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3. Pathophysiology and Risk Factors

AF is a complex and multifaceted condition ranging from an isolated electrophysiological disorder or, more commonly, a manifestation or consequence of other cardiac and noncardiac pathologies (Table 1, Fig. 2).[19] AF generally results from a combination of focal ectopic activity and reentry.[29],[60] Ectopic atrial foci arise from perturbations that cause cells to spontaneously depolarize, either secondary to enhanced automaticity or, more frequently, to triggered activity from after depolarizations. Discrete abnormalities in Ca2þ handling have been identified as centrally involved in after depolarization generation in paroxysmal and persistent AF, as well as postoperative AF (POAF).[61],[62] There is emerging evidence that inflammatory signalling plays a key role in promoting after depolarization generation, as well as other components of AF pathophysiology.[63] These repetitive rapid discharges predominantly originate from the pulmonary veins (PVs), which are a vulnerable region for triggered activity and micro reentry due to the shorter action potential duration, lower resting membrane potentials, and nonuniform myofibril arrangement.[64] When triggered, AF can be maintained by sustained rapid firing of focal impulses that disorganize into fibrillatory waves at their periphery or, in most cases, AF perpetuating reentry. Reentry requires specific conditions for initiation and maintenance. Although reentry is not sustained in the normal atrium, the presence of a vulnerable substrate can perpetuate AF through electrical heterogeneity (eg, regional differences in resting membrane potentials, refractory periods, action potential duration, and conduction velocities). In addition, conduction abnormalities can promote reentrant activity and stabilize reentrant circuits by creating functional barriers that allow recovery of tissue excitability. Structural abnormalities such as atrial fibrosis promote reentry through localized conduction slowing and structural conduction barriers, with atrial chamber dilatation promoting reentry through maintenance of the balance between rotor formation and rotor annihilation. Recently, there has been a renewed focus on the contribution of modifiable cardiovascular risk factors to the causation of AF, because an improved understanding of this relationship is key to providing effective personalized primary and secondary prevention measures.[29],[65],[66] Although the precise mechanistic links between risk factors and AF occurrence remain somewhat uncertain, information available from the literature provides many potential insights.[29] Hypertension, the most significant population attributable modifiable risk factor for AF, causes activation of the sympathetic and renin-angiotensin-aldosterone systems as well as structural and electrophysiological atrial remodelling that enhances AF susceptibility. Diabetes mellitus promotes AF via structural and autonomic remodelling. Tobacco use promotes AF through a combination of the direct effects of nicotine on the atrium (eg, altered atrial conduction and refractoriness) along with structural remodelling, inflammation, and oxidative stress. Alcohol, when consumed in excess, promotes AF through the induction of arrhythmia triggers (increased sympathetic activity/impairment of vagal tone) as well as atrial fibrosis (from the direct toxic effects of alcohol metabolites). Obesity promotes AF through weight-related structural (changes in atrial dimensions and interstitial fibrosis) and electrophysiological remodelling (conduction slowing and shortening of the effective refractory period), autonomic dysfunction, and inflammation. Obstructive sleep apnea (OSA) promotes AF acutely through strongly negative intrathoracic pressures leading to increased venous return (AF-promoting left atrial [LA] volume loading) and hypoxia-induced pulmonary vasoconstriction. Chronic OSA induces electrical and structural remodelling of the atria, autonomic dysregulation, oxidative stress, and inflammation. Regular exercise protects against AF by combating risk factors like obesity and metabolic syndrome but sustained intense exercise might promote AF occurrence (see section 11.3). The relationship between key risk factors and AF are outlined in Table 2.


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