key: cord-1036012-gew0avan
authors: Darwesh, Ahmed M.; Bassiouni, Wesam; Sosnowski, Deanna K.; Seubert, John M.
title: Can N-3 polyunsaturated fatty acids be considered a potential adjuvant therapy for COVID-19-associated cardiovascular complications?
date: 2020-10-05
journal: Pharmacol Ther
DOI: 10.1016/j.pharmthera.2020.107703
sha: 55372d2a96ecabee67e558ff7b05509c7cc14551
doc_id: 1036012
cord_uid: gew0avan

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has currently led to a global pandemic with millions of confirmed and increasing cases around the world. The novel SARS-CoV-2 not only affects the lungs causing severe acute respiratory dysfunction but also leads to significant dysfunction in multiple organs and physiological systems including the cardiovascular system. A plethora of studies have shown the viral infection triggers an exaggerated immune response, hypercoagulation and oxidative stress, which contribute significantly to poor cardiovascular outcomes observed in COVID-19 patients. To date, there are no approved vaccines or therapies for COVID-19. Accordingly, cardiovascular protective and supportive therapies are urgent and necessary to the overall prognosis of COVID-19 patients. Accumulating literature has demonstrated the beneficial effects of n-3 polyunsaturated fatty acids (n-3 PUFA) toward the cardiovascular system, which include ameliorating uncontrolled inflammatory reactions, reduced oxidative stress and mitigating coagulopathy. Moreover, it has been demonstrated the n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors to a group of potent bioactive lipid mediators, generated endogenously, which mediate many of the beneficial effects attributed to their parent compounds. Considering the favorable safety profile for n-3 PUFAs and their metabolites, it is reasonable to consider n-3 PUFAs as potential adjuvant therapies for the clinical management of COVID-19 patients. In this article, we provide an overview of the pathogenesis of cardiovascular complications secondary to COVID-19 and focus on the mechanisms that may contribute to the likely benefits of n-3 PUFAs and their metabolites.

Severe acute respiratory syndrome coronavirus SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 SPM Specialized pro-resolving mediators TLR Toll-like receptor TNF-α Tumor necrosis factor-α TX Thromboxane.

The first outbreak of the novel coronaviruses was triggered by severe and acute respiratory syndrome coronavirus (SARS-CoV) International Committee on Taxonomy of, 2020; L. L. .

amplified and uncontrolled inflammatory response induces cellular apoptosis or necrosis of the affected cells. 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) . 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. Collectively, this indicates the uncontrolled inflammatory response is a major factor in the adverse response observed in COVID-19 patients. 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) .

particularly Toll-like receptors (TLR), to recognize pathogen-associated molecular patterns of the virus including lipids, lipoproteins, proteins and nucleic acids (G. . Activation of the TLR increases the expression of the transcription factors nuclear factor kappa-light-chainenhancer 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) . 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 (I. Y. Chen, Moriyama, Chang, & Ichinohe, 2019; Siu, et al., 2019) . 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) . 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. 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) . 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.

Inflammation is well known to participate in various CVDs, such as atherosclerosis, coagulopathy, coronary artery disease and HF (Libby, Ridker, & Maseri, 2002) . 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). Subsequently, hypercoagulation and disseminated intravascular coagulation would present as thrombosis, thrombocytopenia and gangrene of the limbs (Siddiqi & Mehra, 2020; .

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) . Other evidence indicates increased IL-1β and IL-6 levels detected in patients with acute myocarditis and acute MI (Z. . 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) . 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) . The serum levels of IL-8 are increased in patients with acute MI and is associated with higher mortality rates (Cavusoglu, et al., 2015) . 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.

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. 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) . 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 . 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.

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) . 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. Together, this contributes to the formation of an occlusive thrombus over a ruptured coronary plaque. It is documented that COVID-19 patients are prone to arterial and venous thromboembolisms due to hypoxia, excessive inflammation and diffuse intravascular coagulation. In a Dutch study of 184 ICU patients with proven COVID-19 pneumonia, one-third of patients exhibited blood clots and thrombotic complications. These findings, consequently, reinforced the recommendation to use antiplatelets and other pharmacological thrombosis prophylaxis drugs in all COVID-19 patients J o u r n a l P r e -p r o o f (Klok, et al., 2020) (Table 4) .

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. These patients suffered from hyperlipidemia, increased serum concentrations of free fatty acids, abnormal glucose metabolism and other cardiovascular abnormalities (Q. Wu, et al., 2017) . Considering the genetic similarities between SARS-CoV and SARS-CoV-2, Zhang et al. recently proposed the use of the lipidlowering statins, which also possess anti-inflammatory properties, as a therapeutic option for patients with COVID-19. This study reported that amongst 13,981 cases of COVID-19, inhospital use of statins was associated with a lower risk of death and a significantly lower inflammatory response during the entire hospitalization period (X. J. . Thus, suggesting the use of lipid-lowering drugs with anti-inflammatory properties can improve the cardiovascular outcomes in patients with COVID-19.

COVID-19 patients are susceptible to hypoxemia due to reduced lung performance, impaired gas exchange across the inflamed alveoli and abnormal ventilation/perfusion. This will lead to decreased myocardial oxygen supply, myocardial ischemia and impaired calcium homeostasis. 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 J o u r n a l P r e -p r o o f ischemia, MI, arrhythmias and HF (England, Thiele, Anderson, & Mikuls, 2018; Roubille, et al., 2015) . 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 Cao, et al., 2020) . 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) . 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) . Recently, IFN-α2b was used in an uncontrolled exploratory study including 77 hospitalized adults with confirmed COVID-19 in Wuhan, China (Q. . 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. 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, et al., 2016 ). 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 J o u r n a l P r e -p r o o f stay in patients with mild to moderate infections (Hung, et al., 2020) . 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) . 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; . 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) . 

The long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) are essential fatty acids obtained from both dietary and non-dietary sources. The simplest n-3 PUFA is α-linolenic acid (ALA, 18:3 n-3). Once inside the body, ALA can be converted through a series of elongation and J o u r n a l P r e -p r o o f desaturation reactions into other n-3 PUFAs. 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) . Mammals lack the necessary enzymes (delta-12 and delta-15 desaturase) required to synthesize ALA de novo. 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) . Conversely, linoleic acid (LA, 18:2 n-6) is considered the primary source of the essential n-6 PUFAs. 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. 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) .

