8  Potential cardioprotective mechanisms of n-3 PUFAs in the setting of COVID-19
Based on several clinical reports, COVID-19 patients with severe ALI/ARDS may also suffer from increased risk of sepsis and cardiac arrest (Huang et al., 2020). 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 homeostasis. This section will highlight the cardioprotective mechanisms of n-3 PUFAs and their metabolites hypothesizing how n-3 PUFAs might have a supportive adjuvant utility in treating and protecting against cardiac complications associated with COVID-19 (Fig. 2 ).
Fig. 2 Potential cardioprotective mechanisms of n-3 PUFAs in the setting of COVID-19. (A) N-3 PUFAs ameliorate uncontrolled immune responses and exert anti-inflammatory effects via several mechanisms. (B) N-3 PUFAs attenuate the vicious cycle/interaction of mitochondrial dysfunction and aggravated immune response. (C) N-3 PUFAs have the capability to attenuate viral infections via both direct effects on membrane integrity and indirect mechanisms through activating the humoral response to decrease overall viral load. (D) N-3 PUFAs have the ability to regulate the RAAS system in the favor of the vasodilatory, the anti-inflammatory and the cardioprotective ACE2/Ang (1–7) effectors. (E) N-3 PUFAs enhance antioxidant capacity and attenuate oxidative stress in the tissue. (F) N-3 PUFAs ameliorate coagulopathy by exerting anti-thrombotic effects. (G) The triglyceride-lowering effect of n-3 PUFAs may play a key role in blunting the exaggerated inflammation observed in patients with COVID-19. ACE, Angiotensin-converting enzyme; Ang, Angiotensin; CRP, C-reactive protein; IL, Interleukin; mtDNA, Mitochondrial DNA; PUFA, Poly unsaturated fatty acid; ROS, Reactive oxygen species; TGs, Triglycerides; TNF-α, Tumor necrosis factor alpha; TX, Thromboxane.

8.1  The anti-inflammatory properties of n-3 PUFAs
As mentioned earlier, an exacerbated immune system response and uncontrolled inflammation are fundamental mechanisms in the development of cardiovascular impairment in patients with COVID-19. Accordingly, a plethora of experimental studies and clinical trials demonstrate that targeting different inflammatory components may be considered promising strategies to control cardiovascular impairment during the acute and remission phases of COVID-19 (Fig. 3 ).
Fig. 3 A summary of the anti-inflammatory mechanisms of n-3 PUFAs. (A) N-3 PUFAs can regulate expression of inflammatory cytokines, chemokines and adhesion molecules, inhibit NLRP3 inflammasomes, activate anti-inflammatory transcription factors (PPARα/γ) and activate GPR120 receptors which inhibit TLR4-mediated activation of NF-κB. (B) N-3 PUFAs are metabolized by COX/5-LOX into 5-series LTs which exert anti-inflammatory effects. (C) N-3 PUFAs can replace n-6 PUFAs, such as AA, altering the inflammatory response. N-3 PUFA will alter cell membrane composition, fluidity and mediated signaling. (D) N-3 PUFAs, DHA and EPA, are metabolized by CYP epoxygenases into bioactive epoxylipids with anti-inflammatory properties. (E) N-3 PUFAs are metabolized by COX/LOX into SPMs which act as potent anti-inflammatory modulators. AA, Arachidonic acid; CCL, Chemokine ligand; COX, Cyclooxygenase; CYP, Cytochrome P450; DHA, Docosahexaenoic acid; EDP, Epoxydocosapentaenoic acid; EEQ, Epoxyeicosatetraenoic acid; EPA, Eicosapentaenoic acid; GRP, G-protein coupled receptor; IL, Interleukin; LOX, Lipoxygenase; LT, Leukotriene; PUFA, Poly unsaturated fatty acid; NFκB, Nuclear factor kappa-light-chain enhancer activated B-cells; NLRP3, NACHT, LRR and PYD domains-containing protein 3; PLA2, Phospholipase A2; PMN, Polymorphonuclear neutrophils; PPAR, Peroxisome proliferator-activated receptor; ROS, Reactive oxygen species; SPMs, Specialized pro-resolving mediators; TLR, Toll like receptor; TNF-α, Tumor necrosis factor-α.

