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Review

The Mutual Relationship among Cardiovascular Diseases and COVID-19: Focus on Micronutrients Imbalance

1
Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
2
Anesthesiology and Intensive Care Unit, Sapienza University of Rome, Policlinico Umberto I, 00161 Rome, Italy
3
Medical Emergency Unit, Sapienza University of Rome, Policlinico Umberto I, 00185 Rome, Italy
4
Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Nutrients 2022, 14(16), 3439; https://doi.org/10.3390/nu14163439
Submission received: 24 July 2022 / Revised: 12 August 2022 / Accepted: 15 August 2022 / Published: 21 August 2022
(This article belongs to the Special Issue The Role of Nutrients on Cardio and Cerebrovascular Diseases)

Abstract

:
Micronutrients are ions and vitamins humbly required by the human body. They play a main role in several physiological mechanisms and their imbalance is strongly associated with potentially-fatal complications. Micronutrient imbalance is associated with many cardiovascular diseases, such as arrythmias, heart failure, and ischemic heart disease. It has been also observed in coronavirus disease 2019 (COVID-19), particularly in most severe patients. The relationship between cardiovascular diseases and COVID-19 is mutual: the latter triggers cardiovascular disease onset and worsening while patients with previous cardiovascular disease may develop a more severe form of COVID-19. In addition to the well-known pathophysiological mechanisms binding COVID-19 and cardiovascular diseases together, increasing importance is being given to the impact of micronutrient alterations, often present during COVID-19 and able to affect the balance responsible for a good functioning of the cardiovascular system. In particular, hypokalemia, hypomagnesemia, hyponatremia, and hypocalcemia are strongly associated with worse outcome, while vitamin A and D deficiency are associated with thromboembolic events in COVID-19. Thus, considering how frequent the cardiovascular involvement is in patients with COVID-19, and how it majorly affects their prognosis, this manuscript provides a comprehensive review on the role of micronutrient imbalance in the interconnection between COVID-19 and cardiovascular diseases.

Graphical Abstract

1. Introduction

Diet and a proper lifestyle are known to be very effective weapons in cardiovascular (CV) primary and secondary prevention, beyond the well-known role of pharmacological treatment [1,2]. Electrolytes, vitamins and oligoelements are involved in several physiological pathways and their imbalance has been associated with many CV diseases, such as arrythmias, ischemic heart disease and heart failure (HF). Moreover, the management of nutritional status, through the integration of micronutrients, is a main aspect to improve the general prognosis of patients, to reduce the risk of CV sequelae, and to prevent side effects caused by multidrug therapeutic approach. In this regard, the guidelines for the diagnosis and treatment of acute and chronic HF [3] suggest the importance of a precise control of micronutrient blood levels in HF patients. HF is known to be associated with sodium and potassium disorders, which relate to worse prognosis and to the unleashing of malignant arrhythmias [3].
In addition, coronavirus disease 2019 (COVID-19) is associated with electrolyte imbalance, due to the involvement of the angiotensin-converting enzyme 2 (ACE2) receptor, used by the virus to infect cells. In fact, in the most severe patients affected by COVID-19, different anomalies in fluid distribution and electrolytes concentration have been observed [4].
These subtle, but not indifferent, changes in micronutrients’ blood levels can weave a strong link between CV diseases and COVID-19. Thus, in addition to the major pathophysiological mechanisms that bind these two diseases together, increasing importance is being given to the impact of micronutrients alterations occurring during COVID-19 on the CV system (Figure 1).
Considering the frequency of CV involvement in COVID-19 patients and how it affects prognosis, the importance of studying and understanding the mechanisms that can self-amplify this relationship is substantial.
This review aims to shed light on the role of the imbalance of micronutrients in the interplay among COVID-19 and CV diseases.

2. Coronavirus Disease 2019 and Cardiovascular System

The most common clinical presentation of COVID-19 is a respiratory infection with interstitial pneumonia. Symptoms and signs frequently experienced include fever, dry cough, fatigue, muscle aches, shortness of breath, headache, diarrhea, indigestion, as well as fluid and electrolyte imbalances [4].
Cardiovascular diseases have high prevalence in patients with COVID-19. In particular, arterial hypertension can be found in 56.6% of patients, diabetes mellitus in 33.8%, and acute myocardial injury in 12% of hospitalized patients [5,6]. Patients with CV diseases are prone to develop a more severe form of COVID-19 [5,6,7]. The main CV symptoms experienced by COVID-19 patients are heart palpitations and chest tightness/pain, mostly experienced as early manifestations of the infection [8], but also during long COVID-19 [9,10,11,12]. There is strong evidence to support the interconnection among CV pathologies and COVID-19, leading to high rates of CV morbidity and mortality. In this regard, different hypotheses have been advanced: (a) direct CV injury determined by the virus, (b) aggressive immune response leading to a cytokine storm, (c) hypoxic injury due to severe pneumonia, (d) psychological injury (depression, fear, stress, anxiety) with noradrenergic overactivation, (e) vascular thrombosis, and (f) cardiac damage induced by drugs administered for COVID-19 [7,8,13,14]. Data show that COVID-19 patients, especially those ones affected by pre-existent CV diseases, are prone to develop CV complications, including myocardial injury, myocarditis, myocardial infarction, cardiac arrhythmias, cardiac arrest, venous thromboembolic disease, HF, and Takotsubo cardiomyopathy [15,16,17,18,19,20].
The mechanism of acute myocardial damage is half immune and half ischemic. They are connected to each other. Heart biopsy of COVID-19 patients showed degeneration of myocardial cells, necrosis and presence of inflammatory infiltrates [8,21,22,23,24], showing that myocardial injury is related to the inflammatory reaction against the virus. However, inflammation can also predispose to coronary atherosclerotic plaque rupture. Acute myocardial infarction was reported to be one of the common cardiac complications in COVID-19, together with arrythmias [8]. For instance, cardiac arrhythmias may result from hypokalemia, which is in turn stimulated by the known interaction between COVID-19 and the renin-angiotensin-aldosterone system (RAAS) [25,26].
Moreover, venous thromboembolic disease is promoted by the inflammatory state, but at the same time it predisposes to a hypercoagulability state [8,27,28,29].
As regards the relationship between HF and COVID-19, some hypotheses include deterioration of a pre-existing cardiac dysfunction, but also a new-onset cardiomyopathy or myocarditis, pulmonary hypertension, induced by lung involvement, infection, and acute pulmonary embolism [8,24,30].
Another major aspect to be concerned about when considering the effects of COVID-19 on the CV system is connected to fever. We know that fever is often part of the clinical presentation of symptomatic COVID-19 infections. Fever is known to relevantly affect the CV system first by leading to hypotension, which is most likely due to a redistribution of blood and to nitric oxide (NO)-induced vasodilation. Fever may also lead to several electrocardiogram abnormalities, including conduction defects, ST and QT changes, T wave abnormalities, and malignant arrhythmias. Moreover, it has also been associated to cardiac dysfunction and pulmonary oedema. Additionally, inflammatory response affects myocardium inducing cardiomyocytes damage [31]. Hyperthermia is also known to cause a plethora of metabolic abnormalities, including hypoxia, respiratory alkalosis, metabolic acidosis, and hypoglycemia. It can massively alter electrolytes homeostasis, leading to wide electrolytes imbalance [32]. All these pathophysiological alterations are shared among cardiovascular disease and COVID-19. In fact, the frequent myocardial involvement occurring in COVID-19 is demonstrated by the increase in relevant cardiac biomarkers, including creatine kinase isoenzyme-MB (CK-MB), N-terminal pro-brain natriuretic peptide (NT-proBNP), and high-sensitivity Troponin I (hs-cTnI) and T (hs-cTnT) [24,33].
COVID-19 has definitely impacted on CV diseases. It has represented a challenge for cardiologists worldwide and has forced the adoption of the maximal deployment of health resources, not only in the acute hospital scenario, but also in the outpatient setting [34,35,36,37].

3. Coronavirus Disease 2019 and Cardiovascular Diseases: The Role of Ions

Ions play a pivotal role in the maintenance of homeostasis in the human body, carefully regulated by their distribution in the intracellular and extracellular fluids. Sodium is the main electrolyte in the extracellular space (normal serum range: 135–145 mmol/l). On the other hand, potassium is mainly an intracellular ion (normal serum range: 3.6–5.5 mmol/l). Calcium is mostly present in the extracellular fluid (normal serum range: 8.8–10.7 mg/dL), whereas magnesium is mostly found in the intracellular compartment (normal serum range: 1.46–2.68 mg/dL). As for iron, despite being an essential trace element, it may be highly toxic in excess amounts, for which reason there are several mechanisms aimed at keeping its cellular and whole-body concentrations at the optimal range (body iron amounts range: 3–5 g). For what relates to zinc (normal serum range: 12–16 µM), it is mainly bound to albumin, α-macroglobulin, and transferrin, with only a sub-nanomolar concentration of free. Derangements in ion levels are associated with CV diseases, spanning from arrhythmias to atherosclerosis burden, from arterial blood pressure alterations to coagulation cascade imbalance. Interestingly, electrolyte disturbances have been reported in a substantial number of COVID-19 patients, mainly in the most severe patients, showing a significant impact on their prognosis.

3.1. Sodium

Sodium (Na+) is an essential cation that plays a major role in the regulation of blood volume, blood pressure, osmotic and acid-base equilibrium. Dysnatremia is the most common electrolyte disorder, with a prevalence between 15% and 20% in the hospital setting [38]. Furthermore, it is an independent risk factor for mortality, in hospitalized patients [39]. These data are also confirmed in COVID-19 patients, in which low Na+ levels are associated with an increased risk of encephalopathy and treatment with mechanical ventilation [40]. The most common cause of hyponatremia is the inappropriate antidiuretic hormone secretion syndrome (SIADH), which accounts for up to 40–50% of cases [41], particularly in patients with atypical viral pneumonia, such as COVID-19 [42]. Interestingly, desmopressin, the synthetic form of the antidiuretic hormone, also has a role in the release of coagulation factor VIII and von Willebrand factor by platelets. For this reason, it is used as a procoagulant treatment, for example, in von Willebrand’s disease. Therefore, the increased release of antidiuretic hormone, also called arginine vasopressin, in patients with SIADH-related hyponatremia may be one of the causes leading to the procoagulant state observed in COVID-19 [43].
Moreover, it has been proven that pro-inflammatory cytokines, such as Interleukin 1β (IL-1β) and 6 (IL-6), known to be the key components of the cytokine storm associated with COVID-19, can stimulate hypothalamic vasopressin secretion [44], leading to hyponatremia. This seems to suggest that low levels of Na+ may be associated with a stronger inflammatory condition. In fact, in a small retrospective study, it was shown that IL-6 levels were inversely proportional to serum Na+, with the lowest natremia in patients exhibiting the highest IL-6 levels [45].
However, even though hypernatremia is less common [46], this condition is a negative prognostic marker in critically-ill patients in intensive care unit (ICU) [47]. It has been shown that especially hospital-acquired hypernatremia is a predictor of mortality [48]. Hypernatremia reflects a deficit in total body fluids and, therefore, it suggests that volume depletion is a possible pathophysiological mechanism associated with poor outcomes.
The issue of fluid balance is crucial both in patients with COVID-19, who often present dehydration, and in HF, where patients frequently have fluid excess in the third space and are excessively dehydrated from the use of diuretics. Even if rehydration and volume repletion could be a reasonable therapeutic approach, conservative fluid regimens often need to be applied as a component of lung-protective strategies. This is also true in HF patients, where intravenous rehydration therapy must be administered more cautiously to avoid patient’s fluid overload.
In conclusion, natremia appears to deserve a strict control in both COVID-19 and CV patients, especially in those undergoing ion-depleting treatments, such as proton-pump inhibitors, diuretics, angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and non-steroidal anti-inflammatory drugs [49].

3.2. Magnesium

Magnesium (Mg++) is the fourth most abundant electrolyte in human cells, and it is mainly concentrated in the mitochondria. It is essential for basic biochemical reactions, participating in a cluster of physiological functions, such as cell cycle, muscle contraction, vasomotor tone [50], energy metabolism, and protein and nucleic acid synthesis [51]. Mg++ has anti-inflammation [52] and antioxidant potential [53]. It may induce vasodilation [54], neuroprotection [55] and immunomodulation [56].
Mg++ importance in CV physiology is well-known. It has been demonstrated that its deficiency is associated with an increased incidence of CV diseases [57], in particular arrhythmias, hypertension and atherosclerosis [58]. In fact, its supplementation can lower blood pressure [59], due to Mg++ having a similar property as the one of calcium-channel blockers, making it a physiological calcium antagonist [60]. It also participates in activation of K+ channels, promoting the cellular outflow of calcium (Ca++) ions and it inhibits cellular Ca++ influx and release from the sarcoplasmic reticulum. The result is membrane hyperpolarization and vasodilation. Moreover, it promotes increase in serum nitric oxide (NO) levels, playing an important role in physiological endothelial function and vascular smooth muscle cells relaxation [61,62]. Alterations of Mg++ blood levels as hypomagnesaemia have been found in patients hospitalized with COVID-19, appearing to be significantly correlated to patient’s prognosis. In fact, hypomagnesaemia has been associated with more severe cases of COVID-19 [63]. Alamdari et al. [64] demonstrated that patients with hypomagnesemia at hospital admission were at higher risk of mortality due to the COVID-19. These findings may be related to the high incidence of CV complications in COVID-19 patients, in which serum Mg++ levels may play an important stabilizing role. Furthermore, it has been demonstrated that Mg++ deficiency promotes endothelial dysfunction, increasing the susceptibility of endothelial cells to oxidative damage [65,66]. Endothelial dysfunction has a main role in coronary microvascular dysfunction and HF with preserved ejection fraction (HFpEF) [15,28,67,68,69,70,71].
Mg++ also has antithrombotic effects. In this regard, hypomagnesemia is associated with increased thrombotic risk and slowed fibrinolysis [72,73]. It reduces platelet aggregation, and it increases blood-clotting times in vivo [74]. Moreover, with its important role in membrane stabilization, Mg++ may help to prevent and treat arrhythmias, commonly observed in COVID-19 patients, and associated with negative prognosis [75].
Mg++ has also indirect benefits on the CV system, through its effect on the respiratory system. As a Ca++ antagonist, it inhibits bronchial smooth muscle contraction, promoting bronchodilation [76,77]. Moreover, through its anti-inflammatory and antioxidant power, it contrasts lung inflammation by inhibiting cytokines, such as IL-6, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, and Ca++ channels [78].

