COVID-19-associated stroke risk: Could nutrition and dietary patterns have a contributing role?

Table 1 Summary of available evidence-based associations between stroke and coronavirus disease 2019

Ref.	Study design	Sample/ Aim	Main culprits suggested in the occurrence of stroke result from COVID-19 affliction
Bhaskar et al[26]	REPROGRAM consortium position paper	An overview of cytokine storm and its implications in COVID-19	(1) Cytokine storm; (2) Thromboembolic events; and (3) Large vessel occlusion
Rothstein et al[31]	Retrospective, observational study	844 COVID-19 patients, 28 of them had a stroke	(1) Endothelialitis; (2) Diffuse endothelial inflammation; (3) Infection-induced hypercoagulability; (4) Viral cardiomyopathy; and (5) Diffuse hyperinflammatory state
Valderrama et al[8]	Case study	A 52-year-old man with co-occurrence of stroke and COVID-19 infection	(1) Inflammation; (2) Injury to the myocardium; (3) Thrombogenesis; (4) Increased D-dimer levels; (5) Increased interleukin-6 levels; (6) Hyperviscosity; (7) Vascular endothelial damage; (8) Intracerebral hemorrhage; (9) Microthrombosis; and (10) Fibrinogen consumption coagulopathy
Tan et al[6]	Systematic review and meta-summary of the literature	A total of 39 studies comprising 135 patients, pooled incidence of co-occurrence of stroke and COVID-19 was 1.2%	(1) Elevated D-dimer; (2) Elevated fibrinogen; and (3) Presence of antiphospholipid antibodies
Wang et al[9]	Review article	Summarizing the potential contribution of COVID-19 to hemorrhagic stroke in the elderly and proposing possible mechanisms	(1) Downregulation of ACE2 expression; (2) Increased angiotensin II availability; (3) Severe blood pressure fluctuations; (4) Predisposition to hemorrhagic stroke; (5) Elevated plasma D-dimer levels; (6) Classical inflammatory biomarkers; (7) Viral CNS infections; (8) Cytokine, chemokine, and protease; and (9) Increasing BBB permeability
Ntaios et al[35]	Special report	Pooled all patients who were hospitalized with confirmed COVID-19 and AIS in 28 sites from 16 countries	(1) Endotheliopathy; (2) Potentiate the prothrombotic milieu; (3) Immune-mediated platelet activation; (4) Dehydration; and (5) Infection-induced cardiac arrhythmias

ACE2: Angiotensin-converting enzyme 2; AIS: Acute ischemic stroke; BBB: Blood-brain barrier; CNS: Central nervous system; COVID-19: Coronavirus disease 2019.

Table 2 Summary of available studies related to dietary patterns, some foods, and micronutrients in context of stroke and/or coronavirus disease 2019

