Causes of Paroxysmal Atrial Fibrillation
Paroxysmal atrial fibrillation (PAF) is primarily caused by repetitive rapid spontaneous focal activity arising from myocyte sleeves within the pulmonary veins or directly from the atrial muscle, with autonomic fluctuations playing a crucial triggering role. 1
Electrophysiological Mechanisms
Pulmonary Vein Triggers
- Rapidly firing foci initiating PAF most commonly originate from left atrial myocardial sleeves that extend into the pulmonary veins 1
- Pulmonary veins have unique electrical properties compared to atrial cells, including:
- Smaller L-type Ca²⁺-current (ICa,L) and inward-rectifier current (IK1)
- Larger delayed-rectifier K⁺-currents
- Shorter action potential duration 1
- These properties increase the likelihood of spontaneous ectopy due to early afterdepolarizations (EADs) and re-entry 1
Calcium Handling Abnormalities
- Abnormalities in intracellular Ca²⁺ handling proteins and enzymes play a key role in PAF 1
- These include dysfunction in:
- Protein kinase A (PKA)
- Ca²⁺/calmodulin-dependent protein kinase II (CaMKII)
- Phospholamban
- Ryanodine receptor type 2 (RYR2) 1
- Increased spontaneous Ca²⁺ release from the sarcoplasmic reticulum activates an inward Na⁺ current via Na⁺-Ca²⁺ exchanger, resulting in delayed afterdepolarizations and triggered activity 1
Autonomic Influences
- PAF greatly depends on variations in autonomic tone 1
- Typically involves:
- Primary increase in adrenergic activity
- Followed by an abrupt shift toward vagal predominance 1
- Major cardiac autonomic ganglia that modulate atrial electrical properties are located adjacent to pulmonary veins 1
- Both parasympathetic and sympathetic activation alter intracellular Ca²⁺ handling and can shorten atrial action potential duration and refractoriness 1
- Enhanced Ca²⁺-loading/release produced by adrenergic stimulation predisposes to arrhythmogenesis at the pulmonary veins 1, 2
Perpetuation Mechanisms
- Spontaneous atrial ectopic activity serves as a significant trigger for re-entry 1
- Ectopic impulses propagated to the atrium may result in:
- Continuous chaotic propagation of many independent small excitation wavelets
- Disruption of pulse conduction and re-entry 1
- The number of simultaneously coexisting atrial wavelets is determined by:
- Atrial mass
- Cardiac wavelength (product of atrial conduction velocity and effective refractory period) 1
- Slow conduction velocity and short effective refractory period reduce wavelength size, increasing the likelihood of multiple simultaneous reentrant wavelets and maintenance of AF 1
Structural and Remodeling Factors
- Age and cardiovascular diseases produce complex electrical and structural changes in the atria and pulmonary veins 1
- Electrical remodeling includes:
- Differences in conduction velocity
- Changes in action potential duration and effective refractory period
- Alterations in ion channel expression and activity 1
- Structural remodeling includes:
- Fatty infiltration
- Atrial dilatation
- Hypertrophy
- Fibrosis
- Inflammation 1
- These changes create a stable arrhythmogenic substrate that facilitates the perpetuation of AF 1
- Atrial stretch can induce:
- Triggered activity
- Heterogeneous conduction slowing
- Shortening or prolongation of effective refractory period 1
- Atrial hypertrophy and fibrosis slow impulse conduction, facilitate re-entry, and increase the inducibility of AF 1
Common Triggers
- Alcohol consumption is significantly associated with PAF episodes 2
- Vagal activity (post-meal, during sleep) is a common trigger 2
- Patients with both alcohol and vagal triggers suggest alcohol may precipitate AF through vagal mechanisms 2
- Other common triggers include:
- Sleep deprivation
- Emotional stress
- Stimulants such as caffeine
- Exercise 1
Clinical Implications
- Understanding these mechanisms has led to pulmonary vein isolation as the cornerstone for radiofrequency catheter ablation strategies 1
- Patients with PAF despite prior pulmonary vein isolation show electrical substrates that resemble persistent AF more closely than patients with PAF at first ablation 3
- Endothelial dysfunction in PAF patients is comparable to persistent AF patients, potentially explaining similar thromboembolic risk 4