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CLINICAL STATEMENTS AND GUIDELINES

January 2, 2024 Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 e16

Joglar et al 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation

Calcium mishandling from remodeling increases calcium load in the sarcoplasmic reticulum and dysfunction of ryanodine receptors, which regulate intracellular calcium release. Remodeling in AF of sarcoplasmic reticulum calcium ATPase underlies sequestration of intracellular calcium between beats, and/or altered regulation of sarcoplasmic reticulum calcium ATPase by phospholamban and sarcolipin.11 Increased intracellular sodium from calcium-calmodulin II-induced increased late sodium current or cardiac glycosides can also increase sarcoplasmic reticulum calcium through the sodium-calcium exchanger.12,13 Several upstream mechanisms (eg, oxidative stress, inflammatory signaling) promote calcium-calmodulin II -activation. CaM- KII-mediated and hyperphosphorylation of ryanodine receptor 2 promotes spontaneous diastolic Ca2+ leak by increasing ryanodine receptor 2 channel open probability, leading to higher intracellular Ca2+ levels and the milieu for delayed afterdepolarizations, the most likely trigger for AF initiation.14 Electrogenic action of sodiumcalcium exchanger drives afterdepolarizations, and expression of sodium-calcium exchanger is increased in HF and AF. Action potential alternans related to Ca2+ mishandling can be noted to precede AF onset and increases with age. 2.3.1.1. Triggers of AF The atria of patients with AF tend to have both shorter effective refractory periods and slower conduction, which enhances dispersion of repolarization and favor reentry. This substrate is sensitive to AF initiation, frequently after premature atrial contractions (PACs).1 PAC burden is associated with development of AF.2 Larger LA volume, increased NT-proBNP levels, and impaired LA emptying are associated with increased PAC burden.3 In a study of 100 patients undergoing PV isolation, PACs induced 41 episodes of AF in 22 patients, with most episodes originating in the PVs.4 Earlier studies also reported an LA gradient of background potassium currents, resulting in shorter LA than right atrial effective refractory period in patients with AF.5 Mapping studies of AF electrograms in canine models documented a left-right gradient of high frequency sources (drivers), with the highest frequency regions located near the PVs in the LA.6

2.3.2. Atrial Structural Abnormalities, Remodeling, and Atrial Myopathy Atrial cardiomyopathy has been identified as “any complex of structural, architectural, contractile or electrophysiological changes affecting the atria with the potential to produce clinically relevant manifestations.”1 Atrial cardiomyopathy is common, associated with aging and other comorbidities with metabolic or hemodynamic stress, and often leads to or results from AF. Structural and electrical remodeling promote AF and include interstitial changes, increased myofibroblast activity, and collagen deposition, fibrofatty deposits, altered ion channel expression, calcium signaling and contractility, and inflammatory infiltrates.1 Myeloperoxidase, an oxidase in neutrophils and macrophages, is associated with fibroblast activation, interstitial fibrosis, and inducibility of AF in a mouse model.2 Prothrombotic changes are often evident in the LA, including increased endocardial expression of von Willebrand factor, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 changes, which may increase risk of thrombus formation and stroke.1 Experimental hemodynamic overload, such as reversible aortopulmonary artery shunting promotes atrial dilation, atrial myocyte hypertrophy, interstitial fibrosis, alterations in extracellular matrix composition and vascular dysfunction, and increased vulnerability to atrial ectopy and AF inducibility.3 Electrical remodeling similar to that seen during AF is observed, with characteristic

Figure 5. Pillars for AF Management. AF indicates atrial fibrillation.

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