T642 100279-100551 Sentence denotes Moreover, reduction in the activity and/or number of ACE2 leads to deficiency of Ang-(1–7) production and consequently loss of its anti-inflammatory, vasodilatory, and cardiovascular protective effects (Lelis, Freitas, Machado, Crespo, & Santos, 2019; Patel et al., 2016).
T643 100552-100689 Sentence denotes Therefore, it is hypothesized that inhibition of RAAS may be helpful to attenuate the inflammatory storm and ameliorate end-organ damage.
T644 100690-100972 Sentence denotes Interestingly, recent data indicates individuals with COVID-19 who are being treated with ACE inhibitors or ARBs, for pre-existing conditions, are at lower risk of 28-day all-cause mortality than those not treated with ACE inhibitors or ARBs (Wang et al., 2020; Zhang et al., 2020).
T645 100973-101219 Sentence denotes Although ARBs and ACE inhibitors do not directly impact ACE2, they indirectly elevate ACE2 activity and the beneficial Ang-(1–7) production and counter the excessive production of the harmful Ang II (Hanff, Harhay, Brown, Cohen, & Mohareb, 2020).
T646 101220-101402 Sentence denotes Therefore, it was proposed that maintaining the levels of ACE2 and its downstream effector Ang-(1–7) may limit cardiovascular damage secondary to COVID-19 (Wang, Edin, et al., 2020).
T647 101403-101527 Sentence denotes Interestingly, several reports showed that n-3 PUFAs can regulate the RAAS system by modulating both Ang II and ACE2 levels.
T648 101528-101771 Sentence denotes For instance, emerging literature indicates n-3 PUFAs and their endogenously generated metabolites can directly reduce the expression and activity of ACE, thereby reducing angiotensin II formation and cardiovascular burden (Kumar & Das, 1997).
T649 101772-101977 Sentence denotes Moreover, it has been demonstrated that supplementation of mice with an n-3 PUFA rich diet for three weeks resulted in attenuated Ang-II-induced blood pressure via up-regulation of ACE2 (Ulu et al., 2013).
T650 101978-102254 Sentence denotes Alternatively, as previously discussed, incorporation of n-3 PUFAs into the cell membranes will alter key properties, which can consequently affect protein number and affinity of SARS-CoV-2 to ACE2 (Candelario & Chachisvilis, 2013; Das, 1999, Das, 2020b; Glende et al., 2008).
T651 102255-102548 Sentence denotes Together, these studies suggest a novel role for n-3 PUFAs in regulating SARS-CoV-2 infection where the potential benefit as an adjuvant therapy involves increasing the production of Ang-(1–7) and reducing the levels of Ang II, thereby limiting COVID-19-triggered cardiovascular complications.
T652 102549-102718 Sentence denotes Importantly, evidence demonstrating upregulation and enhanced activity of ACE2 suggested it will facilitate the infectivity of SARS-CoV-2 (South, Diz, & Chappell, 2020).
T653 102719-102865 Sentence denotes Accordingly, some researchers proposed that ACE inhibitors and ARBs should be discontinued in COVID-19 patients (Diaz, 2020; Esler & Esler, 2020).
T654 102866-103070 Sentence denotes However, in addition to the direct effects on cardiac ACE2 other mechanisms such as triggering a cytokine storm will markedly contribute to SARS-CoV-2-induced injury (Chen, Li, Chen, Feng, & Xiong, 2020).
T655 103071-103306 Sentence denotes A recent study conducted by Yang et al., demonstrated COVID-19 patients with hypertension using ACE inhibitors/ARBs had lower mortality rates than hypertensive COVID-19 patients that were not on ACE inhibitors/ARBs (Yang et al., 2020).
T656 103307-103503 Sentence denotes Moreover, Mancia et al. examined 6272 patients and found no association between RAAS inhibitor use and susceptibility or development of COVID-19 (Mancia, Rea, Ludergnani, Apolone, & Corrao, 2020).
T657 103504-103748 Sentence denotes In that sense, a published statement by American Heart Association (AHA), the American College of Cardiology (ACC) and the Heart Failure Society of America strongly recommended continuation of ACE inhibitor/ARBs (Zhang, Zhu, Cai, et al., 2020).
