Neurocognition and Greater Maintenance of Sinus Rhythm in AF (NOGGIN AF)

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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting 1%-3% of the general population, with greater prevalence in older persons (8%-10%). AF is associated with an increased risk for cognitive decline, dementia, stroke, myocardial infarction, heart failure, chronic kidney disease, and mortality, resulting in an incremental yearly cost of AF in the US of $26 billion. AF and cognitive decline share several risk factors including advancing age and comorbidities such as hypertension, diabetes mellitus, and heart failure. Microbleeds from anticoagulation, a proinflammatory and prothrombotic state, and cerebral hypoperfusion can cumulatively result in silent cerebral infarction, white matter hyperintensities, brain atrophy, and disruption of functional network connectivity, and also lead to AF-related cognitive decline. While the link between AF and the development of cognitive impairment has been established, the driving mechanisms and the effect of sinus rhythm restoration are not completely understood. Our long-term goals are to understand the interaction between heart rhythm and neurologic health, and to investigate methods to prevent cognitive dysfunction due to AF. Thus, in the proposed study, we will test our hypothesis that among AF patients receiving oral anticoagulation, restoration of sinus rhythm with catheter ablation vs drug therapy leads to less long-term neurologic damage and dysfunction due to improved cerebral blood flow and lower risk for additional ischemic injury. The primary aims of our prospective, observational clinical trial are to 1) compare structural cortical characteristics in Alzheimer’s disease-risk regions in AF patients treated with catheter ablation vs drug therapy; 2) compare cerebral blood flow in AF patients treated with catheter ablation vs drug therapy; 3) compare cognitive function in AF patients treated with catheter ablation vs drug therapy; and 4) assess the relationship between neurologic outcomes and plasma and imaging biomarkers of coagulation and inflammation. This will be the first study to incorporate a comprehensive neurocognitive test battery, structural and functional neuroimaging, cerebral blood flow assessment, and plasma and imaging biomarkers to a) better delineate the contribution of each of the known risk factors to the development of cognitive decline in patients with AF, and b) assess how restoration of sinus rhythm using catheter ablation vs drug therapy may alter the trajectory of cognitive decline and development of dementia. Our preliminary data showed that catheter ablation did not worsen cognitive function or white matter hyperintensity burden 6 weeks or 1 year later, while drug therapy patients showed greater cortical thinning at 1 year in brain regions associated with Alzheimer’s, and this thinning correlated with worse cognitive performance. Thus, this study is significant, and will vertically advance the field of AF management by revolutionizing our understanding of the mechanisms by which AF induces cognitive decline, and by providing an important and necessary step toward justifying rhythm control by catheter ablation as a strategy to arrest the processes that lead to cognitive impairment and dementia.