8.1.1  N-3 PUFAs regulate the expression of several proinflammatory innate immune components and modulate macrophage response
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 (Huang et al., 2020). 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.
N-3 PUFAs can modulate the transcription and expression of inflammatory genes including cytokines, chemokines and adhesion molecules in cardiomyocytes, fibroblasts, endothelial cells, monocytes and macrophages (Collie-Duguid & Wahle, 1996; De Caterina, Cybulsky, Clinton, Gimbrone, & Libby, 1994; Hughes, Southon, & Pinder, 1996; Miles, Wallace, & Calder, 2000; Sanderson & Calder, 1998). This is primarily achieved through the regulation of key transcription factors, such as inhibiting NF-κB (Kumar, Takada, Boriek, & Aggarwal, 2004; Lo, Chiu, Fu, Lo, & Helton, 1999; Novak, Babcock, Jho, Helton, & Espat, 2003; Zhao, Joshi-Barve, Barve, & Chen, 2004) or activating peroxisome proliferator-activated receptors-α/γ (PPARα/γ) (Gani & Sylte, 2008; Zapata-Gonzalez et al., 2008). 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 protein-coupled 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-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 pro-inflammatory 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; Liu et al., 2014; Mildenberger et al., 2017). Schoeniger et al., showed n-3 PUFAs have the ability to down-regulate inflammatory processes and reduce the production and secretion of pro-inflammatory cytokines from RAW 264.7 macrophages infected with microorganisms, R. equi and P. aeruginosa (Schoeniger, Adolph, Fuhrmann, & Schumann, 2011). Moreover, the inhibitory effects of EPA and DHA on the pro-inflammatory NLRP3 inflammasome pathway has also been well-documented in macrophage cell lines as well as in primary human and mouse macrophages (Iverson et al., 2018; Kumar et al., 2016). Kumar et al., investigated the effects of 15-lipoxygenase (LOX) metabolites of ALA on lipopolysaccharide (LPS) -induced inflammation in RAW 264.7 cells and peritoneal macrophages. The findings revealed the anti-inflammatory effects of these metabolites involve inactivation of the NLRP3 inflammasome complex through the PPAR-γ pathway (Kumar et al., 2016). N-3 PUFAs can increase the phagocytic capacity of macrophages, which has been shown through the engulfment of zymosan particles (Chang, Lee, Kim, & Surh, 2015), Pseudomonas aeruginosa, Rhodococcus equi (Adolph, Fuhrmann, & Schumann, 2012), E.coli (Davidson, Kerr, Guy, & Rotondo, 1998) and apoptotic cells (Chang et al., 2015). 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 (Chang et al., 2015; 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.

8.1.2  Shifting to the anti-inflammatory COX- and LOX-derived metabolites of n-3 PUFAs
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 anti-inflammatory 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 the hydroxyicosatetraenoic acids. These lipid mediators are considered pro-inflammatory and are involved in various pathological processes including cardiovascular disorders (Innes & Calder, 2018; Kalinski, 2012; Lewis, Austen, & Soberman, 1990). The synthesis and production of PGE2 occurs in several cells, including dendritic cells, macrophages, fibroblasts and endothelial cells. PGE2 not only mediates vasodilation, endothelial permeability and increase of pain (Ricciotti & FitzGerald, 2011) but also contributes to the tissue influx of neutrophils, mast cells and macrophages and can affect the differentiation of these cells (Kalinski, 2012).
N-3 PUFAs can also act as a substrate for COX and 5-LOX enzymes resulting in production of the 3-series of PGs and TxAs as well as 5-series LTs, which are a set of less inflammatory or even anti-inflammatory metabolites in comparison to the metabolite family derived from AA (Corey, Shih, & Cashman, 1983; Lee et al., 1984; Surette, 2008). 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 PGE2 and LTB4 by human inflammatory cells was significantly decreased in a diet rich in fish oil (Caughey, Mantzioris, Gibson, Cleland, & James, 1996; Lee et al., 1985; Prescott, 1984; von Schacky, Kiefl, Jendraschak, & Kaminski, 1993). Therefore, the metabolism of n-3 PUFAs by COX and LOX enzymes not only reduce the AA-derived pro-inflammatory metabolites but also alter the metabolic profile towards more biologically active anti-inflammatory mediators (Goldman, Pickett, & Goetzl, 1983; Lee et al., 1984; Lee, Mencia-Huerta, et al., 1984). This may represent one of the central anti-inflammatory and consequently cardioprotective mechanisms of n-3 PUFAs against cardiac complications associated with COVID-19.

