INTRODUCCIÓN: REVISIÓN CRITICA DEL PROBLEMA

Introduction
RESULTADOS
Atrial fibrillation (AF) is the most common cardiac rhythm disturbance 294 . The
fundamental mechanisms underlying AF have been long debated. A growing body
of evidence indicates that inflammation and oxidative stress contribute to the
pathogenesis of AF 295,296 , mediating atrial fibrosis 297 . Related to this, there is a
controversy about the relation between AF and diabetes mellitus (DM) 298 , a
chronic illness with one of the most rapidly growing incidence in the western
countries population. The presence of both pathologies increases the risk of major
cardiovascular events 299 . So, the understanding of this pathophysiological linkage
would be essential to achieve a therapeutic risk reduction.
Non-enzymatic glycation of proteins and lipids occurs with ageing 300 , but the
process is markedly accelerated in the setting of DM and oxidative stress 301 . The
resulting newproducts are defined as advanced glycation end-products (AGEs).
The increase ofAGEs level is determined fundamentally by two factors: long-
standing hyperglycaemia and high degree of oxidative stress 95 . Several lines of
evidence have emerged recently, indicating that the interaction of AGEs with their
receptor (RAGE) is an important player in the initiation and propagation of
inflammatory responses 302 . In this sense, the soluble form of RAGE (sRAGE)may
reflect the activity of the AGE–RAGE axis 272 . Infact, high levels of AGEs and
sRAGE are associated with oxidative stress and inflammatory activity, and they
are even implicated in atrial fibrosis in animal models 303 .
AGEs promote protein cross-linking which alters protein structure and function, as
in the case of type I collagen and elastin in the extracellularmatrix, resulting in
atrial fibrosis 304 . In addition to extracellular actions, AGE–RAGE interaction results
in enhanced production of proinflammatory mediators by the activation of nuclear
factor NF-κB 305 . These findings might explain a linkage between AGE–RAGE axis
and AF 306 . Another mechanism by which AGEs may contribute to AF is by the
generation of reactive oxygen species (ROS) 307 which contributes to atrial
remodelling. Taken together, these observations support an important
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