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].

Index of cardiac electrophysiological balance (iCEB) in patients with COVID-19

Aims: We aimed to examine whether there is abnormal value of index of cardiac electrophysiological balance (iCEB=QT/QRS) in patients with confirmed coronavirus disease 2019 (COVID-19), which can predict ventricular arrhythmias (VAs), including non-Torsades de Pointes-like ventricular tachycardia/ventricular fibrillation (non- TdPs-like VT/VF) in low iCEB and Torsades de Pointes (TdPs) in high iCEB. We also investigated low voltage ECG among COVID-19 group. Methods and Results: This is a cross-sectional, single center study with a total of 53 newly diagnosed COVID-19 patients (confirmed with polymerase chain reaction (PCR) test) and 63 age and sex-matched control subjects were included in the study. Electrocardiographic marker of iCEB were calculated manually from 12-lead ECG. Low voltage ECG defined as peak-to-peak QRS voltage less than 5mm in all limb leads and less than 10mm in all precordial leads. Patients with COVID-19 more often had low iCEB, defined as iCEB below 3.24 compared to control group (56.6% vs 11.1%), (OR=10.435;95%CI 4.015 - 27.123;p=0.000). There were no significant association between COVID-19 and high iCEB, defined as iCEB above 5.24 (OR=1.041;95%CI 0.485 - 2.235;p=0.917). There were no significant difference of the number of low voltage ECG between COVID-19 and control groups (15.1% vs 6.3%), (OR=2.622;95%CI 0.743 - 9.257, p=0.123). Conclusion: In this study showed that patients with COVID-19 are more likely to have low iCEB, suggesting that patients with COVID-19 may be proarrhytmic (towards non- TdPs-like VT/VF event), due to the alleged myocardial involvement in SARS-CoV-2 infection.

Ventricular fibrillation storm in COVID 19 responding to steroid therapy: A case report

Cardiac arrhythmias are common in patients of COVID -19 and frequently complicate the clinical course of critically ill patients. Life threatening arrhythmia including ventricular fibrillation less common but are reported to be more common in patients with elevated cardiac troponins. The mechanisms of arrhythmia in COVID 19 are multifactorial and arise from either direct cardiac involvement, from consequences systemic affection or drug interactions. The successful management requires correct identification of the cause. We report a case of VF storm in a patient with COVID 19 who responded to steroid therapy. Controlling the fulminant inflammation may reduce the burden of arrhythmia in appropriate cases.

Prolonged Exposure to Remdesivir Inhibits the Human Ether-a-go-go-related Gene Potassium Current

Introduction: Remdesivir is indicated for the treatment of COVID-19 in patients requiring hospitalization. However, cases of QTc interval prolongation and torsade de pointes (TdP) have been reported to the FDA Adverse Event Reporting System. Drug-induced QTc prolongation and TdP is the single most common cause of withdrawal, relabeling and use restriction of marketed drugs. Most drugs that prolong the QTc inhibit a potassium current (IKr), which is encoded by the human ether-a-go-go-related gene (hERG) and is crucial for ventricular repolarization and action potential duration. Research Question or Hypothesis: To assess the potential for remdesivir and its metabolite, GS441524, to inhibit hERG-related currents. Study Design: Cell-based hERG Assay Methods: Whole-cell, voltage-clamp experiments were performed in HEK-293 cells stably expressing hERG. Borosilicate glass electrodes (resistance: 2-4 MW) filled with internal solution were used to record tail currents at depolarizing and repolarizing voltages tail current. To assess acute effects, drugs were added to the internal pipette solution, and for prolonged exposure;cells were incubated with remdesivir for 24 hours prior to recording. Results: Acute exposure to remdesivir and GS-441524 did not significantly inhibit peak activation or maximum tail current density. However, prolonged exposure to remdesivir 100 nM and 1 mM, but not 10 nM, inhibited peak activation currents by 32% (19±2 pA/pF, p = 0.03) and 36% (18±2 pA/pF, p = 0.02) respectively. Remdesivir 100 nM and 1 mM, also inhibited the maximum tail current density by 40% (18±2 pA/pF, p = 0.02) and 37% (19±2 pA/pF, p = 0.03), respectively. Conclusion: Prolonged exposure to physiological concentrations of remdesivir inhibits hERG-related currents. These results, coupled with clinical reports of QTc prolongation and TdP, highlight the need for a rigorous assessment of the effect of remdesivir on ventricular repolarization and risk of proarrhythmia.

COVID-19 and Cardiac Arrhythmias

Coronavirus disease-2019 (COVID-19) has impacted the global population, leading to a pandemic, the scale of which the world has never experienced before. This novel coronavirus not only involves the respiratory system, but also affects the heart, leading to significant morbidity and mortality. Arrhythmias in COVID-19 are increasingly being documented and seem to have a prognostic significance, especially in critically ill patients. In patients with COVID-19, a variety of arrhythmias have been reported, ranging from the benign to potentially life-threatening. Multiple mechanisms, such as myocarditis, hypoxia, electrolyte disturbances and QT interval-prolonging drugs (e.g. hydroxychloroquine), are responsible for arrhythmias in patients with COVID-19. The prevalence of cardiac arrhythmias in patients with COVID-19 ranges from 3.6% to 60%, with sinus tachycardia being the most common rhythm abnormality. Other rhythm abnormalities, such as sinus bradycardia, atrial arrhythmias and complete heart block, have also been reported. Malignant ventricular arrhythmias, especially in patients with COVID-19 with multiple comorbidities, portend a bad prognosis. Additionally, the use of QT interval-prolonging drugs, such as hydroxychloroquine or azithromycin, increases the risk of torsades de pointes. Hence, there is a need for continuous rhythm monitoring, with prompt recognition of arrhythmias in critically ill patients and those on QT-prolonging medications. Management of these arrhythmias is similar to those in patients without COVID-19, with a focus on correcting reversible causes and maintaining haemodynamic stability.

COVID-19 infection and cardiac arrhythmias.

As the coronavirus 2019 (COVID-19) pandemic marches unrelentingly, more patients with cardiac arrhythmias are emerging due to the effects of the virus on the respiratory and cardiovascular (CV) systems and the systemic inflammation that it incurs, and also as a result of the proarrhythmic effects of COVID-19 pharmacotherapies and other drug interactions and the associated autonomic imbalance that enhance arrhythmogenicity. The most worrisome of all arrhythmogenic mechanisms is the QT prolonging effect of various anti-COVID pharmacotherapies that can lead to polymorphic ventricular tachycardia in the form of torsade des pointes and sudden cardiac death. It is therefore imperative to monitor the QT interval during treatment; however, conventional approaches to such monitoring increase the transmission risk for the staff and strain the health system. Hence, there is dire need for contactless monitoring and telemetry for inpatients, especially those admitted to the intensive care unit, as well as for outpatients needing continued management. In this context, recent technological advances have ushered in a new era in implementing digital health monitoring tools that circumvent these obstacles. All these issues are herein discussed and a large body of recent relevant data are reviewed.