8.1.3  Anti-inflammatory features of the n-3 PUFAs-derived specialized pro-resolving mediators (SPMs)
Metabolism of n-3 PUFAs also generates another group of highly specialized pro-resolving mediators (SPMs) which include resolvins ‘resolution phase interaction products’ produced from both EPA (E-series, RvE1-2) and DHA (D-series, RvD1-6) as well as protectins and maresins produced from DHA (Serhan et al., 2002; Serhan, Chiang, & Van Dyke, 2008). Both the COX and LOX pathways are involved in the synthesis of these metabolites with distinct epimers being produced in the presence and absence of aspirin (Mas, Croft, Zahra, Barden, & Mori, 2012).
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 (Arita et al., 2007; Serhan et al., 2002; Serhan et al., 2008). 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). Furthermore, Morin et al. demonstrated a diet enriched with DHA and monoglycerides can significantly increase the levels of RvD2 and RvD3, which correlate with reduced levels of proinflammatory mediators CRP, IL-6, TNF-α, and IL-1β in a rat model of hypertension (Morin, Rousseau, Blier, & Fortin, 2015). Additionally, there is growing evidence for a role of SPMs in regulating the humoral immune response. A study conducted by Ramon et al., showed 17-hydroxydocosahexaenoic acid (17-HDHA), the precursor of the D-series SPMs (RvD1, 17R-RvD1, RvD2), can reduce IL-6 secretion in human B cells, increase B cell antibody production and promote B cell differentiation to an antibody secreting cell (Ramon, Gao, Serhan, & Phipps, 2012). These new findings highlight the potential applications of SPMs as non-toxic, supportive adjuvants and as anti-inflammatory therapeutic molecules particularly during infection as in the case of COVID-19.
Resolvins, protectins and maresins play a pivotal role regulating the function of macrophages. Sulciner et al. demonstrates RvD1, RvD2 or RvE1 can inhibit debris-stimulated cancer progression by enhancing clearance of debris via macrophage phagocytosis in multiple tumors. These resolvins suppressed the release of the proinflammatory cytokines/chemokines, including TNFα, IL-6, IL-8, chemokine ligand 4, and chemokine ligand 5, by human macrophages cocultured with tumor cell debris (Sulciner et al., 2018). Maresins are conjugates of sulfides synthetized by macrophages, which are also participants in acute inflammation resolution and seem to promote tissue regeneration (Serhan et al., 2009). Maresin-1 biosynthesis involves an active intermediate (13S,14S-epoxi-DHA) that stimulates macrophage conversion from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotype (Dalli, Ramon, Norris, Colas, & Serhan, 2015). 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; Wang, Yan, Hao, & Jin, 2018; 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; Zhang et al., 2019). Further, it has been demonstrated protectins may reduce the replication of influenza (Morita et al., 2013) and potentially affect the inflammatory manifestations of respiratory viral diseases (Russell & Schwarze, 2014).
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.