3.3. Potassium

Potassium (K+) is the most represented cation in the human body, with a 98% intracellular location, and only the remaining 2% in the extracellular space [79]. The intracellular K+ is critical for cell volume regulation, protein synthesis and transmembrane gradient creation. K+ is also a key determinant of the membrane potential, being essential for ion transportation across the membrane. Furthermore, it is involved in several physiological mechanisms [80], such as vascular tone and systemic blood pressure regulation, gastrointestinal motility, acid–base homeostasis, glucose, and insulin metabolism [81,82]. Several intra- and extra-renal mechanisms are involved in maintaining the K+ serum concentration within a narrow physiological range between 3.5 and 5.0 mEq/L [83].
K+ balance disorders are common among hospitalized patients, with an incidence of hypokalemia up to 21% compared to 2–3% of outpatients. Less common is hyperkalemia, which is detected in up to 3.3% of hospitalized patients, compared to 1% of outpatients [84,85]. Several studies have found a high incidence of K+ imbalance in COVID-19 patients, which seems to be one of the most common electrolyte disorders [86,87,88], independently affecting disease prognosis [89,90]. Tezcan et al. [91] reported high prevalence of hypokalemia among COVID-19 patients. Chen et al. [89] reported that hypokalemia was associated with disease severity. Furthermore, significantly lower levels of serum K+ in confirmed cases of COVID-19 compared with non-infected patients have been reported [92].
A plausible mechanism linking COVID-19 to hypokalemia could be related to ACE2 receptor degradation, after the virus has entered in host cells [93]. The consequent downregulation of ACE2 leads to an increased activity of RAAS, with hypokalemia related to potassium wasting through urine [94]. In addition, viral-mediated neurodegeneration and neuroinflammation may cause hypothalamic paraventricular nucleus and supraoptic nucleus dysfunction and reduced antidiuretic hormone production, leading to urinary potassium loss and hypokalemia [95]. Hypokalemic patients affected by COVID-19 have longer hospitalization and ICU permanence. Moreover, hypokalemia is prevalent in patients with COVID-19 pneumonia, and it represents an independent predictor of invasive mechanical ventilation [96]. Liu et al. found out that severe and moderate hypokalemia were associated with ICU admission [90].
Regarding hyperkalemia, it seems to be more related to kidney injury, which is not rare in hospitalized COVID-19 patients [97]. Huang et al. [98] found higher K+ levels in ICU patients than in patients not admitted to the ICU, showing that also elevated serum K+ is associated with the severity of illness. All these observations may be related to potentially life-threatening complications, such as cardiac dysrhythmias, paralysis, and rhabdomyolysis [99,100].
Coromilas et al. [101] conducted a retrospective analysis, collecting data of COVID-19 patients, and found out that almost 18% had new-onset arrhythmia, 43% of patients who developed arrhythmias were mechanically ventilated, and only 51% survived to hospital discharge. Elias et al. [102] reported arrhythmias’ prognostic value as regards early deterioration in patients with COVID-19 and the association with significant morbidity and mortality.
Hence, the investigation of the modifications of K+ serum level, its consequences on COVID-19 patients and the continuous CV monitoring in those patients is crucial [103].

3.4. Calcium

Ca++ plays an important role in several systemic functions. It’s involved in coagulation and platelet adhesion, myocardial contractility, and relaxation. Proteins involved in the coagulation system, such as C and S protein, as well as clotting factors II, VII, IX, and X, need calcium for their activation. Several studies demonstrated that there was a very high prevalence of hypocalcemia in patients affected by COVID-19 with a negative prognostic value [104,105].
Di Filippo et al. [106] investigated if hypocalcemia was a COVID-19 specific parameter, finding out that COVID-19 patients had lower calcium levels compared to patients without COVID-19, with a doubled rate of hypocalcemia. Other studies showed a lower Ca++ level in COVID-19 patients compared to the negative control group [107,108].
The mechanism through which COVID-19 is associated with serum Ca++ imbalance is still unknown. A potential factor may be gastrointestinal loss due to diarrhea and vomit [109]. Malnutrition and hypovitaminosis-D could reduce the absorption of calcium too. It can be also hypothesized that high viral load may cause Ca++ depletion because calcium ions are involved in viral life processes, such as regulating virus cell-entry, gene expression, and virion formation [110].
Ca++ plays an important role in maintaining heart and coagulation function [111,112,113]. Dysfunction of coagulation/fibrinolysis system can cause diffuse intravascular coagulation, which is a decisive factor in the death of COVID-19 patients and often related to the inflammatory cascade in which Ca++ levels can be involved [114,115,116].
It has been demonstrated that the level of coagulation factors like D-dimer and prothrombin is higher in hypocalcemic compared to normocalcemic COVID-19 patients and that there is a negative correlation between serum calcium and D-dimer levels [117,118].
Qi et al. [119] compared two groups of COVID-19 patients, one made up of patients with mild manifestations and the other made up of severe cases. They demonstrated that severe patients with a worse inflammation status related to a higher level of procalcitonin showed lower levels of Ca++. The severe cases showed higher levels of D-dimer and fibrin degradation product that could be related to a more severe coagulation dysfunction and consequently to a higher risk for thrombotic complications. Furthermore, severe patients showed a worse inflammation status related to a higher level of procalcitonin and calcitonin, which may explain why the Ca++ serum concentration was significantly reduced. In conclusion, decreased Ca++ levels and coagulation dysfunction in COVID-19 patients were related to each other and with the inflammatory status [119].
Due to its relationship with the inflammatory response and severity of COVID-19 manifestations, hypocalcemia has been related to a higher mortality. Several study cohorts demonstrated the relation between lower Ca++ levels at hospital admission and higher risk of in-hospital and 28-day mortality [91,120,121]. Limiting severe acute hypocalcemia could protect from CV and neurological complications that may be fatal. For this reason, a good supplementation of calcium and albumin, but also of Vitamin D, may reduce multiorgan injury [122].

3.5. Iron

Iron is a key element in major human biochemical processes, such as deoxyribonucleic acid (DNA) replication, cellular respiration, and immune defense. Iron can donate or accept electrons because it can shift in two different oxidative forms: divalent (Fe++) or trivalent (Fe+++). However, its blood level needs to be tightly controlled as a low iron level as well as a high blood level can be very dangerous [123].
Iron is generally not an easily-accessible element in the human body. It is mostly stored safely inside the erythrocytes. A low percentage of extracellular iron travels bound to transferrin or to other molecules. Iron is a growth factor and an energetic source, also for pathogens. Many microbes use hemolysis as a damage mechanism to afflict the host and to recover iron sources. The consequent massive release of free iron into the circulation can also cause oxidative damage and immunity inhibition [124,125]. For self-protection during inflammation, macrophages and neutrophils are induced by cytokines to produce hepcidin, responsible for circulating iron levels reduction [126,127]. This is in line with many COVID-19 studies [122,123,124]. In fact, patients admitted to hospital for COVID-19 had a lower level of hemoglobin than other patients [128,129].
Fan et al. [130] compared laboratory data between patients with COVID-19 admitted to ICU and not, finding a significantly lower hemoglobin value in the first group.
In the meta-analysis of Taneri et al. [128], a significant lower hemoglobin value was found in more severe COVID-19 group. Moreover, this difference was greater in patients with systemic arterial hypertension or severe form of infection. In fact, during chronic and prolonged infections, a vicious circle is thus created: the organism tries to defend itself by decreasing the iron levels, but the resulting anemia can aggravate the infection itself, as well as its comorbidities and complications. For this reason, iron therapy during infectious diseases is much debated. In this context, the reduction of iron intake by uptaking chelating agents as adjuvant COVID-19 therapy has been suggested, considering that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), like other viruses, requires iron to carry out replicative cycles [131,132]. In fact, hereditary diseases with iron storage dramatically increase susceptibility to severe infections. In this regard, several studies have shown that iron deficiency is crucial in depressing the immune response [131,133], even more impactful in special populations. In children, for example, anemia is significantly associated with repeated infections of the respiratory and gastroenteric tract [131,134].
Furthermore, HF patients may benefit from iron supplementation [3,131,135]. Iron deficiency and anemia are frequent comorbidities in CV diseases. In HF they represent an independent condition predisposing to CV and overall mortality, rehospitalization, quality of life and symptoms worsening [3,136,137,138]. In HF patients, iron deficiency affects about 50% of the population with a prevalence of 80%, in patients with acute HF [139,140,141,142,143]. Several mechanisms are associated with iron deficiency in both heart failure with reduced ejection fraction (HFrEF) and HFpEF, such as reduced absorption, loss and hyperactivation of systemic inflammatory response [144,145]. The importance of iron supplementation with ferric carboxymaltose in HF patients has been demonstrated [146,147]. Beyond HF, the impact of iron deficiency and the effects of iron supplementation have been evaluated in other CV diseases, which have been often described as COVID-19-related CV complications. As regards, the Effect of Iron Repletion in Atrial Fibrillation study (IRON-AF) will evaluate the role of ferric carboximaltose supplementation in patients with atrial fibrillation and iron deficiency [148]. Iron deficiency has been also described by Vinke et al. in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension [149]. Moreover, in the setting of atherosclerosis and coronary syndromes, iron may have a pivotal role. It is involved in oxidative stress, low-density lipoprotein (LDL) oxidation and inflammation [150]. Meng et al. [151] reported that reduced circulating iron values were a predictor of coronary atherosclerosis.

3.6. Zinc

Zinc (Zn++) is a vital mineral involved in many physiological processes in the human body. First, it contributes to cellular immunity against bacteria and viruses by activating NF-kB, regulating inflammatory cytokine release [152]. Second, it plays a role in the synthesis of NO and in the suppression of reactive oxygen species (ROS), during inflammatory processes [153]. As a result, Zn++ deficiency is associated with oxidative stress [154]. NO signaling promotes vasodilation, increased blood flow, and a reduction in plaque development and progression [155,156]. When this pathway is disrupted, together with abnormal ROS and NF-kB signaling, the groundwork for atherosclerosis is laid [157]. Thus, it is hypothesized that Zn++ may minimize atherosclerotic disease by increasing NO production and NF-kB signaling, as well as by reducing oxidative stress induced by endothelial dysfunction [158].
Zn++ has also been demonstrated to exert an inotropic impact on the heart, inhibiting cardiomyocyte systolic activity and increasing relaxation function by lowering intracellular Ca++ levels [159].
Due to Zn++ related antiviral and pro-cardiogenic qualities, it may have a pivotal role in COVID-19 patients, particularly those with CV complications [158]. A critical factor supporting this hypothesis is the fact that the SARS-CoV-2 receptor, ACE2, is a Zn++-regulated metalloprotein [158]. ACE2 works by converting angiotensin II to angiotensin (1–7), causing vasodilation [158]. ACE2 is an important player in the RAAS because it inhibits the actions of Angiotensin II [160]. The lowering ACE2 expression, often observed in COVID-19 patients, has a negative impact on a variety of diseases, such as arterial hypertension, diabetes mellitus, and CV diseases [161,162]. Extra Zn++ supplementation may help to activate or upregulate functional ACE2 expression, restoring the functional balance of ACE2 [158].
Another mechanism by which Zn++ may be beneficial is by inhibiting SARS-CoV-2 replication through the inhibition of elongation and template binding of SARS-CoV RNA-dependent RNA polymerase [163]. Zn++ is also essential for autophagy, which is especially important during viral infections [158]. According to a prospective research, Zn++ deficiency was associated with more serious complications and an increased length of hospital stay and death, in COVID-19 patients [164].
A summary of ion imbalance effects on CV diseases and COVID-19 is represented in Table 1.

4. Coronavirus Disease 2019 and Cardiovascular Diseases: The Role of Vitamins

Both lipo-soluble and hydro-soluble vitamins are intimately involved in the regulation of different metabolic pathways, concerning energy production, cellular homeo-stasis and clearing of catabolites. Consequently, deficiency in some vitamins is associated with CV diseases, whereas supplementation in these vitamins has been proven beneficial in preventing different kinds of CV alterations. The same is true for COVID-19, where it has been seen that lower levels of some vitamins were linked to worse outcomes.

4.1. Vitamin A

Vitamin A is a fat-soluble vitamin with a broad range of immunological effects. Its deficiency is associated with recurrent infections [165]. The protective role of vitamin A supplementation against various infections has been demonstrated [165]. In this regard, significantly lower vitamin A serum levels in patients with severe COVID-19 symptoms have been observed [166]. Most likely, this is due to the inflammation itself rather than a direct effect of vitamin A deficiency during the illness, suggesting that supplementation may be needed to restore the normal status [167]. A positive association between plasma retinol and dyslipidemia has been pointed out [168], as well as a significant reduction of overall CV and respiratory-disease-related mortality in male patients with higher levels of vitamin A [169].

