Incidentalomas of the heart: lipomatous hypertrophy of the interatrial septum in the GLP-1 era

To the Editor, Lipomatous hypertrophy of the interatrial septum (LHIS) is a benign and often incidental cardiac finding, in which excess, unencapsulated fat accumulates within the interatrial septum. The fossa ovalis is typically spared, resulting in a distinctive dumbbell-shaped appearance on cross-sectional imaging[1]. In prospective thoracic CT cohorts, LHIS has been reported in approximately 2%–3% of patients undergoing routine imaging, most commonly among older individuals and those with obesity[1,2]. Recent imaging studies suggest that LHIS may represent a distinct type of cardiac adipose tissue rather than simple passive fat accumulation. In some patients, features of variable metabolic activity have been observed, including features suggestive of brown or metabolically active fat[3]. Although often asymptomatic, LHIS has been linked to atrial arrhythmias and conduction disturbances, indicating that it may have clinical significance beyond incidental detection[4]. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including semaglutide and tirzepatide, are increasingly prescribed for type 2 diabetes mellitus and obesity due to their potent metabolic and weight-reducing effects. Large clinical trials have also demonstrated cardiovascular benefit with these agents[5]. These agents help regulate appetite and alter how fat cells store and use energy. This can result in rapid and noticeable changes in body fat, particularly at higher doses used for weight loss[6]. Recent imaging studies have demonstrated significant reductions in visceral, epicardial, and pericardial adipose tissue volumes following GLP-1 RA therapy. These findings indicate that the drugs can remodel ectopic fat depots in proximity to the myocardium[7]. In light of evidence that GLP-1 receptor agonists remodel ectopic cardiac fat[6,7] and that the LHIS is metabolically active[3], prominent interatrial septal fat seen in patients on high-dose GLP-1 receptor agonist therapy may reflect altered adipose redistribution. This observation warrants further investigation. Importantly, CT and MRI studies suggest that septal fat in LHIS may behave differently from other cardiac fat depots, exhibiting distinct density and metabolic characteristics that could influence local atrial function[3]. Because interatrial septal fat lies close to the heart’s conduction pathways, sudden structural changes could potentially increase the risk of arrhythmias[4]. Several limitations should be acknowledged. First, establishing causality is challenging, as obesity and metabolic syndrome are common in patients with both LHIS and GLP-1 receptor agonist use, raising the possibility of confounding by indication[2]. Second, detection bias is likely, since patients undergoing intensive pharmacologic weight-loss therapy are more frequently referred for advanced cardiac imaging[7]. Finally, the biological mechanisms linking GLP-1 receptor signaling to focal adipose remodeling within the interatrial septum remain uncertain, as histologic, molecular, and electrophysiological correlation data are currently lacking. In conclusion, these observations raise the possibility that high-dose GLP-1 receptor agonist therapy may influence the imaging appearance or behavior of interatrial septal fat. Longitudinal imaging studies and heart rhythm monitoring will be essential to determine whether these changes are benign or carry potential arrhythmogenic risk. Awareness of this possible association can help clinicians provide careful surveillance and inform future research, without implying premature conclusions about causality. This letter to the Editor adheres to the Transparency in the Reporting of Artificial Intelligence in Research (TITAN) guidelines[8]. Sincerely,