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, DeMichele, Pacht, Wennberg, & Enteral Nutrition in, 2003; Shirai, Yoshida, Matsumaru, Toyoda, & Ogura, 2015; Singer, et al., 2006) . 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. 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 (P. Mancuso, Whelan, DeMichele, Snider, Guszcza, Claycombe, et al., 1997; . Furthermore, J o u r n a l P r e -p r o o f 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) . 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) . Together, these studies demonstrate n-3 PUFA supplementation has favorable results in terms of multiple inflammatory, respiratory and clinical outcomes.

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) . 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) . 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.

Currently, there is an open-label, randomized control study to investigate the effect of n-3 ventilation will be determined. 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) . However, further research is undoubtedly required.

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 cohort study was associated with lower total mortality attributable with fewer cardiovascular compared to non-cardiovascular deaths (Mozaffarian, et al., 2013) . 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) .

The cardiovascular benefits of n-3 PUFAs could be attributed to their pleiotropic effects on the different elements of the cardiovascular system. Evidence suggests a higher intake of n-3 cellular function (Din, et al., 2008) , autonomic tone (Abuissa, O'Keefe, Harris, & Lavie, 2005;  O'Keefe, Abuissa, Sastre, Steinhaus, & Harris, 2006) , elevated arrhythmic thresholds (Anand, Alkadri, Lavie, & Milani, 2008) and ameliorating hypertension (Geleijnse, Giltay, Grobbee, Donders, & Kok, 2002; O'Keefe, et al., 2006) . 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. 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 .

Based on several clinical reports, COVID-19 patients with severe ALI/ARDS may also suffer from increased risk of sepsis and cardiac arrest . 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) . 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 hemostasis. This section will highlight the cardioprotective mechanisms of n-3 PUFAs and their metabolites implicating that n-3 PUFAs might have a supportive adjuvant utility in treating and protecting against cardiac complications associated with COVID-19 ( Figure 2 ). strategies to control cardiovascular impairment during the acute and remission phases of COVID-19 ( Figure 3 ).

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. Therefore, targeting the different components is a promising approach to ameliorate cardiac complications secondary to COVID-19 . 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) . 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) .

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) . 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. Sanderson & Calder, 1998) . This is primarily achieved through the regulation of key transcription factors, such as inhibiting NF-κB (A. 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) . 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) .

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) . Another important immunomodulatory mechanism induced by n-3 PUFAs involves activation of G proteincoupled receptor 120 (GPR120), which mediates strong and wide-ranging anti-inflammatory effects. 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. Knockdown of GPR120 attenuates the protective effects attributed to n-3 PUFA consumption (Oh, et al., 2010) . These studies together provide evidence that n-3 PUFAs mediate anti-inflammatory effects through different mechanistic pathways.

Cardiac macrophages are primarily derived and replenished from inflammatory monocytes in response to an infection with resident macrophages also having a role. Briefly, macrophages will differentiate into classical M1 inflammatory cells to clean cellular and matrix debris (Epelman, et al., 2014) . 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) . Controlling the migration and the polarization of macrophages to the myocardium in the context of COVID-J o u r n a l P r e -p r o o f 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) . In COVID-19, an excessive cardiac recruitment and accumulation of proinflammatory M1 macrophages potentially aggravates cardiovascular injury. 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.

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) .

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; Y. Liu, et al., 2014; Mildenberger, et al., 2017) . Schoeniger et al., showed n-3 PUFAs have the ability to downregulate 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) . 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; N. Kumar, et al., 2016) . Kumar Davidson, Kerr, Guy, & Rotondo, 1998) and apoptotic cells . 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) . 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 Ohue-Kitano, et al., 2018) . 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.

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) .

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 antiinflammatory metabolites. 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

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) .

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; T. H. Lee, Mencia-Huerta, et al., 1984; Surette, 2008) . 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) . For example, the production of PGE 2 and LTB4 by human inflammatory cells was significantly decreased in a diet rich in fish oil (Caughey, Mantzioris, Gibson, Cleland, & James, 1996; T. H. Lee, et al., 1985; Prescott, 1984; von Schacky, Kiefl, Jendraschak, & Kaminski, 1993) . 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 ; T. H. Lee, Mencia-Huerta, et al., 1984; T. H. Lee, Menica-Huerta, et al., 1984) . This may represent one of the central anti-inflammatory and consequently cardioprotective mechanisms of n-3

PUFAs against cardiac complications associated with COVID-19.

Metabolism of n-3 PUFAs also generates another group of highly specialized proresolving 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, Chiang, & Van Dyke, 2008; Serhan, et al., 2002) .

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 ( 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) . Several mechanistic pathways contribute to the anti-inflammatory effects of resolvins, protectins and maresins. 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) . 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) . 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 Serhan, et al., 2008; Serhan, et al., 2002) . 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) . (Sulciner, et al., 2018) . Maresins are conjugates of sulfides synthetized by macrophages, which are also participants in acute inflammation resolution and seem to promote tissue regeneration ). Maresin-1 biosynthesis involves an active intermediate (13S,14S-epoxi-DHA) that stimulates macrophage conversion from M1 (proinflammatory) to M2 (anti-inflammatory) phenotype (Dalli, Ramon, Norris, Colas, & Serhan, 2015) . 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) .

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; Q. Wang, Yan, Hao, & Jin, 2018; H. W. Zhang, et al., 2019) . 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; H. W. Zhang, et al., 2019) . Further, it has been demonstrated protectins may reduce the J o u r n a l P r e -p r o o f replication of influenza (Morita, et al., 2013) and potentially affect the inflammatory manifestations of respiratory viral diseases (Russell & Schwarze, 2014) .

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) . 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) . 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.

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.

