What are the causes of premature atrial contractions (PACs)?

What Causes Premature Atrial Contractions (PACs)?

PACs arise from ectopic electrical activity in the atria, most commonly originating from pulmonary vein myocardial sleeves, with additional triggers including structural heart disease, autonomic dysfunction, metabolic disturbances, and drug-induced mechanisms. 1, 2

Primary Electrophysiological Mechanisms

Pulmonary vein myocardial sleeves represent the most common anatomic source of PACs, accounting for the majority of ectopic atrial activity. 2, 3 These specialized myocytes possess unique arrhythmogenic properties that distinguish them from normal atrial tissue:

• Relatively depolarized resting membrane potentials 4
• Abbreviated action potential duration and shortened refractoriness 4
• Enhanced abnormal automaticity and triggered activity 2, 4
• Abrupt changes in fiber orientation creating conduction heterogeneity 4

Beyond pulmonary veins, other anatomic sites generate PACs including the crista terminalis, para-Hisian region, mitral annulus, right atrial septum, and coronary sinus ostium. 2, 3 These locations demonstrate local tissue heterogeneity that creates conditions for premature firing through abnormal automaticity with shortened coupling intervals. 2

Structural Cardiac Causes

Valvular heart disease, particularly mitral valve pathology, represents the most common structural cardiac cause, increasing PAC risk regardless of severity but correlating directly with left atrial enlargement. 5, 2 The mechanism involves increased atrial pressure, progressive dilation, and altered wall stress leading to structural remodeling. 2, 4

Hypertension with left ventricular hypertrophy creates the substrate for PACs through elevated left atrial pressure and atrial dilation. 5, 2 Additional structural causes include:

• Coronary artery disease and acute myocardial infarction 5
• Cardiomyopathies (hypertrophic, dilated, restrictive) 5, 2
• Congenital heart disease, especially atrial septal defects 5
• Heart failure with associated atrial remodeling 5, 4

Even in patients with paroxysmal PACs without recognized structural heart disease, atrial biopsies reveal inflammatory infiltrates consistent with myocarditis and fibrosis, demonstrating that microscopic pathology exists despite normal imaging. 5, 2

Atrial Remodeling and Fibrosis

Atrial fibrosis represents a critical pathophysiological mechanism, creating heterogeneous electrical conduction that facilitates both focal ectopy and micro-reentry circuits. 2, 4 The aging heart loses cardiomyocytes at 0.5-1.0% per year, with fibrous tissue replacing lost myocytes. 4

Renin-angiotensin-aldosterone system activation generates profibrotic factors including transforming growth factor-beta 1, which drives progressive atrial fibrosis. 5, 4 Atrial stretch from volume or pressure overload activates this cascade. 5

Calcium Handling Abnormalities

Abnormal intracellular calcium homeostasis with sarcoplasmic reticulum calcium leak promotes triggered activity and spontaneous depolarizations. 5, 2 High atrial rates elevate diastolic calcium and alter ion channels controlling calcium reuptake and release, creating conditions for ectopic firing. 5, 2

Specific calcium-related mechanisms include:

• Increased spontaneous calcium release from sarcoplasmic reticulum 5
• Activation of inward sodium current via sodium-calcium exchanger 5
• Delayed afterdepolarizations (DADs) triggering premature beats 5
• Dysregulation of protein kinase A, CaMKII, phospholamban, and RYR2 5

Autonomic Nervous System Dysfunction

Both vagal predominance and sympathetic predominance trigger PACs through distinct mechanisms. 5, 2 Vagally-mediated PACs occur predominantly at rest, during sleep, or after large meals, while adrenergic PACs are triggered by exercise, emotional stress, or stimulants. 5, 4

Changes in autonomic tone alter atrial action potential duration and refractory periods, provoking depolarizations and triggered activity. 5 Athletes with elevated vagal tone represent a specific population prone to atrial ectopy. 2 One in three patients with paroxysmal atrial arrhythmias present with well-defined adrenergic or vagal triggers. 5

Reversible Metabolic and Systemic Causes

Hyperthyroidism must always be excluded as a critical reversible cause, as thyroid hormone excess increases atrial automaticity and successful treatment eliminates the arrhythmia. 5, 2, 6 Thyroid function testing is mandatory for all patients with new-onset frequent PACs. 4

Electrolyte disturbances, particularly hypokalemia and hypomagnesemia, alter atrial cellular electrophysiology and lower the threshold for ectopic firing. 2, 6 Additional reversible causes include:

• Acute infections (viral and bacterial) 4
• Myocarditis and pericarditis 5, 4
• Pulmonary embolism 5, 4
• Sleep apnea syndrome through hypoxia and autonomic dysfunction 5, 2
• Obesity promoting left atrial dilation 2, 4

Drug-Induced PACs

An increasing number of cardiovascular, non-cardiovascular, and anticancer drugs cause or exacerbate PACs, though this etiology is often overlooked in clinical practice. 5, 2 Specific medications include:

• Adenosine (immediate onset within 1 minute of IV administration) 5, 1
• Theophylline/aminophylline through adenosine receptor blockade and phosphodiesterase inhibition 5, 1
• Beta-2 adrenergic agonists (salbutamol, arformoterol) increasing heart rate and reducing serum potassium 5
• Chemotherapeutic agents with variable onset from days to years after treatment 5
• Corticosteroids particularly with short-term oral use 5

Drug-induced mechanisms include alterations in atrial action potential duration, effective refractory period, and intracellular calcium handling. 5, 2

Genetic and Ion Channel Dysfunction

Familial atrial arrhythmias occur more commonly than previously recognized, with specific chromosomal loci (particularly chromosome 4q25 near PITX2 gene) linked to susceptibility. 5, 2 Mutations in cardiac ion channel genes cause monogenic forms of atrial arrhythmias. 5

Ion channel dysfunction from both genetic mutations and acquired changes alters atrial refractoriness and promotes triggered electrical activity. 5, 2 These changes affect sodium channels, calcium channels, and potassium channels, creating the substrate for ectopic firing. 5

Critical Clinical Pitfall

Never dismiss PACs as benign without excluding structural heart disease, reversible causes, and drug-induced etiologies. 1, 2 Frequent PACs (>2,000 per 24 hours) require comprehensive evaluation due to substantially increased risk of atrial fibrillation, stroke, and adverse atrial remodeling. 1 The concept that PACs represent only a benign finding is outdated; they may signal underlying atrial cardiomyopathy even when standard imaging appears normal. 7, 8, 9