T658 103749-104028 Sentence denotes Together, these data suggest therapies targeting ACE and Ang II do not appear to increase the likelihood of SARS-CoV-2 infection, but may have a role in abrogating the inflammatory response and vasoconstriction that contributes to the clinical deterioration in COVID-19 patients.
T659 104029-104225 Sentence denotes In summary, evidence has demonstrated infection with SARS-CoV-2 induces internalization and downregulation of ACE2, which may aggravate a patient's condition by limiting the degradation of Ang II.
T660 104226-104490 Sentence denotes Elevated Ang II levels induce several detrimental effects on the cardiovascular system including elevated blood pressure, excessive recruitment and infiltration of inflammatory immune cells to the heart as well as increased secretion of pro-inflammatory cytokines.
T661 104491-104644 Sentence denotes Reduced ACE2 levels are associated with decreased formation of Ang-(1–7) and thus loss of its vasodilatory, anti-inflammatory and CVD-protective effects.
T662 104645-104807 Sentence denotes Therefore, intervention with treatments to correct an imbalance in the RAAS system, such as ACE inhibitors, ARBs and n-3 PUFAs, can possibly improve the outcomes.
T663 104809-104855 Sentence denotes 8.5 N-3 PUFAs possess anti-oxidant properties
T664 104856-105076 Sentence denotes The pneumonia-induced hypoxemia caused by RNA virus infections reduces the energy production from cell metabolism, increases the anaerobic fermentation, intracellular acidosis and the generation of ROS (Li et al., 2020).
T665 105077-105203 Sentence denotes The subsequent increased ROS production causes damage to different cellular components including the DNA, lipids and proteins.
T666 105204-105463 Sentence denotes The increased ROS levels will deplete the antioxidant defense system resulting in severe oxidative stress and chronic activation of immune responses, aggravating tissue injury and damage (Khomich, Kochetkov, Bartosch, & Ivanov, 2018; Reshi, Su, & Hong, 2014).
T667 105464-105741 Sentence denotes Several studies reveal n-3 PUFAs possess anti-oxidant properties attributable to their ability to up-regulate anti-oxidant enzymes (e.g. superoxide dismutase), down-regulate pro-oxidant enzymes (e.g. nitric oxide synthase) and potential to interact directly with free radicals.
T668 105742-106018 Sentence denotes Antioxidant effects of n-3 PUFAs have been demonstrated in different organs including lungs, kidneys and the cardiovascular system (Darwesh et al., 2020; Darwesh, Jamieson, et al., 2019; Darwesh, Keshavarz-Bahaghighat, et al., 2019; De Caterina, 2011; Mozaffarian & Wu, 2011).
T669 106019-106287 Sentence denotes Anderson et al. reported patients were administered a moderately high dose of n-3 PUFAs (3.4 g/day EPA and DHA ethyl-esters) for a period of 2–3 weeks before having elective cardiac surgery and then myocardial tissue was dissected from the right atrium during surgery.
T670 106288-106624 Sentence denotes Intriguingly, myocardial tissues obtained from patients displayed improved antioxidant capacity attributed to increased expression and activity of key antioxidants such as glutathione peroxidase-1, glutathione peroxidase-4, NADPH-quinone oxido-reductase-1, thioredoxin reductase-2 and total glutathione compared to the control patients.
T671 106625-106874 Sentence denotes Moreover, the mitochondrial outer membrane-bound enzyme monoamine oxidase, a substantial generator of ROS, was also determined to have significantly lower activity in myocardial tissue obtained from n-3 PUFA-treated patients (Anderson et al., 2014).
T672 106875-107111 Sentence denotes Interestingly, isolated mouse hearts perfused with DHA derived epoxylipids had improved postischemic recovery which correlated with better activities of the antioxidants thioredoxin-1 and thioredoxin-2 (Darwesh, Jamieson, et al., 2019).
T673 107112-107376 Sentence denotes Importantly, with COVID-19, especially in advanced stages and in ICU, severe inflammation, hypoxemia and mechanical ventilation with high oxygen concentrations will inevitably increase ROS generation locally and systemically notably within the lungs and the heart.