CYP2J and CYP2C isoforms, the constitutively expressed cytochrome P450 (CYP) epoxygenases found in the cardiovascular system, metabolize EPA into 5 regioisomeric epoxyeicosatetraenoic acids (5, 8, 11, 14, 17, and DHA into 6 regioisomeric epoxydocosapentaenoic acids (4,5-, 7,8-, 10,11-, 13,14-, 16,17-, 19 ,20-EDP) (Arnold, et al., 2010; Westphal, Konkel, & Schunck, 2015) . 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; R. X. Wang, Chai, Lu, & Lee, 2011) . 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 PGE 2 (Fang, et al., 2018) . The cardioprotective effects of n-3 PUFAs are also attributed to their ability to attenuate the NLRP3 J o u r n a l P r e -p r o o f inflammasome complex cascade (Darwesh, Jamieson, Wang, Samokhvalov, & Seubert, 2019 (Kunisawa, et al., 2015; Sharma, et al., 2016) . 17,18-EEQ was able to inhibit TNFα- corresponding diols were inactive, supporting the hypothesis that the epoxylipids mediate many of the beneficial effects of the parent compounds (Morisseau, et al., 2010) . The bacterial endotoxin, LPS, has a marked role in triggering inflammatory injury which can result in several cardiovascular complications. 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) . 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. However, further investigation is required to elucidate whether the protective properties limit cardiovascular injury secondary to J o u r n a l P r e -p r o o f infection.

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., 2020; Lordan, et al., 2017) . 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. These changes will impact membranemediated signaling, protein trafficking, generation of bioactive lipids, cytokine secretion and gene activation in both innate and adaptive immune responses. 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) . 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 ; W. Kim, et al., 2010; McMurray, Bonilla, & Chapkin, 2011; Rockett, Salameh, Carraway, Morrison, & Shaikh, 2010; Shaikh & Edidin, 2006 . 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) .

In most cell types, AA is the predominant n-6 PUFA in membrane phospholipids (Yaqoob, Pala, Cortina-Borja, Newsholme, & Calder, 2000) . Inflammatory immune cells such as monocytes, neutrophils, macrophages and lymphocytes often contain a large amount of AA in their membrane. The high membrane AA composition is important during normal inflammatory responses. 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; Leslie, 2015; J o u r n a l P r e -p r o o f 2003). 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 ).

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) .

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) . 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 (Herst, Rowe, Carson, & Berridge, 2017; Kozlov, Lancaster, 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. Thus, highlighting a vicious cycle of mitochondrial damage and inflammation that has a critical role in aggravating cardiovascular injury. Accordingly, mitochondria are considered a strategic therapeutic target to improve the outcomes in the context of COVID-19.

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. 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) . 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 . 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 . 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) . These 

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) . 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 Importantly, other factors contribute to these opposite results, for example, an initial weight loss is typically observed when mice are supplemented with fish oil (P. M. Byleveld, et al., 1999) . In addition, thoroughly controlled animal studies have not been conducted with the SARS-CoV-2 virus and significant variations between viruses should be considered. 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.

The renin-angiotensin aldosterone system (RAAS) is a key regulator of vascular function J o u r n a l P r e -p r o o f modulating natriuresis, blood volume and blood pressure. Briefly, angiotensin I (Ang I) is metabolized by angiotensin-converting enzyme (ACE) to form the vasoconstrictor angiotensin II (Ang II). 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) . Accumulating literature demonstrates 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) .

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 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. 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; .

Recent evidence has demonstrated SARS-CoV-2 uses ACE2 as an internalization receptor to enter the target cells. 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 J o u r n a l P r e -p r o o f infection cycle (Letko, Marzi, & Munster, 2020; . Excessive binding of spike protein to ACE2 leads to downregulation of the ACE2 receptor (Jung, Choi, You, & Kim, 2020) .

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) . 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) . 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. These effects further increase the cardiovascular burden by worsening hypertension, HF and other cardiovascular disorders in predisposed patients (P. P. Liu, Blet, Smyth, & Li, 2020; Oudit, et al., 2009) . Importantly, the accumulation of Ang II was positively associated to viral load and lung injury (Y. . 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) . Therefore, it is hypothesized that inhibition of RAAS may be helpful to attenuate the inflammatory storm and ameliorate end-organ damage. Interestingly, recent data indicates individuals with COVID-19 who are being treated with ACE inhibitors or ARBs, for preexisting conditions, are at lower risk of 28-day all-cause mortality than those not treated with ACE inhibitors or ARBs (J. J. . 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) . 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 (J. J. .

Interestingly, several reports showed that n-3 PUFAs can regulate the RAAS system by J o u r n a l P r e -p r o o f modulating both Ang II and ACE2 levels. 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 (K. V. Kumar & Das, 1997) . 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) . 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) . 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.

Importantly, evidence demonstrating upregulation and enhanced activity of ACE2 suggested it will facilitate the infectivity of SARS-CoV-2 (South, Diz, & Chappell, 2020).

Accordingly, some researchers proposed that ACE inhibitors and ARBs should be discontinued in COVID-19 patients (Diaz, 2020; Esler & Esler, 2020) . 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 (L. Chen, Li, Chen, Feng, & Xiong, 2020 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. 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. Reduced ACE2 levels are associated with decreased formation of Ang-(1-7) and thus loss of its vasodilatory, anti-inflammatory and CVD-protective effects. 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.

The pneumonia-induced hypoxemia caused by RNA virus infections reduces the energy production from cell metabolism, increases the anaerobic fermentation, intracellular acidosis and 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 prooxidant enzymes (e.g. nitric oxide synthase) and potential to interact directly with free radicals.

J o u r n a l P r e -p r o o f kidneys and the cardiovascular system De Caterina, 2011; Mozaffarian & Wu, 2011) .

(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.

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. 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 PUFAtreated patients (Anderson, et al., 2014) . 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 . 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. Thus, it can be hypothesized that increased n-3 PUFAs and their corresponding metabolites would provide beneficial control of exaggerated inflammation and ROS production.

Laboratory examinations from COVID-19 patients indicate serious coagulopathy has occurred in some individuals. 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 (N. . In a study with 184 Dutch ICU COVID-J o u r n a l P r e -p r o o f 19 patients, 38% were reported to have abnormal blood clotting and 33% with identified clots (Klok, et al., 2020) . Importantly, blood clots may cause lung emboli, cardiovascular complications or stroke. 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; . 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 (N. . 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 (N. .

