The Role of the Immune System on the Cardiac Complications Observed in SARS-CoV-2

Abstract An acute respiratory syndrome caused by SARS-CoV2 was declared a pandemic by the World Health Organization. Current data in the world and in Brazil show that approximately 40% of patients who died have some type of cardiac comorbidity. There are also robust reports showing an increase in IL-6 / IL-1B / TNF-alpha and the presence of lymphopenia in patients with COVID-19. Our team and others have shown that increased cytokines are the link between arrhythmias/Left ventricular dysfunction and the immune system in different diseases. In addition, it has been well demonstrated that lymphopenia can not only be a good marker, but also a factor that causes heart failure. Thus, the present review focused on the role of the immune system upon the cardiac alterations observed in the SARS-CoV2 infection. Additionally, it was well described that SARS-CoV-2 is able to infect cardiac cells. Therefore, here it will be reviewed in deep.

Arrhythmogenesis and COVID-19.

The ongoing coronavirus infection-2019 (COVID-19) global pandemic has had devastating impacts on the global population since 2019. Cardiac complications are a well-documented sequala of COVID-19, with exposed patients experiencing complications such as myocardial infarction, myocarditis, and arrythmias. This article aims to review prominent literature regarding COVID-19 and its link with arrhythmias, as well as to discuss some of the possible mechanisms by which arrhythmogenesis may occur in patients with COVID-19.

Arrhythmogenic mechanisms of interleukin-6 combination with hydroxychloroquine and azithromycin in inflammatory diseases.

Inflammatory diseases including COVID-19 are associated with a cytokine storm characterized by high interleukin-6 (IL-6) titers. In particular, while recent studies examined COVID-19 associated arrhythmic risks from cardiac injury and/or from pharmacotherapy such as the combination of azithromycin (AZM) and hydroxychloroquine (HCQ), the role of IL-6 per se in increasing the arrhythmic risk remains poorly understood. The objective is to elucidate the electrophysiological basis of inflammation-associated arrhythmic risk in the presence of AZM and HCQ. IL-6, AZM and HCQ were concomitantly administered to guinea pigs in-vivo and in-vitro. Electrocardiograms, action potentials and ion-currents were analyzed. IL-6 alone or the combination AZM + HCQ induced mild to moderate reduction in heart rate, PR-interval and corrected QT (QTc) in-vivo and in-vitro. Notably, IL-6 alone was more potent than the combination of the two drugs in reducing heart rate, increasing PR-interval and QTc. In addition, the in-vivo or in-vitro combination of IL-6 + AZM + HCQ caused severe bradycardia, conduction abnormalities, QTc prolongation and asystole. These electrocardiographic abnormalities were attenuated in-vivo by tocilizumab (TCZ), a monoclonal antibody against IL-6 receptor, and are due in part to the prolongation of action potential duration and selective inhibition of Na+, Ca2+ and K+ currents. Inflammation confers greater risk for arrhythmia than the drug combination therapy. As such, in the setting of elevated IL-6 during inflammation caution must be taken when co-administering drugs known to predispose to fatal arrhythmias and TCZ could be an important player as a novel anti-arrhythmic agent. Thus, identifying inflammation as a critical culprit is essential for proper management.

COVID-19 and Cardiac Arrhythmias.

Since the coronavirus disease (COVID-19) pandemic spread unrelentingly all over the world, millions of cases have been reported. Despite a high number of asymptomatic cases, the course of the disease can be serious or even fatal. The affection of the myocardium, called myocardial injury, is caused by multiple triggers. The occurrence of cardiac arrhythmias in COVID-19 patients with myocardial involvement and a critical course is common. In this review, potential mechanisms, incidence, and treatment options for cardiac arrhythmias in COVID-19 patients will be provided by performing a literature research in MESH database and the National Library of Medicine. Common cardiac arrhythmias in COVID-19 patients were sinus tachycardia, atrial fibrillation (AF), ventricular tachycardia (VT), ventricular fibrillation (VF), atrioventricular block, sinusoidal block or QTc prolongation. AF was the most common heart rhythm disorder. About 10% of COVID-19 patients develop new-onset AF and 23 to 33% showed recurrence of AF in patients with known AF. One retrospective trial revealed the incidence of VT or VF to be 5.9% in hospitalized patients. Both AF and VT are clearly associated with worse outcome. Several mechanisms such as hypoxia, myocarditis, myocardial ischemia, or abnormal host immune response, which induce cardiac arrhythmias, have been described. The effect of QT-prolonging drugs in inducing cardiac arrhythmias has become mitigated as these medications are no longer recommended. Acute management of cardiac arrhythmias in COVID-19 patients is affected by the reduction of exposure of health care personnel. More prospective data are desirable to better understand pathophysiology and consecutively adapt management.

