The clinical pathophysiology of atrial fibrillation: outstanding questions from bedside to bench and back

Atrial fibrillation (AF) is a major public health problem, associated with increased risks of heart failure, stroke, dementia, and mortality. The treatment of AF involves multiple potential approaches, all of which presently have significant limitations. Over the past 20 years, tremendous advances have been made in understanding the pathophysiological determinants of AF. The present narrative review article aims to address selected issues that are highly relevant to clinically important questions in AF pathophysiology by reviewing insights from both experimental observations and complementary clinical investigations. Issues that we address include <i>1</i>) introduction and mechanistic concepts; <i>2</i>) the mechanistic basis for the crucial role of the pulmonary veins in AF; <i>3</i>) the progressive natural history of AF; <i>4</i>) the nature and mechanisms of secondary AF; <i>5</i>) AF and heart failure with reduced ejection fraction; <i>6</i>) AF and heart failure with preserved ejection fraction; <i>7</i>) AF burden: importance and mechanistic determinants; and <i>8</i>) the clinical importance of better understanding AF pathophysiology, leveraging new physiological knowledge and technologies to improve AF prevention. We consider in detail changes in ion channel and transporter function, the importance of inflammatory signaling, and the contribution of changes in tissue structure and composition in the development of AF-promoting atrial cardiomyopathy. The developments in our understanding of AF pathophysiology have been enormous and have produced many new conceptual and therapeutic opportunities, along with a wide range of important new questions. To capitalize on these opportunities and address the new questions that have emerged will require substantial additional investigation.