Deep sedation with dexmedetomidine administered by electrophysiologists during COVID-19 pandemic compared with propofol administered by anesthesiologists for transcatheter ablation of atrial fibrillation (preprint)

Background: COVID-19 pandemic, limiting the availability of anesthesiologists, has impacted heavily on the organization of invasive cardiac procedures such as transcatheter atrial fibrillation (AF) ablation. Objective We compared the safety and efficacy of deep sedation with dexmedetomidine administered by electrophysiologists without anesthesiologist supervision, against the standard protocol performed with propofol. Methods We retrospectively included all AF ablation procedures performed in 2020: 23 patients sedated with 1% propofol (2 ml bolus followed by infusion starting at 1 mg/Kg/h), 26 patients with dexmedetomidine (infusion starting at 0.7 mcg/Kg/h). Both groups additionally received 1 mcg/Kg of midazolam as a single bolus and 0.05 mg single boluses of fentanyl prior to ablation on each pair of pulmonary veins (PV). Primary outcomes were oxygen desaturation (<90%) or need for assisted ventilation/intubation, bradycardia (heart rate <45 bpm) and persistent hypotension (systolic blood pressure <90 mmHg). Results Baseline characteristics and hemodynamic variables did not differ between the two groups (all p>0.05). In 8/23 (35%) patients propofol infusion velocity reduction was necessary to maintain the hemodynamic values, compared to 7/26 (27%) with dexmedetomidine. Inter-group comparison of hemodynamic variables during the procedure showed no statistically significant difference, despite a trend in favor of dexmedetomidine (3 respiratory depressions and 3 persistent hypotension episodes with propofol vs. 0 with dexmedetomidine; p = 0.057). Conclusion Deep sedation with dexmedetomidine administered by electrophysiologists without anesthesiologist supervision is safe and effective for AF transcatheter ablation. A trend towards a lower incidence of hypotension and respiratory depression was noted when compared to propofol.

Innate Immune Activation and Mitochondrial ROS Invoke Persistent Cardiac Conduction System Dysfunction after COVID-19 (preprint)

BackgroundCardiac risk rises during acute SARS-CoV-2 infection and in long COVID syndrome in humans, but the mechanisms behind COVID-19-linked arrhythmias are unknown. This study explores the acute and long term effects of SARS-CoV-2 on the cardiac conduction system (CCS) in a hamster model of COVID-19. MethodsRadiotelemetry in conscious animals was used to non-invasively record electrocardiograms and subpleural pressures after intranasal SARS-CoV-2 infection. Cardiac cytokines, interferon-stimulated gene expression, and macrophage infiltration of the CCS, were assessed at 4 days and 4 weeks post-infection. A double-stranded RNA mimetic, polyinosinic:polycytidylic acid (PIC), was used in vivo and in vitro to activate viral pattern recognition receptors in the absence of SARS-CoV-2 infection. ResultsCOVID-19 induced pronounced tachypnea and severe cardiac conduction system (CCS) dysfunction, spanning from bradycardia to persistent atrioventricular block, although no viral protein expression was detected in the heart. Arrhythmias developed rapidly, partially reversed, and then redeveloped after the pulmonary infection was resolved, indicating persistent CCS injury. Increased cardiac cytokines, interferon-stimulated gene expression, and macrophage remodeling in the CCS accompanied the electrophysiological abnormalities. Interestingly, the arrhythmia phenotype was reproduced by cardiac injection of PIC in the absence of virus, indicating that innate immune activation was sufficient to drive the response. PIC also strongly induced cytokine secretion and robust interferon signaling in hearts, human iPSC-derived cardiomyocytes (hiPSC-CMs), and engineered heart tissues, accompanied by alterations in electrical and Ca2+ handling properties. Importantly, the pulmonary and cardiac effects of COVID-19 were blunted by in vivo inhibition of JAK/STAT signaling or by a mitochondrially-targeted antioxidant. ConclusionsThe findings indicate that long term dysfunction and immune cell remodeling of the CCS is induced by COVID-19, arising indirectly from oxidative stress and excessive activation of cardiac innate immune responses during infection, with implications for long COVID Syndrome.