J-waves in acute COVID-19: A novel disease characteristic and predictor of mortality?

BACKGROUND: J-waves represent a common finding in routine ECGs (5-6%) and are closely linked to ventricular tachycardias. While arrhythmias and non-specific ECG alterations are a frequent finding in COVID-19, an analysis of J-wave incidence in acute COVID-19 is lacking. METHODS: A total of 386 patients consecutively, hospitalized due to acute COVID-19 pneumonia were included in this retrospective analysis. Admission ECGs were analyzed, screened for J-waves and correlated to clinical characteristics and 28-day mortality. RESULTS: J-waves were present in 12.2% of patients. Factors associated with the presence of J-waves were old age, female sex, a history of stroke and/or heart failure, high CRP levels as well as a high BMI. Mortality rates were significantly higher in patients with J-waves in the admission ECG compared to the non-J-wave cohort (J-wave: 14.9% vs. non-J-wave 3.8%, p = 0.001). After adjusting for confounders using a multivariable cox regression model, the incidence of J-waves was an independent predictor of mortality at 28-days (OR 2.76 95% CI: 1.15-6.63; p = 0.023). J-waves disappeared or declined in 36.4% of COVID-19 survivors with available ECGs for 6-8 months follow-up. CONCLUSION: J-waves are frequently and often transiently found in the admission ECG of patients hospitalized with acute COVID-19. Furthermore, they seem to be an independent predictor of 28-day mortality.

Prognostic Value of Electrocardiographic QRS Diminution in Patients Hospitalized With COVID-19 or Influenza.

During the clinical care of hospitalized patients with COVID-19, diminished QRS amplitude on the surface electrocardiogram (ECG) was observed to precede clinical decompensation, culminating in death. This prompted investigation into the prognostic utility and specificity of low QRS complex amplitude (LoQRS) in COVID-19. We retrospectively analyzed consecutive adults admitted to a telemetry service with SARS-CoV-2 (n = 140) or influenza (n = 281) infection with a final disposition-death or discharge. LoQRS was defined as a composite of QRS amplitude <5 mm or <10 mm in the limb or precordial leads, respectively, or a ≥50% decrease in QRS amplitude on follow-up ECG during hospitalization. LoQRS was more prevalent in patients with COVID-19 than influenza (24.3% vs 11.7%, p = 0.001), and in patients who died than survived with either COVID-19 (48.1% vs 10.2%, p <0.001) or influenza (38.9% vs 9.9%, p <0.001). LoQRS was independently associated with mortality in patients with COVID-19 when adjusted for baseline clinical variables (odds ratio [OR] 11.5, 95% confidence interval [CI] 3.9 to 33.8, p <0.001), presenting and peak troponin, D-dimer, C-reactive protein, albumin, intubation, and vasopressor requirement (OR 13.8, 95% CI 1.3 to 145.5, p = 0.029). The median time to death in COVID-19 from the first ECG with LoQRS was 52 hours (interquartile range 18 to 130). Dynamic QRS amplitude diminution is a strong independent predictor of death over not only the course of COVID-19 infection, but also influenza infection. In conclusion, this finding may serve as a pragmatic prognostication tool reflecting evolving clinical changes during hospitalization, over a potentially actionable time interval for clinical reassessment.

Usefulness of Mobile Electrocardiographic Devices to Reduce Urgent Healthcare Visits.

Mobile electrocardiogram (mECG) devices are being used increasingly, supplying recordings to providers and providing automatic rhythm interpretation. Given the intermittent nature of certain cardiac arrhythmias, mECGs allow instant access to a recording device. In the current COVID-19 pandemic, efforts to limit in-person patient interactions and avoid overwhelming emergency and inpatient services would add value. Our goal was to evaluate whether a mECG device would reduce healthcare utilization overall, particularly those of urgent nature. We identified a cohort of KardiaMobile (AliveCor, USA) mECG users and compared their healthcare utilization 1 year prior to obtaining the device and 1 year after. One hundred and twenty-eight patients were studied (mean age 64, 47% female). Mean duration of follow-up pre-intervention was 9.8 months. One hundred and twenty-three of 128 individuals completed post-intervention follow-up. Patients were less likely to have cardiac monitors ordered (30 vs 6; p <0.01), outpatient office visits (525 vs 382; p <0.01), cardiac-specific ED visits (51 vs 30; p <0.01), arrhythmia related ED visits (45 vs 20; p <0.01), and unplanned arrhythmia admissions (34 vs 11; p <0.01) in the year after obtaining a KardiaMobile device compared to the year prior to obtaining the device. Mobile technology is available for heart rhythm monitoring and can give feedback to the user. This study showed a reduction of in-person, healthcare utilization with mECG device use. In conclusion, this strategy would be expected to decrease the risk of exposure to patients and providers and would avoid overwhelming emergency and inpatient services.

