Replacement fibrosis, left ventricular ejection fraction and sudden cardiac death in patients after myocardial infarction: a mediation analysis

Objective To evaluate the potential mediating role of left ventricular ejection fraction (LVEF) in the relationship between replacement fibrosis (assessed by late gadolinium enhancement (LGE)) and sudden cardiac death (SCD) post-myocardial infarction (MI) and also to assess this mediation effect in subgroups based on LVEF ≤ 35% and > 35% according to implantable cardioverter-defibrillator (ICD) selection criterion. Methods A retrospective analysis was conducted on 917 post-MI patients (mean age: 56.3±11.0 years, 88.8% male) who underwent cardiac MR from January 2017 to August 2021. The endpoint for SCDs included SCD, aborted SCD and appropriate ICD discharges. The association of LGE with LVEF was quantified using linear regression models. The associations of LGE and LVEF with SCDs were evaluated using competing risk models. Mediation analysis was then used to decompose the total effect of LGE on SCDs into direct and indirect (mediated through LVEF) effects using accelerated failure time models. Results Over a median follow-up of 63.3 (IQR, 43.6 to 76.6) months, 65 patients (7.1%) experienced SCDs. In all patients, LGE was significantly associated with lower LVEF (β=-0.35, p <0.001). Both LGE and LVEF independently predicted SCDs (subdistribution hazard ratio (sHR)=1.06, p <0.001; sHR=0.95, p =0.03, respectively). Mediation analysis showed that LVEF accounted for 19.7% of the total effect of LGE on SCDs ( p <0.001). This mediation effect was 40.4% in patients with LVEF > 35% ( p = 0.02), while no mediation was observed in patients with LVEF ≤ 35% ( p = 0.08). Conclusion LVEF partially mediated the effect of LGE on the SCD, accounting for less than one-fifth of the total effect. LVEF alone inadequately captured the whole SCD risk, irrespective of whether LVEF is greater than 35% or 35% or less.