Isolated left atrial dysfunction in mice leads to sex-dependent progression of left ventricular dysfunction

The left atrium (LA) is essential for cardiac filling, acting as a reservoir during ventricular contraction. Impaired LA function reduces effective left ventricular (LV) filling and elevates filling pressures, key features of heart failure with preserved ejection fraction (HFpEF). Despite the recognized contribution of LA dysfunction to HF progression in humans, studies examining how isolated atrial dysfunction affects cardiac performance and HF progression remain lacking. In the present study, we investigated the effects of isolated LA dysfunction on LV structure and function using a murine model of atrial-specific injury. In this novel model, we induced graded LA dysfunction in mice via Left Atrial Cauterization (LAC). Six-month-old male and female C57BL/6 mice underwent targeted LA cauterization using a fine-tip cautery pen. Graded injury was achieved based on the number of cauterized dots: 6 (severe). Four weeks post-LAC, male mice with mild and moderate injury exhibited diastolic dysfunction with increased E/E’ (sham 22.9±0.54; mild 32.9±2.5**(p< 0.01); moderate 29.36±2.54*(p< 0.05)). Echocardiographic assessment showed preserved LV EF in mild LAC (sham 70.65%±1.31 vs. mild 65.49%±2.54), but a significant decline in moderate LAC (57%±2.41**(p< 0.01)). Speckle-tracking echocardiography demonstrated reduced LA EF, impaired LA and LV longitudinal strains, and increased mechanical desynchrony. Treadmill testing confirmed reduced exercise tolerance in LAC mice. At eight weeks post-mild LAC, female mice exhibited preserved LV EF (sham 67.1±1.41; LAC 65.8±1.89), whereas male mice showed significantly less preserved LV EF (sham 67.7±1.62; LAC 59.8±1.61*(p< 0.05)), despite similar elevations in E/E’. Strain analysis revealed more pronounced reductions in atrial deformation in males. Lung function assessment using whole-body plethysmography showed reduced tidal volume and increased airway resistance in both sexes. Collectively, these findings demonstrate that LA dysfunction alone is sufficient to initiate diastolic dysfunction and impair cardiopulmonary performance, with males exhibiting greater susceptibility to subsequent ventricular systolic decline. The LAC model provides a novel and reproducible method for inducing selective atrial dysfunction while preserving initial ventricular structure, offering a robust platform to investigate atrial–ventricular interactions and generate translational insights. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.