Can chemicals cause atrial fibrillation (a-fib)?

Can Chemicals Cause Atrial Fibrillation?

Yes, chemicals—both pharmaceutical drugs and occupational/environmental exposures—can definitively cause atrial fibrillation through multiple direct and indirect mechanisms affecting cardiac electrophysiology, autonomic tone, and structural remodeling. 1

Drug-Induced Atrial Fibrillation (DIAF)

A progressively increasing number of cardiovascular, non-cardiovascular, and anticancer drugs can cause or exacerbate atrial fibrillation risk. 1 This entity, termed drug-induced atrial fibrillation (DIAF), is particularly relevant in elderly patients with multimorbidity receiving polypharmacy, yet remains underrecognized—notably absent from major AF management guidelines except the 2022 ESC cardio-oncology guidelines. 1

Mechanisms of Drug-Induced AF

Drugs trigger AF through distinct pathophysiological pathways: 1

• Direct electrophysiological effects: Drugs increase atrial automaticity (particularly pulmonary vein ectopic activity), slow intra-atrial conduction, or shorten atrial action potential duration/effective refractory period. Examples include adenosine, dobutamine, dopamine, sympathomimetics (salbutamol, terbutaline), theophylline, and ibrutinib. 1

• Ion channel modulation: Inhibition of cardiac Na+ current (flecainide, propafenone, antidepressants, antipsychotics, taxanes), alterations in L-type Ca2+ current (doxorubicin increases it), and inhibition of Na+-Ca2+ exchange (cisplatin, fluoropyrimidines) create arrhythmogenic substrates. 1

• Calcium handling abnormalities: Drugs like doxorubicin, ibrutinib, and paclitaxel activate CaMKII, increase RyR2 phosphorylation, and promote spontaneous Ca2+ release from sarcoplasmic reticulum, leading to delayed afterdepolarizations and triggered activity. 1

• Autonomic tone changes: β-adrenergic agonists and positive inotropics (dobutamine, milrinone) activate the cAMP/PKA pathway, shortening atrial refractoriness and causing intracellular Ca2+ overload. 1 Drug-induced hypotension produces reflex sympathetic activation.

• Myocardial ischemia: Coronary vasospasm from endothelial dysfunction or vasoconstrictor release (endothelin-1) causes atrial electrical and structural remodeling. 1

• Inflammatory response: Anticancer drugs (alkylating agents, anthracyclines, ibrutinib) activate toll-like receptor 4 and NF-κB, releasing pro-inflammatory cytokines that alter ion channel expression and promote atrial fibrosis. 1 Immune checkpoint inhibitors cause T-lymphocyte-mediated inflammation with lymphocytic infiltration of cardiac nodes. 1

• Oxidative stress: ROS production causes mitochondrial dysfunction, activates CaMKII leading to pathological RyR2 phosphorylation and sarcoplasmic reticulum Ca2+ leak, and prolongs action potential duration through late Na+ current activation. 1

High-Risk Drug Classes

Specific medications with documented AF risk include: 1, 2

• Cardiovascular drugs: Adenosine, dobutamine, dopamine, milrinone, digoxin, amiodarone, flecainide, propafenone
• Respiratory drugs: Sympathomimetics (salbutamol, terbutaline), theophylline, aminophylline
• Anticancer agents: Anthracyclines (doxorubicin), taxanes (paclitaxel), ibrutinib, gemcitabine, alkylating agents (melphalan), immune checkpoint inhibitors
• Antibiotics: Fluoroquinolones including levofloxacin 2
• Other agents: Corticosteroids, ondansetron, sumatriptan, sildenafil, vardenafil, fingolimod

Clinical Presentation and Risk Factors

Most DIAF episodes are paroxysmal (terminating spontaneously or with intervention within 7 days), though some become persistent. 1 Many cases are asymptomatic. 1

Risk factors amplifying DIAF susceptibility include: 2, 3

• Advanced age (>65 years)
• Pre-existing cardiovascular disease (hypertension, coronary artery disease, heart failure, valvular disease, cardiomyopathies)
• Left atrial enlargement
• History of cardiac arrhythmias
• Structural heart disease with atrial fibrosis, hypertrophy, or dilatation
• Polypharmacy
• Non-cardiac comorbidities (diabetes, hyperthyroidism, chronic kidney disease, sleep apnea)

Occupational and Environmental Chemical Exposures

Industrial solvents and pesticides represent underrecognized chemical triggers for AF:

• Halogenated hydrocarbons: Trifluorotrichloroethane (CFC 113) and related halogenated hydrocarbons used as industrial solvents/degreasing agents have caused documented cases of atrial fibrillation and sudden cardiac death with occupational overexposure. 4 These agents should be considered potential precipitants for both atrial and ventricular arrhythmias.

• Insecticides: Methomyl dust exposure has triggered AF through cholinergic mechanisms, with spontaneous resolution after exposure cessation. 5 While cardiac toxicity from organophosphate and carbamate insecticides is well-known, AF represents a rare but documented complication.

Clinical Management Approach

When DIAF is suspected: 2

1. Discontinue the offending agent immediately if clinically feasible and consider alternative therapies that don't prolong QT interval or affect cardiac electrophysiology
2. Monitor ECG in high-risk patients at baseline and after adding medications known to affect cardiac conduction
3. Manage AF according to standard guidelines with rate or rhythm control strategies as appropriate
4. Assess for reversible causes: thyroid dysfunction, acute alcohol intake, infections, pulmonary conditions 3

Critical Pitfalls to Avoid

• Failing to recognize DIAF as a potential adverse effect and not considering drug-induced etiology in new-onset AF differential diagnosis 2
• Overlooking occupational/environmental exposures in patients with unexplained AF, particularly those working with industrial solvents or agricultural chemicals 4, 5
• Continuing the offending medication without recognizing its arrhythmogenic potential
• Inadequate risk stratification before initiating high-risk medications in vulnerable patients (elderly, pre-existing cardiac disease, polypharmacy) 1

Ascribing causality to a specific drug often represents a clinical challenge given that many AF risk factors and comorbidities commonly coexist, particularly in cancer patients and elderly individuals with polypharmacy. 1 Temporal relationship between drug initiation and AF onset, along with resolution after drug discontinuation, strengthens causality assessment.