4.2. Vitamin B

The vitamin B complex is made by eight different water-soluble constituents that humans must absorb from the diet. Deficiency of B12 and B9 is mostly known as it results in megaloblastic anemia. However, a significant role of vitamin B, particularly B6, B9 and B12, in the immune response has been demonstrated too [170]. In particular, it has been shown that vitamin B12 could suppress viral replication in the host cells [171]. Dos Santos et al. hypothesized a therapeutic role of vitamin B12 because it could reduce severe CV sequelae of COVID-19, through the reduction of oxidative stress, anti-inflammatory and analgesic effect [172]. It is well known that vitamin B6, B9 and B12 also contribute to the reduction of blood homocysteine concentrations, which are related to an increased risk of coronary artery disease and stroke. [173,174]. Similarly, deficiency in B1 has been associated with a higher prevalence of CV risk factors as dyslipidemia, obesity and diabetes [175]. Interestingly, B9 supplementation has been shown to improve the endothelial dysfunction by increasing endothelial nitric oxide production and by scavenging superoxide radicals [176], which suggests a possible beneficial role in COVID-19 patients, where endothelial dysfunction is known to be one of the leading causes of mortality. However, despite this theoretical evidence, vitamin B group supplementation has no significant effect on major adverse CV events, overall mortality, cardiac death, myocardial infarction, and stroke [177], while B12 supplementation was shown to decrease the severity of COVID-19 symptoms [178].

4.3. Vitamin C

Vitamin C is known for its antioxidant effects and its role in immunomodulation. Due to its ability to readily donate electrons, it protects LDL from oxidation. Different studies have shown its role in reducing harmful oxidants in the stomach and promoting iron absorption [179], as well as protecting cells during exposure to toxins and pollutants [180].
As for its immunomodulation effect, its action on lymphocytes is not completely clear, but it has been proven that vitamin C regulates genes responsible for B and T cell generation, differentiation, and proliferation. Moreover, amongst its pleiotropic effects, it has been reported to have an antithrombotic function by inhibiting platelet expression of CD40 ligand [181,182] and another important role as co-factor to produce catecholamines, vasopressin, norepinephrine, and cortisol, in the human body [183,184]. This last evidence provides the rationale for evaluating intravenous vitamin C administration in septic shock to achieve a sparing effect on vasopressor requirements [177]. Early trials have indicated some potentially beneficial effects of intravenous vitamin C also in severe COVID-19 patients [185,186]. The upcoming findings from the larger randomized control trials currently underway, such as the Lessening Organ Dysfunction with Vitamin C-COVID (LOVIT-COVID) trial, should provide more definitive evidence (NCT04401150).

4.4. Vitamin D

Vitamin D plays a central role in the absorption of Ca++, Mg ++, and phosphate, as well as in the bone metabolism. Strong evidence suggests a critical role for vitamin D in the modulation of the immune function [187]. Furthermore, vitamin D deficiency has been reported in several chronic conditions associated with increased inflammation and deregulation of the immune system, such as diabetes mellitus, asthma, and rheumatoid arthritis [187]. Similarly, an association between vitamin D deficiency and inflammation was shown in patients with COVID-19. In a prospective study by Jain et al. [188], serum 25(OH)D concentrations were significantly lower in patients requiring ICU admission than in asymptomatic patients with COVID-19. Moreover, epidemiological data indicate that vitamin D deficiency in humans is associated with arterial stiffness, arterial hypertension, left ventricular hypertrophy, and endothelial dysfunction, implying that vitamin D might also have a protective role in CV diseases, and that it may lower the risk for HF [189].
It is well known that diabetes mellitus is associated with an increased risk for severe COVID-19, as hyperglycemia might modulate immune and inflammatory response leading to possible lethal outcomes [190]. Vitamin D insufficiency plays a negative role in this dysregulation, leading to impaired glucose homeostasis. In fact, Vitamin D is essential for pancreatic β-cell functioning and insulin sensitivity. It plays a role in controlling gene transcription and cell signaling, alleviating the onset of insulin resistance, especially in adipose tissue [191].
For what concerns the CV system, data from several experimental studies support the anti-fibrotic and anti-hypertrophic role of Vitamin D, suggesting that it has a beneficial role against cardiac dysfunction, hypertrophy, and fibrosis [192,193].
Vitamin D is also involved in the regulation of the RAAS even though the mechanism is not completely understood [194]. It has been reported that vitamin D3 supplementation reduces blood pressure in patients with essential arterial hypertension [195,196] and 1,25(OH)2D3 treatment reduces blood pressure, plasma renin activity, and angiotensin II levels, in patients affected by hyperparathyroidism [197,198]. Moreover, it has been shown that Vitamin D is also involved in the regulation of thrombotic pathways, and its deficiency is associated with an increase of thrombotic episodes probably because it allows the production of certain neuroprotective growth factors and inhibition of ROS [199,200]. This finding is of crucial importance when looking at COVID-19, since vascular thrombosis is one of the most serious complications often leading to death.

4.5. Vitamin E

Vitamin E is a fat-soluble vitamin, primarily known for its role as an antioxidant. It appears to prevent the polyunsaturated fatty acids (PUFAs) in the cell-membrane from oxidation, regulate the production of ROS and reactive nitrogen species, and modulate cell signaling. Immune cells are particularly sensitive to oxidative damage due to their high metabolic activity and PUFAs contents [201]. Therefore, vitamin E plays an important role in fostering the immune system. Vitamin E has also been shown to have suppressor effects on prostaglandin E2 (PGE2) synthesis, which is an important T cell-suppressing mediator.
Furthermore, it is well known that one of the key complications of the respiratory distress syndrome associated with severe COVID-19 is acute cardiac injury [202], which is associated with oxidative stress, characterized by enhanced nicotinamide adenine dinucleotide phosphate oxidase2 (NOX2) activity, activation of platelets phospholipase A, and excess of PGE2 [203].
Moreover, other effects of Vitamin E on CV diseases have been investigated in basic science trials, showing a preventive role of α-tocopherol, the biologically most active form of vitamin E, in CV diseases [204,205,206]. These beneficial effects include inhibition of cell proliferation and LDL oxidation by modulating protein kinase C (PKC) activity [204], protection against atherosclerotic lesion development and aorta damage [205], and a reduction of apoptotic activity in cardiomyocytes [206].
Thus, because of its proven antioxidant effects and its theoretical beneficial effects against plaque formation, an anti-oxidative therapy with Vitamin E could be proposed to reduce the burden of cardiac complications caused by COVID-19 [207].

4.6. Vitamin K

Vitamin K is a fat-soluble vitamin necessary for the synthesis and activation of both procoagulant or anticoagulant factors. Most importantly, protein S, a vitamin K-dependent glycoprotein, not only has a major role in the anti-coagulation pathway, but also prevents the production of inflammatory cytokines associated with the cytokine storm observed in acute lung, liver and heart injury seen in COVID-19 patients [208]. Low protein S levels, often due to pneumonia-induced vitamin K depletion, were correlated lately with higher thrombogenicity, clinical severity, and fatal outcome in COVID-19 patients, independently of age or inflammatory biomarkers [209]. Furthermore, ample evidence has shown that vitamin K exerts a potent calcification-inhibitory function by allowing carboxylation of Matrix Gla Protein [210].
A summary regarding the relationship among vitamins, CV diseases, and COVID-19 is reported in Table 2.

5. Conclusions

Although the human body needs very small quantities of micronutrients, their importance for human physiology is relevant [211]. The deficiency of electrolytes and vitamins is widespread in hospitalized patients, and it is strongly related to potential life-threatening conditions. Adequate nutrition and supplementation are pivotal to reduce the risks associated with micronutrients imbalance [211].
Micronutrient imbalance has been extensively observed in patients with CV disease and COVID-19, significantly worsening their prognosis. The causal relationship between COVID-19 and cardiovascular diseases is mutual. In fact, COVID-19 has been shown to affect the CV system extensively and, at the same time, patients affected by a CV disease are more prone to develop a severe infection form. Apart from the already well-known pathophysiological mechanisms promoting CV diseases in the setting of COVID-19 infection, derangements in the concentration of several important micronutrients, such as ions and vitamins, may have a non-negligible role in the pathophysiological continuum between these two entities. In particular, hypokalemia is a very common electrolytes imbalance in COVID-19, and it is associated with cardiac arrythmias [84,89]. Hyponatremia is an independent risk factor for mortality in COVID-19 patients, related to worse patient’s prognosis affecting blood volume regulation, osmotic equilibrium, and arterial pressure [38,40]. Hypomagnesemia at hospital admission has been associated with a higher risk of mortality and arrythmias in COVID-19 [63,64]. Vitamin D deficiency has been associated with thromboembolic events [199,200], endothelial dysfunction, left ventricular hypertrophy [189], and it is more frequent in patients admitted to ICU. Vitamin A deficiency is associated with COVID-19 symptoms severity and lipid metabolism imbalance [166,169], while vitamin E and C are closely related to good functioning of the immune system [177,201] and cardioprotection [181,182,204,205,206].

