COVID-19-associated arrhythmia and conduction system disease

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Main article: COVID-19

For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sara Zand, M.D.[2] Tayyaba Ali, M.D.[3]

Synonyms and keywords:COVID-19-associated dysrhythmia

Overview

Sever acute respiratory syndrome coronavirus-2 (SARS-COV-2) is the virus that causes coronavirus disease 2019 may affect every organ system including the heart. Arrhythmia is a disorder of conduction system including atrial arrhythmia, ventricular arrhythmia, bradyarrhythmia , resulting from direct effect of virus by attaching viral spike protein to ACE2 receptors on myocardium and inducing myocardial injury and conduction damage system or indirect effect of covid-19 such as coexisting hypoxia, electrolytes disarray, and the administration of arrhythmogenic medications (hydroxychloroquine, azithromycin). Reported case about new onset atrial fibrillation in covid-19 infection may indicate the atrial arrhythmogenicity of covid-19 infection. In the presence of covid-19, approperiate approach to life threatening arrhythmia and considering fulminant myocarditis are warranted. High number of out-of hospital cardiac arrest in Italy during the 40 first days of initiation of pandemic, raised the concerns about the risk of arrhythmia in covid-19. Incidence of arrhythmia in ICU admitted covid-19 patients increased to 10 folds. Cardiac arrhythmia was associated with increased mortality and morbidity in hospitalized covid-19 patients.

Historical Perspective

• Diseases of heart and lung are the most common causes of COVID-19-related death.
• Cardiac rhythm problems are increasingly recognized as a clinical manifestation of COVID-19.
• There is anecdotal evidence of sudden cardiac death among COVID-19 patients. According to a study, 51 of 85 fatal cases of COVID-19 from Wuhan developed an arrhythmia, and 2 patients died of malignant arrhythmia.
• In 137 subjects from Hubei province, 10 patients (7.3%) noted palpitations as one of the initial symptoms.

To browse the historical perspective of COVID-19, click here.

Classification

• Arrhythmia related to COVID-19 may be classified into atrial arrhythmia (81.8%), ventricular arrhythmia (21%), bradyarrhythmia (22.6%) as follows:
• Atrial fibrillation
• Atrial flutter
• Supraventricular tachycardia
• Nonsustained ventricular tachycardia
• Ventricular tachycardia
• Ventricular fibrillation
• Atrioventricular block
• Marked sinus bradycardia (heart rate<40 bpm)

Pathophysiology

• Respiratory disease is the chief target of COVID-19.
• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes S-spike to bind to angiotensin-converting enzyme 2 (ACE2) receptors to enter the cells.
• Type 1 and type 2 pneumocytes exhibit ACE 2 receptors in the lung.
• Studies report that coronary endothelial cells in the heart and intrarenal endothelial cells and renal tubular epithelial cells in the kidney exhibit ACE2. ACE2 is an inverse regulator of the renin-angiotensin system.
• The interaction between SARS-CoV-2 and ACE2 can bring about changes in ACE2 pathways prompting intense injury to the lung, heart, and endothelial cells.
• Hypoxia and electrolyte abnormalities that are common in the acute phase of severe COVID-19 can potentiate cardiac arrhythmias.
• Binding of SARS-CoV-2 to ACE2 receptors can result in hypokalemia which causes various types of arrhythmia.
• Elevated levels of cytokines as a result of the systemic inflammatory response of the severe Coronavirus disease 2019 (COVID-19) can cause injury to multiple organs, including cardiac myocytes.
• In COVID-19 patients, excessive ranges of circulating cytokines, especially interleukin (IL)-6 is related to in-hospital death.
• As a result of cytokine storm triggered by SARS-CoV-2 that includes IL-6, tumor necrosis factor (TNF) α, and IL-1, duration of ventricular action potential can be prolonged.
• Studies suggest that cytokine storm can modulate the function of cardiomyocyte ion channels such as Na+, K+ and Ca+ channels (inflammatory cardiac channelopathies).
• According to the data based on studies on previous Severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) epidemic and the ongoing COVID-19 outbreak, multiple mechanisms have been suggested for cardiac damage.
• Use of hydroxychloroquine and azithromycin was associated with QT prolongation and ventricular arrhythmia due to action potential prolongation, inhibition of hERG-K channels, and early afterdepolarization.
• It is thought that abnormal host immune response is due to over activation of the cardiac sympathetic system, immune cell-mediated injury and inhibition of CYP450 by IL6.
• Inhibition of CYP450 by IL6 may lead to increased bioavailability of QT prolongation drugs and ventricular arrhythmia.
• immune cell-mediated injury may cause inflammatory myocardial scarring and ventricular arrhythmia by the mechanisms of electrical imbalance and reentry
• Overactivity of the cardiac sympathetic system is the precursor of myocardial ischemia and cardiac arrhythmia.

