Is arrhythmicity of microvascular "flowmotion" responsible for COVID-19-related acute respiratory distress syndrome and might it be treated through an adequate Mg supplementation?

Since the report of an emergence of severe respiratory viral infections of unknown etiology in China in December 2019, termed COVID-19-associated acute respiratory distress syndrome (ARDS), a large number of cases and deaths have been documented worldwide, with the pandemic still spreading around the world. In most critical cases, the acute symptoms may be accompanied by uncontrolled inflammatory cytokine responses and by multiorgan failure. The clinical observation that in severely ill patients, COVID-19 was characterized by cytokine storm and endothelial dysfunction, leading to fast and fatal progression of the disease, has prompted many investigators to consider COVID-19 as a systemic disease that primarily injures the vascular endothelium. Aim of this brief review is not to refute or even question a quite possible role of the vascular endothelial dysfunction as a potential trigger for ARDS, but rather to highlight a more probable role for the main function of the smooth muscle cells in the microcirculation, called "vasomotion", which helps physiologically to ensure an optimized energy supply to the tissues. Alterations in the rhythms of this microcirculatory vaso motion might thus play a similar role as a trigger of the ARDS diagnosed in COVID-19 patients. Furthermore, since obesity, type 2 diabetes, arterial hypertension, decrease in immune response, cytokine storm, endothelial dysfunction, and arrhythmias, which are frequent in COVID-19 patients, have been reported to be associated with hypomagnesemia, an adequate treatment with magnesium supplementation could be beneficial for COVID-19 patients in some specific cases and should also be taken into consideration.

Magnesium - Update 2021: Ionized magnesium as an early marker of a magnesium deficiency

The role of magnesium is of growing interest in internal medicine, especially in cardiovascular diseases and in patients with diabetes mellitus or in geriatrics. Ionized magnesium is the physiologically active component of blood magnesium, so total serum magnesium is not always an accurate indicator of magnesium status, whereas ionized magnesium is probably as an early marker indicating a magnesium loss. Our presentation will describe recent studies showing statistically significant decreased ionized magnesium in patients with various diseases, e.g., heart insufficiency, arteriosclerosis, lipid disorder, hypertension, heart rhythm disorders, diabetes mellitus, bone stiffness, and immune function in COVID-19 disease. The presentation describes why measurement of ionized magnesium is a better tool to manage magnesium handling more correctly.

Magnesium and COVID- 19 - cardiovascular implications

The novel coronavirus SARSCoV- 2 is causing an ongoing worldwide pandemic of COVID-19. The infection with this single-stranded RNA virus appears to be completely asymptomatic in a large fraction of people and many other patients may experience mild symptoms such as fever, cough, anosmia, and myalgia. Some patients need hospitalization and some will develop an acute respiratory distress syndrome (ARDS), and a significant subset will require treatment in the intensive care unit to provide respiratory ventilator support. Unfortunately, there is no causal curative treatment, so far. In this context, the potential prophylactic and therapeutic options for the novel SARS-CoV-2 infection and corresponding COVID-19, as well as interventions with special nutrients like zinc or vitamin D are discussed, especially due to their role in the immune system [1]. Possible drugs for the treatment of COVID-19 increase the risk of QT interval prolongation, e.g., chloroquine, hydroxychloroquine, azithromycin, lopinavir, ritonavir. QT prolongation can provoke life-threatening torsade-de-pointes arrhythmias (TdP) and sudden cardiac death. Mg deficiency and other electrolyte imbalances also belong to the known risk factors for QT prolongation and TdP. Consequently, it is recommended to obtain baseline assessment of Mg and other electrolytes and to correct deficiencies before using QT-prolonging drugs. Keeping serum potassium levels and Mg levels above 4 mmol/L and 3 mg/ dL (= 1.23 mmol/L), respectively, in COVID-19 patients treated with QT-prolonging drugs proved to be effective in preventing QT prolongation, and no arrhythmias or sudden cardiac arrest were registered. This is above the upper limit of the reference range (usually ∼ 1.1 mmol/L). In a single-center study (n = 524), a specially designed monitoring process in COVID-19 patients (with COVID-19-related medication) identified a high proportion of patients with QT prolongation (n = 103, corresponding to 19.7%). As part of the medical support, reaching Mg and potassium in the reference range was recommended [2, 3]. Administration of intravenous Mg sulfate is the therapy of choice for hemodynamically stable TdP, regardless of whether the patient is hypomagnesemic or has a normal serum Mg concentration. This may be a relevant reason why the German Federal Institute of Drugs and Medical Devices (BfArM) put Mg (parenteral) on a list with drugs whose need is greatly increased with treatment of COVID-19 patients in intensive care units [4]. On the other hand, hypomagnesemia generally is a common occurrence in intensive care patients (regardless of COVID-19) with a prevalence up to 65%, associated with an increased mortality rate, higher need for ventilator support, increased incidence of sepsis, and longer hospital stays [5]. There is increasing evidence that viral infection of the endothelial cells plays a key role in multiorgan participation and severe courses of COVID-19. This finding provides a rationale for therapies to stabilize the endothelium, in particular for vulnerable patients with pre-existing endothelial dysfunction which can be found for example in cardiovascular disease, diabetes, hypertension, obesity, all of which are associated with adverse outcomes in COVID-19. Interestingly, Mg is known to be crucial for endothelial function and its deficiency causes endothelial dysfunction with impaired endothelial-dependent vasodilation. In a meta-analysis of randomized, controlled trials (RCTs), oral Mg supplementation was shown to improve flow-mediated dilation as a marker of endothelial function. It is therefore plausible to assume that Mg deficiency further worsens the consequences of an infection with SARS-CoV-2 via induction of endothelial dysfunction. In this context, the frequent occurrence of thrombotic embolism in COVID-19 is worth mentioning. Animal and human data suggest that Mg functions as an antithrombotic agent. Hence, increased platelet reactivity and thrombosis are possible cardiovascular manifestations of Mg deficiency [6, 7]. Furthermore, increased inflammation in Mg deficiency has to be kept in mind. Experimental studies show an increased incidence of markers for inflammation in case of Mg deficiency, e.g., leukocyte and macrophage activation, pro-inflammatory molecules such as interleukin-1, interleukin-6, tumor necrosis factor, vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, and excessive production of free radicals. Generally, Mg deficiency is considered as a significant contributor to chronic lowgrade inflammation and, therefore, risk factor for a variety of pathological conditions such as cardiovascular disease, hypertension, and diabetes. In meta-analyses of RCTs, Mg supplementation was shown to reduce C-reactive protein levels. Whether Mg deficiency or Mg supplementation may impact the inflammatory event in COVID-19 has to be investigated in clinical studies [7, 8]. To our knowledge, there are no systematic studies so far examining Mg status in COVID-19 patients. In a pooled analysis, Lippi et al. [6] confirmed that COVID-19 severity was associated with lower serum concentrations of sodium, potassium, and calcium. Therefore, measuring electrolytes at initial presentation and monitoring during hospitalization is recommended in order to be able to take appropriate corrective measures in good time. Unfortunately, serum Mg was not determined in the studies analyzed. In the above-mentioned study of Jain et al. [3], 30.1% of the COVID-19 patients with QT prolongation showed hypomagnesemia. Conclusion: In view of the relationships described, it is plausible to assume that Mg deficiency may decrease the resistance against infection with SARS-CoV-2 and, most notably, may worsen the course of COVID-19. Hence, Mg deficiency could be a risk factor for severe COVID-19, comparable to cardiovascular disease, diabetes, chronic respiratory disease, older age, obesity, amongst others. Interestingly, Mg deficiency is often associated with these risk factors or seen as comorbidity. However, more research questions need to be addressed before definitive conclusions can be drawn [8, 9].

