The Pathophysiology of Atrial Fibrillation (AF) and the Importance of Sinus Rhythm

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The Pathophysiology of Atrial Fibrillation (AF) and the Importance of Sinus Rhythm

Remodeling of the atria caused by atrial fibrillation makes it more difficult to return to sinus rhythm, more difficult to respond to treatment, and increases vulnerability to relapse.1


  • The American College of Cardiology (ACC), the American Heart Association Task Force (AHA), and the European Society of Cardiology Committee (ESC), in collaboration with the Heart Rhythm Society have established guidelines for the classification of AF2
  • First-detected episode of AF – may or may not be symptomatic; the actual duration of the episode and previous undetected episodes may be uncertain2
  • Recurrent AF – 2 or more episodes2
    • Paroxysmal AF – self-terminating, spontaneously converts to sinus rhythm2
    • Persistent AF – lasts longer than 7 days, is not self-terminating and usually requires medical intervention2
  • Permanent AF – refractory to cardioversion or has persisted for a long period of time2
  • Lone AF – occurring in a patient younger than 60 years who has no clinical or echocardiographic evidence of cardiopulmonary disease, including hypertension2
  • Valvular and nonvalvular AF – occurs in a patient who has evidence or history of rheumatic mitral valve disease, who has a prosthetic heart valve, or who has valve repair; all other forms of AF are classified as nonvalvular AF2

Atrial Fibrillation Begets Atrial Fibrillation

  • One of the main challenges of atrial fibrillation is the tendency of the disease to become chronic over time, during which a combination of molecular and structural changes make it difficult to achieve and maintain sinus rhythm3

Electrical Remodeling

  • The concept that AF is self-perpetuating has been studied extensively in a goat model using an automatic atrial fibrillator that detected spontaneous termination of AF and reinduced AF by electrical stimulation. At first, the electrically induced AF terminated spontaneously. However, with repeated inductions, AF episodes became progressively more sustained until AF persisted and at a more rapid rate. The increasing propensity to AF was associated with progressive shortening of the effective refractory period as well as with increasing episode duration2 (See Figure)
  • Electrophysiological remodeling has led to the phrase “atrial fibrillation begets atrial fibrillation,” originally coined by Wijffels and colleagues2,3
  • In addition to remodeling and changes in electrical refractoriness, prolonged AF disturbs atrial contractile function. After a period of persistent AF, recovery of atrial contraction can be delayed for days or weeks following the restoration of sinus rhythm2
Figure 2-1
Figure. Posterior view of principal electrophysiological mechanisms of atrial fibrillation. A. Focal activation. The initiating focus (indicated by the star) often lies within the region of the pulmonary veins. The resulting wavelets represent fibrillatory conduction, as in multiple-wavelet reentry. B. Multiple wavelet reentry. Wavelets (indicated by arrows) randomly reenter tissue previously activated by the same or another wavelet. The routes the wavelets travel vary. LA indicates left atrium; PV, pulmonary vein; ICV, inferior vena cava; SCV, superior vena cava; and RA, right atrium. Adapted from Konings.2,4


  • Electrophysiological remodeling occurs on 2 time scales: rapid (seconds or minutes) and slower (days or weeks)3
    • Rapid electrophysiological remodeling involves translational modulation of Ica and ITO ionic currents by altered pH, intracellular Ca2+, phosphorylation and oxidation state, and metabolic regulation of pore forming alpha and beta subunits3
    • Slower changes are due to changes in the rate of translation, synthesis, and degradation of ion channel subunits in the myocyte membrane3

Structural Remodeling

  • The most frequent structural changes in AF are atrial fibrosis and loss of atrial muscle mass2
  • Atrial fibrosis may precede the onset of AF. Nonhomogeneity of conduction may result from the juxtaposition of patchy fibrosis with normal atrial fibers2
  • Interstitial fibrosis may be triggered by atrial dilation in any type of heart disease associated with AF. Also, interstitial fibrosis may result from apoptosis leading to replacement of atrial myocytes, loss of myofibrils, disruption of cell coupling gap junctions and organelle aggregates, or accumulation of glycogen granules2
  • Apoptosis, or programmed cell death, provides temporal and spatial control of a cell and determines the cell’s lifetime. Apoptosis may occur inappropriately under pathophysiological conditions. When this happens in the heart, myocytes die and contractile capacity as well as electrical activity is permanently lost. The pathways of electrical activation may be altered due to replacement fibrosis. The presence of apoptotic myocytes in the atrial tissues of patients with chronic AF was documented by Aime-Sempe and colleagues3
  • Structural changes in AF occur at a slow rate, significantly slower than electrophysiological remodeling, and probably most structural changes are irreversible3

Molecular Changes in AF

  • In atrial tissue specimens from a total of 53 explanted hearts of transplantation recipients with dilated cardiomyopathy, 18 had persistent, 19 had permanent, and 16 had no documented AF. Extracellular matrix remodeling including selective upregulation of matrix metalloproteinase 2 (MMP-2), type 1 collagen volume fraction (CVF-1) and downregulation of insulin-like growth factor II mRNA-binding protein 2 (IMP-2) were associated with sustained AF2
  • The concentration of membrane-bound glycoproteins that regulate cell-cell and cell-matrix interactions (disintegrin and metalloproteinases) in human atrial myocardium has been reported to double during AF, potentially contributing to atrial dilation. Dilation of the atria activates several molecular pathways including the renin-angiotensin-aldosterone system (RAAS). Angiotensin II is upregulated in response to stretch, and atrial tissue from patients with persistent AF demonstrates increased expression in angiotensin-converting enzyme (ACE). Angiotensin inhibition and angiotensin II receptor blockage may prevent AF by reducing fibrosis2
  • A genetic defect, such as mutations in lamin AC gene, has been associated with AF. Other triggers of fibrosis include inflammation as seen in cardiac sarcoidosis and autoimmune disorder2

Long-term Impact of AF

  • A retrospective analysis demonstrated that 20% of patients with intermittent AF were in permanent AF after 4 years5
  • 77% of patients with paroxysmal AF were in permanent AF after a mean of 14 years.5 Independent risk factors for early progression to permanent AF included age, dilated left atrium, MI, and valvular disease5
  • The longer one waits to initiate a rhythm treatment strategy, the harder it is to regain sinus rhythm. Patients who converted to sinus rhythm within 3 months of onset of AF were more likely to remain in sinus rhythm at 6 months than patients who converted more than 12 months after onset of AF (67% versus 27%)6
  • By shortening the atrial refractory period, reducing conduction velocity and provoking contractile and structural remodeling, AF sets the stage for self-perturbation

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