**2. Atrial remodeling: electrical and structural factors**

According to Coumel´s triangle of arrhythmogenesis, three cornerstones are required in the onset of clinical arrhythmia[15] – the arrhythmogenic substrate, the trigger factor and the modulation factors such as autonomic nervous system or inflammation. Once es‐ tablished, AF itself alters electrical and subsequently structural properties of the atrial tissue and these changes cause or "beget" further AF self-perpetuation.[12] The mecha‐ nisms responsible for the onset and persistence of the arrhythmia involve electrical as well as structural determinants, that are very complex and yet poorly understood. From the electrical standpoint, there is still debate on the three models that were proposed in 1924[16] by Garrey for describing the mechanisms of spatiotemporal organization of electrical activity in the atria during AF. According to the *focal mechanism theory,* AF is provoked and perhaps also driven further by the rapid firing of a single or multiple ec‐ topic foci, whereas the *single circuit re-entry theory* assumes the presence of a single dom‐ inant re-entry circuit, and the *multiple wavelet theory* postulates the existence of multiple reentry circuits with randomly propagating wave-fronts that must find receptive tissue in order to persist.[17] It has to be recognized that all three models are non-exclusive and each may be applicable to certain subgroups of AF patients, or that they may even coexist in the same subject during different stages of AF development. Moreover, AF persistence is associated with modifications in the atrial myocyte electrical properties (the so-called *electrical remodeling*), that may stabilize the arrhythmia by decreasing the circuit size. The electrophysiological properties of the atrial myocardium may be further modified by changes in autonomic nervous system activity as well as by the interfer‐ ence of drugs and hormones, that may therefore participate in arrhythmogenesis.

Beyond these electrical determinants, AF onset and persistence may be affected by the struc‐ tural factors, such as the dimensions and geometry of the atrial chambers, the atrial tissue structure and the amount and the composition of the extracellular matrix surrounding the atrial myocytes (i.e. *structural remodeling).* Together, these alterations create an arrhythmo‐ genic substrate essential for the persistence of AF. Atrial structure is modified by volume and pressure overload, due to either mitral valve disease or left ventricular diastolic dys‐ function in the setting of arterial hypertension, coronary artery disease or aortic valve dis‐ ease. Also diabetes is associated with changes in atrial structure and function. It is not therefore surprising that all these clinical conditions are associated with an increased AF in‐ cidence and prevalence. Beyond being a possible substrate for AF onset, atrial structure is profoundly altered by the effects of rapid atrial rate. Prolonged rapid atrial pacing induces changes in atrial myocytes such as an increase in cell-size, myocyte lysis, perinuclear accu‐ mulation of glycogen, alterations in connexin expression, fragmentation of sarcoplasmic re‐ ticulum and changes in mitochondrial shape.[18] Moreover, structural remodeling is characterized by changes in extracellular matrix composition, with both diffuse interstitial and patchy fibrosis.[19] All these alterations results in electrical tissue non-homogeneity, slowed conduction and electrical uncoupling, that facilitate AF continuation. In contrast to electrical remodeling, structural changes are far less reversible and they tend to persist even after sinus rhythm restoration. Among the several mechanisms and signaling pathways in‐ volved in structural remodeling and atrial fibrosis, a key role is played by the renin-angio‐ tensin system, and by the transforming growth-factor β<sup>1</sup> (TGF-β1) pathway, associated with tissue inflammation[19] and reactive oxygen species production.[20,21]

inflammatory diseases. Whatever the cause, AF is characterized by very rapid, chaotic elec‐ trical activity of the atria, resulting in accelerated and irregular ventricular activity, loss of

Many studies have shown that the recurrence of AF may be partially related to a phenomen‐ on known as "atrial remodeling", in which the electrical, mechanical, and structural proper‐ ties of the atrial tissue and cardiac cells are progressively altered, creating a more favorable substrate for AF development and maintenance.[12,13] Atrial remodeling is both a cause and a consequence of the arrhythmia, and in recent years it has become more and more evi‐ dent that treatment should also be based on an "upstream" therapy[14,10] aimed at modify‐

According to Coumel´s triangle of arrhythmogenesis, three cornerstones are required in the onset of clinical arrhythmia[15] – the arrhythmogenic substrate, the trigger factor and the modulation factors such as autonomic nervous system or inflammation. Once es‐ tablished, AF itself alters electrical and subsequently structural properties of the atrial tissue and these changes cause or "beget" further AF self-perpetuation.[12] The mecha‐ nisms responsible for the onset and persistence of the arrhythmia involve electrical as well as structural determinants, that are very complex and yet poorly understood. From the electrical standpoint, there is still debate on the three models that were proposed in 1924[16] by Garrey for describing the mechanisms of spatiotemporal organization of electrical activity in the atria during AF. According to the *focal mechanism theory,* AF is provoked and perhaps also driven further by the rapid firing of a single or multiple ec‐ topic foci, whereas the *single circuit re-entry theory* assumes the presence of a single dom‐ inant re-entry circuit, and the *multiple wavelet theory* postulates the existence of multiple reentry circuits with randomly propagating wave-fronts that must find receptive tissue in order to persist.[17] It has to be recognized that all three models are non-exclusive and each may be applicable to certain subgroups of AF patients, or that they may even coexist in the same subject during different stages of AF development. Moreover, AF persistence is associated with modifications in the atrial myocyte electrical properties (the so-called *electrical remodeling*), that may stabilize the arrhythmia by decreasing the circuit size. The electrophysiological properties of the atrial myocardium may be further modified by changes in autonomic nervous system activity as well as by the interfer‐

ence of drugs and hormones, that may therefore participate in arrhythmogenesis.

Beyond these electrical determinants, AF onset and persistence may be affected by the struc‐ tural factors, such as the dimensions and geometry of the atrial chambers, the atrial tissue structure and the amount and the composition of the extracellular matrix surrounding the atrial myocytes (i.e. *structural remodeling).* Together, these alterations create an arrhythmo‐ genic substrate essential for the persistence of AF. Atrial structure is modified by volume

atrial mechanical function and increased risk of atrial clot formation.

4 Atrial Fibrillation - Mechanisms and Treatment

ing the arrhythmia substrate and at reducing the extent of atrial remodelling.

**2. Atrial remodeling: electrical and structural factors**

Profibrotic signals act on the balance between matrix metalloproteinases (MMPs) – the main enzymes responsible for extracellular matrix degradation – and their local tissue inhibitors (TIMPs), that can be differentially altered in compensated as opposed to decompensated pressure-overload hypertrophy.[22-25] Furthermore, profibrotic signals stimulate the prolif‐ eration of fibroblasts and extracellular deposition of fibronectin, collagens I and III, prote‐ glycans and other matrix components. In a canine model of congestive heart failure, Li *et al.* showed that the development of atrial fibrosis is angiotensin-II dependent,[26] via mecha‐ nisms that are partly mediated by the local production of cytokine TGF-β1.[27] In transgenic mice, overexpression of the latter cytokine has been shown to lead to selective atrial fibrosis, increased conduction heterogeneity and enhanced AF susceptibility, despite normal atrial action potential duration and normal ventricular structure and function.[28]