Clinical Features and Short-Term Outcomes in Virus-Induced Bradycardia: Comparison Between Covid and non-Covid Infected Patients (preprint)

Covid-19 outbreak has drawn attention to the fact that viral infections might present with clinical bradycardia. Seeking its clinical significance, not yet unveiled by the literature, we come across other viral infections that also show clinical bradycardia during its clinical course, such as dengue fever and viral diarrhea. The clinical presentation of the latest seems to be severe, often presenting with orthostatic intolerance and fatigue symptoms, requiring expert consultation irrespective of the infection stage, and in case of dengue fever, frequently during the recovery phase. Meanwhile, in Covid-19 infected patients, the bradycardia observed is mild, frugal, and usually asymptomatic. Thus, we conducted a comparison between two different groups of patients with viral infection displaying clinical bradycardia during hospital stay: Covid and non-Covid patients regarding clinical and Holter monitoring parameters. All patients had other causes of bradycardia excluded and echocardiography and cardiac biomarkers ruled out acute myocarditis. The results showed that non-Covid patients presented with significantly lower mean and minimum heart rates (HR) on Holter monitoring, as well as longer times in with HR < 50 beats per minute (bpm).  SDNN and pNN>50% were also significantly higher in non-Covid patients. The minimum systolic BP was significantly lower in non-Covid patients. The study shows that Covid-19 is not the only viral infection that may display with clinical bradycardia, but it’s much milder than other viral infections such as dengue fever and viral diarrhea. It remains unclear the mechanism throughout Covid-related bradycardia comes about.

Remdesivir-associated bradycardia in COVID-19: a rapid review protocol.

INTRODUCTION: Remdesivir is an antiviral medication that is used in the treatment of severe COVID-19. Research has highlighted the potential cardiac side effects of remdesivir, including the occurrence of remdesivir-associated bradycardia (RAB), but these findings have not been consistent. In addition, very little is known about the clinical implications and outcomes of RAB. The aim of this rapid systematic review is to determine the event rate of developing bradycardia while receiving remdesivir treatment compared with not receiving remdesivir in patients diagnosed with COVID-19. METHODS AND ANALYSIS: This study follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol guidelines and will include original papers related to COVID-19, remdesivir and bradycardia. Only English language papers published from 1 December 2019 to 31 December 2022 will be included. The following databases will be searched using keywords and controlled vocabulary: Ovid MEDLINE, Ovid EMBASE, Scopus, Cochrane, PubMed and Web of Science. Two reviewers will independently perform screening and data abstraction. Data will be synthesised qualitatively as well as quantitatively. A random-effects model will be used to calculate the pooled estimates. ETHICS AND DISSEMINATION: This review will systematically analyse the clinical studies available to help better characterise RAB. The results will support a retrospective study investigating RAB that is currently being conducted at the University Medical Center of Southern Nevada in Las Vegas, Nevada. PROSPERO REGISTRATION NUMBER: This protocol has been submitted to and approved by PROSPERO (Protocol ID: CRD42022331614).

The Clinical Utility of Relative Bradycardia for Identifying Cases of Coronavirus Disease 2019 Pneumonia: A Retrospective Pneumonia Cohort Study.

Objective Both coronavirus disease 2019 (COVID-19) pneumonia and relative bradycardia are common conditions among clinicians; however, the association between these has not been well studied. The present study assessed whether or not relative bradycardia on admission was more predominant in patients with COVID-19 pneumonia than in those with other infectious pneumonia. Methods For this single-center, retrospective cohort study, we collected data through electronic medical records and examined the occurrence of relative bradycardia on admission. We used logistic regression analyses to compare outcomes with and without relative bradycardia on admission. The primary outcome was COVID-19 pneumonia. The secondary outcome was hypoxemia during the hospital stay. We performed multivariable regression with adjusting for the effects of age, sex, healthcare-associated pneumonia, body mass index, Charlson comorbidity index, and bilateral infiltration on computed tomography (CT) as confounding factors. Patients Adult patients with new-onset hospitalized infectious pneumonia confirmed by CT between January 1, 2020, and July 31, 2021. Results This study included 395 participants. On admission, 87 (22.0%) participants exhibited relative bradycardia, and 302 (76.5%) participants had COVID-19. Relative bradycardia on admission was not significantly associated with COVID-19 pneumonia [adjusted odds ratio (OR) 1.32; 95% confidence interval (CI) 0.49-3.54, p=0.588] but was associated with hypoxemia (adjusted OR 4.74; 95%CI 2.64-8.52, p<0.001). Conclusion The study results showed that relative bradycardia on admission was not associated with COVID-19 in cases of infectious pneumonia. However, relative bradycardia may be associated with the incidence of hypoxemia in pneumonia.