• Acute renal injury and diarrhea may lead to intravascular volume imbalance , electrolytes imblance resulting arrhythmia.
• Pulmonary hypertension and pulmonary embolism may cause increased right sided pressures and myocardial injury and arrhythmia.

To browse the pathophysiology of COVID-19, click here.

Causes

• Potential causes of arrhythmia in covid-19 include: (doi:10.1016/j.jacep.2020.08.002)
• Hypoxia
• Myocarditis
• Abnormal host immune response
• Myocardial ischemia
• Myocardial strain
• Electrolytes derangement
• Intravascular volume imbalance
• Drug side effects

• Common causes of bradyarrhythmia in covid-19 patients include:

  Use of remdesivir

  Hypoxia

  Viral myocarditis

  Damage to pacemaker cells due to inflammatory cytokines

Differentiating COVID-19-associated arrhythmia from other Diseases

• Differentiation diagnosis of arrhythmia and conduction disorder related to COVID-19 include the following:
• Atrial fibrillation
• Atrial flutter
• Supraventricular tachycardia
• Nonsustained ventricular tachycardia
• Ventricular tachycardia
• Ventricular fibrillation
• Atrioventricular block

To browse the differential diagnosis of COVID-19, click here.

Epidemiology and Demographics

Incidence

• The incidence of cardiac arrhythmia including AF, atrial flutter, SVT, nonsustained VT, VT, VF, marked sinus bradycardia, atrioventricular block, or pauses> 3 seconds was estimated to be 12900 per 100,000 covid-19 patients.

Age

The mean age of covid-19 patients who developed arrhythmia was 71± 14 years.

Gender

Arrhythmia in covid-19 patients was more common in men.

Race

• Asian individuals with COVID-19 are less likely to develop atrial arrhythmia compared with other continents (34% versus 81%). However, the incidence of bradyarrhythmia and atrioventricular block were higher in asian than other continents.
• Distribution of ventricular arrhythmia was similar to other continents.

To browse the epidemiology and demographics of COVID-19, click here.

Risk Factors

• Concomitant comorbidities among covid-19 patients with arrhythmia include:

  Hypertension (69%)

  Diabetes mellitus (42%)

  Congestive heart failure (30%)

  Coronary artery disease (24%)

• Independent predictors of QTc prolongation≥ 500 ms in covid-19 patients include:
• Older age
• Lower body mass index
• Higher creatinine level
• Higher peak of troponin
• Congestive heart failure
• Use of hydroxychloroquine, azithromycin

Screening

• There is no established screening method for detecting arrhythmia related to covid-19. However, QT interval measurement is recommended in covid-19 patients before initiation of treatment with hydroxychloroquine, azithromycin, remdesivir, lopinavir/ritonavir.

Natural History, Complications and Prognosis

• The majority of patients with covid-19 who developed arrhythmias were intubated.
• Atrial fibrillation is the most common arrhythmia in covid-19 patients and is associated with severe disease and poor outcome.
• Reported case about new onset atrial fibrillation in covid-19 patients may indicate the arrhythmogenicity of covid-19 infection.
• Early clinical features include deterioration of underlying covid-19 disease, ACS, decompensated heart failure, pre-syncope, syncope.
• If left untreated, patients with arrhythmia may progress to developed decompensated heart failure, myocardial ischemia, cardiac arrest, intubation, death.
• Common complications of arrhythmia are congestive heart failure, ACS, stroke, sudden cardiac death.
• Prognosis is related to the type of arrhythmia and underlying mechanism of arrhythmia, and survival rate to hospital discharge of covid-19 patients with arrhythmia is approximately 51%.
• Among covid-19 patients with ventricular arrhythmia, mortality rate (1.4×) and risk of developing to mechanical ventilation (1.3×) were higher than other arrhythmias, and survival rate to discharge was approximately 38%.
• Presence of atrial arrhythmia in covid-19 patients was associated with severe disease and poor outcome.
• Use of remdesivir was associated with bradycardia and complete heart block, especially in patients with preexisting conduction disorder, older patients or concomitant use of betablocker.
• Use of hydroxychloroquine, azithromycin were associated with QTc prolongation. However, the likelihood of torsades de pointes and mortality were low.
• Before prescription of hydroxychloroquine and azithromycin, potential risk factors of QT prolongation and ECG monitoring strategy should be noticed.
• In the presence of QTc prolongation≥ 500 ms, hydroxychloroquine and azithromycin should be withdrawn.
• Reported cases of life-threatening arrhythmia such as high grade atrioventricular block, polymorphic ventricular tachycardia, accelerated ideoventricular rhythm and atrial fibrillation in covid-19 patients without severe lung involvement, showed the need for appropriate rhythm monitoring, particularly if fulminant myocarditis is suspected.

