Abstract 4358298: Atrial Hypertrophy, Fibrosis and Compliance Loss in a Mouse Model of Heart Failure with Preserved Ejection Fraction

Abstract

Background: Heart-failure with preserved ejection fraction (HFpEF) is traditionally viewed as a left-ventricular diastolic disorder, but is increasingly recognized as a multi-chamber syndrome involving atrial enlargement, fibrosis, and contractile failure that contribute to atrial fibrillation risk and poor prognosis. Mechanistic studies in HFpEF models are limited, and new therapies targeting atrial abnormalities are needed. Hypothesis: Metabolic and hemodynamic stress in HFpEF stiffens the ventricle and thereby impacts the atria, driving (i) atrial enlargement, (ii) diffuse fibrosis and (iii) atrial contractile dysfunction. Methods: Male and female C57BL/6N mice were fed high-fat diet(HFD) + L-NAME for 14 weeks to induce HFpEF. Weekly tail-cuff blood pressure, body-weight tracking, and a forced-running tests indicated hypertension, obesity, and exercise intolerance. High-frame-rate echocardiography measured LVEF, E/A, E/e′ and reservoir-, conduit- and contractile LA strain. Post-mortem, atrial mass was normalised to tibia length, and atrial collagen fraction was mapped with picrosirius red and regressed against strain loss. Results: HFD + L-NAME depresses every phasic component of left-atrial mechanics—reservoir, conduit and contractile strain fell by 47 % (p < 0.0001), 42 % (p = 0.0004) and 38 % (p = 0.0028), respectively—while LVEF remained intact. Tissue analysis after sacrifice provided evidence for structural change including an increase in atrial mass/tibia length by 45 % in males (p = 0.0014) and 30 % in females (p = 0.0007), and an increase in collagen content by 2.6-fold ( 7.9 ± 0.5 % to 20.6 ± 1.5 %, p < 0.0001). Collagen burden was tightly coupled to stiffness; each 1 % rise in fibrosis added 0.13 ± 0.02 units to the composite LA stiffness index (R 2 = 0.83, p < 0.0001), identifying diffuse hypertrophy-fibrosis remodelling as a dominant substrate for atrial strain loss in this HFpEF model. Conclusion: The two-hit HFD + L-NAME regimen drives atrial enlargement, diffuse fibrotic remodeling, and impaired strain despite preserved LVEF. These changes are clinically relevant, as reduced atrial contractile function can increase stroke risk and elevated atrial fibrosis is linked to atrial fibrillation. The close coupling between collagen burden and mechanical impairment singles out atrial fibrosis as a key therapeutic target and confirms this model as a robust platform for probing upstream mechanisms and evaluating anti-fibrotic strategies in early HFpEF.