Remdesivir-Induced Bradycardia.

Remdesivir, a viral RNA-dependent RNA polymerase inhibitor, found extensive use in coronavirus disease 2019-infected patients because it curbs the viral load expansion. Among patients hospitalized as a result of lower respiratory tract infection, remdesivir proved to improve recovery time; however, remdesivir also can induce significant cytotoxic effects on cardiac myocytes. In this narrative review, we discuss the pathophysiological mechanism of remdesivir-induced bradycardia and diagnostic and management strategies for these patients. We conclude that further research is necessary to understand better the mechanism of bradycardia in coronavirus disease 2019 patients with or without cardiovascular disorder treated with remdesivir.

Remdesivir Use in Pediatric Patients for SARS-CoV-2 Treatment: Single Academic Center Study.

BACKGROUND: Millions of children in the United States have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with many infections leading to hospitalization. For pediatric patients, especially younger children, treatment options are limited. Remdesivir has demonstrated a positive safety and efficacy profile in adults, but little data is published regarding remdesivir use in pediatric patients. Additional data for SARS-CoV-2 treatments in pediatric patients is required to prevent further SARS-CoV-2-related morbidity and mortality. At a single pediatric academic medical center, the safety and efficacy of remdesivir was evaluated. METHODS: A retrospective review of patients admitted to a pediatric academic medical center who received remdesivir over a 17-month period was completed. All pediatric patients who received at least 1 dose of remdesivir were included. Safety and efficacy were assessed using national organization's definitions of clinical improvement, bradycardia, hypertension, acute kidney injury and drug-induced liver injury. RESULTS: There were 48 pediatric patients included in this study with 29% of patients admitted to the pediatric intensive care unit. Less than one-third of patients received the full treatment course of remdesivir, with over half of patients not completing therapy due to symptomatic improvement or hospital discharge. Majority of patients required some level of supplemental oxygen support. The median World Health Organization score was consistent throughout all 5 days of therapy. No patients experienced significant bradycardia, hypertension, acute kidney injury, or drug-induced liver injury. CONCLUSIONS: Remdesivir may correlate with clinical stability or improvement and demonstrates safety when used in pediatric patients. A randomized controlled trial is needed to confirm these findings.

Remdesivir-induced bradycardia in patients hospitalized with SARS-CoV2 infection: a possible vagally-mediated mechanism.

Recently, case series studies on patients with SARS-CoV-2 infection reported an association between remdesivir (RDV) administration and incidental bradycardia. However, the phenomenon has not yet been described in detail. We conducted a retrospective case-control study to evaluate the occurrence of RDV-related bradycardia in patients hospitalized for SARS-CoV2 pneumoniae. We retrospectively evaluated 71 patients, hospitalized in six internal medicine wards of the Milan area, affected by mild-to-moderate COVID-19 who received RDV (RDV group) and 54 controls, matched for sex, age and disease severity on admission (CTR group). The mean heart rate value recorded during the first two days of hospitalization was considered as baseline heart rate (HRb). Heart rate values relative to the 5-days treatment and the 5-days post-treatment were extracted for RDV group, while heart rate values relative to 10 days of hospitalization were considered for the CTR group. ΔHR values were calculated as maximum HR drop versus HRb. Possible associations between ΔHR and clinical-demographic factors were assessed through regression analysis. The RDV group experienced a significantly higher incidence of bradycardia compared to the CTR group (56% vs 33%, OR 2.6, 95% CI 1.2-5.4, p value = 0.011). Moreover, the RDV group showed higher ΔHR values than the CTR group. The HR progressively decreased with daily administration of RDV, reaching the maximun drop on day six (-8.6±1.9 bpm). In RDV group, patients who experienced bradycardia had higher drop in HR, higher alanine aminotransferase (ALT) values at the baseline (bALT) and during the RDV administration period. ΔHR was positively associated with HRb (ß = 0.772, p < 0.001) and bALT (ß = 0.245, p = 0.005). In conclusion, our results confirmed a significant association between RDV administration and development of bradycardia. This effect was proportional to baseline HR and was associated with higher levels of baseline ALT, suggesting a possible interaction between RDV liver metabolism and a vagally-mediated effect on HR due to increased availability of RDV metabolites.