Author Contributions

Conceptualization (P.S., P.C., G.G., V.M. (Vincenzo Maestrini), G.d., M.M. and F.F.); Data curation (A.D., S.P., V.M. (Vincenzo Myftari), A.L.F., M.Ö., C.N., I.P., E.S.C., M.Y.R. and L.I.B.); Writing—original draft preparation (A.D., S.P., V.M. (Vincenzo Myftari), A.L.F., M.Ö., C.N., I.P., E.S.C., M.Y.R. and L.I.B.); Writing—review and editing (P.S., L.I.B., P.C., G.G., V.M. (Viviana Maestrini), G.d., M.M. and F.F.); Visualization (A.D., S.P., A.L.F., C.N., I.P. and E.S.C.); Supervision (F.F.). All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Vest, A.R.; Chan, M.; Deswal, A.; Givertz, M.M.; Lekavich, C.; Lennie, T.; Litwin, S.E.; Parsly, L.; Rodgers, J.E.; Rich, M.W.; et al. Nutrition, Obesity, and Cachexia in Patients With Heart Failure: A Consensus Statement from the Heart Failure Society of America Scientific Statements Committee. J. Card. Fail. 2019, 25, 380–400. [Google Scholar] [CrossRef]
  2. Bozkurt, B.; Aguilar, D.; Deswal, A.; Dunbar, S.B.; Francis, G.S.; Horwich, T.; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; Council on Hypertension; et al. Contributory risk and management of comorbidities of hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome in chronic heart failure: A scientific statement from the American Heart Association. Circulation 2016, 134, e535–e578. [Google Scholar] [CrossRef]
  3. McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Böhm, M.; Burri, H.; Butler, J.; Čelutkienė, J.; Chioncel, O.; et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 2021, 42, 3599–3726. [Google Scholar] [CrossRef]
  4. Pourfridoni, M.; Abbasnia, S.M.; Shafaei, F.; Razaviyan, J.; Heidari-Soureshjani, R. Fluid and Electrolyte Disturbances in COVID-19 and Their Complications. Biomed. Res. Int. 2021, 2021, 6667047. [Google Scholar] [CrossRef]
  5. Maestrini, V.; Birtolo, L.I.; Francone, M.; Galardo, G.; Galea, N.; Severino, P.; Alessandri, F.; Colaiacomo, M.C.; Cundari, G.; Chimenti, C.; et al. Cardiac involvement in consecutive unselected hospitalized COVID-19 population: In-hospital evaluation and one-year follow-up. Int. J. Cardiol. 2021, 339, 235–242. [Google Scholar] [CrossRef]
  6. Azevedo, R.B.; Botelho, B.G.; Hollanda, J.V.G.; Ferreira, L.V.L.; Junqueira de Andrade, L.Z.; Oei, S.S.M.L.; Mello, T.S.; Muxfeldt, E.S. COVID-19 and the cardiovascular system: A comprehensive review. J. Hum. Hypertens. 2021, 35, 4–11. [Google Scholar] [CrossRef]
  7. Mitacchione, G.; Schiavone, M.; Curnis, A.; Arca, M.; Antinori, S.; Gasperetti, A.; Mascioli, G.; Severino, P.; Sabato, F.; Caracciolo, M.M.; et al. Impact of prior statin use on clinical outcomes in COVID-19 patients: Data from tertiary referral hospitals during COVID-19 pandemic in Italy. J. Clin. Lipidol. 2021, 15, 68–78. [Google Scholar] [CrossRef]
  8. Luo, J.; Zhu, X.; Jian, J.; Chen, X.; Yin, K. Cardiovascular disease in patients with COVID-19: Evidence from cardiovascular pathology to treatment. Acta Biochim. Biophys. Sin. 2021, 53, 273–282. [Google Scholar] [CrossRef]
  9. Chilazi, M.; Duffy, E.Y.; Thakkar, A.; Michos, E.D. COVID and Cardiovascular Disease: What We Know in 2021. Curr. Atheroscler. Rep. 2021, 23, 37. [Google Scholar] [CrossRef]
  10. Greenhalgh, T.; Knight, M.; A’Court, C.; Buxton, M.; Husain, L. Management of post-acute covid-19 in primary care. BMJ 2020, 370, m3026. [Google Scholar] [CrossRef]
  11. Dani, M.; Dirksen, A.; Taraborrelli, P.; Torocastro, M.; Panagopoulos, D.; Sutton, R.; Lim, P.B. Autonomic dysfunction in ‘long COVID’: Rationale, physiology and management strategies. Clin. Med. 2021, 21, e63–e67. [Google Scholar] [CrossRef]
  12. Tenforde, M.W.; Kim, S.S.; Lindsell, C.J.; Billig Rose, E.; Shapiro, N.I.; Files, D.C.; Gibbs, K.W.; Erickson, H.L.; Steingrub, J.S.; Smithline, H.A.; et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network-United States, March–June 2020. MMWR Morb. Mortal. Wkly Rep. 2020, 69, 993–998. [Google Scholar] [CrossRef]
  13. Adams, J.G.; Walls, R.M. Supporting the health care workforce during the COVID-19 global epidemic. JAMA 2020, 323, 1439–1440. [Google Scholar] [CrossRef] [Green Version]
  14. Wang, C.; Pan, R.; Wan, X.; Tan, Y.; Xu, L.; Ho, C.S.; Ho, R.C. Immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (COVID-19) epidemic among the general population in China. Int. J. Environ. Res. Public Health 2020, 17, 1729. [Google Scholar] [CrossRef] [Green Version]
  15. Cenko, E.; Badimon, L.; Bugiardini, R.; Claeys, M.J.; De Luca, G.; de Wit, C.; Derumeaux, G.; Dorobantu, M.; Duncker, D.J.; Eringa, E.C.; et al. Cardiovascular disease and COVID-19: A consensus paper from the ESC Working Group on Coronary Pathophysiology & Microcirculation, ESC Working Group on Thrombosis and the Association for Acute CardioVascular Care (ACVC), in collaboration with the European Heart Rhythm Association (EHRA). Cardiovasc. Res. 2021, 117, 2705–2729. [Google Scholar] [CrossRef]
  16. Driggin, E.; Madhavan, M.V.; Bikdeli, B.; Chuich, T.; Laracy, J.; Biondi-Zoccai, G.; Brown, T.S.; Der Nigoghossian, C.; Zidar, D.A.; Haythe, J.; et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J. Am. Coll. Cardiol. 2020, 75, 2352–2371. [Google Scholar] [CrossRef]
  17. Deng, S.Q.; Peng, H.J. Characteristics of and public health responses to the coronavirus disease 2019 outbreak in China. J. Clin. Med. 2020, 9, 575. [Google Scholar] [CrossRef] [Green Version]
  18. Zhang, Y.; Coats, A.J.S.; Zheng, Z.; Adamo, M.; Ambrosio, G.; Anker, S.D.; Butler, J.; Xu, D.; Mao, J.; Khan, M.S.; et al. Management of heart failure patients with COVID-19: A joint position paper of the Chinese Heart Failure Association & National Heart Failure Committee and the Heart Failure Association of the European Society of Cardiology. Eur. J. Heart Fail. 2020, 22, 941–956. [Google Scholar] [CrossRef]
  19. Chen, T.; Wu, D.; Chen, H. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: Retrospective study. BMJ 2020, 368, m1091. [Google Scholar] [CrossRef] [Green Version]
  20. Chen, N.; Zhou, M.; Dong, X.; Qu, J.; Gong, F.; Han, Y.; Qiu, Y.; Wang, J.; Liu, Y.; Wei, Y.; et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020, 395, 507–513. [Google Scholar] [CrossRef] [Green Version]
  21. Sandoval, Y.; Smith, S.W.; Sexter, A.; Thordsen, S.E.; Bruen, C.A.; Carlson, M.D.; Dodd, K.W.; Driver, B.E.; Hu, Y.; Jacoby, K.; et al. Type 1 and 2 myocardial infarction and myocardial injury: Clinical transition to high-sensitivity cardiac troponin I. Am. J. Med. 2017, 130, 1431–1439.e4. [Google Scholar] [CrossRef] [Green Version]
  22. Sarkisian, L.; Saaby, L.; Poulsen, T.S.; Gerke, O.; Jangaard, N.; Hosbond, S.; Diederichsen, A.C.; Thygesen, K.; Mickley, H. Clinical characteristics and outcomes of patients with myocardial infarction, myocardial injury, and non elevated troponins. Am. J. Med. 2016, 129, 446.e5–446.e21. [Google Scholar] [CrossRef]
  23. Xu, Z.; Shi, L.; Wang, Y.; Zhang, J.; Huang, L.; Zhang, C.; Liu, S.; Zhao, P.; Liu, H.; Zhu, L.; et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 2020, 8, 420–422. [Google Scholar] [CrossRef]
  24. Chimenti, C.; Magnocavallo, M.; Ballatore, F.; Bernardini, F.; Alfarano, M.; Della Rocca, D.G.; Severino, P.; Lavalle, C.; Francesco, F.; Frustaci, A. Prevalence and Clinical Implications of COVID-19 Myocarditis. Card. Electrophysiol. Clin. 2022, 14, 53–62. [Google Scholar] [CrossRef]
  25. Tajbakhsh, A.; Gheibi Hayat, S.M.; Taghizadeh, H.; Akbari, A.; Inabadi, M.; Savardashtaki, A.; Johnston, T.P.; Sahebkar, A. COVID-19 and cardiac injury: Clinical manifestations, biomarkers, mechanisms, diagnosis, treatment, and follow up. Expert Rev. Anti Infect. Ther. 2021, 19, 345–357. [Google Scholar] [CrossRef]
  26. Kochi, A.N.; Tagliari, A.P.; Forleo, G.B.; Fassini, G.M.; Tondo, C. Cardiac and arrhythmic complications in patients with COVID-19. J. Cardiovasc. Electrophysiol. 2020, 31, 1003–1008. [Google Scholar] [CrossRef] [Green Version]
  27. Connors, J.M.; Levy, J.H. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020, 135, 2033–2040. [Google Scholar] [CrossRef]
  28. Severino, P.; D’Amato, A.; Pucci, M.; Infusino, F.; Adamo, F.; Birtolo, L.I.; Netti, L.; Montefusco, G.; Chimenti, C.; Lavalle, C.; et al. Ischemic Heart Disease Pathophysiology Paradigms Overview: From Plaque Activation to Microvascular Dysfunction. Int. J. Mol. Sci. 2020, 21, 8118. [Google Scholar] [CrossRef]
  29. Della Rocca, D.G.; Magnocavallo, M.; Lavalle, C.; Romero, J.; Forleo, G.B.; Tarantino, N.; Chimenti, C.; Alviz, I.; Gamero, M.T.; Garcia, M.J.; et al. Evidence of systemic endothelial injury and microthrombosis in hospitalized COVID-19 patients at different stages of the disease. J. Thromb. Thrombolysis 2021, 51, 571–576. [Google Scholar] [CrossRef]
  30. Zhou, F.; Yu, T.; Du, R.; Fan, G.; Liu, Y.; Liu, Z.; Xiang, J.; Wang, Y.; Song, B.; Gu, X.; et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020, 395, 1054–1062. [Google Scholar] [CrossRef]
  31. Walter, E.J.; Hanna-Jumma, S.; Carraretto, M.; Forni, L. The pathophysiological basis and consequences of fever. Crit. Care 2016, 20, 200. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Simon, H.B. Hyperthermia. N. Engl. J. Med. 1993, 329, 483–487. [Google Scholar] [CrossRef] [PubMed]
  33. Han, H.; Xie, L.; Liu, R.; Yang, J.; Liu, F.; Wu, K.; Chen, L.; Hou, W.; Feng, Y.; Zhu, C. Analysis of heart injury laboratory parameters in 273 COVID-19 patients in one hospital in Wuhan, China. J. Med. Virol. 2020, 92, 819–823. [Google Scholar] [CrossRef] [PubMed]
  34. Severino, P.; D’Amato, A.; Prosperi, S.; Magnocavallo, M.; Maraone, A.; Notari, C.; Papisca, I.; Mancone, M.; Fedele, F. Clinical Support through Telemedicine in Heart Failure Outpatients during the COVID-19 Pandemic Period: Results of a 12-Months Follow Up. J. Clin. Med. 2022, 11, 2790. [Google Scholar] [CrossRef]
  35. Piro, A.; Magnocavallo, M.; Della Rocca, D.G.; Neccia, M.; Manzi, G.; Mariani, M.V.; Straito, M.; Bernardini, A.; Severino, P.; Iannucci, G.; et al. Management of cardiac implantable electronic device follow-up in COVID-19 pandemic: Lessons learned during Italian lockdown. J. Cardiovasc. Electrophysiol. 2020, 31, 2814–2823. [Google Scholar] [CrossRef] [PubMed]
  36. Magnocavallo, M.; Vetta, G.; Bernardini, A.; Piro, A.; Mei, M.C.; Di Iorio, M.; Mariani, M.V.; Della Rocca, D.G.; Severino, P.; Quaglione, R.; et al. Impact of COVID-19 Pandemic on Cardiac Electronic Device Management and Role of Remote Monitoring. Card. Electrophysiol. Clin. 2022, 14, 125–131. [Google Scholar] [CrossRef]
  37. Severino, P.; D’Amato, A.; Saglietto, A.; D’Ascenzo, F.; Marini, C.; Schiavone, M.; Ghionzoli, N.; Pirrotta, F.; Troiano, F.; Cannillo, M.; et al. Reduction in heart failure hospitalization rate during coronavirus disease 19 pandemic outbreak. ESC Heart Fail. 2020, 7, 4182–4188. [Google Scholar] [CrossRef]
  38. Spasovski, G.; Vanholder, R.; Allolio, B.; Annane, D.; Ball, S.; Bichet, D.; Decaux, G.; Fenske, W.; Hoorn, E.J.; Ichai, C.; et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol. Dial. Transplant. 2014, 29 (Suppl. 2), i1–i39. [Google Scholar] [CrossRef] [Green Version]
  39. Hoorn, E.J.; Betjes, M.G.; Weigel, J.; Zietse, R. Hypernatraemia in critically ill patients: Too little water and too much salt. Nephrol. Dial. Transplant. 2008, 23, 1562–1568. [Google Scholar] [CrossRef] [Green Version]
  40. Frontera, J.A.; Valdes, E.; Huang, J.; Lewis, A.; Lord, A.S.; Zhou, T.; Kahn, D.E.; Melmed, K.; Czeisler, B.M.; Yaghi, S.; et al. Prevalence and Impact of Hyponatremia in Patients With Coronavirus Disease 2019 in New York City. Crit. Care Med. 2020, 48, e1211–e1217. [Google Scholar] [CrossRef]
  41. Cuesta, M.; Thompson, C.J. The syndrome of inappropriate antidiuresis (SIAD). Best Pract. Res. Clin. Endocrinol. Metab. 2016, 30, 175–187. [Google Scholar] [CrossRef]
  42. Cuesta, M.; Slattery, D.; Goulden, E.L.; Gupta, S.; Tatro, E.; Sherlock, M.; Tormey, W.; O’Neill, S.; Thompson, C.J. Hyponatraemia in patients with community-acquired pneumonia; prevalence and aetiology, and natural history of SIAD. Clin. Endocrinol. 2019, 90, 744–752. [Google Scholar] [CrossRef] [PubMed]