N-3 PUFAs contain polar lipids that exhibit potent antithrombotic effects against plateletactivating factor and other prothrombotic pathways, including thrombin, collagen, and adenosine diphosphate (Lordan, et al., 2020; Tsoupras, O'Keeffe, Lordan, Redfern, & Zabetakis, 2019) . 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. 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) . 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) . While the evidence is limited, it appears EPA is more active than DHA in altering platelet function because it is a COX substrate. However, DHA appears to decrease TxA2 and PGH2 receptor affinity (Park & Harris, 2002) . 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 J o u r n a l P r e -p r o o f hyperactivity prothrombotic conditions such as in CVD (Adili, et al., 2018) . These anticoagulant properties of n-3 PUFAs suggest potential effects on the platelet aggregation in severe cases of SARS-CoV-2 infected subjects. Our current level of knowledge only permits speculation on whether n-3 PUFAs can mitigate the coagulopathy associated with severe COVID-19.

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 (T. Petersen, et al., 2020; Shi, et al., 2020; . The acute inflammatory syndrome associated with COVID-19 has the capacity to destabilize plaques, which can lead to ischemic events (Madjid, et al., 2007) . 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- levels causing reduced lipoprotein lipase activity (T. Skevaki, Fragkou, Cheng, Xie, & Renz, 2020) . Triglyceride-glucose index, a product of fasting triglyceride and fasting plasma glucose levels, is used as a surrogate marker for insulin resistance (H. . COVID-19 patients with a higher triglyceride-glucose index have been shown to experience more severe COVID-19 infection and death. 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) .

Generally, HDL-c is considered to be anti-inflammatory and antithrombotic (Suzuki, et al., 2010; van der Stoep, Korporaal, & Van Eck, 2014 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 diseaseconditions that are risk factors for severe COVID-19

outcomes (Stone, et al., 2014) . 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 antiinflammatory properties, was associated with a reduced rate of mortality compared to non-statin users (X. J. . 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. 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; M. H. Davidson, et al., 2007) . 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) . 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) . Additionally, n-3 PUFAs have been shown to significantly lower CRP in patients with hypertriglyceridemia (Ballantyne, et al., 2012) .

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.

An important aspect in considering n-3 PUFAs as adjunctive therapy in critically or severe J o u r n a l P r e -p r o o f ill patients is the time of intervention, duration of treatment, dose, composition of the preparation and route of administration. The type and intensity of supportive treatment required by a patient is dependent upon the severity of disease and the possible need for hospitalization. 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. 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) . 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. This was associated with a decreased duration of mechanical ventilation, ICU length of stay and mortality (Gadek, et al., 1999; Singer, et al., 2006) . 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) .

There are many studies suggesting the beneficial effects of parenteral fish oil emulsions in critically ill patients. 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) . 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. 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) . Furthermore, a parenteral lipid emulsion J o u r n a l P r e -p r o o f enriched in n-3 PUFA for 7 days was found to reduce acetic acid-induced colitis in rats (Campos, et al., 2002) . 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. 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 (X. Wang, Li, Li, & Li, 2008) .

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.

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. 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. 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.

In summary, COVID-19 is rapidly spreading around the globe and our understanding of the virus is limited. To date, there is no effective, approved therapy or vaccination to treat the disease or protect against its complications. 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. Cardiovascular injury has been noted as a protruding clinical feature in COVID-19

patients. The dysregulation of RAAS can lead to a harmful inflammatory response and J o u r n a l P r e -p r o o f worsening of cardiovascular consequences in patients with COVID-19. Therefore, intervention with drugs that counteract Ang II may have a potential role in preventing the deleterious cardiovascular outcomes. 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.

In 

The authors declare that there are no conflicts of interest. 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, 2020; Rizk, et al., 2020) Anti-TNF  Infliximab, adalimumab, etanercept, golimumab, certolizumab as TNF neutralizing therapies suggested as potential agents for COVID-19 hyperinflammatory state which may ameliorate (Convertino, et al., 2020) J o u r n a l P r e -p r o o f organ damage including acute cardiac injury 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) 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) Granulocytemacrophage-colony stimulating factor (GM-CSF) inhibition  GM-CSF can play a pro-inflammatory role signaling to macrophages  COVID-19 patients have been demonstrated to have elevated GM-CSF levels  Literature proposes that targeting GM-CSF upstream of inflammatory cytokines ex. gimsilumab, may be useful to blunt cytokine storm (Rizk, et al., 2020) 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) 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) N-acetylcysteine (NAC)

 Anti-oxidant and anti-inflammatory properties of NAC proposed as an adjuvant therapy for COVID-19 and secondary cardiovascular complications  Suggested role for NAC in prevention of hypertension, atherosclerosis-associated inflammation, acute heart failure, thromboinflammation, and myocardial ischemia (De Flora, Balansky, & La Maestra, 2020; Guglielmetti, et al., 2020) Eicosanoids and soluble epoxide hydrolase (sEH) inhibitors  Epoxyeicosatrienoic acids (EETs) are cardioprotective, anti-inflammatory and proresolving  Inhibition of their metabolizing enzyme, sEH, may be beneficial by maintaining eicosanoid levels and reducing endoplasmic reticulum (ER) stress  Potential to limit inflammatory storm and resolve inflammation in addition to their established cardioprotective properties  Co-treatment with sEH inhibitors and omega-3 fatty acids may provide synergistic effects (Hammock, Wang, Gilligan, & Panigrahy, 2020) (Biran, et al., 2020) J o u r n a l P r e -p r o o f (Aouba, et al., 2020) J o u r n a l P r e -p r o o f (Huet, et al., 2020) (Lala, et al., 2020) J o u r n a l P r e -p r o o f Journal Pre-proof outcomes studied (Maes, et al., 2020) J o u r n a l P r e -p r o o f 

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Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections

Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution

Activity of Bradykinin B2 Receptor Is Regulated by Long-Chain Polyunsaturated Fatty Acids

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial

The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil

& Coalition Covid-19 Brazil

Elevated baseline plasma IL-8 levels are an independent predictor of long-term allcause mortality in patients with acute coronary syndrome

Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity

Docosahexaenoic acid induces M2 macrophage polarization through peroxisome proliferator-activated receptor gamma activation

Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice

Severe Acute Respiratory Syndrome Coronavirus Viroporin 3a Activates the NLRP3 Inflammasome

The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

A multicenter, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (COVID-19)

Mitophagy and Innate Immunity in Infection

Risk Evaluation of Azithromycin-Induced QT Prolongation in Real-World Practice

Pharmacological (or Synthetic) and Nutritional Agonists of PPAR-gamma as Candidates for Cytokine Storm Modulation

Modification of pro-inflammatory signaling by dietary components: The plasma membrane as a target

Acute cardiac events in severe community-acquired pneumonia: A multicenter study

Inhibitory effect of fish oil N-3 polyunsaturated fatty acids on the expression of endothelial cell adhesion molecules

Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies

Exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in COVID-19 patients

Docosahexaenoic acid is a strong inhibitor of prostaglandin but not leukotriene biosynthesis

The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2

Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease

Acute pneumonia and the cardiovascular system

Cardiac complications in patients with community-acquired pneumonia: incidence, timing, risk factors, and association with short-term mortality

Cardiac complications in patients with community-acquired pneumonia: a systematic review and meta-analysis of observational studies

Angiotensin-converting enzyme 2 is an essential regulator of heart function

Origin and evolution of pathogenic coronaviruses

Novel proresolving and tissueregenerative resolvin and protectin sulfido-conjugated pathways

Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents

A Synthetic Epoxydocosapentaenoic Acid Analogue Ameliorates Cardiac Ischemia/Reperfusion Injury: The Involvement of the Sirtuin 3-NLRP3 Pathway

Cardioprotective effects of CYP-derived epoxy metabolites of docosahexaenoic acid involve limiting NLRP3 inflammasome activation (1)

Genetic Deletion or Pharmacological Inhibition of Soluble Epoxide Hydrolase Ameliorates Cardiac Ischemia/Reperfusion Injury by Attenuating NLRP3 Inflammasome Activation

Insights into the cardioprotective properties of n-3 PUFAs against ischemic heart disease via modulation of the innate immune system

GLUT-4, tumor necrosis factor, essential fatty acids and daf-genes and their role in insulin resistance and non-insulin dependent diabetes mellitus

Is sepsis a pro-resolution deficiency disorder? Med Hypotheses

Arachidonic acid and other unsaturated fatty acids and some of their metabolites function as endogenous antimicrobial molecules: A review

Can Bioactive Lipids Augment Anti-cancer Action of Immunotherapy and Prevent Cytokine Storm

Can Bioactive Lipids Inactivate Coronavirus (COVID-19)

Reply to: Bioactive Lipids and Coronavirus (COVID-19)-further Discussion

Prostaglandin and fatty acid modulation of Escherichia coli O157 phagocytosis by human monocytic cells

Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study

n-3 fatty acids in cardiovascular disease

The omega-3 fatty acid docosahexaenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells

Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19

SARS and MERS: recent insights into emerging coronaviruses

Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized

CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts

Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19

Targeted overexpression of transmembrane tumor necrosis factor provokes a concentric cardiac hypertrophic phenotype

Dietary intervention with oil rich fish reduces platelet-monocyte aggregation in man

Acute infectious pneumonia is accompanied by a latent vasopressin-dependent impairment of renal water excretion

omega-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential

Safety and efficacy of peginterferon alpha plus ribavirin in patients with chronic hepatitis C and coexisting heart disease

Initiation and perpetuation of NLRP3 inflammasome activation and assembly

Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications

Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation

Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?

Supplementation with a fish oil-enriched, high-protein medical food leads to rapid incorporation of EPA into white blood cells and modulates immune responses within one week in healthy men and women

17(R),18(S)-epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: structure-activity relationships and stable analogues

Omega-3 PUFA attenuate mice myocardial infarction injury by emerging a protective eicosanoid pattern

Patients After an Acute Coronary Syndrome: Observations From the SOLID-TIMI 52 (Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52)

Association of Mitochondrial Dysfunction and Fatigue: A Review of the Literature

The rapid and reversible activation of a calcium-independent plasmalogen-selective phospholipase A2 during myocardial ischemia

Cardiac macrophages and their role in ischaemic heart disease

Fatty acids as modulators of the immune response

Cardioprotective function of cardiac macrophages

Role of angiotensin II in blood pressure regulation and in the pathophysiology of cardiovascular disorders

Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group

Molecular recognition of docosahexaenoic acid by peroxisome proliferatoractivated receptors and retinoid-X receptor alpha

Resolvin D1 Improves the Resolution of Inflammation via Activating NF-kappaB p50/p50-Mediated Cyclooxygenase-2 Expression in Acute Respiratory Distress Syndrome

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials

Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2

Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II

The effects of short-and long-term supplementation with fish oil on the incorporation of n-3 polyunsaturated fatty acids into cells of the immune system in healthy volunteers

Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind

Importance of cholesterol-rich membrane microdomains in the interaction of the S protein of SARS-coronavirus with the cellular receptor angiotensin-converting enzyme 2

Human neutrophil chemotactic and degranulating activities of leukotriene B5 (LTB5) derived from eicosapentaenoic acid

Aging, imbalanced inflammation and viral infection

Macrophage heterogeneity in tissues: phenotypic diversity and functions

Modulation of peritoneal macrophage activity by the saturation state of the fatty acid moiety of phosphatidylcholine

Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells

What are the sources of hydrogen peroxide production by heart mitochondria?

War to the knife" against thromboinflammation to protect endothelial function of COVID-19 patients

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease

Mitochondria: diversity in the regulation of the NLRP3 inflammasome

Eicosanoids: The Overlooked Storm in Coronavirus Disease 2019 (COVID-19)?

