Left Atrial Stiffness Trajectories Identify Distinct Prognostic Phenotypes in Heart Failure with Reduced Ejection Fraction

ABSTRACT Background Treatment response in heart failure with reduced ejection fraction (HFrEF) is assessed predominantly through left ventricular (LV) functional recovery, while longitudinal changes in left atrial (LA) hemodynamic burden remain underexplored. The LA stiffness index (LASI), derived from E/e′ and LA reservoir strain, integrates LV filling pressure and LA compliance. Objectives We investigated longitudinal trajectories of LASI and their prognostic implications in HFrEF treated with angiotensin receptor–neprilysin inhibitor (ARNI)-based therapy. Methods From the multicenter STRATS-HF-ARNI registry, 1,039 patients with HFrEF who underwent serial echocardiography at baseline and one-year follow-up were classified into four LASI trajectory patterns dichotomized at the cohort median (1.22): persistently compliant (Group A, 46.8%), reverse remodeling (B, 28.5%), progressive stiffening (C, 3.2%), and persistently stiff (D, 21.6%). Results On multivariable Cox regression, Group D was independently associated with elevated risks of all-cause mortality (adjusted hazard ratio [aHR] 2.68, 95% CI 1.57–4.59), cardiovascular mortality (aHR 4.36, 1.97–9.64), and HF hospitalization (aHR 3.83, 2.22–6.60), whereas Group B showed outcomes comparable to Group A. One-year LASI progression independently predicted all three outcomes. LASI elevation at one year predicted adverse outcomes even among patients with recovered LV function, and LASI trajectory classification provided incremental prognostic discrimination beyond conventional diastolic and strain parameters. Among sinus-rhythm patients (n=786), Group C exhibited the highest risk of new-onset atrial fibrillation. Conclusions In HFrEF treated with ARNI-based therapy, LASI trajectories identify distinct prognostic phenotypes. Persistent LA stiffness confers adverse outcomes independent of LV recovery, and serial LASI assessment may enhance risk stratification beyond LV-centric metrics. CONDENSED ABSTRACT In 1,039 patients with HFrEF treated with ARNI-based therapy, four longitudinal left atrial stiffness index (LASI) trajectories were identified using serial echocardiography. Persistent LA stiffness was independently associated with elevated all-cause mortality, cardiovascular mortality, and HF hospitalization. The prognostic value of one-year LASI persisted even among patients with recovered LV function, and LASI trajectory provided incremental prognostic discrimination beyond conventional diastolic and strain parameters. Progressive stiffening of an initially compliant left atrium identified the highest risk of new-onset atrial fibrillation. Serial assessment of LA stiffness may enhance risk stratification beyond LV-centric metrics in HFrEF.