8.1.4  Role of CYP-mediated metabolites in ameliorating inflammation
CYP2J and CYP2C isoforms, the constitutively expressed cytochrome P450 (CYP) epoxygenases found in the cardiovascular system, metabolize EPA into 5 regioisomeric epoxyeicosatetraenoic acids (5,6-, 8,9-, 11,12-, 14,15-, 17,18-EEQ) and DHA into 6 regioisomeric epoxydocosapentaenoic acids (4,5-, 7,8-, 10,11-, 13,14-, 16,17-, 19,20-EDP) (Arnold et al., 2010; Konkel & Schunck, 2011; Westphal, Konkel, & Schunck, 2015). Recent evidence suggests that 17,18-EEQ and 19,20-EDP mediate several anti-inflammatory effects of n-3 PUFAs in various models of tissue injury (Arnold et al., 2010; Ulu et al., 2014; Wang, Chai, Lu, & Lee, 2011). For example, Fang et al. demonstrated a n-3 PUFA-rich diet attenuates MI injury in mice by producing a protective eicosanoid pattern, which results in shifting the metabolite profile to a more anti-inflammatory state by increasing the levels of the 19,20-EDP and 17,18-EEQ and decreasing the pro-inflammatory PGE2 (Fang et al., 2018). The cardioprotective effects of n-3 PUFAs are also attributed to their ability to attenuate the NLRP3 inflammasome complex cascade (Darwesh, Jamieson, Wang, Samokhvalov, & Seubert, 2019). Importantly, the anti-inflammatory features of CYP-derived epoxy metabolites have been reported in numerous models. For example, in TNFα-induced retinal vascular inflammation, Capozzi et al. demonstrated 19,20-EDP can ameliorate vascular adhesion molecule and intracellular adhesion molecule expression and reduce leukocyte adherence to human retinal microvascular endothelial cell monolayers (Capozzi, Hammer, McCollum, & Penn, 2016). Additionally, evidence demonstrates intraperitoneal infusions of 17,18-EEQ and 19,20-EDP protect against allergic intestinal inflammation and kidney fibrosis in corresponding mouse models (Kunisawa et al., 2015; Sharma et al., 2016). 17,18-EEQ was able to inhibit TNFα-induced inflammation in human lung tissue obtained from patients undergoing surgery for lung carcinoma via inhibition of NF-κB and activation of the transcription factor PPAR-γ (Morin, Sirois, Echave, Albadine, & Rousseau, 2010). The anti-inflammatory properties of DHA epoxides were also well demonstrated using animal models of inflammatory pain. For example, Morisseau et al. demonstrated that direct injection of the DHA epoxides, EDPs, together with the pro-inflammatory carrageenan into the paw or spinal cord of male Sprague-Dawley rats resulted in significant antihyperalgesic activity. Surprisingly, both the parent free fatty acid DHA and the corresponding diols were inactive, supporting the hypothesis that the epoxylipids mediate many of the beneficial effects of the parent compounds (Morisseau et al., 2010). 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 COVID-19 infection.

8.1.5  N-3 PUFAs alter cell membrane structure and function - modulation of the lipid raft
Within a cell, n-3 PUFAs can be found incorporated into phospholipid membranes where elevating levels will replace existing n-6 PUFAs thereby altering the composition and properties of lipid rafts (Lordan et al., 2017; Lordan et al., 2020). 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 membrane-mediated 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; Kim et al., 2010; McMurray, Bonilla, & Chapkin, 2011; Rockett, Salameh, Carraway, Morrison, & Shaikh, 2010; Shaikh and Edidin, 2006, Shaikh and Edidin, 2008). 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; Hazen, Ford, & Gross, 1991; Leslie, 2015; Mancuso et al., 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).

8.2  N-3 PUFAs have the potential to ameliorate mitochondrial dysfunction in the pathogenesis of COVID-19
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 damaged mitochondria through mitophagy (Bayeva, Gheorghiade, & Ardehali, 2013; Meyers, Basha, & Koenig, 2013). Mitochondrial damage, decreased biogenesis and impaired mitophagy has been implicated in several pathologies including diabetes, CVDs, aging, as well as viral and bacterial infections (Cho, Kim, & Jo, 2020; Kim, Ahn, Syed, & Siddiqui, 2018; Rovira-Llopis et al., 2017; Srivastava, 2017; Wu, Zhang, & Ren, 2019). While the intrinsic mechanism(s) involved in the pathogenesis of cardiovascular insult secondary to COVID-19 are not fully understood, altered mitochondrial homeostasis could be a major contributing factor (Grivennikova, Kareyeva, & Vinogradov, 2010; Melser, Lavie, & Benard, 2015; Murphy, et al., 2016; Saleh, Peyssonnaux, Singh, & Edeas, 2020). Notably, symptoms such as sleep and appetite disturbance, loss of energy, fatigue and muscle weakness, observed in COVID-19 patients, are cardinal signs of mitochondrial distress (Filler et al., 2014).