Is There an Association Between COVID-19 Mortality and the Renin-Angiotensin System? A Call for Epidemiologic Investigations

Effects of eicosapentaenoic acid and docosahexaenoic acid on plasma membrane fluidity of aortic endothelial cells

Activation of a membrane-associated phospholipase A2 during rabbit myocardial ischemia which is highly selective for plasmalogen substrate

Inflammatory Biomarkers Interleukin-6 and C-Reactive Protein and Outcomes in Stable Coronary Heart Disease: Experiences From the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy)

Lipid composition of membrane microdomains isolated detergent-free from PUFA supplemented RAW264.7 macrophages

Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome

Functional Mitochondria in Health and Disease

Effects of first-line use of nucleoside analogues, efavirenz, and ritonavir-boosted protease inhibitors on lipid levels

Virucidal effect of lipids on visna virus, a lentivirus related to HIV

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Impact of oral omega-3 fatty acids supplementation in early sepsis on clinical outcome and immunomodulation

COVID-19 dashboard by theCenter for Systems Science and Engineering (CSSE) at Johns Hopkins

Declined serum high density lipoprotein cholesterol is associated with the severity of COVID-19 infection

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet

Anakinra for severe forms of COVID-19: a cohort study

-3) Polyunsaturated fatty acids modulate the expression of functionally associated molecules on human monocytes in vitro

Triple combination of interferon beta-1b, lopinavir-ritonavir

Modulation of host defence against bacterial and viral infections by omega-3 polyunsaturated fatty acids

Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Unsaturated fatty acid requirement in Escherichia coli: mechanism of palmitate-induced inhibition of growth of strain WN1

Omega-6 fatty acids and inflammation

Omega-3-carboxylic acids provide efficacious anti-inflammatory activity in models of crystalmediated inflammation

Cytochrome P450-derived eicosanoids and heart function

Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-alpha

Molecular mechanisms regulating NLRP3 inflammasome activation

Enhancement of bactericidal capacity of alveolar macrophages by human alveolar lining material

Association of renin-angiotensin-aldosterone system inhibitors with COVID-19-related outcomes in Korea: a nationwide population-based cohort study

Regulation of immune responses by prostaglandin E2

A role for lipid rafts in immune cell signaling

Mitochondrial Dysfunction and Inflammaging in Heart Failure: Novel Roles of CYP-Derived Epoxylipids. Cells, 9

Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: a randomized controlled trial

The essential role of mitochondrial dynamics in antiviral immunity

Regulatory activity of polyunsaturated fatty acids in T-cell signaling

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Unsaturated free fatty acids inactivate animal enveloped viruses

Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids

Resolution of inflammation and sepsis survival are improved by dietary Omega-3 fatty acids

Mitochondria-meditated pathways of organ failure upon inflammation

Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease

Resolvin D1 binds human phagocytes with evidence for proresolving receptors

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

Repurposed immunomodulatory drugs for Covid-19 in pre-ICu patients -mulTi-Arm Therapeutic study in pre-ICu patients admitted with Covid-19 -Repurposed Drugs (TACTIC-R): A structured summary of a study protocol for a randomised controlled trial

Nuclear factor-kappaB: its role in health and disease

Effect of cis-unsaturated fatty acids, prostaglandins, and free radicals on angiotensin-converting enzyme activity in vitro

(S)-HPOTrE and 13-(S)-HOTrE], mediate anti-inflammatory effects by inactivating NLRP3 inflammasome

Hemodynamic effects of pneumonia. II. Expansion of plasma volume

Dietary omega3 fatty acid exerts anti-allergic effect through the conversion to

Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection

Omega-3 polyunsaturated fatty acids in critically ill patients with acute respiratory distress syndrome: A systematic review and metaanalysis

Activation and regulation of the inflammasomes

Chronic inflammation: a failure of resolution?

Systemic and Cardiac Depletion of M2 Macrophage through CSF-1R Signaling Inhibition Alters Cardiac Function Post Myocardial Infarction

Omega-3 fatty acids: cardiovascular benefits, sources and sustainability

Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function

Effects of exogenous arachidonic, eicosapentaenoic, and docosahexaenoic acids on the generation of 5-lipoxygenase pathway products by ionophore-activated human neutrophils

Characterization and biologic properties of 5,12-dihydroxy derivatives of eicosapentaenoic acid, including leukotriene B5 and the double lipoxygenase product

Antioxidant and Cardioprotective Effects of EPA on Early Low-Severity Sepsis through UCP3 and SIRT3 Upholding of the Mitochondrial Redox Potential

Angiotensin

Cytosolic phospholipase A(2): physiological function and role in disease

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases

Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China

Coronavirus infections and immune responses

Left ventricular performance in patients with severe acute respiratory syndrome: a 30-day echocardiographic follow-up study

Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers

Inflammation and atherosclerosis

Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial

The Science Underlying COVID-19: Implications for the Cardiovascular System

The fish oil ingredient, docosahexaenoic acid, activates cytosolic J o u r n a l P r e -p r o o f phospholipase A(2) via GPR120 receptor to produce prostaglandin E(2) and plays an antiinflammatory role in macrophages

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NF kappa B activity

Inflammation and cardiovascular disease: are marine phospholipids the answer?

Phospholipids of Animal and Marine Origin: Structure, Function, and Anti-Inflammatory Properties. Molecules

Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes

Treatment of severely ill COVID-19 patients with anti-interleukin drugs (COV-AID): A structured summary of a study protocol for a randomised controlled trial

A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT trial)

Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19

Cardiac ischemia activates calcium-independent phospholipase A2beta, precipitating ventricular tachyarrhythmias in transgenic mice: rescue of the lethal electrophysiologic phenotype by mechanism-based inhibition

Effects of eicosapentaenoic and gamma-linolenic acid on lung permeability and alveolar macrophage eicosanoid synthesis in endotoxic rats

Dietary fish oil and fish and borage oil suppress intrapulmonary proinflammatory eicosanoid biosynthesis and attenuate pulmonary neutrophil accumulation in endotoxic rats

Omega-3 fatty acids in critical illness

Resolvins D1, D2, and other mediators of self-limited resolution of inflammation in human blood following n-3 fatty acid supplementation

Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoEdeficient mice

Parenteral nutrition with fish oil modulates cytokine response in patients with sepsis

n-3 Fatty acids uniquely affect anti-microbial resistance and immune cell plasma membrane organization

COVID-19: consider cytokine storm syndromes and immunosuppression

Mitochondrial degradation and energy metabolism

Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease

Functional Role of Dietary Intervention to Improve the Outcome of COVID-19: A Hypothesis of Work