  43. Sjöström, A.; Rysz, S.; Sjöström, H.; Höybye, C. Electrolyte and acid-base imbalance in severe COVID-19. Endocr. Connect. 2021, 10, 805–814. [Google Scholar] [CrossRef] [PubMed]
  44. Swart, R.M.; Hoorn, E.J.; Betjes, M.G.; Zietse, R. Hyponatremia and Inflammation: The Emerging Role of Interleukin-6 in Osmoregulation. Nephron. Physiol. 2011, 118, p45–p51. [Google Scholar] [CrossRef] [PubMed]
  45. Berni, A.; Malandrino, D.; Parenti, G.; Maggi, M.; Poggesi, L.; Peri, A. Hyponatremia, IL-6, and SARS-CoV-2 (COVID-19) infection: May all fit together? J. Endocrinol. Invest. 2020, 43, 1137–1139. [Google Scholar] [CrossRef]
  46. Hirsch, J.S.; Uppal, N.N.; Sharma, P.; Khanin, Y.; Shah, H.H.; Malieckal, D.A.; Bellucci, A.; Sachdeva, M.; Rondon-Berrios, H.; Jhaveri, K.D.; et al. Prevalence and outcomes of hyponatremia and hypernatremia in patients hospitalized with COVID-19. Nephrol. Dial. Transplant. 2021, 36, 1135–1138. [Google Scholar] [CrossRef]
  47. Olsen, M.H.; Møller, M.; Romano, S.; Andersson, J.; Mlodzinski, E.; Raines, N.H.; Sherak, R.; Jeppesen, A.N. Association Between ICU-Acquired Hypernatremia and In-Hospital Mortality: Data From the Medical Information Mart for Intensive Care III and the Electronic ICU Collaborative Research Database. Crit. Care Explor. 2020, 2, e0304. [Google Scholar] [CrossRef]
  48. Tzoulis, P.; Waung, J.A.; Bagkeris, E.; Hussein, Z.; Biddanda, A.; Cousins, J.; Dewsnip, A.; Falayi, K.; McCaughran, W.; Mullins, C.; et al. Dysnatremia is a Predictor for Morbidity and Mortality in Hospitalized Patients with COVID-19. J. Clin. Endocrinol. Metab. 2021, 106, 1637–1648. [Google Scholar] [CrossRef]
  49. Zhang, X.; Li, X.Y. Prevalence of hyponatremia among older inpatients in a general hospital. Eur. Geriatr. Med. 2020, 11, 685–692. [Google Scholar] [CrossRef]
  50. Gröber, U.; Schmidt, J.; Kisters, K. Magnesium in Prevention and Therapy. Nutrients 2015, 7, 8199–8226. [Google Scholar] [CrossRef] [Green Version]
  51. Dominguez, L.J.; Veronese, N.; Guerrero-Romero, F.; Barbagallo, M. Magnesium in Infectious Diseases in Older People. Nutrients 2021, 13, 180. [Google Scholar] [CrossRef] [PubMed]
  52. Rochelson, B.; Dowling, O.; Schwartz, N.; Metz, C.N. Magnesium sulfate suppresses inflammatory responses by human umbilical vein endothelial cells (HuVECs) through the NFkappaB pathway. J. Reprod. Immunol. 2007, 73, 101–107. [Google Scholar] [CrossRef]
  53. Kao, M.C.; Jan, W.C.; Tsai, P.S.; Wang, T.Y.; Huang, C.J. Magnesium sulfate mitigates lung injury induced by bilateral lower limb ischemia-reperfusion in rats. J. Surg. Res. 2011, 171, e97–e106. [Google Scholar] [CrossRef] [PubMed]
  54. Shimosawa, T.; Takano, K.; Ando, K.; Fujita, T. Magnesium inhibits norepinephrine release by blocking N-type calcium channels at peripheral sympathetic nerve endings. Hypertension 2004, 44, 897–902. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Bachnas, M.A.; Akbar, M.I.A.; Dachlan, E.G.; Dekker, G. The role of magnesium sulfate (MgSO4) in fetal neuroprotection. J. Matern. Fetal. Neonatal. Med. 2021, 34, 966–978. [Google Scholar] [CrossRef]
  56. DiNicolantonio, J.J.; O’Keefe, J.H. Magnesium and Vitamin D Deficiency as a Potential Cause of Immune Dysfunction, Cytokine Storm and Disseminated Intravascular Coagulation in COVID-19 patients. Mo. Med. 2021, 118, 68–73. [Google Scholar] [PubMed]
  57. Severino, P.; Netti, L.; Mariani, M.V.; Maraone, A.; D’Amato, A.; Scarpati, R.; Infusino, F.; Pucci, M.; Lavalle, C.; Maestrini, V.; et al. Prevention of Cardiovascular Disease: Screening for Magnesium Deficiency. Cardiol. Res. Pract. 2019, 2019, 4874921. [Google Scholar] [CrossRef] [Green Version]
  58. Saris, N.E.; Mervaala, E.; Karppanen, H.; Khawaja, J.A.; Lewenstam, A. Magnesium. An update on physiological, clinical and analytical aspects. Clin. Chim. Acta 2000, 294, 1–26. [Google Scholar] [CrossRef]
  59. Kim, J.E.; Shin, C.S.; Lee, Y.C.; Lee, H.S.; Ban, M.; Kim, S.Y. Beneficial effect of intravenous magnesium during endoscopic submucosal dissection for gastric neoplasm. Surg. Endosc. 2015, 29, 3795–3802. [Google Scholar] [CrossRef]
  60. Altura, B.M.; Altura, B.T.; Carella, A.; Gebrewold, A.; Murakawa, T.; Nishio, A. Mg2+-Ca2+ interaction in contractility of vascular smooth muscle: Mg2+ versus organic calcium channel blockers on myogenic tone and agonist-induced responsiveness of blood vessels. Can. J. Physiol. Pharmacol. 1987, 65, 729–745. [Google Scholar] [CrossRef]
  61. Ko, E.A.; Han, J.; Jung, I.D.; Park, W.S. Physiological roles of K+ channels in vascular smooth muscle cells. J. Smooth Muscle Res. 2008, 44, 65–81. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Zhang, A.; Cheng, T.P.; Altura, B.T.; Altura, B.M. Mg2+ and caffeine-induced intracellular Ca2+ release in human vascular endothelial cells. Br. J. Pharmacol. 1993, 109, 291–292. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Quilliot, D.; Bonsack, O.; Jaussaud, R.; Mazur, A. Dysmagnesemia in COVID-19 cohort patients: Prevalence and associated factors. Magnes. Res. 2020, 33, 114–122. [Google Scholar] [CrossRef]
  64. Alamdari, N.M.; Afaghi, S.; Rahimi, F.S.; Tarki, F.E.; Tavana, S.; Zali, A.; Fathi, M.; Besharat, S.; Bagheri, L.; Pourmotahari, F.; et al. Mortality Risk Factors among Hospitalized COVID-19 Patients in a Major Referral Center in Iran. Tohoku J. Exp. Med. 2020, 252, 73–84. [Google Scholar] [CrossRef] [PubMed]
  65. Wiles, M.E.; Wagner, T.L.; Weglicki, W.B. Effect of acute magnesium deficiency (MgD) on aortic endothelial cell (EC) oxidant production. Life Sci. 1997, 60, 221–236. [Google Scholar] [CrossRef]
  66. Wolf, F.I.; Trapani, V.; Simonacci, M.; Ferré, S.; Maier, J.A. Magnesium deficiency and endothelial dysfunction: Is oxidative stress involved? Magnes. Res. 2008, 21, 58–64. [Google Scholar]
  67. Severino, P.; D’Amato, A.; Netti, L.; Pucci, M.; Infusino, F.; Maestrini, V.; Mancone, M.; Fedele, F. Myocardial Ischemia and Diabetes Mellitus: Role of Oxidative Stress in the Connection between Cardiac Metabolism and Coronary Blood Flow. J. Diabetes Res. 2019, 2019, 9489826. [Google Scholar] [CrossRef]
  68. Cuijpers, I.; Simmonds, S.J.; van Bilsen, M.; Czarnowska, E.; González Miqueo, A.; Heymans, S.; Kuhn, A.R.; Mulder, P.; Ratajska, A.; Jones, E.A.V.; et al. Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities. Basic Res. Cardiol. 2020, 115, 39. [Google Scholar] [CrossRef]
  69. Rush, C.J.; Berry, C.; Oldroyd, K.G. Prevalence of Coronary Artery Disease and Coronary Microvascular Dysfunction in Patients With Heart Failure With Preserved Ejection Fraction. JAMA Cardiol. 2021, 6, 1130–1143. [Google Scholar] [CrossRef]
  70. Alexander, Y.; Osto, E.; Schmidt-Trucksäss, A.; Shechter, M.; Trifunovic, D.; Duncker, D.J.; Aboyans, V.; Bäck, M.; Badimon, L.; Cosentino, F.; et al. Endothelial function in cardiovascular medicine: A consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis. Cardiovasc. Res. 2021, 117, 29–42. [Google Scholar] [CrossRef] [Green Version]
  71. Severino, P.; D’Amato, A.; Prosperi, S.; Fanisio, F.; Birtolo, L.I.; Costi, B.; Netti, L.; Chimenti, C.; Lavalle, C.; Maestrini, V.; et al. Myocardial Tissue Characterization in Heart Failure with Preserved Ejection Fraction: From Histopathology and Cardiac Magnetic Resonance Findings to Therapeutic Targets. Int. J. Mol. Sci. 2021, 22, 7650. [Google Scholar] [CrossRef] [PubMed]
  72. Sobczak, A.I.S.; Phoenix, F.A.; Pitt, S.J.; Ajjan, R.A.; Stewart, A.J. Reduced Plasma Magnesium Levels in Type-1 Diabetes Associate with Prothrombotic Changes in Fibrin Clotting and Fibrinolysis. Thromb. Haemost. 2020, 120, 243–252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Çiçek, G.; Açıkgoz, S.K.; Yayla, Ç; Kundi, H.; İleri, M. Magnesium as a predictor of acute stent thrombosis in patients with ST-segment elevation myocardial infarction who underwent primary angioplasty. Coron. Artery Dis. 2016, 27, 47–51. [Google Scholar] [CrossRef] [PubMed]
  74. Mussoni, L.; Sironi, L.; Tedeschi, L.; Calvio, A.M.; Colli, S.; Tremoli, E. Magnesium inhibits arterial thrombi after vascular injury in rat: In vivo impairment of coagulation. Thromb. Haemost. 2001, 86, 1292–1295. [Google Scholar] [PubMed]
  75. Crisponi, G.; Nurchi, V.M.; Cappai, R.; Zoroddu, M.A.; Gerosa, C.; Piras, M.; Faa, G.; Fanni, D. The Potential Clinical Properties of Magnesium. Curr. Med. Chem. 2021, 28, 7295–7311. [Google Scholar] [CrossRef] [PubMed]
  76. Hirota, K.; Sato, T.; Hashimoto, Y.; Yoshioka, H.; Ohtomo, N.; Ishihara, H.; Matsuki, A. Relaxant effect of magnesium and zinc on histamine-induced bronchoconstriction in dogs. Crit. Care Med. 1999, 27, 1159–1163. [Google Scholar] [CrossRef] [PubMed]
  77. Landon, R.A.; Young, E.A. Role of magnesium in regulation of lung function. J. Am. Diet. Assoc. 1993, 93, 674–677. [Google Scholar] [CrossRef]
  78. Güzel, A.; Dogan, E.; Türkçü, G.; Kuyumcu, M.; Kaplan, I.; Çelik, F.; Yıldırım, Z.B. Dexmedetomidine and magnesium sulfate: A good combination treatment for acute lung injury? J. Invest. Surg. 2019, 32, 331–342. [Google Scholar] [CrossRef]
  79. Rastegar, A.; Soleimani, M. Hypokalaemia and hyperkalaemia. Postgrad. Med. J. 2001, 77, 759–764. [Google Scholar] [CrossRef]
  80. McDonough, A.A.; Youn, J.H. Potassium Homeostasis: The Knowns, the Unknowns, and the Health Benefits. Physiology 2017, 32, 100–111. [Google Scholar] [CrossRef]
  81. Palmer, B.F.; Clegg, D.J. Physiology and Pathophysiology of Potassium Homeostasis: Core Curriculum 2019. Am. J. Kidney Dis. 2019, 74, 682–695. [Google Scholar] [CrossRef] [PubMed]
  82. Stone, M.S.; Martyn, L.; Weaver, C.M. Potassium Intake, Bioavailability, Hypertension, and Glucose Control. Nutrients 2016, 8, 444. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Clase, C.M.; Carrero, J.-J.; Ellison, D.H.; Grams, M.E.; Hemmelgarn, B.R.; Jardine, M.J.; Kovesdy, C.P.; Kline, G.A.; Lindner, G.; Obrador, G.T.; et al. Potassium homeostasis and management of dyskalemia in kidney diseases: Conclusions from a kidney disease: Improving global outcomes (KDIGO) controversies conference. Kidney Int. 2020, 97, 42–61. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Greco, A.; Rabito, G.; Pironi, M.; Bissig, M.; Parlato, S.; Andreocchi, L.; Bianchi, G.; Poretti Guigli, M.; Llamas, M.; Monotti, R.; et al. Hypokalaemia in hospitalised patients. Swiss Med. Wkly 2016, 146, w14320. [Google Scholar] [CrossRef]
  85. Paice, B.J.; Paterson, K.R.; Onyanga-Omara, F.; Donnelly, T.; Gray, J.M.; Lawson, D.H. Record linkage study of hypokalaemia in hospitalized patients. Postgrad. Med. J. 1986, 62, 187–191. [Google Scholar] [CrossRef] [Green Version]
  86. Sarvazad, H.; Cahngaripour, S.H.; Roozbahani, N.E.; Izadi, B. Evaluation of electrolyte status of sodium, potassium and magnesium, and fasting blood sugar at the initial admission of individuals with COVID-19 without underlying disease in Golestan Hospital, Kermanshah. New Microbes New Infect. 2020, 38, 100807. [Google Scholar] [CrossRef]
  87. Rosenthal, N.; Cao, Z.; Gundrum, J.; Sianis, J.; Safo, S. Risk factors associated with in-hospital mortality in a US national sample of patients with COVID-19. JAMA Network Open 2020, 3, e2029058. [Google Scholar] [CrossRef]
  88. Mallow, P.J.; Belk, K.W.; Topmiller, M.; Hooker, E.A. Outcomes of hospitalized COVID-19 patients by risk factors: Results from a United States hospital claims database. J. Health Econ. Outcomes Res. 2020, 7, 165–175. [Google Scholar] [CrossRef]
  89. Chen, D.; Li, X.; Song, Q.; Hu, C.; Su, F.; Dai, J.; Ye, Y.; Huang, J.; Zhang, X. Assessment of hypokalemia and clinical characteristics in patients with coronavirus disease 2019 in Wenzhou, China. JAMA Network Open 2020, 3, e2011122. [Google Scholar] [CrossRef]
  90. Liu, S.; Zhang, L.; Weng, H.; Yang, F.; Jin, H.; Fan, F.; Zheng, X.; Yang, H.; Li, H.; Zhang, Y.; et al. Association between average plasma potassium levels and 30-day mortality during hospitalization in patients with COVID-19 in Wuhan, China. Int. J. Med. Sci. 2021, 18, 736–743. [Google Scholar] [CrossRef]