Corona, influenza, and co – immune-relevant micronutrients in viral respiratory tract infections

Worldwide the pandemic of Covid-19 spreads rapidly and has an enormous public health impact with substantial fatal outcomes especially in high-risk groups, such as older people and patients with comorbidities like diabetes, dementia, or cancer. In the absence of a vaccine against Covid-19 there is an urgent need to find supportive therapies that can stabilize the immune system and can help to deal with the infection. As is well known, the incidence of malnutrition in German geriatric clinics is up to 60% among the hospitalized elderly population. The nutritional (= macro- and micronutrient) status of each infected patient should be evaluated before the administration of general treatments. In this context, the role of immune-relevant micronutrients, such as vitamin D, retinol, vitamin C, selenium, and zinc is of special importance. The laboratory assessment of 25(OH)D, selenium, or omega-3 index is therefore mandatory. Micronutrient deficiencies should be compensated by individual supplementation.

The importance of complementary supportive therapy in immunosuppressed oncological patients - a case report

The high-dose parenteral application of Vitamin C is one of numerous complementary medical methods that are often used for the treatment of tumor-associated fatigue symptoms and as complementary supportive therapy, and now also in the phase of the COVID-19 pandemic for immune stimulation and as an antiviral option. The casuistry presented here describes, in addition to a serious interaction of this drug supportive therapy with a high-tech medical device, also modern conventional therapy options for triple negative breast cancer. Various immune-relevant micronutrients are used, which on the one hand support modern checkpoint inhibition with atezolizumab, and on the other hand are intended to ensure the best possible defense in the pandemic phase. Current data has just been published for selenium and Vitamin D.

Immune-relevant Micronutrients for Viral Respiratory Infections

Worldwide the pandemic of Covid-19 spreads rapidly and has an enormous public health impact with substantial fatal outcomes especially in high-risk groups, such as older people and patients with comorbidities like diabetes, dementia or cancer. In the absence of a vaccine against Covid-19 there is an urgent need to find supportive therapies that can stabilize the immune system and can help to deal with the infection. As is well known the incidence of malnutrition in German geriatric clinics ranges up to 60% among the hospitalized elderly population. The nutritional (=macro- A nd micronutrient) status of each infected patient should be evaluated before the administration of general treatments. In this context the role of immune-relevant micronutrients, such as Vitamin D, retinol, Vitamin C, selenium and zinc is of special importance. The laboratory assessment of 25(OH)D, selenium or omega-3-index is therefore mandatory. Micronutrient deficiencies should be right away compensated by individual supplementation.