The impact of late-onset reverse remodeling in heart failure with reduced ejection fraction

Background Left ventricular reverse remodeling (LVRR) is a surrogate marker of treatment response in heart failure with reduced ejection fraction (HFrEF), usually observed within 24 months. Some patients experience LVRR beyond this period, but its prognostic significance remains unclear. Methods We retrospectively analyzed symptomatic HFrEF patients with left ventricular ejection fraction (LVEF) ≤40%. All patients underwent echocardiography at baseline and at two follow-up points: 6–24 months (Follow-up 1) and 24–78 months (Follow-up 2). LVRR was defined as an LVEF increase ≥10% to >40% and classified as Early (at Follow-up 1) or Late (at Follow-up 2). The Simple-GDMT Score was used to assess guideline-directed medical therapy (GDMT). The primary outcome was a composite of all-cause death or HF hospitalization, evaluated from Follow-up 2 onward. Results Of 213 patients, 84 (39.4%) achieved Early LVRR, 25 (11.7%) Late LVRR, and 104 (48.8%) showed no LVRR. The primary endpoint was lower in both Early and Late LVRR groups compared with the No-LVRR group (vs Early; p < 0.001, vs Late; p = 0.015). The Simple-GDMT Score increased over time in all groups, but trajectories differed, with a gradual up-titration only in the Late LVRR group. In Cox models, Late LVRR was independently associated with a lower risk of the composite outcome compared with the No-LVRR group. Conclusions Both early- and late-onset LVRR were associated with improved prognosis compared with no LVRR. Even delayed remodeling carried prognostic value, underscoring the importance of long-term follow-up in HFrEF management. (245/250 words) Clinical Perspective What is New? This study demonstrates that late-onset LVRR, occurring beyond 24 months, is associated with favorable prognosis in HFrEF, extending its prognostic relevance across a broader timeframe and multiple etiologies. In patients with late LVRR, reverse remodeling was seen alongside gradual GDMT intensification, suggesting that delayed titration may have contributed. What are the Clinical Implications? Early initiation and optimization of GDMT is ideal, yet even patients with initially inadequate or delayed therapy should still undergo intensification, as this can promote reverse remodeling and improve outcomes. Such patients should not be excluded from aggressive management; timely escalation of therapy remains essential to achieving survival benefit.