T674 107377-107547 Sentence denotes Thus, it can be hypothesized that increased n-3 PUFAs and their corresponding metabolites would provide beneficial control of exaggerated inflammation and ROS production.
T675 107549-107609 Sentence denotes 8.6 N-3 PUFAs have the potential to ameliorate coagulopathy
T676 107610-107720 Sentence denotes Laboratory examinations from COVID-19 patients indicate serious coagulopathy has occurred in some individuals.
T677 107721-108018 Sentence denotes This is reflected by widespread microvascular thrombosis and consumption of coagulation factors as evidenced by markers such as thrombocytopenia, prolongation of the prothrombin, elevation of D-dimer, increased fibrin degradation product levels and decreased fibrinogen levels (Tang et al., 2020).
T678 108019-108168 Sentence denotes In a study with 184 Dutch ICU COVID-19 patients, 38% were reported to have abnormal blood clotting and 33% with identified clots (Klok et al., 2020).
T679 108169-108256 Sentence denotes Importantly, blood clots may cause lung emboli, cardiovascular complications or stroke.
T680 108257-108428 Sentence denotes In addition, long-term bed rest has been linked to increased risk of venous thromboembolism in severe SARS-CoV-2 infected patients (Iba, et al., 2019; Zhang et al., 2020).
T681 108429-108645 Sentence denotes Accordingly, the active application of anticoagulants (such as heparin) for patients with severe SARS-CoV-2 infection has been recommended and appears to be associated with better prognosis (Tang, Bai, et al., 2020).
T682 108646-108862 Sentence denotes Tang et al. recently published a study indicating anticoagulant therapy, mainly with low molecular weight heparin, is associated with better prognosis in severe SARS-CoV-2 infected patients (Tang, Bai, et al., 2020).
T683 108863-109163 Sentence denotes N-3 PUFAs contain polar lipids that exhibit potent antithrombotic effects against platelet-activating factor and other prothrombotic pathways, including thrombin, collagen, and adenosine diphosphate (Lordan et al., 2020; Tsoupras et al., 2019; Tsoupras, O'Keeffe, Lordan, Redfern, & Zabetakis, 2019).
T684 109164-109361 Sentence denotes Increased levels of n-3 PUFAs may alter platelet phospholipid membrane composition and affect platelet function, which can be predicted to alter the progression and thrombotic complications of CVD.
T685 109362-109710 Sentence denotes Adili et al. outlined that EPA and DHA act on the platelet membrane to reduce platelet aggregation and TX release via COX-1 and 12-LOX, which metabolize fatty acids into a group of beneficial oxylipins in platelets that contribute significantly to the regulation of platelet function in hemostasis and thrombosis (Adili, Hawley, & Holinstat, 2018).
T686 109711-109909 Sentence denotes This is supported by Park and Harris who demonstrated healthy subjects supplemented with EPA for 4 weeks had reduced platelet activation, an early step in platelet aggregation (Park & Harris, 2002).
T687 109910-110040 Sentence denotes While the evidence is limited, it appears EPA is more active than DHA in altering platelet function because it is a COX substrate.
T688 110041-110128 Sentence denotes However, DHA appears to decrease TxA2 and PGH2 receptor affinity (Park & Harris, 2002).
T689 110129-110399 Sentence denotes Although dietary supplementation of EPA and DHA has been shown to reduce platelet activation and aggregation in healthy subjects, a higher recommended dose of n-3 PUFAs may be needed in platelet hyperactivity prothrombotic conditions such as in CVD (Adili et al., 2018).
T690 110400-110546 Sentence denotes These anticoagulant properties of n-3 PUFAs suggest potential effects on the platelet aggregation in severe cases of SARS-CoV-2 infected subjects.
T691 110547-110686 Sentence denotes Our current level of knowledge only permits speculation on whether n-3 PUFAs can mitigate the coagulopathy associated with severe COVID-19.
T692 110688-110758 Sentence denotes 8.7 Lipid-lowering properties of n-3 PUFAs in the context of COVID-19
T693 110759-111110 Sentence denotes Patients with comorbidities such as diabetes, dyslipidemia, aberrations in plasma cholesterol and triglycerides and coronary heart disease are more susceptible to severe COVID-19 outcomes such as cardiac complications, sepsis, ARDS and death (Chen et al., 2020; Petersen et al., 2020; Shi et al., 2020; Wang, Hu, et al., 2020; Zhou, Yu, et al., 2020).