Pediatric severe COVID – 19 and MIS-C in the Brazilian Amazon: independent risk factors to mortality (preprint)

Purpose: SARS-CoV-2 infection in children is usually asymptomatic/mild. However, some patients may develop critical forms. Our aim was to evaluate the independent risk factors associated to in-hospital mortality in children with critical disease related to SARS-CoV-2. Methods: This is multicenter prospective cohort included critically ill children (1 month/18 years of age), with confirmed critical disease related to SARS-CoV-2 admitted to three tertiary Pediatric Intensive Care Units (PICU) in Brazilian Amazon, between April 2020/July 2022. Main outcome was in-hospital mortality. The independent risk factors associated with mortality were evaluated with a multivariable Cox proportional regression. Results: 208 patients were assessed. Median age was 33 months and median follow-up was 277 days (range, 2-759). Death occurred in 37 (17.8%) patients with a median follow-up of 7 (4-13) days. Most non-survivors had at least one comorbidity - 34 (91.9%). Substantial clinical features, laboratory and ventilatory parameters were associated with mortality. Independent risk factors for mortality were underweight status (HR= 6.64, p=0.01), vasoactive inotropic score (VIS) > 84 (HR=4.76, p=0.05), acute respiratory distress syndrome (HR=8.63, p=0.02) and erythrocyte sedimentation rate (ESR) >18 mm/hour (HR=3.95, p=0.03). Conclusions: This study of critically ill patients with COVID-19 and MIS-C from the Brazilian Amazon showed a high mortality rate. The risk of death was higher for underweight individuals, those with higher levels of VIS and ESR, presence of ARDS. The majority of deaths occurred within 10 days of hospitalization, highlighting the importance of prompt recognition in regard to these patients.

Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project.

Importance: The rapid spread and mortality associated with COVID-19 emphasized a need for surveillance system development to identify adverse events (AEs) to emerging therapeutics. Bradycardia is a remdesivir infusion-associated AE listed in the US Food and Drug Administration-approved prescribing information. Objective: To evaluate the magnitude and duration of bradycardic events following remdesivir administration. Design, Setting, and Participants: A multicenter cohort study of patients with recorded heart rate less than 60 beats per minute within 24 hours after administration of a remdesivir dose was conducted between November 23, 2020, and October 31, 2021. Participants included patients hospitalized with COVID-19 at 15 medical centers across the US. Patients excluded had AEs unrelated to bradycardia, AEs in addition to bradycardia, or first onset of bradycardia after 5 remdesivir doses. Exposures: Remdesivir administration. Main Outcomes and Measures: Linear mixed-effect models for the minimum HR before starting remdesivir and within 24 hours of each dose included doses as fixed effects. Baseline covariates were age (≥65 years vs <65 years), sex (male vs female), cardiovascular disease history (yes vs no), and concomitant use of bradycardia-associated medications. The interactions between variables and doses were considered fixed-effects covariates to adjust models. Results: A total of 188 patients were included in the primary analysis and 181 in the secondary analysis. The cohort included 108 men (57.4%); 75 individuals (39.9%) were non-Hispanic White and mean (SD) age was 61.3 (15.4) years. Minimum HR after doses 1 to 5 was lower than before remdesivir. Mean minimum HR was lowest after dose 4, decreasing by -15.2 beats per minute (95% CI, -17.4 to -13.1; P < .001) compared with before remdesivir administration. Mean (SD) minimum HR was 55.6 (10.2) beats per minute across all 5 doses. Of 181 patients included in time-to-event analysis, 91 had their first episode of bradycardia within 23.4 hours (95% CI, 20.1-31.5 hours) and 91 had their lowest HR within 60.7 hours (95% CI, 54.0-68.3 hours). Median time to first bradycardia after starting remdesivir was shorter for patients aged 65 years or older vs those younger than 65 years (18.7 hours; 95% CI, 16.8-23.7 hours vs 31.5 hours; 95% CI, 22.7-39.3 hours; P = .04). Median time to lowest HR was shorter for men vs women (54.2 hours; 95% CI, 47.3-62.0 hours vs 71.0 hours; 95% CI, 59.5-79.6 hours; P = .02). Conclusions and Relevance: In this cohort study, bradycardia occurred during remdesivir infusion and persisted. Given the widespread use of remdesivir, practitioners should be aware of this safety signal.

