Cardiac resynchronization in heart failure with mildly reduced ejection fraction and electrical dyssynchrony without primary indication for pacing: A systematic review and meta-analysis

Background Patients with heart failure with mildly reduced ejection fraction (HFmrEF) and electrical dyssynchrony often experience progressive adverse remodeling, yet current guidelines restrict cardiac resynchronization therapy (CRT) to left ventricular ejection fraction (LVEF) ≤ 35% or pacing indications. The benefits of CRT or conduction system pacing (CSP) in HFmrEF remain uncertain. Methods We performed a systematic review and meta-analysis of comparative and single-arm studies involving adults with HFmrEF (LVEF 36%–50%) and no conventional primary pacing indication who underwent de novo CRT or conduction system pacing (CSP). MEDLINE and Embase were searched from inception. For continuous variables, mean differences (MD) with corresponding 95% confidence intervals (CI) were calculated. Comparative analyses were performed between CRT/CSP and control groups. For single-arm cohorts, within-patient change from baseline and its standard error were calculated and synthesized as effect estimates relative to zero using generic inverse-variance methods. Random-effects models were used for the primary analyses because of substantial heterogeneity among studies. Results Seven studies (one randomized trial, one prospective comparative cohort, and five single-arm cohorts) comprising 311 patients were included. In comparative analyses, no significant difference in LVEF was observed between CRT/CSP and usual care using a random-effects model. Compared with baseline, CRT/CSP was associated with increased LVEF (MD 7.88% points; 95% CI 2.80–12.95; p < 0.01), reduced LV end-diastolic volume (MD 28.97 mL; 95% CI 11.88–46.07; p < 0.01) and LV end-systolic volume (MD 24.19 mL; 95% CI 5.56–42.83; p = 0.01), and decreased LV end-diastolic and end-systolic diameters. Early resynchronization was also associated with improved 6-minute walk distance (MD 68.30 m; 95% CI 43.08–93.53; p < 0.01), lower New York Heart Association class (MD 0.96; 95% CI 0.78–1.13; p < 0.01), narrower QRS duration (MD 40.93 ms; 95% CI 34.65–47.20 p < 0.01), and lower NT-proBNP levels (MD 430.58 pg/mL; 95% CI 298.06–563.11; p < 0.01) at follow-up. Conclusions In patients with HFmrEF and electrical dyssynchrony, CRT/CSP was associated with favorable remodeling, functional, electrical, and biomarker changes relative to baseline. However, the available evidence remains limited and largely non-randomized. These findings are hypothesis-generating and should be confirmed in adequately powered randomized trials.