Fehmi Keçe

Chapter 1 16 disease, hypertension, obesity, sleep apnoea, diabetes, but also AF itself can result in fibrosis of the atria (19). The structural remodelling finally results in electrical dissociation of neighbouring atrial muscles bundles resulting in AF (19, 22). 1.2.8 Electrical Remodelling During AF, auto-protective mechanisms become initiated by regulating the ion channel function in such a way that it promotes arrhythmias. As Ca 2+ enters atrial cells with each action potential, rapid atrial rates increase Ca 2+ loading initiating autoprotectivemechanisms that reduce Ca 2+ entry. Hereby the action potential duration decreases and atrial re-entry rotors stabilize. These mechanisms increase the atrial vulnerability to atrial arrhythmias leading to contractile dysfunction and tachycardia-induced atrial cardiomyopathy (18). 1.2.9 Autonomic and neural remodelling Nerves and ganglionic neurons show great plasticity. Neural remodelling includes an increase in the atrial innervation (nerve sprouting), which results in initiation and maintenance of AF (18). Atrial fibrillation is associated with oxidative stress, which can cause neurodegeneration in the central nervous system. It is possible that oxidative stress causes cardiac nerve injury, which triggers the re-expression of nerve growth factor or other neurotrophic factor genes in the nonneural cells around the site of injury, leading to nerve regeneration through nerve sprouting. Moreover, the atrial rate is high during AF and the atria are deficient in coronary vessel distribution which makes the atrial myocardium prone to ischemic damage. Ischemic myocardial injury results in nerve degeneration followed by regeneration (23). 1.2.10 Genetics AF has also an genetic component, which is independent of concomitant cardiovascular conditions. Especially early-onset AF is associated with heritability. Predominantly genes that encode cardiac ion channels with predicted mutation effects on the atrial action potential duration are thought to be responsible for AF. However, more recent studies have expanded the spectrum of disease-associated genes to myocardial structural components and cardiac transcription factors (24). More than 30 genes have been identified from studies of familial cases or individuals with lone atrial fibrillation. Genome-wide association studies (so called GWAS), test a large sample size comparing allele and genotype frequencies of single-nucleotide polymorphisms (SNPs) between individuals with atrial fibrillation and healthy controls. The power of any single SNP associated with atrial fibrillation is too weak to use as an informative marker to develop atrial fibrillation. However aggregating a set of SNPs associated with atrial fibrillation increases the risk for an individual to develop atrial fibrillation.