T694 111111-111265 Sentence denotes The acute inflammatory syndrome associated with COVID-19 has the capacity to destabilize plaques, which can lead to ischemic events (Madjid et al., 2007).
T695 111266-111562 Sentence denotes Recent studies indicated serum triglyceride concentrations were significantly higher in individuals who died as a result of COVID-19 likely due to augmented inflammatory TNF-α levels causing reduced lipoprotein lipase activity (Chen, Wu, et al., 2020; Skevaki, Fragkou, Cheng, Xie, & Renz, 2020).
T696 111563-111732 Sentence denotes Triglyceride-glucose index, a product of fasting triglyceride and fasting plasma glucose levels, is used as a surrogate marker for insulin resistance (Ren et al., 2020).
T697 111733-111863 Sentence denotes COVID-19 patients with a higher triglyceride-glucose index have been shown to experience more severe COVID-19 infection and death.
T698 111864-112067 Sentence denotes Furthermore, levels of high density lipoprotein cholesterol (HDL-c) are also reduced in COVID-19 patients with the magnitude of reduction correlating with disease severity (Hu, Chen, Wu, He, & Ye, 2020).
T699 112068-112207 Sentence denotes Generally, HDL-c is considered to be anti-inflammatory and antithrombotic (Suzuki et al., 2010; van der Stoep, Korporaal, & Van Eck, 2014).
T700 112208-112421 Sentence denotes So, the robust, maladaptive inflammatory and hypercoagulability responses observed in more severe COVID-19 cases could possibly be attributed– in part – to reduced levels of HLD-c and a dysregulated lipid profile.
T701 112422-112722 Sentence denotes Given the potential for COVID-19 infection to alter the lipid profile acutely and the association of dyslipidemia with conditions such as diabetes, coronary artery disease, and obesity raises the question whether normalization of plasma lipid profiles in COVID-19 patients can offer clinical benefit.
T702 112723-113029 Sentence denotes Use of statins and other lipid-modulating therapies can reduce the risk of primary or secondary cardiovascular events in at-risk individuals, including those with diabetes, metabolic syndrome, and coronary artery disease – conditions that are risk factors for severe COVID-19 outcomes (Stone et al., 2013).
T703 113030-113315 Sentence denotes A large retrospective study of over 13,000 COVID-19 patients has shown the in-hospital use of statin therapy, potent lipid-lowering agents with anti-inflammatory properties, was associated with a reduced rate of mortality compared to non-statin users (Zhang, Qin, Cheng, et al., 2020).
T704 113316-113513 Sentence denotes This important study disrupts the previous dogma that statins may enhance the COVID-19 virus pathology via ACE2 expression and may in fact be overwhelmingly beneficial in the treatment of COVID-19.
T705 113514-113820 Sentence denotes However, despite statin monotherapy, many patients with dyslipidemia still suffer from persistently elevated triglyceride levels which may continue to be a risk factor for coronary artery disease, cardiac events and more severe COVID-19 infection outcomes (Ballantyne et al., 2012; Davidson, et al., 2007).
T706 113821-114065 Sentence denotes The triglyceride-lowering effect of n-3 PUFA supplementation has been demonstrated in a plethora of clinical trials (Abdelhamid et al., 2020; Ballantyne et al., 2012; Chan et al., 2003; Maki et al., 2013; Yanai et al., 2018; Zhou et al., 2019).
T707 114066-114267 Sentence denotes Lower levels of triglycerides present a lower risk of developing a cytokine storm based on the score from the available secondary haemophagocytic lymphohistiocytosis score system (Mehta, et al., 2020).
T708 114268-114399 Sentence denotes Additionally, n-3 PUFAs have been shown to significantly lower CRP in patients with hypertriglyceridemia (Ballantyne et al., 2012).