  91. Tezcan, M.E.; Dogan Gokce, G.; Sen, N.; Zorlutuna Kaymak, N.; Ozer, R.S. Baseline electrolyte abnormalities would be related to poor prognosis in hospitalized coronavirus disease 2019 patients. New Microbes New Infect. 2020, 37, 100753. [Google Scholar] [CrossRef] [PubMed]
  92. Szoke, D.; Caruso, S.; Aloisio, E.; Pasqualetti, S.; Dolci, A.; Panteghini, M. Serum potassium concentrations in COVID-19. Clin. Chim. Acta 2021, 512, 26–27. [Google Scholar] [CrossRef] [PubMed]
  93. Muhanna, D.; Arnipalli, S.R.; Kumar, S.B.; Ziouzenkova, O. Osmotic Adaptation by Na(+)-Dependent Transporters and ACE2: Correlation with Hemostatic crisis in COVID-19. Biomedicines 2020, 8, 460. [Google Scholar] [CrossRef] [PubMed]
  94. Silhol, F.; Sarlon, G.; Deharo, J.-C.; Vaïsse, B. Downregulation of ACE2 induces overstimulation of the renin–angiotensin system in COVID-19: Should we block the renin–angiotensin system? Hypertens Res. 2020, 43, 854–856. [Google Scholar] [CrossRef]
  95. de Melom, I.S.; Sabino-Silva, R.; Cunha, T.M.; Goulart, L.R.; Reis, W.L.; Jardim, A.C.G.; Shetty, A.K.; de Castro, O.W. Hydroelectrolytic disorder in COVID-19 patients: Evidence supporting the Involvement of subfornical organ and paraventricular nucleus of the Hypothalamus. Neurosci. Biobehav. Rev. 2021, 124, 216–223. [Google Scholar] [CrossRef]
  96. Alfano, G.; Ferrari, A.; Fontana, F.; Perrone, R.; Mori, G.; Ascione, E.; Magistroni, R.; Venturi, G.; Pederzoli, S.; Margiotta, G.; et al. Hypokalemia in patients with COVID-19. Clin. Exp. Nephrol. 2021, 25, 1–409. [Google Scholar] [CrossRef]
  97. Xu, Z.; Tang, Y.; Huang, Q.; Fu, S.; Li, X.; Lin, B.; Xu, A.; Chen, J. Systematic review and subgroup analysis of the incidence of acute kidney injury (AKI) in patients with COVID-19. BMC Nephrol. 2021, 22, 52. [Google Scholar] [CrossRef]
  98. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [Google Scholar] [CrossRef] [Green Version]
  99. Bowling, C.B.; Pitt, B.; Ahmed, M.I.; Aban, I.B.; Sanders, P.W.; Mujib, M.; Campbell, R.C.; Love, T.E.; Aronow, W.S.; Allman, R.M.; et al. Hypokalemia and outcomes in patients with chronic heart failure and chronic kidney disease: Findings from propensity-matched studies. Circ. Heart Fail. 2010, 3, 253–260. [Google Scholar] [CrossRef] [Green Version]
  100. Goyal, A.; Spertus, J.A.; Gosch, K.; Venkitachalam, L.; Jones, P.G.; Van den Berghe, G.; Kosiborod, M. Serum potassium levels and mortality in acute myocardial infarction. JAMA 2012, 307, 157–164. [Google Scholar] [CrossRef]
  101. Coromilas, E.J.; Kochav, S.; Goldenthal, I.; Biviano, A.; Garan, H.; Goldbarg, S.; Kim, J.H.; Yeo, I.; Tracy, C.; Ayanian, S.; et al. Worldwide survey of COVID-19 associated arrhythmias. Circ. Arrhyth. Electrophysiol. 2021, 14, e009458. [Google Scholar] [CrossRef] [PubMed]
  102. Elias, P.; Poterucha, T.J.; Jain, S.S.; Sayer, G.; Raikhelkar, J.; Fried, J.; Clerkin, K.; Griffin, J.; DeFilippis, E.M.; Gupta, A.; et al. The prognostic value of electrocardiogram at presentation to emergency department in patients with COVID-19. Mayo Clin. Proc. 2020, 95, 2099–2109. [Google Scholar] [CrossRef] [PubMed]
  103. Noori, M.; Nejadghaderi, S.A.; Sullman, M.J.M.; Carson-Chahhoud, K.; Kolahi, A.A.; Safiri, S. Epidemiology, prognosis and management of potassium disorders in Covid-19. Rev. Med. Virol. 2022, 32, e2262. [Google Scholar] [CrossRef] [PubMed]
  104. Di Filippo, L.; Formenti, A.M.; Rovere-Querini, P.; Carlucci, M.; Conte, C.; Ciceri, F.; Zangrillo, A.; Giustina, A. Hypocalcemia is highly prevalent and predicts hospitalization in patients with COVID-19. Endocrine 2020, 68, 475–478. [Google Scholar] [CrossRef] [PubMed]
  105. Cappellini, F.; Brivio, R.; Casati, M.; Cavallero, A.; Contro, E.; Brambilla, P. Low levels of total and ionized calcium in blood of COVID-19 patients. Clin. Chem. Lab. Med. 2020, 58, e171–e173. [Google Scholar] [CrossRef]
  106. di Filippo, L.; Formenti, A.M.; Doga, M.; Frara, S.; Rovere-Querini, P.; Bosi, E.; Carlucci, M.; Giustina, A. Hypocalcemia is a distinctive biochemical feature of hospitalized COVID-19 patients. Endocrine 2021, 71, 9–13. [Google Scholar] [CrossRef]
  107. Pal, R.; Ram, S.; Zohmangaihi, D.; Biswas, I.; Suri, V.; Yaddanapudi, L.N.; Malhotra, P.; Soni, S.L.; Puri, G.D.; Bhalla, A.; et al. High Prevalence of Hypocalcemia in Non-severe COVID-19 Patients: A Retrospective Case-Control Study. Front. Med. 2021, 7, 590805. [Google Scholar] [CrossRef]
  108. Hernandez, J.L.; Nan, D.; Fernandez-Ayala, M.; García-Unzueta, M.; Hernández-Hernández, M.A.; López-Hoyos, M.; Muñoz-Cacho, P.; Olmos, J.M.; Gutiérrez-Cuadra, M.; Ruiz-Cubillán, J.J.; et al. Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection. J Clin. Endocrinol. Metab. 2021, 106, e1343–e1353. [Google Scholar] [CrossRef]
  109. Pan, L.; Mu, M.; Yang, P.; Sun, Y.; Wang, R.; Yan, J.; Li, P.; Hu, B.; Wang, J.; Hu, C.; et al. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: A descriptive, cross-sectional, multicenter study. Am. J. Gastroenterol. 2020, 115, 766–773. [Google Scholar] [CrossRef]
  110. Zhou, Y.; Frey, T.K.; Yang, J.J. Viral calciomics: Interplays between Ca2+ and virus. Cell Calcium. 2009, 46, 1–17. [Google Scholar] [CrossRef]
  111. Singh, S.; Dodt, J.; Volkers, P.; Hethershaw, E.; Philippou, H.; Ivaskevicius, V.; Imhof, D.; Oldenburg, J.; Biswas, A. Structure functional insights into calcium binding during the activation of coagulation factor XIII A. Sci. Rep. 2019, 9, 11324. [Google Scholar] [CrossRef] [PubMed]
  112. Terrar, D.A. Calcium signaling in the heart. Adv. Exp. Med. Biol. 2020, 1131, 395–443. [Google Scholar] [CrossRef] [PubMed]
  113. Hoydal, M.A.; Kirkeby-Garstad, I.; Karevold, A.; Wiseth, R.; Haaverstad, R.; Wahba, A.; Stølen, T.L.; Contu, R.; Condorelli, G.; Ellingsen, Ø.; et al. Human cardiomyocyte calcium handling and transverse tubules in mid-stage of post-myocardial-infarction heart failure. ESC Heart Fail. 2018, 5, 332–342. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Tang, N.; Li, D.; Wang, X.; Sun, Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J. Thromb. Haemost. 2020, 18, 844–847. [Google Scholar] [CrossRef] [Green Version]
  115. Wang, X.; Du, B.; Li, J.; Wang, S.; Wang, X.; Guo, M.; Yang, B.; Si, D.; Bai, O. D-dimer surge and coagulation disorders in COVID-19 related pneumonia patients with cardiac injury: A case series. Medicine 2020, 99, e21513. [Google Scholar] [CrossRef] [PubMed]
  116. Asakura, H.; Ogawa, H. Perspective on fibrinolytic therapy in COVID-19: The potential of inhalation therapy against suppressed-fibrinolytic-type DIC. J. Intensive Care 2020, 8, 71. [Google Scholar] [CrossRef]
  117. Liu, J.; Han, P.; Wu, J.; Gong, J.; Tian, D. Prevalence and predictive value of hypocalcemia in severe COVID-19 patients. J. Infect. Public Health 2020, 13, 1224–1228. [Google Scholar] [CrossRef]
  118. Sun, J.K.; Zhang, W.H.; Zou, L.; Liu, Y.; Li, J.J.; Kan, X.H.; Dai, L.; Shi, Q.K.; Yuan, S.T.; Yu, W.K.; et al. Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019. Aging 2020, 12, 11287–11295. [Google Scholar] [CrossRef]
  119. Qi, X.; Kong, H.; Ding, W.; Wu, C.; Ji, N.; Huang, M.; Li, T.; Wang, X.; Wen, J.; Wu, W.; et al. Abnormal Coagulation Function of Patients With COVID-19 Is Significantly Related to Hypocalcemia and Severe Inflammation. Front. Med. 2021, 8, 638194. [Google Scholar] [CrossRef]
  120. Bennouar, S.; Cherif, A.B.; Kessira, A.; Bennouar, D.E.; Abdi, S. Vitamin D Deficiency and Low Serum Calcium as Predictors of Poor Prognosis in Patients with Severe COVID-19. J. Am. Coll. Nutr. 2021, 40, 104–110. [Google Scholar] [CrossRef]
  121. Linli, Z.; Chen, Y.; Tian, G.; Guo, S.; Fei, Y. Identifying and quantifying robust risk factors for mortality in critically ill patients with COVID-19 using quantile regression. Am. J. Emerg. Med. 2020, 45, 345–351. [Google Scholar] [CrossRef] [PubMed]
  122. El-Kurdi, B.; Khatua, B.; Rood, C.; Snozek, C.; Cartin-Ceba, R.; Singh, V.P.; Lipotoxicity in COVID-19 Study Group. Mortality From Coronavirus Disease 2019 Increases With Unsaturated Fat and May Be Reduced by Early Calcium and Albumin Supplementation. Gastroenterology 2020, 159, 1015–1018.e4. [Google Scholar] [CrossRef] [PubMed]
  123. Cassat, J.E.; Skaar, E.P. Iron in infection and immunity. Cell Host Microbe 2013, 13, 509–519. [Google Scholar] [CrossRef] [Green Version]
  124. Nairz, M.; Weiss, G. Iron in infection and immunity. Mol. Asp. Med. 2020, 75, 100864. [Google Scholar] [CrossRef] [PubMed]
  125. Martins, R.; Maier, J.; Gorki, A.D.; Huber, K.V.; Sharif, O.; Starkl, P.; Saluzzo, S.; Quattrone, F.; Gawish, R.; Lakovits, K.; et al. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nat. Immunol. 2016, 17, 1361–1372. [Google Scholar] [CrossRef] [PubMed]
  126. Barton, J.C.; Acton, R.T. Hepcidin, iron, and bacterial infection. Vitam. Horm. 2019, 110, 223–242. [Google Scholar] [CrossRef] [PubMed]
  127. Ueda, N.; Takasawa, K. Impact of Inflammation on Ferritin, Hepcidin and the Management of Iron Deficiency Anemia in Chronic Kidney Disease. Nutrients 2018, 10, 1173. [Google Scholar] [CrossRef] [Green Version]
  128. Taneri, P.E.; Gómez-Ochoa, S.A.; Llanaj, E.; Raguindin, P.F.; Rojas, L.Z.; Roa-Díaz, Z.M.; Salvador, D., Jr.; Groothof, D.; Minder, B.; Kopp-Heim, D.; et al. Anemia and iron metabolism in COVID-19: A systematic review and meta-analysis. Eur. J. Epidemiol. 2020, 35, 763–773. [Google Scholar] [CrossRef]
  129. Wang, L.; He, W.; Yu, X.; Hu, D.; Bao, M.; Liu, H.; Zhou, J.; Jiang, H. Coronavirus disease 2019 in elderly patients: Characteristics and prognostic factors based on 4-week follow-up. J. Infect. 2020, 80, 639–645. [Google Scholar] [CrossRef]
  130. Fan, B.E.; Chong, V.C.L.; Chan, S.S.W.; Lim, G.H.; Lim, K.G.E.; Tan, G.B.; Mucheli, S.S.; Kuperan, P.; Ong, K.H. Hematologic parameters in patients with COVID-19 infection. Am. J. Hematol. 2020, 95, E131–E134. [Google Scholar] [CrossRef] [Green Version]
  131. Akhtar, S.; Das, J.K.; Ismail, T.; Wahid, M.; Saeed, W.; Bhutta, Z.A. Nutritional perspectives for the prevention and mitigation of COVID-19. Nutr. Rev. 2021, 79, 289–300. [Google Scholar] [CrossRef] [PubMed]
  132. Liu, W.; Zhang, S.; Nekhai, S.; Liu, S. Depriving Iron Supply to the Virus Represents a Promising Adjuvant Therapeutic Against Viral Survival. Curr. Clin. Microbiol. Rep. 2020, 7, 1–7. [Google Scholar] [CrossRef] [PubMed]
  133. de Pontual, L. Fer et prédisposition aux infections [Iron and susceptibility to infections]. Arch. Pediatr. 2017, 24, 5S14–5S17. [Google Scholar] [CrossRef]
  134. Jayaweera, J.A.A.S.; Reyes, M.; Joseph, A. Childhood iron deficiency anemia leads to recurrent respiratory tract infections and gastroenteritis. Sci. Rep. 2019, 9, 12637. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Weinkove, R.; McQuilten, Z.; Adler, J.; Agar, M.R.; Blyth, E.; Cheng, A.C.; Conyers, R.; Haeusler, G.M.; Hardie, C.; Jackson, C.; et al. Managing haematology and oncology patients during the COVID-19 pandemic: Interim consensus guidance. Med. J. Aust. 2020, 212, 481–489. [Google Scholar] [CrossRef]
  136. Iorio, A.; Senni, M.; Barbati, G.; Greene, S.J.; Poli, S.; Zambon, E.; Di Nora, C.; Cioffi, G.; Tarantini, L.; Gavazzi, A.; et al. Prevalence and prognostic impact of non-cardiac co-morbidities in heart failure outpatients with preserved and reduced ejection fraction: A community-based study. Eur. J. Heart Fail. 2018, 20, 12571266. [Google Scholar] [CrossRef] [Green Version]
  137. Anand, I.S.; Gupta, P. Anemia and iron deficiency in heart failure: Current concepts and emerging therapies. Circulation 2018, 138, 8098. [Google Scholar] [CrossRef]
  138. McDonagh, T.; Damy, T.; Doehner, W.; Lam, C.S.P.; Sindone, A.; van der Meer, P.; Cohen-Solal, A.; Kindermann, I.; Manito, N.; Pfister, O.; et al. Screening, diagnosis and treatment of iron deficiency in chronic heart failure: Putting the 2016 European Society of Cardiology heart failure guidelines into clinical practice. Eur. J. Heart Fail. 2018, 20, 1664–1672. [Google Scholar] [CrossRef] [Green Version]