Mitochondrial cardiomyopathy: pathophysiology, diagnosis, and management

Prevalence and significance of coagulation abnormalities in community-acquired pneumonia

N-3 PUFAs induce inflammatory tolerance by formation of KEAP1-containing SQSTM1/p62-bodies and activation of NFE2L2

Dietary fish oil reduces intercellular adhesion molecule 1 and scavenger receptor expression on murine macrophages

Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway

Reactive oxygen species in inflammation and tissue injury

COVID-19-associated cardiovascular morbidity in older adults: a position paper from the Italian Society of Cardiovascular Researches

Platelet aggregation and aspirin non-responsiveness increase when an acute coronary syndrome is complicated by an infection

Acc Clinical Bulletin: Cardiac Implications of Novel Wuhan Coronavirus

Mitochondria: the indispensable players in innate immunity and guardians of the inflammatory response

Effect of docosahexaenoic acid monoacylglyceride on systemic hypertension and cardiovascular dysfunction

18-epoxyeicosatetraenoic acid targets PPARgamma and p38 mitogen-activated protein kinase to mediate its anti-inflammatory effects in the lung: role of soluble epoxide hydrolase

Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids

The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza

Resolvins and omega three polyunsaturated fatty acids: Clinical implications in inflammatory diseases and cancer

JELIS, fish oil, and cardiac events

Plasma phospholipid long-chain omega-3 fatty acids and total and causespecific mortality in older adults: a cohort study

Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events

American Heart Association Council on Basic Cardiovascular Sciences

Mitochondrial Function, Biology, and Role in Disease: A Scientific Statement From the American Heart Association

Macrophage Polarization

Protective and pathogenic functions of macrophage subsets

Mitochondrial reactive oxygen species drive proinflammatory cytokine production

Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome

Lipid emulsions in the treatment and prevention of parenteral nutrition-associated liver disease in infants and children

Losartan for Patients With COVID-19 Not Requiring Hospitalization

Losartan for Patients With COVID-19 Requiring Hospitalization

Evaluation of the Efficacy and Safety of Sarilumab in Hospitalized Patients With COVID-19

Treatment of Moderate to Severe Coronavirus Disease (COVID-19) in Hospitalized Patients

An Observational Study of the Use of Siltuximab (SYLVANT) in Patients Diagnosed With COVID-19 Infection Who Have Developed Serious Respiratory Complications (SISCO)

Colchicine Coronavirus SARS-CoV2 Trial (COLCORONA) (COVID-19

Cohort Multiple Randomized Controlled Trials Open-label of Immune Modulatory Drugs and Other Treatments in COVID-19 Patients -Sarilumab Trial -CORIMUNO-19 -SARI

A randomized controlled study of eicosapentaenoic acid (EPA-FFA) gastro-resistant capsules to treat hospitalized subjects with confirmed SARS-CoV-2

Phase 3 Randomized, Double-blind, Placebo-controlled Multi-center Study to Assess the Efficacy and Safety of Ruxolitinib in Patients With COVID-19 Associated Cytokine Storm (RUXCOVID) (RUXCOVID)

Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants on antioxidant status in patients with acute respiratory distress syndrome

Resolvin D3 multi-level proresolving actions are host protective during infection

NF-kappa B inhibition by omega -3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcription

Effects of omega-3 fatty acids on resting heart rate, heart rate recovery after exercise, and heart rate variability in men with healed myocardial infarctions and depressed ejection fractions

GPR120 is an omega-3 fatty acid receptor mediating potent antiinflammatory and insulin-sensitizing effects

alpha-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40

SARScoronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS

Transplantation Committees of the Council on Clinical, C., Council on Cardiovascular

EPA, but not DHA, decreases mean platelet volume in normal subjects

Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure

Renin-angiotensin-aldosterone system: fundamental aspects and clinical implications in renal and cardiovascular disorders

The role of visceral adiposity in the severity of COVID-19: Highlights from a unicenter cross-sectional pilot study in Germany

Atherosclerotic plaque rupture: emerging insights and opportunities

Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock

The use of an inflammation-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of outcome data

COX-2, aspirin and metabolism of arachidonic, eicosapentaenoic and docosahexaenoic acids and their physiological and clinical significance

Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging

omega-3 Fatty-Acid Enriched Parenteral Nutrition in Hospitalized Patients: Systematic Review With Meta-Analysis and Trial Sequential Analysis

The effect of eicosapentaenoic acid on leukotriene B production by human neutrophils

Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19

The specialized proresolving mediator 17-HDHA enhances the antibody-mediated immune response against influenza virus: a new class of adjuvant?

The Protectin PCTR1 Is Produced by Human M2 Macrophages and Enhances Resolution of Infectious Inflammation

Specialized proresolving mediators enhance human B cell differentiation to antibody-secreting cells

Association of the insulin resistance marker TyG index with the severity and mortality of COVID-19

Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study

RNA Viruses: ROS-Mediated Cell Death

Pneumonia as a cardiovascular disease

Prostaglandins and inflammation

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

The peroxisome proliferator-activated receptor(PPARgamma) as a regulator of monocyte/macrophage function

A prospective, randomised, double blind placebo-controlled trial to evaluate the efficacy and safety of tocilizumab in patients with severe COVID-19 pneumonia (TOC-COVID): A structured summary of a study protocol for a randomised controlled trial

Resolution of inflammation in obesity-induced liver disease

Pharmaco-Immunomodulatory Therapy in COVID-19

n-3 PUFA improves fatty acid composition, prevents palmitate-induced apoptosis, and differentially modifies B cell cytokine secretion in vitro and ex vivo

A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in patients with COVID-19 admitted to the intensive care unit

Potential benefits and risks of omega-3 fatty acids supplementation to patients with COVID-19

The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis

Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

The role of pro-resolution lipid mediators in infectious disease

Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the

Anti-inflammatory effects of long-chain n-3 PUFA in rhinovirus-infected cultured airway epithelial cells

Mitochondria and microbiota dysfunction in COVID-19 pathogenesis

Deficiency of Soluble Epoxide Hydrolase Protects Cardiac Function Impaired by LPS-Induced Acute Inflammation

