Magnesium and COVID- 19 - cardiovascular implications

ABSTRACT

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].