  139. Rocha, B.M.L.; Cunha, G.J.L.; Falcao Menezes, L.F. The burden of iron deficiency in heart failure: Therapeutic approach. J. Am. Coll. Cardiol. 2018, 71, 782793. [Google Scholar] [CrossRef]
  140. von Haehling, S.; Jankowska, E.A.; van Veldhuisen, J.; Ponikowski, P.; Anker, S.D. Iron deficiency and cardiovascular disease. Nat. Rev. Cardiol. 2015, 12, 659–669. [Google Scholar] [CrossRef]
  141. Klip, I.T.; Comin-Colet, J.; Voors, A.A.; Ponikowski, P.; Enjuanes, C.; Banasiak, W.; Lok, D.J.; Rosentryt, P.; Torrens, A.; Polonski, L.; et al. Iron deficiency in chronic heart failure: An international pooled analysis. Am. Heart J. 2013, 165, 575582.e3. [Google Scholar] [CrossRef] [PubMed]
  142. Jankowska, E.A.; Rozentryt, P.; Witkowska, A.; Nowak, J.; Hartmann, O.; Ponikowska, B.; Borodulin-Nadzieja, L.; Banasiak, W.; Polonski, L.; Filippatos, G.; et al. Iron deficiency: An ominous sign in patients with systolic chronic heart failure. Eur. Heart J. 2010, 31, 18721880. [Google Scholar] [CrossRef] [PubMed]
  143. van Dalen, D.H.; Kragten, J.A.; Means, M.E.; van Ofwegen-Hanekamp, C.E.E.; Klaarwater, C.C.R.; Spanjers, M.H.A.; Hendrick, R.; van Deursen, C.T.B.M.; Brunner-La Rocca, H.P. Acute heart failure and iron deficiency: A prospective, multicentre, observational study. ESC Heart Fail. 2022, 9, 398–407. [Google Scholar] [CrossRef] [PubMed]
  144. Sierpinski, R.; Josiak, K.; Suchocki, T.; Wojtas-Polc, K.; Mazur, G.; Butrym, A.; Rozentryt, P.; van der Meer, P.; Comin-Colet, J.; von Haehling, S.; et al. High soluble transferrin receptor in patients with heart failure: A measure of iron deficiency and a strong predictor of mortality. Eur. J. Heart Fail. 2020, 23, 919–932. [Google Scholar] [CrossRef]
  145. Fitzsimons, S.; Poppe, K.K.; Choi, Y.; Devlin, G.; Lund, M.; Lam, C.S.; Troughton, R.; Richards, A.M.; Doughty, R.N. Relationship between soluble transferrin receptor and clinical outcomes in patients with Heart Failure According to Ejection Fraction Phenotype: The New Zealand PEOPLE Study. J. Card. Fail. 2022, 28, 1255–1263. [Google Scholar] [CrossRef] [PubMed]
  146. Ponikowski, P.; Kirwan, B.A.; Anker, S.D.; McDonagh, T.; Dorobantu, M.; Drozdz, J.; Fabien, V.; Filippatos, G.; Göhring, U.M.; Keren, A.; et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: A multicentre, double-blind, randomised, controlled trial. Lancet 2020, 396, 18951904. [Google Scholar] [CrossRef]
  147. López-Vilella, R.; Lozano-Edo, S.; Arenas Martín, P.; Jover-Pastor, P.; Ezzitouny, M.; Sorolla Romero, J.; Calvo Asensio, M.; Martínez-Solé, J.; Guerrero Cervera, B.; Sánchez Martínez, J.C.; et al. Impact of intravenous ferric carboxymaltose on heart failure with preserved and reduced ejection fraction. ESC Heart Fail. 2022, 9, 133–145. [Google Scholar] [CrossRef]
  148. Tu, S.J.; Elliott, A.D.; Hanna-Rivero, N.; Gallagher, C.; Mishima, R.S.; Lyrtzis, E.; Wlochowicz, D.; Clarke, N.A.; Roberts-Thomson, K.C.; Stokes, M.B.; et al. Rationale and design of the IRON-AF study: A double-blind, randomised, placebo-controlled study to assess the effect of intravenous ferric carboxymaltose in patients with atrial fibrillation and iron deficiency. BMJ Open 2021, 11, e047642. [Google Scholar] [CrossRef]
  149. Vinke, P.; Koudstaal, T.; Muskens, F.; van den Bosch, A.; Balvers, M.; Poland, M.; Witkamp, R.F.; van Norren, K.; Boomars, K.A. Prevalence of Micronutrient Deficiencies and Relationship with Clinical and Patient-Related Outcomes in Pulmonary Hypertension Types I and IV. Nutrients 2021, 13, 3923. [Google Scholar] [CrossRef]
  150. Gürgöze, M.T.; Kardys, I.; Akkerhuis, K.M.; Oemrawsingh, R.M.; Groot, H.E.; van der Harst, P.; Umans, V.A.; Kietselaer, B.; Ronner, E.; Lenderink, T.; et al. Relation of Iron Status to Prognosis After Acute Coronary Syndrome. Am. J. Cardiol. 2022, 168, 22–30. [Google Scholar] [CrossRef]
  151. Meng, H.; Wang, Y.; Ruan, J.; Chen, Y.; Wang, X.; Zhou, F.; Meng, F. Decreased Iron Ion Concentrations in the Peripheral Blood Correlate with Coronary Atherosclerosis. Nutrients 2022, 14, 319. [Google Scholar] [CrossRef] [PubMed]
  152. Bao, B.; Prasad, A.S.; Beck, F.W.J.; Sarkar, F.H. Zinc up-regulates NF-κB activation via phosphorylation of IκB in HUT-78 (Th0) cells. FEBS Lett. 2007, 581, 4507–4511. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Gammoh, N.Z.; Rink, L. Zinc in infection and inflammation. Nutrients 2017, 9, 624. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Choi, S.; Liu, X.; Pan, Z. Zinc deficiency and cellular oxidative stress: Prognostic implications in cardiovascular diseases review-article. Acta Pharmacol. Sin. 2018, 39, 1120–1132. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Vanhoutte, P.M. Endothelial dysfunction-The first step toward coronary arteriosclerosis. Circ. J. 2009, 73, 595–601. [Google Scholar] [CrossRef] [Green Version]
  156. Severino, P.; D’Amato, A.; Prosperi, S.; Magnocavallo, M.; Mariani, M.V.; Netti, L.; Birtolo, L.I.; De Orchi, P.; Chimenti, C.; Maestrini, V.; et al. Potential Role of eNOS Genetic Variants in Ischemic Heart Disease Susceptibility and Clinical Presentation. J. Cardiovasc. Dev. Dis. 2021, 8, 116. [Google Scholar] [CrossRef]
  157. Förstermann, U.; Xia, N.; Li, H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ. Res. 2017, 120, 713–735. [Google Scholar] [CrossRef]
  158. Karim, M.M.; Sultana, S.; Sultana, R.; Rahman, M.T. Possible Benefits of Zinc supplement in CVD and COVID-19 Comorbidity. J. Infect. Public Health 2021, 14, 1686–1692. [Google Scholar] [CrossRef]
  159. Yi, T.; Vick, J.S.; Vecchio, M.J.H.; Begin, K.J.; Bell, S.P.; Delay, R.J.; Palmer, B.M. Identifying cellular mechanisms of zinc-induced relaxation in isolated cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol. 2013, 305, H706–H715. [Google Scholar] [CrossRef]
  160. Santos, R.A.S.; Sampaio, W.O.; Alzamora, A.C.; Motta-Santos, D.; Alenina, N.; Bader, M.; Campagnole-Santos, M.J. The ACE2/Angiotensin-(1-7)/Mas axis of the renin-angiotensin system: Focus on Angiotensin-(1-7). Physiol. Rev. 2018, 98, 505–553. [Google Scholar] [CrossRef] [Green Version]
  161. South, A.M.; Diz, D.I.; Chappell, M.C. COVID-19, ACE2, and the cardiovascular consequences. Am. J. Physiol. Heart Circ. Physiol. 2020, 318, H1084–H1090. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  162. Verdecchia, P.; Cavallini, C.; Spanevello, A.; Angeli, F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur. J. Intern. Med. 2020, 76, 14–20. [Google Scholar] [CrossRef]
  163. Rahman, M.T.; Idid, S.Z. Can Zn Be a Critical Element in COVID-19 Treatment? Biol. Trace Elem. Res. 2020, 199, 550–558. [Google Scholar] [CrossRef] [PubMed]
  164. Jothimani, D.; Kailasam, E.; Danielraj, S.; Nallathambi, B.; Ramachandran, H.; Sekar, P.; Manoharan, S.; Ramani, V.; Narasimhan, G.; Kaliamoorthy, I.; et al. COVID-19: Poor outcomes in patients with zinc deficiency. Int. J. Infect. Dis. 2020, 100, 343–349. [Google Scholar] [CrossRef] [PubMed]
  165. Villamor, E.; Mbise, R.; Spiegelman, D.; Hertzmark, E.; Fataki, M.; Peterson, K.E.; Ndossi, G.; Fawzi, W.W. Vitamin A supplements ameliorate the adverse effect of HIV-1, malaria, and diarrheal infections on child growth. Pediatrics 2002, 109, E6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Al-Saleh, I.; Alrushud, N.; Alnuwaysir, H.; Elkhatib, R.; Shoukri, M.; Aldayel, F.; Bakheet, R.; Almozaini, M. Essential metals, vitamins and antioxidant enzyme activities in COVID-19 patients and their potential associations with the disease severity. Biometals 2022, 35, 125–145. [Google Scholar] [CrossRef]
  167. Stephensen, C.B.; Lietz, G. Vitamin A in resistance to and recovery from infection: Relevance to SARS-CoV2. Br. J. Nutr. 2021, 126, 1663–1672. [Google Scholar] [CrossRef]
  168. Wang, N.; Ru, Y.; Yang, Z.; Sun, C.; Li, S.; Min, Y.; Zhao, X.; Lu, Y.; Hsing, A.W.; Zhu, S. Metabolomic Profiles of Plasma Retinol-Associated Dyslipidemia in Men and Women. Front. Nutr. 2021, 8, 740435. [Google Scholar] [CrossRef]
  169. Huang, J.; Weinstein, S.J.; Yu, K.; Männistö, S.; Albanes, D. Association between serum retinol and overall and cause-specific mortality in a 30-year prospective cohort study. Nat. Commun. 2021, 12, 6418. [Google Scholar] [CrossRef]
  170. Mikkelsen, K.; Stojanovska, L.; Prakash, M.; Apostolopoulos, V. The effects of vitamin B on the immune/cytokine network and their involvement in depression. Maturitas 2017, 96, 58–71. [Google Scholar] [CrossRef]
  171. Maggini, S.; Pierre, A.; Calder, P.C. Immune Function and Micronutrient Requirements Change over the Life Course. Nutrients 2018, 10, 1531. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  172. dos Santos, L.M.J. Can vitamin B12 be an adjuvant to COVID-19 treatment? GSC Biol. Pharm. Sci. 2020, 11, 1–5. [Google Scholar] [CrossRef]
  173. Robinson, K.; Mayer, E.L.; Miller, D.P.; Green, R.; van Lente, F.; Gupta, A.; Kottke-Marchant, K.; Savon, S.R.; Selhub, J.; Nissen, S.E.; et al. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation 1995, 92, 2825–2830. [Google Scholar] [CrossRef] [PubMed]
  174. Perry, I.J.; Refsum, H.; Morris, R.W.; Ebrahim, S.B.; Ueland, P.M.; Shaper, A.G. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995, 346, 1395–1398. [Google Scholar] [CrossRef]
  175. Eshak, E.S.; Arafa, A.E. Thiamine deficiency and cardiovascular science. Nutr. Metab. Cardiovasc. Dis. 2018, 28, 965–972. [Google Scholar] [CrossRef]
  176. Stanhewicz, A.E.; Kenney, W.L. Role of folic acid in nitric oxide bioavailability and vascular endothelial function. Nutr. Rev. 2017, 75, 61–70. [Google Scholar] [CrossRef]
  177. Zhang, C.; Wang, Z.Y.; Qin, Y.Y.; Yu, F.F.; Zhou, Y.H. Association between B vitamins supplementation and risk of cardiovascular outcomes: A cumulative meta-analysis of randomized controlled trials. PLoS ONE 2014, 9, e107060. [Google Scholar] [CrossRef] [Green Version]
  178. Tan, C.W.; Ho, L.P.; Kalimuddin, S.; Cherng, B.P.Z.; Teh, Y.E.; Thien, S.Y.; Wong, H.M.; Tern, P.J.W.; Chandran, M. A cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients. Nutrition 2020, 79, 111017. [Google Scholar] [CrossRef]
  179. Carr, A.C.; Frei, B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am. J. Clin. Nutr. 1999, 69, 1086–1107. [Google Scholar] [CrossRef] [Green Version]
  180. Carr, A.; Frei, B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J. 1999, 13, 1007–1024. [Google Scholar] [CrossRef] [Green Version]
  181. Huang, J.; Fu, G.; Yao, Q.; Cheng, G. Relation of thrombomodulin, TFPI and plasma antioxidants in healthy individuals and patients with coronary heart disease. Acta Cardiol. 2008, 63, 341–346. [Google Scholar] [CrossRef] [PubMed]
  182. Pignatelli, P.; Sanguigni, V.; Paola, S.G.; Lo Coco, E.; Lenti, L.; Violi, F. Vitamin C inhibits platelet expression of CD40 ligand. Free Radic. Biol. Med. 2005, 38, 1662–1666. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  183. Carr, A.C.; Shaw, G.M.; Fowler, A.A.; Natarajan, R. Ascorbate-dependent vasopressor synthesis: A rationale for vitamin C administration in severe sepsis and septic shock? Crit. Care 2015, 19, 418. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  184. Zabet, M.H.; Mohammadi, M.; Ramezani, M.; Khalili, H. Effect of high-dose Ascorbic acid on vasopressor’s requirement in septic shock. J. Res. Pharm. Pract. 2016, 5, 94–100. [Google Scholar] [CrossRef]
  185. Zhang, J.; Rao, X.; Li, Y.; Zhu, Y.; Liu, F.; Guo, G.; Luo, G.; Meng, Z.; De Backer, D.; Xiang, H.; et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann. Intensive Care 2021, 11, 5. [Google Scholar] [CrossRef]
  186. Infusino, F.; Marazzato, M.; Mancone, M.; Fedele, F.; Mastroianni, C.M.; Severino, P.; Ceccarelli, G.; Santinelli, L.; Cavarretta, E.; Marullo, A.G.M.; et al. Diet Supplementation, Probiotics, and Nutraceuticals in SARS-CoV-2 Infection: A Scoping Review. Nutrients 2020, 12, 1718. [Google Scholar] [CrossRef] [PubMed]
  187. Sassi, F.; Tamone, C.; D’Amelio, P. Vitamin D: Nutrient, Hormone, and Immunomodulator. Nutrients 2018, 10, 1656. [Google Scholar] [CrossRef] [Green Version]