• Reported ECG changes prompting arrhythmia complication associated medications in covid-19 include:
• Remdesivir:

  QT prolongation

  Non specific T waves change

  Cardiac arrest (1.1%)

  Severe bradycardia

  Transient complete heart block

  Atrial fibrillation (4%)

• Azithromycin

  Bradycardia, prolonged PR interval, QTc prolongation with very low risk of torsades de pointes

  Severe interaction with amiodarione, disopyramide, dofetilide, flecainide, sotalol, propafenone

  Moderate interaction with betablocker, digoxin

• Hydroxychloroquine

  Bradycardia, prolonged PR interval, QTc prolongation with very low risk of torsades de pointes

  Severe interaction with amiodarone, flecainide, mexiletine, sotalol, dofetilide

  Moderate interaction with disopyramide, propafenone, quinidine, digoxin

  Mild interaction with metoprolol, nebivolol, propranolol, timolol, verapamil

• Lopinavir/ ritonavir

  Prolonged PR interval, QTc prolongation with very low risk of torsades de pointes

  Severe interaction with amiodarone, drondarone, disopyramide, dofetilide, flecainide, sotalol

  Moderate interaction with lidocaine, mexiletine, propafenone, quinidine, digoxin, batablocker, calcium channel blocker

Diagnosis

Diagnostic Study of Choice

• ECG:

• Most patients with the severe COVID-19, and especially patients who receive QT-prolonging medications, should have a baseline electrocardiogram (ECG) performed at the time of admission to the hospital.
• The best technique to get the QT interval is with a 12-lead electrocardiogram (ECG). However, to scale back exposure to hospital workers, this could not perpetually be possible.
• A single-lead ECG might underestimate the QT interval, and there ought to be an effort to use a multiple-lead telemetry system to observe the QT interval.

• Transthoracic echocardiography:

• Transthoracic echocardiography is recommended for an inpatient with heart failure, arrhythmia, ECG changes, or newly diagnosed cardiomegaly on chest x-ray or CT-chest.

To browse the diagnostic study of choice of COVID-19, click here.

History and Symptoms

Arrhythmia or conduction system disease is the nonspecific clinical presentation of COVID-19. Patients may be tachycardic (with or without palpitations) in the setting of other COVID-19-related symptoms (eg, fever, shortness of breath, pain, etc).

• Arrhythmia presents with the history of:
  • Slow or irregular heartbeat or pauses between heartbeats
  • Skipping a heartbeat
  • Heart pounding or racing
  • Anxiety
  • Blurred vision
  • Chest pain
  • Difficulty breathing
  • Fainting or nearly fainting
  • Foggy thinking
  • Fatigue
  • Sweating
  • Weakness, dizziness, and light-headedness

Physical Examination

• Patients with COVID-19-associated arrhythmia and conduction system disease on cardiac auscultation reveal tachycardia or arrhythmias (irregular beat).
• Sinus tachycardia, the most common type of arrhythmia in COVID-19 patients can be due to fever, hypoxia, shock due to sepsis, and anxiety. Some pathologic causes of arrhythmias include ventricular arrhythmia, atrial fibrillation (pulse rate 100 to 175 bpm) and atrial flutter (pulse rate 150 bpm).
• To browse the physical examination of COVID-19, click here.