Ref.	Study design	Sample/ Aim	Possible pathways in which nutritional factors may be involved in pathogenesis of stroke and/ or COVID-19–associated stroke
Hansen et al[23]	Danish cohort study	Incident cases of stroke among 55338 men and women	(1) Higher Healthy Nordic Food Index score was associated with a lower risk of total stroke; (2) Reduction in blood pressure; (3) Improved blood lipids; (4) Induced weight loss; (5) Lower total and low-density lipoprotein cholesterol; and (6) Increased antioxidant and flavonoid levels
Feng et al[22]	Meta-analysis of prospective studies	Included 12 prospective cohort studies comprising a total of 548632 participants	(1) Higher adherence to the DASH diet was related to a reduced risk of developing stroke; (2) Blood pressure-lowering effects; (3) Improved lipid profiles and body weight; (4) Decreased the risk of metabolic syndrome; (5) Improved serum inflammatory biomarkers; (6) Reduced oxidative stress; and (7) Anti-inflammatory and antioxidative effects
Estruch et al[24]	Randomized clinical trial	A total of 7447 persons randomly assigned to one of three diets: a Med-diet suppl with extra-virgin olive oil, a Med-diet suppl with mixed nuts, or a control diet	(1) A Med-diet suppl with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events; (2) High biologic plausibility; (3) Anti-inflammatory and antioxidative effects; (4) Improved endothelial dysfunction; (5) Resistance to vasoreactivity; (6) Insulin sensitivity; and (7) Improved blood lipids
Chiu et al[47]	Two prospective cohort studies	Cohort 1, n = 5050; Cohort 2, n = 8302	(1) Taiwanese vegetarian diet is associated with a lower risk of ischemic and hemorrhagic strokes; (2) Shift in the gut microbial community to reduce the production of trimethylamine N-oxide; and (3) Consequent decrease in platelet hyperreactivity and thrombosis
D’Elia et al[49]	Meta-analysis	Pooled analysis of 14 cohorts (overall 333250 participants and 10659 events)	(1) An inverse and significant association between K intake and risk of stroke; and (2) Decreased blood pressure
Zhao et al[50]	Systematic review and meta-analysis	18 prospective cohort studies on Mg intake and the incidence of stroke	(1) Increasing Mg intake may be a crucial component of stroke prevention that acts in a dose-dependent manner; and (2) Improved cardiovascular health
Iacoviello et al[51]	Systematic review	Prospective studies that focused on primary prevention of stroke by nutrition	Nutrients, food groups and dietary patterns are effective in preventing stroke, such as: (1) Vitamin D, dairy calcium, folate (not supplementation), vitamin C, chocolate, coffee, tea, and the regular and moderate alcohol consumption; (2) Calcium and dairy intake are inversely associated with low-grade systemic inflammation; (3) Low-fat dairy and milk consumption decreased the incidence of hypertension; (4) Vitamin D involved in the modulation of the renin- angiotensin system, endothelial function, vascular smooth muscle proliferation, insulin sensitivity, and systemic inflammation; (5) Vitamin C, beta-carotene, and flavonoids are antioxidant compounds and can be reduce blood pressure and improve microvascular function; and (6) Chocolate intake resulted in increased HDL, decreased LDL oxidation, improved endothelial function and reduced blood pressure
Bousquet et al[52]	Review article	Role of diet in COVID-19 death rates	(1) Countries where the major daily intake originates from uncooked or fermented kale, cabbages, and fermented dairy products have lower COVID-19 death rates than the others; (2) Mentioned foods known as good sources for anti-ACE activity and rich in antioxidants; and (3) Improving high blood pressure and subsequent hemorrhagic stroke
Kalantar-Zadeh et al[20]	Perspective study	Impact of dietary patterns and the commensal microbiome on susceptibility to and severity of COVID-19	(1) A healthy, diverse, and balanced diet based on plants, high fiber, and fermented foods could be a preventative strategy, mitigating harmful effects of SARS-CoV-2; and (2) Probiotics can modulate the immune system, thereby reducing the susceptibility to affliction or morbidity and mortality from COVID-19
Tan et al[55]	Prospective observational study	AIS patients, n = 140;Healthy controls, n = 92	(1) Gut-brain axis has been brought to attention; (2) Probiotics and beneficial microbes exert beneficial alterations in the gut microbiome towards producing more SCFAs; (3) There was dysbiosis (low fecal SCFAs level) in AIS patients; and (4) The SCFAs’ levels were negatively correlated with stroke severity and prognosis
Zabetakis et al[14]	Review article	Speculates on the importance of nutrition as a mitigation strategy to support immune function amid the COVID-19 pandemic	(1) A person’s nutritional status, and nutrients and foods’ intake, may exert anti-inflammatory and immunomodulatory effects; (2) Nutrients such as vitamin C, vitamin D, and zinc may hold some promise for the treatment of COVID-19; (3) Nutrients with anti-inflammatory, antithrombotic, and antioxidant properties may prevent or attenuate the inflammatory and vascular manifestations associated with COVID-19; and (4) It is vitally important to maintain a healthy diet and lifestyle during the pandemic
Kanki et al[56]	Animal study	Adult male C57BL6N mice included in two groups: NCD or HFD	(1) Mice with a HFD have higher levels of endogenous thrombin; (2) Thrombin was considered as a stimulator of PAR-1-based signaling; (3) PAR signaling involved in the neuroinflammatory complications; and (4) HFD mice experience larger infarcts and worse outcomes after stroke induction
Wallace et al[21]	Review article	Summary of clinical and prospective cohort studies assessing the relationship of Mg with IL-6, a prominent drug target for treating COVID-19	(1) Nutrition plays an important and safe role in helping mitigate patient morbidity and mortality from COVID-19; (2) Mg participates in the function of many enzymes involved in the severe immune and inflammatory responses that are manifestations of COVID-19; (3) Mg modulates IL-6, NF-kB, and CRP; (4) Mg enhances vitamin D functionality; (5) Mg is essential in preventing the serious consequences of COVID-19; (6) K restores ACE2 functionality; and (7) Hypokalemia is seen in most patients with severe and critical COVID-19
Rhodes et al[2]	Perspective study	Review of the evidence relevant to vitamin D and COVID-19	(1) Vitamin D has potential to reduce COVID-19 risk, severity, and mortality; (2) Inflammation and cytokine storm suppression; (3) Inverse modulatory role in the renin-angiotensin system; (4) Downregulating renin and increasing ACE2; and (5) Inverse association between serum level of vitamin D and anti-phospholipid antibodies
Infusino et al[57]	Scoping review	Nutraceuticals and supplements studied thus far on COVID-19	(1) Vitamin E, D and C, carotenoids, minerals (Zn, Mn, Cu, and Se), polyphenols, and curcumin have benefit; and (2) Anti-inflammatory, anticoagulant, antioxidant, binding to SARS-CoV-2 target receptor, and antiviral properties

ACE: Angiotensin-converting enzyme; AIS: Acute ischemic stroke; COVID-19: Coronavirus disease 2019; CRP: C-reactive protein; Cu: Copper; DASH: Dietary approaches to stop hypertension; HDL: High density lipoproteins; HFD: High fat diet; IL-6: Interleukin-6; K: Potassium; LDL: Low density lipoproteins; Med-diet: Mediterranean dietary pattern; Mg: Magnesium; Mn: Manganese; NCD: Normal diet; PAR: Protease-activated receptor; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; SCFAs: Short-chain fatty acids; Se: Selenium; suppl: supplemented; Zn: Zinc.