  188. Jain, A.; Chaurasia, R.; Sengar, N.S.; Singh, M.; Mahor, S.; Narain, S. Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Sci. Rep. 2020, 10, 20191. [Google Scholar] [CrossRef]
  189. Latic, N.; Erben, R.G. Vitamin D and Cardiovascular Disease, with Emphasis on Hypertension, Atherosclerosis, and Heart Failure. Int. J. Mol. Sci. 2020, 21, 6483. [Google Scholar] [CrossRef]
  190. Lim, S.; Bae, J.H.; Kwon, H.S.; Nauck, M.A. COVID-19 and diabetes mellitus: From pathophysiology to clinical management. Nat. Rev. Endocrinol. 2021, 17, 11–30. [Google Scholar] [CrossRef]
  191. Infante, M.; Ricordi, C.; Sanchez, J.; Clare-Salzler, M.J.; Padilla, N.; Fuenmayor, V.; Chavez, C.; Alvarez, A.; Baidal, D.; Alejandro, R.; et al. Influence of Vitamin D on Islet Autoimmunity and Beta-Cell Function in Type 1 Diabetes. Nutrients 2019, 11, 2185. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  192. Qu, H.; Lin, K.; Wang, H.; Wei, H.; Ji, B.; Yang, Z.; Peng, C.; Xiao, X.; Deng, H. 1,25(OH)2 D3 improves cardiac dysfunction, hypertrophy, and fibrosis through PARP1/SIRT1/mTOR-related mechanisms in type 1 diabetes. Mol. Nutr. Food Res. 2017, 61, 1600338. [Google Scholar] [CrossRef] [PubMed]
  193. Chen, S.; Law, C.S.; Grigsby, C.L.; Olsen, K.; Hong, T.T.; Zhang, Y.; Yeghiazarians, Y.; Gardner, D.G. Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy. Circulation 2011, 124, 1838–1847. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  194. Li, Y.C.; Kong, J.; Wei, M.; Chen, Z.F.; Liu, S.Q.; Cao, L.P. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J. Clin. Invest. 2002, 110, 229–238. [Google Scholar] [CrossRef] [PubMed]
  195. Lind, L.; Wengle, B.; Wide, L.; Ljunghall, S. Reduction of blood pressure during long-term treatment with active vitamin D (alphacalcidol) is dependent on plasma renin activity and calcium status. A double-blind, placebo-controlled study. Am. J. Hypertens 1989, 2, 20–25. [Google Scholar] [CrossRef]
  196. Pfeifer, M.; Begerow, B.; Minne, H.W.; Nachtigall, D.; Hansen, C. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J. Clin. Endocrinol. Metab. 2001, 86, 1633–1637. [Google Scholar] [CrossRef] [Green Version]
  197. Kimura, Y.; Kawamura, M.; Owada, M.; Oshima, T.; Murooka, M.; Fujiwara, T.; Hiramori, K. Effectiveness of 1,25-dihydroxyvitamin D supplementation on blood pressure reduction in a pseudohypoparathyroidism patient with high renin activity. Intern. Med. 1999, 38, 31–35. [Google Scholar] [CrossRef] [Green Version]
  198. Park, C.W.; Oh, Y.S.; Shin, Y.S.; Kim, C.M.; Kim, Y.S.; Kim, S.Y.; Choi, E.J.; Chang, Y.S.; Bang, B.K. Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with secondary hyperparathyroidism. Am. J. Kidney Dis. 1999, 33, 73–81. [Google Scholar] [CrossRef]
  199. Mohammad, S.; Mishra, A.; Ashraf, M.Z. Emerging Role of Vitamin D and its Associated Molecules in Pathways Related to Pathogenesis of Thrombosis. Biomolecules 2019, 9, 649. [Google Scholar] [CrossRef] [Green Version]
  200. Lim, S.; Shin, H.; Kim, M.J.; Ahn, H.Y.; Kang, S.M.; Yoon, J.W.; Choi, S.H.; Kim, K.W.; Song, J.H.; Choi, S.I.; et al. Vitamin D inadequacy is associated with significant coronary artery stenosis in a community-based elderly cohort: The Korean Longitudinal Study on Health and Aging. J. Clin. Endocrinol. Metab. 2012, 97, 169–178. [Google Scholar] [CrossRef] [Green Version]
  201. Lee, G.Y.; Han, S.N. The Role of Vitamin E in Immunity. Nutrients 2018, 10, 1614. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  202. De Carvalho, H.; Richard, M.C.; Chouihed, T.; Goffinet, N.; Le Bastard, Q.; Freund, Y.; Kratz, A.; Dubroux, M.; Masson, D.; Figueres, L.; et al. Electrolyte imbalance in COVID-19 patients admitted to the Emergency Department: A case-control study. Intern. Emerg. Med. 2021, 16, 1945–1950. [Google Scholar] [CrossRef] [PubMed]
  203. Loffredo, L.; Martino, F.; Zicari, A.M.; Carnevale, R.; Battaglia, S.; Martino, E.; Cammisotto, V.; Peruzzi, M.; De Castro, G.; Duse, M.; et al. Enhanced NOX-2 derived oxidative stress in offspring of patients with early myocardial infarction. Int. J. Cardiol. 2019, 293, 56–59. [Google Scholar] [CrossRef] [PubMed]
  204. Boscoboinik, D.; Szewczyk, A.; Azzi, A. Alpha-tocopherol (vitamin E) regulates vascular smooth muscle cell proliferation and protein kinase C activity. Arch. Biochem. Biophys. 1991, 286, 264–269. [Google Scholar] [CrossRef]
  205. Meydani, M.; Kwan, P.; Band, M.; Knight, A.; Guo, W.; Goutis, J.; Ordovas, J. Long-term vitamin E supplementation reduces atherosclerosis and mortality in Ldlr-/- mice, but not when fed Western style diet. Atherosclerosis 2014, 233, 196–205. [Google Scholar] [CrossRef] [Green Version]
  206. Qin, F.; Yan, C.; Patel, R.; Liu, W.; Dong, E. Vitamins C and E attenuate apoptosis, beta-adrenergic receptor desensitization, and sarcoplasmic reticular Ca2+ ATPase downregulation after myocardial infarction. Free Radic. Biol. Med. 2006, 40, 1827–1842. [Google Scholar] [CrossRef]
  207. Wang, J.Z.; Zhang, R.Y.; Bai, J. An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients. Int. J. Cardiol. 2020, 312, 137–138. [Google Scholar] [CrossRef]
  208. Role of Vitamin K-Dependent Factors Protein S and GAS6 and TAM Receptors in SARS-CoV-2 Infec-tion and COVID-19-Associated Immunothrombosis. Cells 2020, 9, 2186. [CrossRef]
  209. Baicus, C.; Stoichitoiu, L.E.; Pinte, L.; Badea, C. Anti-coagulant Protein S in COVID-19: The Low Activity Level Is Probably Secondary. Am. J. Ther. 2021, 28, e139–e140. [Google Scholar] [CrossRef]
  210. Jaminon, A.M.G.; Dai, L.; Qureshi, A.R.; Evenepoel, P.; Ripsweden, J.; Söderberg, M.; Witasp, A.; Olauson, H.; Schurgers, L.J.; Stenvinkel, P. Matrix Gla pro-tein is an independent predictor of both intimal and meDial. vascular calcification in chronic kidney disease. Sci. Rep. 2020, 10, 6586. [Google Scholar] [CrossRef] [Green Version]
  211. Available online: https://www.who.int/health-topics/micronutrients#tab=tab_1 (accessed on 10 July 2022).
Figure 1. Micronutrients imbalance may contribute to cardiovascular complications observed during COVID-19. NO: nitric oxide; DNA: deoxyribonucleic acid; Mg2+: magnesium; K+: potassium; Zn2+: zinc; Ca2+: calcium; Fe2+/3+: iron; Na2+: sodium.
Figure 1. Micronutrients imbalance may contribute to cardiovascular complications observed during COVID-19. NO: nitric oxide; DNA: deoxyribonucleic acid; Mg2+: magnesium; K+: potassium; Zn2+: zinc; Ca2+: calcium; Fe2+/3+: iron; Na2+: sodium.
Nutrients 14 03439 g001
Table 1. A summary of the most important ions imbalance during COVID-19 and their effects on CV system.
Table 1. A summary of the most important ions imbalance during COVID-19 and their effects on CV system.
IonRelationship among CV Diseases and IonsRelationship among
COVID-19 and Ions
Reference
Sodium (Na+)
  • Sodium imbalance is the most common electrolyte disorder
  • Sodium imbalance affects blood volume, blood pressure, osmotic and acid-base equilibrium regulation
  • Dysnatremia is an independent risk factor for mortality in hospitalized patients, including COVID-19 patients
  • Hyponatremia is associated with increased risk of encephalopathy and mechanical ventilation necessity
[38,40]
Magnesium (Mg++)
  • Magnesium deficiency is associated with increased incidence of arrhythmias, arterial hypertension and atherosclerosis
  • Hypomagnesaemia has been associated with more severe COVID-19 cases
[63,64]
Potassium (K+)
  • Alterations in potassium levels predispose to cardiac arrhythmias
  • Potassium imbalance leads to derangements in vascular tone and systemic blood pressure regulation
  • High incidence of potassium imbalance has been found in COVID-19 patients
  • Hypokalemia is the most common disorder, and it is associated with worse prognosis
  • Hyperkalemia occurs less frequently than hypokalemia
[84,89]
Calcium (Ca++)
  • Hypocalcemia is associated with derangements in coagulation and platelet adhesion
  • Hypocalcemia affects myocardial contractility and relaxation
  • COVID-19 patients have lower calcium levels compared to patients without COVID-19
[106,114,115]
Iron (Fe++/Fe+++)
  • Iron deficiency and anemia are frequent comorbidities in CV diseases
  • In HF anemia and iron deficiency represent an independent condition predisposing to CV and overall mortality, rehospitalization and quality of life and symptoms worsening
  • Significantly lower levels of hemoglobin have been found in COVID-19 patients admitted to ICU compared to those who were not admitted to ICU
  • Iron deficiency is crucial in depressing immune response
[128,129,130,131,133]
Zinc (Zn++)
  • Zinc deficiency causes oxidative stress, laying the groundwork for atherosclerosis.
  • Zinc deficiency can reduce cardiac inotropism.
  • Zinc supplementation can promote the restoration of ACE2 expression in COVID-19 patients.
[158,159]
COVID-19: coronavirus disease 2019; CV: cardiovascular; ICU: intensive care unit; HF: heart failure; ACE2: angiotensin-converting enzyme 2.
Table 2. A summary of the most important vitamins imbalance during COVID-19 and their effects on CV system.
Table 2. A summary of the most important vitamins imbalance during COVID-19 and their effects on CV system.
VitaminRelationship among CV Diseases and VitaminsRelationship among COVID-19 and VitaminsReference
Vitamin A
  • Improvement of dyslipidemia.
  • Reduction of overall mortality in CV diseases
  • Low vitamin A serum levels are associated with COVID-19 symptoms severity
[166,169]
Vitamin B
  • Reduction in homocysteine responsible for increased risk of coronary artery disease and stroke (B6, B9, B12).
  • Protection against metabolic syndrome (B1).
  • Antioxidant effects and improvement of endothelial function (B9).
  • Suppression of viral replication in host cells (B12)
  • Vitamin B12 therapy could reduce severe damages induced by COVID-19 and related symptoms.
[171,172,176,178]
Vitamin C
  • Antioxidant effect, contrasting ROS and inflammation
  • Immunomodulant activity on T and B cells
  • Antithrombotic activity through platelet expression of CD40 ligand.
[181,182,186]
Vitamin D
  • Anti-fibrotic and anti-hypertrophic role.
  • Regulation of RAAS.
  • Vitamin D deficiency is associated with an increase of thrombotic episodes.
[191,192,193,194,195,196,199]
Vitamin E
  • Antioxidant effect.
  • Inhibition of LDL oxidation.
  • Reduction of cardiomyocytes apoptotic activity.
  • Suppression of PGE2 synthesis, an important T cell-suppressing mediator.
[199,201,203,204]
Vitamin K
  • Inhibition of cardiovascular calcification
  • Anti-coagulation role
  • Activation of Protein S and inhibition of cytokine storm.
[208,209,210]
COVID-19: coronavirus disease 2019; CV: cardiovascular; ROS; reactive oxygen species; RAAS: renin-angiotensin-aldosterone system; PGE2: prostaglandin E2; LDL: low density lipoprotein.
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Severino, P.; D’Amato, A.; Prosperi, S.; Myftari, V.; Labbro Francia, A.; Önkaya, M.; Notari, C.; Papisca, I.; Canuti, E.S.; Yarden Revivo, M.; et al. The Mutual Relationship among Cardiovascular Diseases and COVID-19: Focus on Micronutrients Imbalance. Nutrients 2022, 14, 3439. https://doi.org/10.3390/nu14163439

AMA Style

Severino P, D’Amato A, Prosperi S, Myftari V, Labbro Francia A, Önkaya M, Notari C, Papisca I, Canuti ES, Yarden Revivo M, et al. The Mutual Relationship among Cardiovascular Diseases and COVID-19: Focus on Micronutrients Imbalance. Nutrients. 2022; 14(16):3439. https://doi.org/10.3390/nu14163439

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Severino, Paolo, Andrea D’Amato, Silvia Prosperi, Vincenzo Myftari, Aurora Labbro Francia, Merve Önkaya, Claudia Notari, Ilaria Papisca, Elena Sofia Canuti, Mia Yarden Revivo, and et al. 2022. "The Mutual Relationship among Cardiovascular Diseases and COVID-19: Focus on Micronutrients Imbalance" Nutrients 14, no. 16: 3439. https://doi.org/10.3390/nu14163439

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