Impact of COVID-19 on the incidence of cardiac arrhythmias in implantable cardioverter defibrillator recipients followed by remote monitoring.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has been a fast-growing worldwide pandemic. AIMS: We aimed to investigate the incidence of cardiac arrhythmias among a large French cohort of implantable cardioverter defibrillator recipients over the first 5 months of 2020. METHODS: Five thousand nine hundred and fifty-four implantable cardioverter defibrillator recipients were followed by remote monitoring during the COVID-19 period (from 01 January to 31 May 2020). Data were obtained from automated remote follow-up of implantable cardioverter defibrillators utilizing the Implicity® platform. For all patients, the type of arrhythmia (atrial fibrillation, ventricular tachycardia or ventricular fibrillation), the number of ventricular arrhythmia episodes and the type of implantable cardioverter defibrillator-delivered therapy were recorded. RESULTS: A total of 472 (7.9%) patients presented 4917 ventricular arrhythmia events. An increase in ventricular arrhythmia incidence was observed after the first COVID-19 case in France, and especially during weeks #10 and #11, at the time of major governmental measures, with an increase in the incidence of antitachycardia pacing delivered therapy. During the 11 weeks before the lockdown order, the curve of the percentage of live-stream television coverage of COVID-19 information matched the ventricular arrhythmia incidence. During the lockdown, the incidence of ventricular arrhythmia decreased significantly compared with baseline (0.05±0.7 vs. 0.09±1.2 episodes per patient per week, respectively; P<0.001). Importantly, no correlation was observed between ventricular arrhythmia incidence and the curve of COVID-19 incidence. No changes were observed regarding atrial fibrillation/atrial tachycardia episodes over time. CONCLUSIONS: An increase in ventricular arrhythmia incidence was observed in the 2 weeks before the lockdown order, at the time of major governmental measures. Ventricular arrhythmia incidence decreased dramatically during the lockdown.

When Manual Analysis of 12-Lead ECG Holter Plays a Critical Role in Discovering Unknown Patterns of Increased Arrhythmogenic Risk: A Case Report of a Patient Treated with Tamoxifen and Subsequent Pneumonia in COVID-19.

Several medicines, including cancer therapies, are known to alter the electrophysiological function of ventricular myocytes resulting in abnormal prolongation and dispersion of ventricular repolarization (quantified by multi-lead QTc measurement). This effect could be amplified by other concomitant factors (e.g., combination with other drugs affecting the QT, and/or electrolyte abnormalities, such as especially hypokalemia, hypomagnesaemia, and hypocalcemia). Usually, this condition results in higher risk of torsade de point and other life-threatening arrhythmias, related to unrecognized unpaired cardiac ventricular repolarization reserve (VRR). Being VRR a dynamic phenomenon, QT prolongation might often not be identified during the 10-s standard 12-lead ECG recording at rest, leaving the patient at increased risk for life-threatening event. We report the case of a 49-year woman, undergoing tamoxifen therapy for breast cancer, which alteration of ventricular repolarization reserve, persisting also after correction of concomitant recurrent hypokalemia, was evidenced only after manual measurements of the corrected QT (QTc) interval from selected intervals of the 12-lead ECG Holter monitoring. This otherwise missed finding was fundamental to drive the discontinuation of tamoxifen, shifting to another "safer" therapeutic option, and to avoid the use of potentially arrhythmogenic antibiotics when treating a bilateral pneumonia in recent COVID-19.

Prognostic value of right ventricular strain pattern on ECG in COVID-19 patients.