Laboratory Findings

• There are no specific laboratory findings associated with COVID-19-associated arrhythmia.
• COVID-19 patients with elevated troponin T experienced higher risk of ventricular arrhythmias (17.3% in high troponin T group versus 1.5% in normal troponin T group, P < 0.001).

Electrocardiogram

COVID-19-associated arrhythmia findings include:

• Prolong QT Interval:

• According to a multicenter study done in New York that involved 4250 COVID-19 patients, 260 patients (6.1%) had corrected QT interval (QTc) >500 milliseconds at the time of admittance.
• However, in another study that involved 84 patients who got hydroxychloroquine and azithromycin, the baseline QTc interval was 435 milliseconds before receiving these medications.

• Atrial Arrhythmia:

• According to a study, among 393 patients with COVID-19, atrial arrhythmias were more common among patients requiring invasive mechanical ventilation than noninvasive mechanical ventilation (17.7% versus 1.9%).

• Ventricular Arrhythmia:

• According to a study done in Wuhan, China. among 187 hospitalized patients with COVID-19, 11 patients (5.9%) developed ventricular tachyarrhythmias.

• Cardiac Arrest:

• According to a Lombardia Cardiac Arrest Registry (Lombardia CARe) in the region of Lombardy, Italy.
  • Out of 9806 cases of COVID-19, 362 cases of out-of-hospital cardiac arrest were reported during the study time frame in 2020.
  • During a similar period in 2019, 229 cases of out-of-hospital cardiac arrest were reported, which means an increment of 58% was observed in 2020 among COVID-19 patients.
    
• According to the records from a tertiary care hospital in Wuhan. Out of 761 patients with severe COVID-19, 151 patients developed in-hospital cardiac arrest.
  • 136 patients received resuscitation. Out of 136 patients, 119 patients had a respiratory cause.
  • 10 patients had a cardiac cause. 7 patients had other causes.
  • Ventricular fibrillation or pulseless ventricular tachycardia was observed in 8 patients (5.9%), Pulseless electrical activity in 6 patients (4.4%), and asystole in 122 COVID-19 patients (89.7%).

• To browse the electrocardiogram findings of COVID-19, click here.

X-Ray

• To browse the X-ray finding of COVID-19, click here.

Echocardiography/Ultrasound

• There are no specific echocardiography/ultrasound findings associated with coronavirus infection.
• Non specific echocardiographic findings can include:

• Left ventricular systolic dysfunction
• Pericardial effusion
• Myocardial edema
• Increased wall thickness with diffuse biventricular hypokinesis

CT Scan

• To browse the CT-Scan findings of COVID-19, click here.

MRI

• We ought to consider that myocardial injury may bring about atrial or ventricular fibrosis, the substrate for resulting cardiovascular arrhythmias.
• COVID-19 patients with evidence of myocardial injury should undergo cardiac magnetic resonance to assess the extent of myocardial scar.

Other Imaging Findings

• There are no other imaging findings associated with COVID-19-associated arrhythmia.

Other Diagnostic Studies

• Myocardial biomarkers should be assessed in all patients with COVID‐19.
• American Heart Association (AHA) recommends the following tests to diagnose arrhythmia:
  • Holter monitor
  • Transtelephonic monitor
  • Treadmill testing
  • Tilt-table test
  • Electrophysiologic testing (EP study)
  • Esophageal electrophysiologic procedure
  • Echocardiogram

Treatment

Medical Therapy based on 2020 ESC Guidline for management of arrhythmia in covid-19 patients

• The mainstay of therapy of arrhythmia in patients with covid-19 is limiting exposure and minimizing drug-drug interactions.
• Treatment of tachyarrhythmia and bradyarrhythmia in patients with covid-19 is similar to any patients with arrhythmia due to infection and transient metabolic disturbance.
• In patients who use QTc prolongation drugs, or have a history of inherited arrhythmia, specific consideration should be given.

Bradyarrhythmia

• Causes of bradycardia (sinus node block or AV block) in covid-19 patients:

  Side effects of drugs such as hydroxychloroquine, lopinavir/ritonavir, azithromycin

  Myocarditis: if conduction system involved

  Transient bradycardia during suction of secretion in intubated patients or proning position leading to increased vagal tone

1. In patients with persistent bradycardia, before insertion of temporary pacemaker, atropine or isoprenaline are considered.
2. Temporary pacemaker is the first option before making decision for permanent pacemaker because of the transient nature of bradyarrhythmia, critical illness, risk of bacterial superinfection, risk of device infection.
3. After recovery of covid-19 , reevaluation about permanent pacemaker implantation should be considered.