T709 114400-114670 Sentence denotes Thus, the rationale for the use of n-3 PUFAs in COVID-19 patients not only focuses on the attenuation of the infection-induced respiratory disorders but also on an overall improvement of patients' wellbeing and prevention of potential complications due to comorbidities.
T710 114672-114742 Sentence denotes 9 When and how to intervene with n-3 PUFAs in the context of COVID-19
T711 114743-114964 Sentence denotes An important aspect in considering n-3 PUFAs as adjunctive therapy in critically or severe ill patients is the time of intervention, duration of treatment, dose, composition of the preparation and route of administration.
T712 114965-115118 Sentence denotes The type and intensity of supportive treatment required by a patient is dependent upon the severity of disease and the possible need for hospitalization.
T713 115119-115285 Sentence denotes Existing literature demonstrates it may take weeks or months for standard doses of n-3 PUFAs to exert a biological effect due to a gradual replacement of membrane AA.
T714 115286-115475 Sentence denotes It has been hypothesized the acute supplementation with n-3 PUFAs may influence the inflammatory response in critically ill patients, particularly those with ALI (Martin & Stapleton, 2010).
T715 115476-115707 Sentence denotes For example, a randomized clinical trial showed daily enteral feeding of critically ill ALI patients with elevated levels EPA, DHA and gamma-linolenic acid significantly reduced lung inflammation and improved oxygenation by 4 days.
T716 115708-115856 Sentence denotes This was associated with a decreased duration of mechanical ventilation, ICU length of stay and mortality (Gadek et al., 1999; Singer et al., 2006).
T717 115857-116267 Sentence denotes In a trial conducted by Pontes-Arruda et al. who studied patients with sepsis requiring mechanical ventilation, a diet enriched with EPA, gamma-linolenic acid and antioxidants delivered at a constant rate during a minimum of 4 days contributed to better ICU and hospital outcomes, oxygenation status, ventilator-free days and was associated with lower mortality at 28-day interval (Pontes-Arruda et al., 2006).
T718 116268-116385 Sentence denotes There are many studies suggesting the beneficial effects of parenteral fish oil emulsions in critically ill patients.
T719 116386-116618 Sentence denotes For example, parenteral supplementation of severe ill patients with lipid emulsions containing fish oil was associated with reduced inflammation, improved gas exchange and shorter length of ICU and hospital stay (Zhao & Wang, 2018).
T720 116619-116805 Sentence denotes In a study by Mayer et al., patients with sepsis were randomized in an open-label trial to receive an omega-3 FA rich lipid emulsion or a standard omega-6 rich lipid emulsion for 5 days.
T721 116806-117078 Sentence denotes Within 2 days of fish oil infusion, free n-3 fatty acids increased and the n-3/n-6 ratio was reversed favoring EPA and DHA over AA, with rapid incorporation of n-3 fatty acids into mononuclear leukocyte membranes and reaching maximum effect in 3 days (Mayer et al., 2003).
T722 117079-117230 Sentence denotes Furthermore, a parenteral lipid emulsion enriched in n-3 PUFA for 7 days was found to reduce acetic acid-induced colitis in rats (Campos et al., 2002).
T723 117231-117589 Sentence denotes In a randomized controlled trial conducted by Wang et al., patients with severe acute pancreatitis were randomly assigned to receive parenteral nutrition for 5 days containing similar amounts of amino acids, glucose and fat but different lipid compositions: the control group received a soybean oil-based fat solution and the omega-3 group received fish oil.
T724 117590-117791 Sentence denotes Interestingly, patients treated with the fish oil or n-3 PUFAs had a markedly lower inflammatory marker CRP and better oxygenation index after 5 days of parenteral nutrition (Wang, Li, Li, & Li, 2008).
T725 117792-117973 Sentence denotes Together, these studies demonstrated that acute enteral or parenteral administration of n-3 PUFAs in the setting of severe illness could significantly improve the clinical outcomes.
T726 117974-118306 Sentence denotes Notably, it has been shown that fish oil emulsions containing substantial amounts of EPA and DHA have an excellent safety record in both critically ill adults and children (Calder, 2009, Calder, 2019; Nandivada, Fell, Gura, & Puder, 2016) making them a suitable candidate for use in severe stress conditions as in COVID-19 patients.
