Innovative therapies are needed in the face of a lack of a comprehensive, in-depth understanding of the complex mechanisms underlying atrial fibrillation (AF). There is recognition of a need for deeper understanding and novel therapeutic approaches, especially in atrial cardiomyopathy (ACM). ACM is considered a separate entity characterized by structural, architectural, contractile, or electrophysiological changes, increasing the potential for clinical atrial pathology. Evidence indicating a role for ACM in atrial disorders is that, in some cases, thromboembolic risk and persistent AF continue despite treatments such as ablation of isolated regions of the pulmonary vein known to set off AF. Here we review a possible role for modifications at the level of atrial sarcomeres as a common mechanism inducing genetic and acquired AF/ACM. Our review indicates the likelihood that these modifications induce adverse signaling resulting in fibrosis, inflammation, neuro-humoral activity, and arrhythmias, in turn promoting atrial pathology. We discuss genetic and acquired ACM through the lens of a new era of understanding of sarcomere control mechanisms. This advanced understanding has not been thoroughly discussed previously in the case of atrial sarcomeres. Significant new evidence has revealed atrial sarcomere specific mechanisms with the potential for novel control of the pressure-volume relation that is vulnerable in ACM. These mechanisms in atrial sarcomeres have taken on new significance with the identification and clinical development of small-molecule sarcomere activators and inhibitors with possible use and further development in ACM therapy.
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