Recent studies identified a level of interaction or interplay between mitochondria and innate immune inflammatory responses. Mitochondrial dysfunction is considered both a trigger and target of uncontrolled inflammatory responses (Gurung, Lukens, & Kanneganti, 2015; Mohanty, Tiwari-Pandey, & Pandey, 2019; Yu et al., 2014). As such, this implicates the potential role of impaired mitochondrial homeostasis in the aggravation of cardiovascular injury secondary to COVID-19 (Darwesh, Jamieson, et al., 2019; Darwesh, Keshavarz-Bahaghighat, Jamieson, & Seubert, 2019; Keshavarz-Bahaghighat, Darwesh, Sosnowski, & Seubert, 2020; Samokhvalov et al., 2018). Inflammatory mediators are well documented to trigger several intracellular cascades that alter mitochondrial metabolism and function. For example, the pro-inflammatory cytokines TNF-α, IL-1β and IL-6, found in the serum from COVID-19 patients, can impede mitochondrial oxidative phosphorylation, inhibit ATP production and mitochondrial ROS production exacerbating injury (Jo, Kim, Shin, & Sasakawa, 2016; Naik & Dixit, 2011). Furthermore, IFN-γ and IL-6 can increase mitochondrial ROS production and directly affect the activity of the electron transport chain, which may cause mitochondrial membrane permeabilization, altered mitochondrial dynamics and cell death (Li et al., 2013).
Conversely, direct mitochondrial damage was found to aggravate the production of proinflammatory cytokines and worsen disease prognosis. Briefly, the pathological changes observed in patients infected with SARS-CoV-2 such as pneumonia, hypoxia and impaired calcium homeostasis can indirectly induce mitochondrial dysfunction. Moreover, a very recent study conducted by Singh et al. interestingly showed both RNA and RNA transcripts of SARS-CoV-2 can directly target and localize to mitochondria hijacking the host cell's mitochondrial function to viral advantage (Singh, Chaubey, Chen, & Suravajhala, 2020). Subsequently, SARS-CoV-2 will manipulate the host cell's mitochondrial function to evade removal and facilitate virus replication and progression. These effects lead to the release of mitochondrial DNA and ROS in the cytosol (Herst, Rowe, Carson, & Berridge, 2017; Kozlov, Lancaster Jr., Meszaros, & Weidinger, 2017; Mittal, Siddiqui, Tran, Reddy, & Malik, 2014; Starkov, 2008; Twig & Shirihai, 2011; West et al., 2015), which drives the activation and release of central pro-inflammatory cytokines such as NLRP3 inflammasomes, IL-1β and IL-6 (Jo et al., 2016; Naik & Dixit, 2011; Nakahira et al., 2011; West et al., 2015), the hallmark cytokines of the COVID-19 severity. 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 (Darwesh, Jamieson, et al., 2019). Moreover, recent data indicates a synthetic EDP analogue imparts cardioprotective effects against ischemia reperfusion injury via preservation of mitochondrial homeostasis and anti-oxidant defenses, which blunted a detrimental innate NLRP3 inflammasome response (Darwesh et al., 2020). 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 data suggest n-3 PUFAs and their metabolites provide beneficial protective responses in models of cardiovascular injury via maintaining mitochondrial quality and ameliorating detrimental immune responses. However, further research is required to investigate the proposed hypothesis in the context of COVID-19.

8.3  Direct and indirect effects of n-3 PUFAs on the viral load
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). Morita et al. demonstrated n-3 PUFA-derived lipid mediator, protectin D1, exhibits antiviral activity, markedly attenuates influenza A virus replication and improves survival in severe influenza infection in male C57Bl/6J mice. This study highlighted the importance of the endogenous protectin D1 as an innate suppressor of influenza virus replication attenuating lethal infection (Morita et al., 2013). In another study, Ramon et al. evaluated the ability of 17-HDHA, a SPM derived from DHA, for improving the immune response to H1N1 influenza virus. The results showed 17-HDHA was able to enhance the humoral immunity against viruses by increasing the number of antibody-secreting cells and the levels of H1N1 antibodies, which resulted in greater protection against live H1N1 influenza infection in mice (Ramon et al., 2014). More recently, Braz-De-Melo highlighted the beneficial effects of n-3 PUFAs against viral infections by showing that DHA pre-treatment to neuroblastoma SH-SY5Y cells infected with Zika virus increased their viability and proliferation, restored mitochondrial function, reduced viral load and triggered an anti-inflammatory response identifying n-3 PUFAs as useful therapeutic tools in combating viruses (Braz-De-Melo et al., 2019). Additionally, Yan et al. has shown that EPA and DHA can inhibit the replication of both enterovirus A71 and coxsackievirus A16 the most common causes of hand, foot, and mouth disease (Yan et al., 2019). Collectively, we can conclude that n-3 PUFAs have the capability to attenuate viral infections via both direct effects on membrane integrity and indirect mechanisms activating the humoral response to decrease overall viral load.
