**1. Introduction**

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting approximately 1% of the general population and up to 8% of subjects over the age of 80 years.[1] AF is a major contributor to cardiovascular mortality and morbidity, being associated with de‐ creased quality of life, increased incidence of congestive heart failure,[2] embolic phe‐ nomena, including stroke,[2,3] and a 30 % higher risk of death.[3,4] AF-associated morbidity includes a four- to five-fold increased risk for stroke, [2,5] a two-fold in‐ creased risk for dementia,[6,7] and a tripling of risk for heart failure.[5] According to the Framingham Study, the percentage of strokes attributable to AF increases steeply from 1.5% at 50–59 years of age to 23.5% at 80–89 years of age, [2] and the presence of AF ac‐ counts for a 50–90% increased risk for overall mortality.[3] From the viewpoint of the AF-related socio-economic burden, it has been estimated that it is consuming between 0.9% and 2.4% of total National Health Service expenditure in the UK,[8] while in the USA, total costs are 8.6–22.6% higher for AF patients in all age- and sex- population strata.[9] Therefore significant clinical, human, social and economical benefits are there‐ fore expected from any improvement in AF prevention and treatment.

It has to be noted that although multiple treatment options are currently available, no single modality is effective for all patients.[10] AF can occasionally affect a structurally normal heart of otherwise healthy individuals (so-called "lone AF")[11], but most typically it occurs in subjects with previous cardiovascular damage due to hypertension, coronary artery dis‐ ease and diabetes. Moreover, it can be associated with clinical conditions such as hyperthyr‐ oidism, acute infections, recent cardiothoracic or abdominal surgery, and systemic

© 2013 Perlini et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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 atrial mechanical function and increased risk of atrial clot formation.

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

Atrial Fibrillation and the Renin-Angiotensin-Aldosterone System

http://dx.doi.org/10.5772/53917

5

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

tissue inflammation[19] and reactive oxygen species production.[20,21]

action potential duration and normal ventricular structure and function.[28]

**factor for AF**

**3. The renin-angiotensin-aldosterone system (RAAS) as a "novel" risk**

Among many others, two factors contribute to the search of different therapeutic ap‐ proaches to AF specifically targeting substrate development and maintenance:[29] the recog‐ nition of novel risk factors for the development of this arrhythmia and the well-known limitations of the current antiarrhythmic drug therapy to maintain sinus rhythm, still having inadequate efficacy and potentially serious adverse effects.[30] In this setting, the inhibition of the renin-angiotensin-aldosterone system (RAAS) has been considered useful in both pri‐ mary and secondary prevention of AF, particularly in patients presenting left ventricular hypertrophy (LVH) or heart failure. The RAAS is a major endocrine/paracrine system in‐ volved in the regulation of the cardiovascular system.[31] Its key mediator is angiotensin II, an octapeptide that is cleaved from the liver-derived 485-aminoacid precursor angiotensino‐

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