21 PATHOPHYSIOLOGY OF INCREASED ISCHAEMIC STROKE RISK IN AF deep vein thrombosis, and vice versa, underpinning that ischaemic stroke risk in AF is also (at least partly) related to a hypercoagulable or prothrombotic state.11 ATRIAL FIBRILLATION: A SYSTEMIC CARDIOVASCULAR DISEASE As is commonly known, haemostatic response starts with platelet adhesion, wherein damaged endothelial cells and collagen attract platelets to the site of injury according to Virchow’s triad. Following adhesion, platelets undergo activation, transitioning to an active state and responding to various stimuli such as thrombin. This platelet activation leads to further adhesion and the formation of a platelet plug at the injured site. Ultimately platelet aggregation occurs, wherein activated platelets adhere to each other, forming a blood clot. The view that AF is a complex systemic cardiovascular disease that, together with comorbidities, maintains a systemic hypercoagulable or prothrombotic state, thereby contributing to AF related complications such as ischaemic stroke, can be clarified using Virchow’s triad for thrombogenesis. Below, we explain that, apart from abnormal decreased blood flow (i.e. stasis of the blood), also abnormal changes in the walls of blood vessels and atria and abnormal changes in blood constituents complete this triad for thrombogenesis in patients with AF.12,13 First of all, studies have shown abnormal changes in the walls of blood vessels and atria in patients with AF compared to patients without AF, a finding currently described as atrial cardiomyopathy. For example, a post mortem study in patients with ischaemic stroke described a ‘rough’ endocardium with a wrinkled appearance (due to oedema and fibrinous transformation), areas of denudation of the endothelium and aggregation of thrombi in those with AF compared to those without AF.14 In addition, Weijs et al. showed that, over a period of five years, patients diagnosed with AF compared to those without AF, develop cardiovascular disease (such as ischaemic stroke, myocardial infarction and heart failure) more often (49% versus 20%, P=0.006), at a younger age (59 versus 64 years, P=0.027), and with a more severe disease profile.15 Moreover, the presence of a complex plaque (i.e. a plaque with a thickness greater than 4 millimetre, or containing ulceration, pedunculation, or mobile elements) in the aorta of AF patients is a risk factor for ischaemic stroke.16 These findings mean that AF patients, especially those with atherosclerosis or associated vascular risk factors (e.g. hypertension, hypercholesterolaemia, diabetes mellitus, obesity, long-lasting stress, smoking, family history for vascular disease), are more prone to developing ischaemic stroke. Monitoring the left atrial volume index as a biomarker of vascular remodelling may thus be useful to predict the risk of ischaemic stroke.17 2
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