In contrast, the immunosuppressive effects of EPA and DHA supplementation can decrease the immune response against viral infections and thus compromising removal from the body. C57BL/6J mice supplemented with fish oil and infected with H1N1 influenza virus showed a 40% higher mortality rate and 70% higher viral load compared to the corresponding control. Moreover, the treated mice had markedly reduced numbers of CD8+ T lymphocytes and reduced mRNA expression of inflammatory mediators IL-6 and TNF-α (Schwerbrock, Karlsson, Shi, Sheridan, & Beck, 2009). Similarly, BALB/c mice fed a high-fat diet rich in EPA and DHA had reduced levels of IFN-γ, serum immunoglobulin G and lung immunoglobulin A-specific antibodies following infection with the influenza virus, indicating a virus-specific lung T cell cytotoxicity. These results suggested supplementation with a diet rich in EPA and DHA could impair immune response by delaying virus clearance. However, differences noticed during the course of infection did not affect the ultimate outcome as n-3 PUFA-fed mice were finally able to clear the virus and returned to pre-infection food consumption and body weight similar to the control group (Byleveld, Pang, Clancy, & Roberts, 1999; Byleveld, Pang, Clancy, & Roberts, 2000). Importantly, other factors contribute to these opposite results, for example, an initial weight loss is typically observed when mice are supplemented with fish oil (Byleveld et al., 1999). 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.

8.4  Role of n-3 PUFAs in modulating the renin-angiotensin aldosterone system in the setting of COVID-19
The renin-angiotensin aldosterone system (RAAS) is a key regulator of vascular function 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). Earlier literature demonstrated Ang II may act as a proinflammatory cytokine potentially having a significant role in cardiac remodeling (Gibbons, Pratt, & Dzau, 1992; Griendling, Minieri, Ollerenshaw, & Alexander, 1994). Conversely, the master regulator ACE2, a type 1 integral membrane glycoprotein expressed in most tissues including the lungs, kidneys, heart and vascular endothelium layers, can metabolize Ang II to produce the vasodilator angiotensin (Ang 1–7) which protects the cardiovascular system against the actions of Ang II (Das, 2018; Kumar & Das, 1997; Yan et al., 2020). Beside its vasodilatory properties, Ang-(1–7) promotes resolution of inflammation by decreasing TNF-α, IL-6, vascular adhesion molecule, monocyte chemoattractant protein-1 and macrophage infiltration enhancing the survival of cardiomyocytes and endothelial cells during severe immune responses (Simoes e Silva, Silveira, Ferreira, & Teixeira, 2013; Zhang et al., 2015). 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; Wang, Gheblawi, & Oudit, 2020).
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 infection cycle (Letko, Marzi, & Munster, 2020; Yan et al., 2020). Excessive binding of spike protein to ACE2 leads to downregulation of the ACE2 receptor (Jung et al., 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 (Liu, Blet, Smyth, & Li, 2020; Oudit et al., 2009). Importantly, the accumulation of Ang II was positively associated to viral load and lung injury (Liu et al., 2020). 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 pre-existing conditions, are at lower risk of 28-day all-cause mortality than those not treated with ACE inhibitors or ARBs (Wang et al., 2020; Zhang et al., 2020). 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 (Wang, Edin, et al., 2020).
Interestingly, several reports showed that n-3 PUFAs can regulate the RAAS system by 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 (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 (Chen, Li, Chen, Feng, & Xiong, 2020). A recent study conducted by Yang et al., demonstrated COVID-19 patients with hypertension using ACE inhibitors/ARBs had lower mortality rates than hypertensive COVID-19 patients that were not on ACE inhibitors/ARBs (Yang et al., 2020). Moreover, Mancia et al. examined 6272 patients and found no association between RAAS inhibitor use and susceptibility or development of COVID-19 (Mancia, Rea, Ludergnani, Apolone, & Corrao, 2020). In that sense, a published statement by American Heart Association (AHA), the American College of Cardiology (ACC) and the Heart Failure Society of America strongly recommended continuation of ACE inhibitor/ARBs (Zhang, Zhu, Cai, et al., 2020). Together, these data suggest therapies targeting ACE and Ang II do not appear to increase the likelihood of SARS-CoV-2 infection, but may have a role in abrogating the inflammatory response and vasoconstriction that contributes to the clinical deterioration in COVID-19 patients.