OBJECTIVE: COVID-19 spread worldwide, causing severe morbidity and mortality and this process still continues. The aim of this study to investigate the prognostic value of right ventricular (RV) strain in patients with COVID-19. METHODS: Consecutive adult patients admitted to the emergency room for COVID-19 between 1 and 30 April were included in this study. ECG was performed on hospital admission and was evaluated as blind. RV strain was defined as in the presence of one or more of the following ECG findings: complete or incomplete right ventricular branch block (RBBB), negative T wave in V1-V4 and presence of S1Q3T3. The main outcome measure was death during hospitalization. The relationship of variables to the main outcome was evaluated by multivariable Cox regression analysis. RESULTS: A total of 324 patients with COVID-19 were included in the study; majority of patients were male (187, 58%) and mean age was 64.2 ± 14.1. Ninety-five patients (29%) had right ventricular strain according to ECG and 66 patients (20%) had died. After a multivariable survival analysis, presence of RV strain on ECG (OR: 4.385, 95%CI: 2.226-8.638, p < 0.001), high-sensitivity troponin I (hs-TnI), d-dimer and age were independent predictors of mortality. CONCLUSION: Presence of right ventricular strain pattern on ECG is associated with in hospital mortality in patients with COVID-19.

Prolonged care delivery time and reduced rate of electrophysiological procedures during the lockdown period due to Covid-19 outbreak.

OBJECTIVES: The aim of this study is to demonstrate how Electrophysiology activity has been impacted by the pandemic Coronavirus disease 2019 (COVID-19). METHODS: In this multicenter retrospective study, we analyze all consecutive patients admitted for electrophysiological procedures during the COVID-19 lockdown in the Tuscany region of Italy, comparing them to patients hospitalized in the corresponding period of the previous year. RESULTS: The impact of COVID-19 on cardiac arrhythmia management was impressive, with a reduction of more than 50% in all kinds of procedures. A gender gap was observed, with a more relevant reduction for female patients. Arrhythmic urgencies requiring a device implant showed a reduced time from symptoms to first medical contact but the time from first medical contact to procedure was significantly prolonged. CONCLUSION: Hospitals need to consider how outbreaks may affect health systems beyond the immediate infection. Routine activity should be based on a risk assessment between the prompt performance of procedure and its postponement. Retrospective observational analysis such as this study could be decisive in evidence-based medicine of any future pathogen outbreak.Nonstandard Abbreviations and Acronyms PM= pacemakerICD= implantable cardioverter defibrillatorECV= electrical cardioversionEPS= electrophysiological studyAP= ablations proceduresCIED= cardiac implantable electronic devicesWCD= wearable cardioverter defibrillatorEP Lab= Electrophysiology LaboratoriesAVNRT =atrioventricular nodal reentry tachycardiaAVRT= atrioventricular reentry tachycardiaAFL= atrial flutterAF= atrial fibrillationVT= ventricular tachycardiaAT= atrial tachycardia.

SARS-CoV 2 Infection (Covid-19) and Cardiovascular Disease in Africa: Health Care and Socio-Economic Implications.

The current pandemic of SARS-COV 2 infection (Covid-19) is challenging health systems and communities worldwide. At the individual level, the main biological system involved in Covid-19 is the respiratory system. Respiratory complications range from mild flu-like illness symptoms to a fatal respiratory distress syndrome or a severe and fulminant pneumonia. Critically, the presence of a pre-existing cardiovascular disease or its risk factors, such as hypertension or type II diabetes mellitus, increases the chance of having severe complications (including death) if infected by the virus. In addition, the infection can worsen an existing cardiovascular disease or precipitate new ones. This paper presents a contemporary review of cardiovascular complications of Covid-19. It also specifically examines the impact of the disease on those already vulnerable and on the poorly resourced health systems of Africa as well as the potential broader consequences on the socio-economic health of this region.

Impact of COVID-19 lockdown in patients with implantable cardioverter and cardiac resynchronization therapy defibrillators: insights from daily remote monitoring transmissions.

In Italy, a strict lockdown was imposed from 8 March 2020 to stop the spread of the coronavirus disease 2019 (COVID-19). We explored the effect of this lockdown on data transmitted by remote monitoring (RM) of implantable cardioverter and cardiac resynchronization therapy defibrillators (ICDs/CRT-Ds). RM daily transmissions from ICDs and CRT-Ds were analyzed and compared in two consecutive 1 month frames pre and post-lockdown: period I (7 February-7 March 2020) and period II (8 March-7 April 2020). The study cohort included 180 patients (81.1% male, 63.3% ICDs and 36.7% CRT-Ds) with a median age of 70 (interquartile range 62-78) years. The median value of physical activity provided by accelerometric sensors showed a significant reduction between period I and II [13.1% (8.2-18.1%) versus 9.4% (6.3-13.8%), p < 0.001]. Eighty nine % of patients decreased their activity, for 43.3% the relative reduction was ≥ 25%. The mean heart rate decreased significantly [69.2 (63.8-75.6) bpm vs 67.9 (62.7-75.3) bpm, p < 0.001], but with greater reduction (≈3 beats/minute) in patients aged < 70 years. Resting heart rate and thoracic impedance showed minor variations. No differences were observed in device pacing % and arrhythmias. In cardiac patients, the lockdown imposed to contain COVID-19 outbreak significantly reduced the amount of physical activity and the mean heart rate. These side effects of in-home confinement quarantine should be taken in consideration for frail patients.

