Mechanistic Insights
Hemodynamics
As noted in many of the epidemiologic studies, patients with AF often have concurrent diagnoses such as hypertension, previous stroke, and other cardiovascular diseases that confound the association and delineation of underlying mechanism. Atrial fibrillation decreases cardiac output secondarily to loss of atrioventricular synchrony and impairment of left ventricular filling. As a result of this decreased cardiac output, cerebral hypoperfusion may occur, particularly in the elderly in whom compensatory autoregulation is impaired. Regional cerebral blood flow in chronic AF patients without neurologic symptoms was lower than age-matched controls, with a differential from anterior to posterior but not between hemispheres. The magnitude of reduction differed by age, highest in younger patients (17.5% in aged 35–50 years vs 5.5% in age >66). Transcranial Doppler studies of various cardiac dysfunctional states showed lower diastolic cerebral perfusion compared with controls; in AF patients, patients with presyncope had lower diastolic blood flow velocity compared with AF patients without neurologic symptoms. The role of ventricular rates was examined in 1 study that found that, in the presence of AF, both rapid and slow ventricular rates were a major predictor of dementia, showing another theoretic mechanism linking reduced cardiac output to cognitive impairment; however, this study was underpowered and unadjusted. Although the known hemodynamic consequences of AF have been quantified in these studies, no studies have clearly shown an association to cognitive impairment.
Role of Inflammation and Thrombosis Biomarkers
Elevated levels of various inflammatory biomarkers have been associated with AF. Although inflammation is linked to a prothrombotic state, the mechanisms and associations with cognitive impairment remain unclear. Elevated C-reactive protein both independently and incrementally predicted AF in registry data after adjusting for coexisting cardiovascular disease. The role of the proinflammatory cytokine interleukin (IL) 6 as a stimulant of C-reactive protein has been demonstrated in human hepatocytes, and a review of studies showed correlation of various inflammatory markers with echocardiographic and clinical risk factors of thromboembolism. Soluble CD40L, another biomarker of enhanced inflammation and platelet aggregation, is elevated in patients with AF and related to levels of the angiogenesis factors vascular endothelial growth factor and angiopoietin 2 and the prothrombotic tissue factor. Soluble CD40L was inversely correlated with adinopectin, an anti-inflammatory, antiplatelet agent. Other biomarkers studied include fibrinogen, elevated in both persistent and paroxysmal AF; von Willebrand factor, elevated in persistent AF; and soluble P-selectin, elevated in paroxysmal AF. Data correlating inflammatory markers to clinical outcomes include tumor necrosis factor α as a significant predictor of ischemic stroke and von Willebrand factor as a predictor of stroke/vascular events.D-Dimer, prothrombin fragment 1 + 2, and thrombin-antithrombin complexes were higher in patients with AF who subsequently developed dementia than those without, although this significance became borderline after age adjustment. Cerebral vascular damage leads to local hypoxia and oxidative neurologic damage resulting in increased release of inflammatory cytokines, which can increase production of amyloid precursor protein, resulting in Alzheimer disease (Figure 2); however, although the evidence supports a proinflammatory, prothrombotic state, the definitive link to cognitive dysfunction remains elusive.
(Enlarge Image)
Figure 2.
Atrial fibrillation can result in cognitive dysfunction.
Brain Imaging: Silent Cerebral Ischemia
In persons with persistent or paroxysmal AF, silent cerebral ischemia (SCI) is present in approximately 90% versus 46% of patients in sinus rhythm, with those in persistent AF having significantly more areas of SCI than those in either paroxysmal AF or sinus rhythm. In this study, cognitive performance was significantly worse in patients with AF, but the association between cognitive decline and SCI was not studied. The Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation study found a 14.7% incidence of SCI among neurologically normal patients in chronic AF and an annual SCI development rate of 1.01% with placebo and 1.57% with warfarin. The sample size was too small to determine the effect of warfarin on incident SCI development, and SCI did not independently predict subsequent stroke. A community-based prospective cohort study of 935 stroke-free patients found that incident AF predicted greater annual average rates of decline in cognitive function, but only in the presence of SCI, whether at entry or on late magnetic resonance imaging (MRI). Silent cerebral ischemia development with incident AF was double that of patients without AF; however, secondary analysis showed that SCI was significantly associated with greater decline in cognitive function even in participants without AF, suggesting that SCI and not AF per se was related to cognitive function.
Brain Volume
Knecht et al found that persons with AF had a reduction in hippocampal volume, a hallmark of amnestic mild cognitive impairment and Alzheimer disease. An autopsy study showed no significant association of hippocampal infarcts with AF, but the method of clinical data collection particularly with regard to AF was limited. Atrial fibrillation, along with hypertension, was a predictor of smaller amygdala volumes, which correlated to visual new learning; however, this study was limited to stroke/transient ischemic attack patients. In elderly patients, only age and number of lacunar infarcts were predictive of cognitive function. In a cross-sectional study in Reykjavik of 4,251 persons without dementia, brain volumes were lower in persons with AF. Longer time from diagnosis of AF and persistent, compared to paroxysmal, AF had a stronger relationship with the reduction in brain volumes. There was a greater reduction in gray matter than white matter, which has been shown to be associated with cerebral hypoperfusion. Treatment with warfarin did not prevent brain volume reduction.
Cerebral Microbleeds
Although the thromboembolic state of AF poses risks of microinfarction and tissue loss, cerebral microbleeds (CMBs) have been associated with AF as well. Atrial fibrillation conferred a 2.21 risk of CMB in stroke/transient ischemic attack patients. When controlling for other small vessel manifestations (white matter hyperintensities and lacunar infarcts), the presence and number of CMB were related to global cognitive function; most of these were lobar in location again suggesting cerebral amyloid angiopathy as an etiology, but this study was in a broader population.