The relationship between the severity of coronary artery disease in angiography and the incidence of short-term major cardiovascular events of patients with Covid-19 and myocardial infarction: a cross-sectional study in Iran (preprint)

Background Coronary artery disease (CAD) has been frequently recognized as a risk factor for poor prognosis in COVID-19 patients. Syntax score is an invasive coronary angiographic-based tool used to determine the severity of CAD. In this study, we aim to investigate the prognostic significance of syntax score for mortality and morbidity among COVID-19 patients.Methods In this cross-sectional study, we have included patients with confirmed COVID-19 diagnosis who underwent percutaneous coronary intervention (PCI). Based on angiographic records, the CAD complexity was measured by Syntax score, and echocardiographic variables were documented. The laboratory data were obtained from the HISS database of the hospital. All patients were followed up one month after discharge for new cardiovascular events, rehospitalization, heart failure (HF), stent thrombosis, cerebrovascular accidents, and death.Results In one month, 108 patients were included in the study. The mean age was 64.8 ± 11.6, and 74% were male. The Cox regression model found no association between the Syntax score and the composite outcomes. In the univariate cox proportional HR model, MPV, LDH, and ESR were found to have predictive significance for in-hospital death. AKI was resulted to be significantly associated with rehospitalization in multivariate analysis.Conclusion The present study did not find a significant association between adverse outcomes and syntax score in COVID-19 patients referred for PCI. Acute kidney injury and duration of ICU stay was found to be the main factor predicting rehospitalization and HF. Future studies are needed to confirm these findings.

Electrocardiographic changes in hospitalised children with COVID-19.

OBJECTIVES: Cardiac manifestations of the coronavirus disease 2019 (COVID-19) have mainly been reported in adults. Therefore, we aimed to determine the electrocardiographic abnormalities in hospitalised paediatric patients with COVID-19 and multisystemic inflammatory syndrome in children. METHODS: We retrospectively evaluated hospitalised paediatric patients <18 years of age with a diagnosis of COVID-19 (n = 168) and multisystem inflammatory syndrome in children (n = 48) between March 2021 and December 2021. A daily electrocardiography was performed for the patients who had electrocardiographic abnormalities on admission or developed electrocardiographic abnormality on the follow-up. The characteristics of these patients, underlying predisposing conditions, and clinical course were also examined. RESULTS: Two-hundred sixteen paediatric patients (55% were male) with a mean age of 10.7 ± 4.69 years were evaluated. There was an underlying disease in 84 (38.8%) patients and 51 (23.6%) required paediatric ICU admission. Electrocardiography abnormality was detected in 12 (5.5%) which were as follows: 7 (3.2%) had sinus bradycardia, 3 (1.4%) patients had transient ST elevation and concomitant T negativity, and 2 (0.9%) developed first-degree Atrioventricular (AV) block. The median time from the onset of disease symptoms to detecting electrocardiographic abnormality was 9 days. Electrocardiographic abnormalities returned to normal uneventfully 3 days later. CONCLUSIONS: The prevalence of arrhythmia in paediatric patients with COVID-19 was detected in 5.5% of the patients. While two-thirds of the electrocardiography abnormalities were sinus bradycardia, ST elevation was remarkable (1.4%). Clinicians should be aware of electrocardiographic abnormalities and consider electrocardiographic monitoring in paediatric patients with COVID-19 and multisystemic inflammatory syndrome in children.

