LAUSR

A trial fibrillation (AF) is the most common cause of cardioembolic stroke, accounting for 1 in every 4 ischemic strokes (1). According to the current paradigm, cardioembolic stroke in nonvalvular AF is caused by thrombus formation in the left atrium, most often in the left atrial appendage, from a lack of organized atrial contraction. Echocardiographic markers of blood stasis, including spontaneous echocardiographic contrast (smokelike pattern caused by swirling blood flow most often seen in the left atrium) and low left atrial appendage emptying velocity, are associated with increased risk for left atrial appendage thrombus and thromboembolism in AF (2). The presence of left atrial thrombus or left atrial appendage thrombus in sinus rhythm is very rare and is almost exclusively seen in patients with mitral stenosis, a prosthetic valve, endocarditis, left atrial myxoma, or underlying cardiomyopathy (such as cardiac amyloidosis). In patients with stroke, AF detection has important treatment implications by identifying those in whom anticoagulation is superior to antiplatelet therapy for reducing risk for recurrent stroke. But AF is detected with an implantable loop recorder in only up to 30% of patients with ischemic stroke (1). “Atrial cardiopathy” has been hypothesized to cause nonvalvular left atrial thromboembolism in the absence of AF and may be responsible for a subset of patients with embolic stroke of undetermined source, a diagnosis that requires a complete stroke workup to exclude significant intracranial and extracranial stenosis, lacunar infarction, and cardioembolism. Currently, there is no formal definition for “atrial cardiopathy”; it is broadly defined as any atrial structural and electrophysiologic abnormality occurring most often with AF but also without AF (3). Prior epidemiologic studies have reported that biomarkers of atrial cardiopathy, such as left atrial enlargement, P wave abnormality, and elevated N-terminal pro–B-type natriuretic peptide level, are associated with cardioembolism independent of AF (4). In a post hoc analysis of the WARSS (Warfarin-Aspirin Recurrent Stroke Study) trial, in which warfarin was shown to have no benefit over aspirin for prevention of recurrent stroke and death among patients with noncardioembolic stroke, warfarin was associated with reduced risk for the primary outcome compared with aspirin among patients with Nterminal pro–B-type natriuretic peptide levels above 750 pg/mL (5). These data served as the rationale for the ARCADIA (AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke) trial, which is testing apixaban, 5 mg or 2.5 mg twice daily, against aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source and atrial cardiopathy, defined as the presence of P wave terminal force in lead V1 above 5000 μV·ms, serum N-terminal pro–B-type natriuretic peptide level above 250 pg/mL, and left atrial diameter index of 3 cm/m or greater. In the NAVIGATE ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) and RE-SPECT ESUS (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source) trials, rivaroxaban, 15 mg once daily, and dabigatran, 150 mg or 110 mg twice daily, respectively, did not reduce risk for recurrent stroke compared with aspirin. In addition, NAVIGATE ESUS was terminated early because of increased risk for bleeding in the rivaroxaban treatment group (6, 7). Therefore, the proportion of patients with embolic stroke of undetermined source in whom left atrial thromboembolism due to atrial cardiopathy (or undetected AF) is the culprit may be small. We eagerly await the results of the ARCADIA trial to identify patients with embolic stroke of undetermined source and without AF who may benefit from anticoagulation for secondary stroke prevention. In their article, Maheshwari and colleagues (8) report an association between left atrial strain and the risk for ischemic stroke independent of AF. The authors analyzed data on 4917 participants from the ARIC (Atherosclerosis Risk in Communities) study after excluding persons with prevalent stroke, prevalent AF, or anticoagulation use. Exposure variables were echocardiographic markers of left atrial cardiopathy: left atrial volume index and left atrial strain in each cardiac cycle phase. The primary outcome was a composite of noncarotid embolic strokes and all thrombotic strokes, which occurred in 176 participants (3.6%) over a mean of 6.6 years of follow-up. In multivariable Cox proportional hazards analyses adjusting for age, sex, and the individual components of the CHA2DS2-VASc score, the model with left atrial reservoir strain and without other left atrial measures had the lowest Akaike information criterion. Left atrial conduit strain, contractile strain, and size were not significantly associated with the primary outcome in models accounting for reservoir strain. Several methodological issues of the study must be discussed. First, the results might have been more clinically meaningful if the authors had excluded “noncarotid embolic stroke,” which is almost always due to cardioembolism, and had focused on embolic stroke of undetermined source. The diagnosis of cardioembolic stroke requires underlying cardiac abnormalities; left atrial function would be anticipated to be abnormal and, more importantly, once ischemic stroke is deemed to be cardioembolic appropriate treatment is initiated for secondary stroke prevention regardless of left atrial function. Second, as the authors pointed out, underascertainment of asymptomatic, paroxysmal AF likely occurred in this study, in which AF was ascertained using hospital medical records. Given that atrial cardiopathy is associated with incident AF