T727 118307-118521 Sentence denotes However, with the research that has been completed to date, it is not possible to definitively determine the dose, route of administration and the best timing to intervene with n-3 PUFAs in the setting of COVID-19.
T728 118522-118828 Sentence denotes More research is undoubtedly needed before definitive recommendations about the routine use of n-3 PUFAs in the context of COVID-19 can be made particularly that dosing data and pharmacokinetics studies of both enteral and parenteral n-3 PUFAs in critically ill patients are highly variable and incomplete.
T729 118830-118856 Sentence denotes 10 Summary and conclusion
T730 118857-118962 Sentence denotes In summary, COVID-19 is rapidly spreading around the globe and our understanding of the virus is limited.
T731 118963-119085 Sentence denotes To date, there is no effective, approved therapy or vaccination to treat the disease or protect against its complications.
T732 119086-119230 Sentence denotes Although the lungs are considered the main target organ of SARS-CoV-2, the virus can affect many other organs, leading to multiple organ damage.
T733 119231-119322 Sentence denotes Cardiovascular injury has been noted as a protruding clinical feature in COVID-19 patients.
T734 119323-119464 Sentence denotes The dysregulation of RAAS can lead to a harmful inflammatory response and worsening of cardiovascular consequences in patients with COVID-19.
T735 119465-119603 Sentence denotes Therefore, intervention with drugs that counteract Ang II may have a potential role in preventing the deleterious cardiovascular outcomes.
T736 119604-119910 Sentence denotes Although increased ACE2 levels may raise the concern of increased SARS-CoV-2 infectivity, we propose here that n-3 PUFAs may be beneficial rather than harmful for cardiovascular outcomes in COVID-19 patients by limiting Ang II-induced detrimental signaling and enhancing Ang (1-7) cardioprotective effects.
T737 119911-120123 Sentence denotes In this review we highlight the different mechanisms of cardiovascular complications secondary to COVID-19 and draw attention toward the potential roles n-3 PUFAs in mitigating these cardiovascular complications.
T738 120124-120237 Sentence denotes Currently, there is no direct evidence of any beneficial or deleterious effect of n-3 PUFAs in COVID-19 patients.
T739 120238-120481 Sentence denotes However, it is evident from the preceding discussion the dietary or non-dietary intake of n-3 PUFAs and/or their biologically active metabolites have many beneficial actions leading to prevention and management of cardiovascular complications.
T740 120482-120945 Sentence denotes N-3 PUFAs and/or their biologically active metabolites have the potential to modulate many of the adverse effects of an exaggerated immune response, inactivate enveloped viruses, enhance macrophage phagocytic capacity, ameliorate coagulopathy, modify cell signaling and gene expression, shift the pattern of the lipid metabolites produced under stress conditions to a more anti-inflammatory metabolite profile and enhance the anti-oxidative capacity of the heart.
T741 120946-121163 Sentence denotes Despite these promising effects of n-3 PUFAs, more experimental, randomized control trials and epidemiological research is warranted to test and translate these proposed effects in the setting of SARS-CoV-2 infection.
T742 121165-121186 Sentence denotes Authors contributions
T743 121187-121310 Sentence denotes A.D. and J.M.S. designed the outline of the review, A.D. screened the studies, extracted the data and wrote the manuscript.
T744 121311-121388 Sentence denotes W.B. and D.S. provided significant contribution to the content of the review.
T745 121389-121431 Sentence denotes J.M.S. reviewed and edited the manuscript.
T746 121433-121440 Sentence denotes Funding
T747 121441-121563 Sentence denotes This work was supported by a grant from 10.13039/501100000024Canadian Institutes of Health Research (FRN 156393) to J.M.S.
T748 121564-121726 Sentence denotes A.D. is supported by both an 10.13039/501100009192Alberta Innovates Graduate Studentship in Health Innovation and by the Izaak Walton Killam Memorial Scholarship.
T749 121727-121819 Sentence denotes W.B. is supported by an 10.13039/501100009192Alberta Innovates Graduate Student Scholarship.
T750 121821-121854 Sentence denotes Declaration of Competing Interest
T751 121855-121915 Sentence denotes The authors declare that there are no conflicts of interest.