Pharmacokinetic interaction between verapamil and ritonavir-boosted nirmatrelvir: implications for the management of COVID-19 in patients with hypertension.

A woman in her 80s was brought to the emergency department for acute onset of generalised weakness, lethargy and altered mental state. The emergency medical service found her to have symptomatic bradycardia, and transcutaneous pacing was done. Medical history was notable for hypertension, hyperlipidaemia, type 2 diabetes, and a recently diagnosed SARS-CoV-2 (COVID-19) infection for which she was prescribed ritonavir-boosted nirmatrelvir (Paxlovid) two days before the presentation. On arrival at the hospital, she was found to have marked bradycardia with widened QRS, hyperglycaemia and metabolic acidosis. Transvenous pacing along with pressor support and insulin were initiated, and she was admitted to the intensive care unit. Drug interaction between ritonavir-boosted nirmatrelvir and verapamil leading to verapamil toxicity was suspected of causing her symptoms, and both drugs were withheld. She reverted to sinus rhythm on the fourth day, and the pacemaker was discontinued.

Use of Remdesivir in children with COVID-19: report of an Italian multicenter study (preprint)

Introduction COVID-19 is generally milder in children than in adults, however severe infection has been described in some patients. Few data are available on use of Remdesivir (RDV) in children, as most clinical trials focused on adult patients. We report a multicenter study to investigate the safety of RDV in children affected by COVID-19.Methods We collected the clinical data of children with COVID-19 treated with RDV between March 2020 and February 2022 in 10 Italian hospitals. Clinical data were compared according to the duration of RDV therapy. Linear and logistic regression models were used to determine the association of significant variables from the bivariate analysis to the duration of RDV therapy.Results A total of 50 patients were included, with a median age of 12.8 years. Many patients had at least one comorbidity (78%), mostly obesity. Symptoms were fever (88%), cough (74%) and dyspnea (68%). Most patients were diagnosed with pneumonia of either viral and/or bacterial etiology. Blood test showed leukopenia in 66% and increased C-reactive protein (CRP) levels in 63% of cases. Thirty-six patients received RDV for 5 days, nine patients up to 10 days. Most children who received RDV longer were admitted to the PICU (67%). Treatment with RDV was well tolerated with rare side effects (Table 1): bradycardia was recorded in 6% of cases, solved in less than 24 hours after discontinuation. A mild elevation of transaminases was observed in 26% of cases, however for the 8%, it was still detected before the RDV administration. Therefore, in these cases, we could not establish if it was caused by COVID-19, RDV o both. Patients who received RDV for more than 5 days waited longer for its administration after pneumonia diagnosis. The presence of comorbidities and the duration of O2 administration significantly correlated with the duration of RDV therapy at the linear regression analysis.Conclusion Our experience indicates that RDV against SARS-CoV-2 is safe and well-tolerated in pediatric populations at high risk of developing severe COVID-19. Our data suggest that delaying RDV therapy after diagnosis of pneumonia may be associated with a longer duration of antiviral therapy, especially in patients with comorbidities.

Symptomatic Bradycardia in Covid-19 Hospitalized Patients: A Case Series.