Latin-American Registry of Cardiovascular Disease and COVID-19: Rationale and Design of the CARDIO COVID 19-20 Registry.

Background: Infection caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) exhibits a strong infectivity but less virulence compared to severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS). In terms of cardiovascular morbidity, susceptible population include elderly and patients with certain cardiovascular conditions. This infection has been associated with cardiac injury, cardiovascular complications and higher mortality. Objectives: The main objective of the CARDIO COVID 19-20 Registry is to determine the presence of cardiovascular comorbidities and cardiovascular complications in COVID-19 infected patients that required in-hospital treatment in different Latin American institutions. Methods: The CARDIO COVID 19-20 Registry is an observational, multicenter, ambispective, and hospital-based registry of patients with confirmed COVID-19 infection who required in-hospital treatment in Latin America. Enrollment of patients started on May 01, 2020 and was initially planned to last three months; based on the progression of pandemic in Latin America, enrollment was extended until December 2020, and could be extended once again based on the pandemic course in our continent at that moment. Conclusions: The CARDIO COVID 19-20 Registry will characterize the in-hospital population diagnosed with COVID-19 in Latin America in order to identify risk factors for worsening of cardiovascular comorbidities or for the appearance of cardiovascular complications during hospitalization and during the 30-day follow up period.

COVID-19 FAQs in paediatric and congenital cardiology: AEPC position paper.

The COVID-19 pandemic has had a huge influence in almost all areas of life, affecting societies, economics, and health care systems worldwide. The paediatric cardiology community is no exception. As the challenging battle with COVID-19 continues, professionals from the Association for the European Paediatric and Congenital Cardiology receive many questions regarding COVID-19 in a Paediatric and Congenital Cardiology setting. The aim of this paper is to present the AEPC position on frequently asked questions based on the most recent scientific data, as well as to frame a discussion on how to take care of our patients during this unprecedented crisis. As the times are changing quickly and information regarding COVID-19 is very dynamic, continuous collection of evidence will help guide constructive decision-making.

Cardiovascular sequalae in uncomplicated COVID-19 survivors.

BACKGROUND: A high proportion of COVID-19 patients were reported to have cardiac involvements. Data pertaining to cardiac sequalae is of urgent importance to define subsequent cardiac surveillance. METHODS: We performed a systematic cardiac screening for 97 consecutive COVID-19 survivors including electrocardiogram (ECG), echocardiography, serum troponin and NT-proBNP assay 1-4 weeks after hospital discharge. Treadmill exercise test and cardiac magnetic resonance imaging (CMR) were performed according to initial screening results. RESULTS: The mean age was 46.5 ± 18.6 years; 53.6% were men. All were classified with non-severe disease without overt cardiac manifestations and did not require intensive care. Median hospitalization stay was 17 days and median duration from discharge to screening was 11 days. Cardiac abnormalities were detected in 42.3% including sinus bradycardia (29.9%), newly detected T-wave abnormality (8.2%), elevated troponin level (6.2%), newly detected atrial fibrillation (1.0%), and newly detected left ventricular systolic dysfunction with elevated NT-proBNP level (1.0%). Significant sinus bradycardia with heart rate below 50 bpm was detected in 7.2% COVID-19 survivors, which appeared to be self-limiting and recovered over time. For COVID-19 survivors with persistent elevation of troponin level after discharge or newly detected T wave abnormality, echocardiography and CMR did not reveal any evidence of infarct, myocarditis, or left ventricular systolic dysfunction. CONCLUSION: Cardiac abnormality is common amongst COVID-survivors with mild disease, which is mostly self-limiting. Nonetheless, cardiac surveillance in form of ECG and/or serum biomarkers may be advisable to detect more severe cardiac involvement including atrial fibrillation and left ventricular dysfunction.