What is the pathophysiology of atrial fibrillation in adults with a history of cardiovascular disease?

Pathophysiology of Atrial Fibrillation

Atrial fibrillation results from a complex interplay of electrical triggers, structural remodeling, and autonomic dysfunction that creates and maintains an arrhythmogenic substrate in the atria. 1, 2

Primary Electrical Mechanisms

The initiation and perpetuation of AF involves two fundamental electrical processes that work in concert:

Focal Triggers and Rapid Firing

• Rapidly firing atrial foci, most commonly located in the pulmonary veins (particularly the superior pulmonary veins), serve as the primary triggers for AF initiation in susceptible patients. 1 These ectopic foci can also originate from the right atrium, superior vena cava, or coronary sinus. 1
• Focal mechanisms appear more important in paroxysmal AF than persistent AF, and ablation of these foci can be curative in selected patients. 1
• Enhanced automaticity and triggered activity from these focal sources result from calcium handling abnormalities and altered ion channel function. 2, 3

Multiple Wavelet Reentry

• The multiple wavelet hypothesis explains AF perpetuation through continuous conduction of several independent wavelets propagating through atrial musculature in a chaotic manner. 1 Fibrillation wavefronts continuously undergo wavefront-waveback interactions, resulting in wavebreak and generation of new wavefronts. 1
• In paroxysmal AF, localized sources can be identified, but in persistent or permanent AF, sites with high dominant frequency spread throughout the entire atria, making ablation or conversion more difficult. 1
• The number of wavelets depends on atrial refractory period, atrial mass, and conduction velocity in different atrial regions. 1

Structural Remodeling

Atrial fibrosis represents the most common and critical structural finding, causing heterogeneous electrical conduction and creating multiple reentry circuits that perpetuate AF. 2, 3

Fibrotic Changes

• Patchy fibrosis with juxtaposition of normal and diseased atrial fibers accounts for nonhomogeneity of atrial refractoriness and creates the substrate for reentry. 1
• The aging heart loses cardiomyocytes at approximately 0.5-1.0% per year, with fibrous tissue replacing lost myocytes. 3
• Histological changes consistent with myocarditis were reported in 66% of biopsy specimens from patients with lone AF, suggesting inflammatory processes even without obvious structural disease. 1

Atrial Dilation and Hypertrophy

• Progressive atrial dilatation occurs in patients with AF and can be both a cause and consequence of persistent AF. 1
• Atrial fiber hypertrophy has been described as a major and sometimes sole histological feature in AF patients. 1

Three-Dimensional Conduction Abnormalities

• Impaired electrical coupling between myocytes within the epicardial layer and between epicardial and endocardial networks fosters three-dimensional conduction abnormalities that increase AF stability. 3, 4 This endo-epicardial dissociation allows fibrillation waves to propagate between layers, appearing as "breakthrough waves" that add complexity. 4

Electrical Remodeling

Electrical remodeling involves modulation of ion channels and gap junction function that creates an AF-prone substrate. 5

Ion Channel Dysfunction

• Both acquired and genetic ion channel abnormalities alter atrial refractoriness and promote triggered electrical activity. 2, 3
• Mutations in cardiac sodium channel gene SCN5A or gain of function in cardiac potassium channels contribute to familial AF. 1
• L-type calcium current modulation and various potassium current changes occur during AF. 5

Calcium Handling Abnormalities

• Elevated diastolic calcium and intracellular calcium storage result from high atrial rates and early cardiomyocyte reactivation. 2, 3 These calcium handling abnormalities contribute to both triggered activity and contractile dysfunction. 1

Neurohormonal and Autonomic Mechanisms

Activation of the renin-angiotensin-aldosterone system (RAAS) generates profibrotic factors including transforming growth factor-beta 1, inflammatory mediators, and oxidative stress. 1, 2

RAAS Activation

• Direct effects of activated RAAS on structural remodeling and anisotropic conduction promote AF substrate development. 1
• Volume retention, increased ventricular filling pressures, and functional mitral regurgitation lead to atrial stretch and fibrosis. 1

Autonomic Dysregulation

• Elevated vagal tone and increased sympathetic activity in atrial tissue contribute to ectopic activity and AF initiation. 2, 3
• Fluctuations in sympathetic and parasympathetic tone result in variability of ventricular rate during AF. 1

Bidirectional Relationship with Heart Failure

The concept that "AF begets HF and HF begets AF" reflects the vicious cycle between these conditions. 1

AF-Induced Cardiomyopathy

• Acute loss of coordinated atrial mechanical function after AF onset reduces cardiac output by 5-15%, with more pronounced effects in patients with reduced ventricular compliance. 1
• Rhythm irregularity during AF may itself decrease cardiac output, explaining why patients with severe heart failure gain rapid hemodynamic improvement with immediate cardioversion. 1

HF-Induced Atrial Changes

• Ventricular dysfunction promotes atrial structural and electrical changes through hemodynamic, mechanical, and neurohormonal mechanisms. 1
• HF-associated alterations in calcium handling and calcium overload contribute to atrial arrhythmogenesis. 1

Genetic Predisposition

AF has a significant familial component, especially in early-onset cases, with multiple genetic loci identified. 1

• Mutations in genes coding for atrial natriuretic peptide, cardiac sodium channels, and potassium channels cause familial AF. 1
• Several genetic loci close to PITX2 and ZFHX3 genes associate with AF and cardioembolic stroke in population-wide studies. 1
• Inherited cardiac syndromes including long QT syndrome, short QT syndrome, Brugada syndrome, and hypertrophic cardiomyopathy are associated with AF. 1, 2

Critical Clinical Pitfalls

Always screen for reversible causes in new-onset AF: hyperthyroidism, acute alcohol intake, infections, and pulmonary conditions must be evaluated before attributing AF solely to structural heart disease. 2, 6

• Do not overlook AF without obvious structural disease on standard imaging, as inflammatory infiltrates and early fibrosis may be present at the cellular level. 2
• Recognize that AF developing during acute myocardial infarction portends worse prognosis compared to pre-infarct AF or sinus rhythm. 1, 6
• In patients with pre-excitation syndromes, administration of compounds that slow AV nodal conduction without prolonging atrial/accessory pathway refractory periods (verapamil, diltiazem, digitalis) can accelerate conduction via the accessory pathway and cause life-threatening ventricular rates. 1