SARS COV-2 infection has become a global threat. Cardiovascular manifestations associated with Covid-19 have been noted in several publications, and bradycardia related to Covid-19 is a commonly reported complication. This study reports six serial cases of bradycardia attributable to Covid-19; four of them developed complete atrioventricular block. These patients experienced clinical symptoms related to bradycardia and initially required permanent pacemaker implantation. However, one patient did not require permanent pacing later on due to spontaneous conversion to sinus rhythm. In comparison, the other two patients who developed transient sinus bradycardia experienced a self-limiting condition during their hospitalization period without requiring any cardiac pacing device or medication to increase heart rate. Complete atrioventricular block and transient sinus bradycardia in these patients, despite not having any history of bradycardia, might be due to complex processes in the systemic inflammatory response in Covid-19. Cardiac monitoring, hemodynamic evaluation, and strategy for permanent pacemaker in these patients should be treated on a case-by-case basis.

Remdesivir (VEKLURY) for Treating COVID-19: Guinea Pig Ex Vivo and In Vivo Cardiac Electrophysiological Effects.

ABSTRACT: Bradycardia and QTc interval prolongation on the ECG have been reported with remdesivir (Veklury), an antiviral drug recently approved for treating severely ill patients with COVID-19. The objective was to evaluate the effects of remdesivir on cardiac electrophysiology ex vivo and in vivo. Ex vivo: Langendorff retroperfusion experiments were performed on isolated hearts from male Hartley guinea pigs (n = 23, total) exposed to either remdesivir 3, 10, or 30 µmol/L to assess drug-induced prolongation of the monophasic action potential duration measured at 90% repolarization (MAPD 90 ). In vivo: ECG recordings using wireless cardiac telemetry were performed in guinea pigs (n = 6) treated with daily i.p. doses of remdesivir 5 mg/kg on day 1 and 2.5 mg/kg on days 2-10. Ex vivo remdesivir (3, 10, and 30 µmol/L) had no statistically significant effect on MAPD 90 , while pacing the hearts at basic stimulation cycle lengths of 200 or 250 milliseconds, or when the hearts were not paced and beating at their intrinsic heart rate. In a second set of similar ex vivo experiments, remdesivir 10 µmol/L did not potentiate the MAPD 90 -prolonging effects of dofetilide 20 nmol/L (n = 4) hearts. In vivo remdesivir caused small but statistically significant prolongations of the RR and QTc F intervals at day 1 (5 mg/kg) and at day 10 (2.5 mg/kg). No ventricular arrhythmias were ever observed under the effect of remdesivir. Remdesivir causes bradycardia, and mild QTc prolongation, which nonetheless, could be of clinical relevance in many hospitalized patients with COVID-19 concomitantly treated with multiple drugs.

Angiotensin 1-7 in severe COVID-19 patients: a phase 1 clinical trial (preprint)

Background: The coronavirus-related disease (COVID-19) is mainly characterized by a respiratory involvement, with few available therapeutics for critically cases. The renin-angiotensin system (RAS) has a relevant role in the pathogenesis of COVID-19, as the virus enter host's cells via the angiotensin-converting enzyme 2 (ACE2) and RAS disequilibrium promote inflammation and fibrosis. Exogenous angiotensin-(1-7) might modulate RAS in COVID-19 patients; however, no data on its safety are available in this setting. Methods: This investigator-initiated, open label, phase I clinical trial was conducted to test the safety of intravenous administration of Angiotensin-(1-7) in severe COVID-19 patients admitted in two intensive care units (ICU) in Belo Horizonte, Brazil. In addition to standard of care, intravenous administration of Angiotensin-(1-7) was started at 5 mcg/Kg*day and increased to 10 mcg/Kg*day after 24 hours and continued for a maximum of 7 days or until ICU discharge. The rate of serious adverse events (SAEs) served as the primary outcome of the study. Results: Between August and December 2020, 28 patients were included (mean age of 55.8 + or -12.0 years). All but one patient underwent dose escalation after 24 hours and 8 (28.5%) received the treatment until day 7. No significant differences in mean blood pressure and heart rate were observed before and after the initiation of the drug. During the period of intervention, 5/28 (17.8%) patients required vasopressors, 4 at low dose norepinephrine (i.e. <0.05 mcg/kg*min), while one patient required higher doses because of septic shock. One patient presented with sinus bradycardia, which was considered possibly related to the study drug and resolved after discontinuation. Six patients (21.4%) died before ICU discharge. Conclusions: Intravenous infusion of Angiotensin-(1-7) up to 10 mcg/Kg*day was safe in severe COVID-19 patients and could represent a potential therapeutic strategy in this setting.