CYP-epoxygenase metabolites of docosahexaenoic acid protect HL-1 cardiac cells against LPS-induced cytotoxicity Through SIRT1

Dietary fish oil diminishes lymphocyte adhesion to macrophage and endothelial cell monolayers

The impact of membrane lipid composition on macrophage activation in the immune defense against Rhodococcus equi and Pseudomonas aeruginosa

LPS-or Pseudomonas aeruginosa-mediated activation of the macrophage TLR4 signaling cascade depends on membrane lipid composition

Therapeutic potential of omega-3 fatty acid-derived epoxyeicosanoids in cardiovascular and inflammatory diseases

Resolvin E1 and protectin D1 activate inflammation-resolution programmes

Fish oil-fed mice have impaired resistance to influenza infection

Novel endogenous small molecules as the checkpoint controllers in inflammation and resolution: entree for resoleomics

Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators

Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing

Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals

Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions

Polyunsaturated fatty acids, membrane organization, T cells, and antigen presentation

Polyunsaturated fatty acids and membrane organization: elucidating mechanisms to balance immunotherapy and susceptibility to infection

Novel Omega-3 Fatty Acid Epoxygenase Metabolite Reduces Kidney Fibrosis

Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan

Effect of enteral diet enriched with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with sepsis-induced acute respiratory distress syndrome

COVID-19 illness in native and immunosuppressed states: A clinicaltherapeutic staging proposal

ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis

Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury

Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis

Omega-3 Polyunsaturated Fatty Acid (Fish Oil) Supplementation and the Prevention of Clinical Cardiovascular Disease: A Science Advisory From the

Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC

Laboratory characteristics of patients infected with the novel SARS-CoV-2 virus

COVID-19, ACE2, and the cardiovascular consequences

Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis

Biochemistry of essential fatty acids

The role of mitochondria in reactive oxygen species metabolism and signaling

CytoResc -"CytoSorb" Rescue for critically ill patients undergoing the COVID-19 Cytokine Storm: A structured summary of a study protocol for a randomized controlled trial

2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk

Heart Association Task Force on Practice Guidelines

Resolvins suppress tumor growth and enhance cancer therapy

The science behind dietary omega-3 fatty acids

High-density lipoprotein suppresses the type I interferon response, a family of potent antiviral immunoregulators, in macrophages challenged with lipopolysaccharide

Combination of n-3 polyunsaturated fatty acids reduces atherogenesis in apolipoprotein E-deficient mice by inhibiting macrophage activation

Supplementation with eicosapentaenoic acid and docosahexaenoic acid reduces high levels of circulating proinflammatory cytokines in aging adults: A randomized, controlled study

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label

Modulators of Macrophage Polarization Influence Healing of the Infarcted Myocardium

The function of human alveolar macrophages

Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial

Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype

Response to Bistrian BR. Parenteral Fish-Oil Emulsions in Critically Ill COVID-19 Emulsions

Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study

In Vitro Antithrombotic Properties of Salmon (Salmo salar) Phospholipids in a Novel Food-Grade Extract

Bioprospecting for Antithrombotic Polar Lipids from Salmon, Herring, and Boarfish By-Products. Foods, 8. Twig

Resolvins: natural agonists for resolution of pulmonary inflammation

Anti-inflammatory effects of omega-3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin-II-dependent hypertension

An Omega-3 Epoxide of Docosahexaenoic Acid Lowers Blood Pressure in Angiotensin-II-Dependent Hypertension

Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice

High-density lipoprotein as a modulator of platelet and coagulation responses

A paradigm for gene regulation: inflammation, NF-kappaB and PPAR

Effects of docosahexaenoic acid-rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study

Risk stratification and prognosis of acute cardiac events in hospitalized adults with community-acquired pneumonia

Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study

A rampage through the body

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in

Good or bad: Application of RAAS inhibitors in COVID-19 patients with cardiovascular comorbidities

An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients

Angiotensin Converting Enzyme 2: A Double-Edged Sword

Specialized Pro-resolving Mediators Regulate Alveolar Fluid Clearance during Acute Respiratory Distress Syndrome

Activation of vascular BK channels by docosahexaenoic acid is dependent on cytochrome P450 epoxygenase activity

Comorbidities and multi-organ injuries in the treatment of COVID-19

Omega-3 fatty acids-supplemented parenteral nutrition decreases hyperinflammatory response and attenuates systemic disease sequelae in severe acute pancreatitis: a randomized and controlled study

Mitochondrial DNA stress primes the antiviral innate immune response

Cytochrome p450 enzymes in the bioactivation of polyunsaturated Fatty acids and their role in cardiovascular disease

PUFAs: Structures, Metabolism and Functions

Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study

A new coronavirus associated with human respiratory disease in China

Mitophagy, Mitochondrial Dynamics, and Homeostasis in Cardiovascular Aging

Altered Lipid Metabolism in Recovered SARS Patients Twelve Years after Infection. Sci Rep

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention

Effective treatment of severe COVID-19 patients with tocilizumab

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Lipidomic Profiling Reveals Significant Perturbations of Intracellular Lipid Homeostasis in Enterovirus-Infected Cells

Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

An Improvement of Cardiovascular Risk Factors by Omega-3 Polyunsaturated Fatty Acids

Effects of Angiotensin II Receptor Blockers and ACE (Angiotensin-Converting Enzyme) Inhibitors on Virus Infection, Inflammatory Status, and Clinical Outcomes in Patients With COVID-19 and Hypertension: A Single-Center Retrospective Study. Hypertension

Encapsulated fish oil enriched in alpha-tocopherol alters plasma phospholipid and mononuclear cell fatty acid compositions but not mononuclear cell functions

Cardiovascular complications of severe acute respiratory syndrome

Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy

SARS-Coronavirus Open Reading Frame-3a drives multimodal necrotic cell death

Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia

Human dendritic cell activities are modulated by the omega-3 fatty acid, docosahexaenoic acid, mainly through PPAR(gamma):RXR heterodimers: comparison with other polyunsaturated fatty acids

RvD1 ameliorates LPS-induced acute lung injury via the suppression of neutrophil infiltration by reducing CXCL2 expression and release from resident alveolar macrophages

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