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.

8.5  N-3 PUFAs possess anti-oxidant properties
The pneumonia-induced hypoxemia caused by RNA virus infections reduces the energy production from cell metabolism, increases the anaerobic fermentation, intracellular acidosis and the generation of ROS (Li et al., 2020). The subsequent increased ROS production causes damage to different cellular components including the DNA, lipids and proteins. The increased ROS levels will deplete the antioxidant defense system resulting in severe oxidative stress and chronic activation of immune responses, aggravating tissue injury and damage (Khomich, Kochetkov, Bartosch, & Ivanov, 2018; Reshi, Su, & Hong, 2014).
Several studies reveal n-3 PUFAs possess anti-oxidant properties attributable to their ability to up-regulate anti-oxidant enzymes (e.g. superoxide dismutase), down-regulate pro-oxidant enzymes (e.g. nitric oxide synthase) and potential to interact directly with free radicals. Antioxidant effects of n-3 PUFAs have been demonstrated in different organs including lungs, kidneys and the cardiovascular system (Darwesh et al., 2020; Darwesh, Jamieson, et al., 2019; Darwesh, Keshavarz-Bahaghighat, et al., 2019; De Caterina, 2011; Mozaffarian & Wu, 2011). Anderson et al. reported patients were administered a moderately high dose of n-3 PUFAs (3.4 g/day EPA and DHA ethyl-esters) for a period of 2–3 weeks before having elective cardiac surgery and then myocardial tissue was dissected from the right atrium during surgery. 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 PUFA-treated 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 (Darwesh, Jamieson, et al., 2019). 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.

8.6  N-3 PUFAs have the potential to ameliorate coagulopathy
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 (Tang et al., 2020). In a study with 184 Dutch ICU COVID-19 patients, 38% were reported to have abnormal blood clotting and 33% with identified clots (Klok et al., 2020). 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; Zhang et al., 2020). Accordingly, the active application of anticoagulants (such as heparin) for patients with severe SARS-CoV-2 infection has been recommended and appears to be associated with better prognosis (Tang, Bai, et al., 2020). Tang et al. recently published a study indicating anticoagulant therapy, mainly with low molecular weight heparin, is associated with better prognosis in severe SARS-CoV-2 infected patients (Tang, Bai, et al., 2020).
N-3 PUFAs contain polar lipids that exhibit potent antithrombotic effects against platelet-activating factor and other prothrombotic pathways, including thrombin, collagen, and adenosine diphosphate (Lordan et al., 2020; Tsoupras et al., 2019; Tsoupras, O'Keeffe, Lordan, Redfern, & Zabetakis, 2019). 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 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.

8.7  Lipid-lowering properties of n-3 PUFAs in the context of 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 (Chen et al., 2020; Petersen et al., 2020; Shi et al., 2020; Wang, Hu, et al., 2020; Zhou, Yu, 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-α levels causing reduced lipoprotein lipase activity (Chen, Wu, et al., 2020; 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 (Ren et al., 2020). 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). So, the robust, maladaptive inflammatory and hypercoagulability responses observed in more severe COVID-19 cases could possibly be attributed– in part – to reduced levels of HLD-c and a dysregulated lipid profile. Given the potential for COVID-19 infection to alter the lipid profile acutely and the association of dyslipidemia with conditions such as diabetes, coronary artery disease, and obesity raises the question whether normalization of plasma lipid profiles in COVID-19 patients can offer clinical benefit.
Use of statins and other lipid-modulating therapies can reduce the risk of primary or secondary cardiovascular events in at-risk individuals, including those with diabetes, metabolic syndrome, and coronary artery disease – conditions that are risk factors for severe COVID-19 outcomes (Stone et al., 2013). A large retrospective study of over 13,000 COVID-19 patients has shown the in-hospital use of statin therapy, potent lipid-lowering agents with anti-inflammatory properties, was associated with a reduced rate of mortality compared to non-statin users (Zhang, Qin, Cheng, et al., 2020). 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; 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.