Clinical Characteristics and Implications of Bradycardia in COVID-19 Patients Treated with Remdesivir: A Single-Center Retrospective Cohort Study.

BACKGROUND AND OBJECTIVES: Remdesivir is an antiviral drug used to treat coronavirus disease 2019 (COVID-19) with a relatively obscure cardiac effect profile. Previous studies have reported bradycardia associated with remdesivir, but few have examined its clinical characteristics. The objective of this study was to investigate remdesivir associated bradycardia and its associated clinical characteristics and outcomes. METHODS: This is a single-institution retrospective study that investigated bradycardia in 600 patients who received remdesivir for treatment of COVID-19. A total of 375 patients were included in the study after screening for other known causes of bradycardia (atrioventricular [AV] nodal blockers). All patients were analyzed for episodes of bradycardia from when remdesivir was initiated up to 5 days after completion, a time frame based on the drug's putative elimination half-life. Univariate and multivariate statistical tests were conducted to analyze the data. RESULTS: The mean age of the sample was 56.63 ± 13.23 years. Of patients who met inclusion criteria, 49% were found to have bradycardia within 5 days of remdesivir administration. Compared to the cohort without a documented bradycardic episode, patients with bradycardia were significantly more likely to experience inpatient mortality (22% vs 12%, p = 0.01). The patients with bradycardia were found to have marginally higher serum D-dimer levels (5.2 vs 3.4 µg/mL, p = 0.05) and were more likely to undergo endotracheal intubation (28% vs 14%, p = 0.008). Male sex, hyperlipidemia, and bradycardia within 5 days of completing remdesivir were significant predictors of inpatient mortality. No significant differences in length of stay were found. CONCLUSIONS: Bradycardia that occurs during or shortly after remdesivir treatment in COVID-19 patients may be associated with an increased rate of in-hospital mortality. However, COVID-19 and its cardiac complications cannot be excluded as potential contributors of bradycardia in the present study. Future studies are needed to further delineate the cardiac characteristics of COVID-19 and remdesivir.

An observational, retrospective, comprehensive pharmacovigilance analysis of hydroxychloroquine-associated cardiovascular adverse events in patients with and without COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic. Hydroxychloroquine (HCQ)-associated cardiovascular adverse events (CVAEs) have been increasingly reported. AIM: This study aimed to present an observational, retrospective, and comprehensive pharmacovigilance analysis of CVAE associated with HCQ in patients with and without COVID-19 using the US Food and Drug Administration Adverse Events Reporting System (FAERS) data from January 2020 to December 2020. METHOD: We identified 3302 adverse event reports from the FAERS database in the year 2020 and divided them into COVID-19 and non-COVID-19 groups, respectively. Then we analyzed whether there were differences in CVAEs between the two groups. RESULTS: We found that CVAE was higher in cases with COVID-19 compared to those without COVID-19, odds ratio (OR) of 1.26 and a 95% confidence interval (95% CI) of 1.02-1.54. Cases with COVID-19 treated with HCQ exhibited relatively higher proportions of torsade de points (TdP) and QT prolongation (OR 3.10, 95% CI 2.24-4.30), shock-associated TdP (OR 2.93, 95% CI 2.13-4.04), cardiac arrhythmias (OR 2.07, 95% CI 1.60-2.69), cardiac arrhythmia terms (including bradyarrhythmias and tachyarrhythmias) (OR 2.15, 95% CI 1.65-2.80), bradyarrhythmias (including conduction defects and disorders of sinus node function) (OR 2.56, 95% CI 1.86-3.54), and conduction defects (OR 2.56, 95% CI 1.86-3.54). CONCLUSION: Our retrospective observational analysis suggested that the proportion of CVAE associated with HCQ, especially TdP and QT prolongation, was higher in patients with COVID-19. Understanding the effects of COVID-19 on the cardiovascular system is essential to providing comprehensive medical care to patients receiving HCQ treatment.