• If the use of remdesivir is associated with severe bradycardia, remdesivir should be discontinued, and ECG monitoring is recommended.

Atrial tachyarrhythmia (supraventricular tachycardia, atrial fibrillation, atrial flutter)

• Treatment of underlying causes including hypoxia, metabolic imbalance, electrolytes imbalance, proarrhythmic effect of drugs, myocardial ischemia
• In the presence of supraventricular tachycardia: administration of adenosine, low threshold shock in refractory cases with hemodynamic instability, administration of betablocker or calcium channel blocker with concerns about interaction with antiviral drug or the risk of bradycardia and QTc prolongation should be noticed.
• In patients with atrial fibrillation or atrial flutter, betablockers and calcium channel blockers are preferred to rating control and discontinuation of antiarrhythmic drug such as sotalol, flecainide, amiodarone and propafenone is recommended because of serious drug-drug interaction with antiviral drugs.
• Rhythm control strategy should be reserved only for patients with unstable hemodynamic and congestive heart failure.
• Anticoagulant therapy should be considered in covid-19 patients with atrial fibrillation due to hypercoagulability state in such condition.
• Immunosupressant therapy is considered for patients with myocarditis.

Ventricular arrhythmia

• Treatment of underlying causes of ventricular arrhythmia such as hypoxia, electrolytes imbalance, proarrhythmic effect of drugs are recommended.
• Amiodarone , lidocaine are first choice of VT storm therapy, especially in the setting of myocardial ischemia.
• Esmolol, sedation, intubation are further choices for treatnig ventricular arrhythmia storm.
• Lidocaine and mexiletine are useful in the context of prolonged QT interval and torsades de pointes due to slightly shortening of QT interval.
• In the presence of polymorphic ventricular tachycardia due to QT prolongation by antiviral therapy, discontinuation the antiviral therapy and infusion of magnesium and correction of hypokalemia and infusion of isoprenaline are recommended.
• In case of recurrent torsades de pointes and bradycardia, arrhythmia can be suppressed by overdrive pacing of temporary pacemaker implantation.
• Echocardiogtaphy is needed if there is new onset of malignant ventricular arrhythmia unrelated to prolonged QTc.

QT prolongation in covid-19 therapy

• QT prolongation has been found in 12% of patients recieving hydroxychloroquine, azithromycin, or both. However, there was no torsades de pointes.
• High dose of chloroquine (600 mg BD for 10 days compared with 450 mg BD for one day then 450mg daily for 4 days) was associated with increased adverse effects.
• High risk patients for QT prolongation include:

  Age> 68 years

  Female sex

  Use of loop diuretic

  Serum potassium level ≤3.5 mEq/l

  Baseline QTc≥ 450 ms

  Acute myocardial infarction

  Use of numbers QT prolongation medications

  Sepsis

  Heart failure

• In the presence of baseline QTc≥ 500 ms, or increased greater than 60 ms after 2-3 hours of administration of hydroxychloroquine or other QT prolongation drugs, risk of torsades de pointes should be considered.

Cardiac medications interaction with covid-19 therapy

• The level of drug that are metabolized by CP450 isoenzyme such as amiodarone, propafenon, flecainide, quinidine, apixaban, rivaroxaban can be increased by administration of lopinavir/ritonavir.

Surgery

Electrophysiology study in an elective procedure and should be planned for management of specific arrhythmias after recovery of covid-19 infection.

Primary Prevention

• Effective measurement for primary prevention of ventricular arrhythmia in covid-19 patients who recieve hydroxychloroquine and azithromycin or other QTc prolongation drugs is determination baseline QTc on ECG.
• If baseline QTc is > 500ms for QRS< 120 ms, or if QTc is >550 ms for QRS> 120ms, or QTc prolonged by 60 ms, these medications should be withheld.
• Primary prevention strategy in covid-19 patients with brugada pattern type 1 is controlling fever by acetaminophen for reducing the risk of ventricular arrhythmia and self isolation.

Secondary Prevention

Secondary prevention for covid-19 associated with arrhythmia is implantation of ICD after recovery of covid-19 in case of ventricular arrhythmia and low LVEF based on the guideline.