Physiological Left Atrial Staging and the Risk of New-Onset Atrial Fibrillation in Hypertrophic Cardiomyopathy

BACKGROUND: Atrial fibrillation (AF) is pervasive and an independent driver of stroke and death in hypertrophic cardiomyopathy (HCM). Despite guideline recommendations for AF surveillance, effective risk stratification remains elusive, and the hemodynamic and functional states of the left atrium (LA) preceding AF onset remain poorly characterized. OBJECTIVES: We aimed to delineate the hemodynamic and functional states of the LA in HCM, derive a novel LA staging system, and evaluate its prognostic performance for new-onset atrial fibrillation (NOAF). METHODS: This multicenter retrospective study included consecutive HCM patients with normal left ventricular systolic function from January 2007 to February 2024 at 2 academic referral centers. Patients with valvular heart disease or prior AF were excluded. Patients were categorized by combining the presence of elevated LA pressure (hemodynamic load) and LA contractile strain (intrinsic LA function): stage 1 (normal LA pressure and function), stage 2 (relative contractile augmentation for a given LA pressure), stage 3 (loss of relative contractile augmentation despite elevated LA pressure), stage 4 (elevated LA pressure with decreased LA contractile strain), and isolated LA contractile dysfunction. The primary outcome was NOAF. External validation was conducted in an independent HCM cohort. RESULTS: Of 1,856 patients screened, 705 were eligible (mean age 57.6 ± 13.0 years, 30.1% female). During a median follow-up of 7.5 years (Q1-Q3: 3.6-11.0 years), NOAF occurred in 101. The staging system was independently associated with a significant, stepwise increase in the risk of NOAF (adjusted HR: 1.83 per increment; 95% CI: 1.42-2.37; P < 0.001) and conferred incremental predictive value beyond established risk models (CHARGE-AF and HCM-AF). Consistent results were demonstrated in 1-year landmark and competing-risk analyses, as well as in an external validation cohort (n = 425; age 59.7 ± 13.5 years, 33.9% female). Importantly, serial echocardiography performed in 217 patients 4 to 6 years after baseline revealed a predominantly unidirectional evolution of the proposed LA stage, with most patients remaining stable (39.6%) or progressing to higher stages or AF (43.8%). CONCLUSIONS: The proposed LA staging framework offers mechanistic insights into how the LA adapts to progressive diastolic dysfunction in HCM. It is associated with a graded risk of NOAF and may help tailor AF surveillance strategies.