Functional Mitral Regurgitation Trajectories in CRT-Treated HFrEF During Medical Therapy Optimization: Association with Reverse Remodeling

Background: Functional mitral regurgitation (MR) is common in patients with heart failure with reduced ejection fraction (HFrEF) and may persist despite cardiac resynchronization therapy (CRT). Sacubitril/valsartan is associated with reverse remodeling in HFrEF, but MR dynamics in CRT-treated patients receiving sacubitril/valsartan remain insufficiently characterized. We aimed to characterize longitudinal changes in MR severity and assess their association with ventricular reverse remodeling in CRT-treated patients with HFrEF receiving sacubitril/valsartan. Methods: This retrospective cohort study included 188 patients with HFrEF previously treated with CRT who subsequently initiated sacubitril/valsartan. Clinical and echocardiographic assessments were performed at baseline and 10–14 months. The primary endpoint was MR improvement, defined a priori as a reduction of at least one MR grade. Changes in paired MR grade distribution were assessed using Bowker’s test of symmetry. Associations between MR improvement and changes in left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), and left atrial volume (LAV) were evaluated. Multivariable logistic regression was used to identify factors independently associated with MR improvement. Results: MR improvement occurred in 116 patients (62%), while 72 (38%) had unchanged grades; no worsening was documented in the paired assessments. A significant shift toward lower MR grades was observed between baseline and follow-up (χ2 = 116.0, df = 5, p < 0.001). The proportion meeting the endpoint increased from 0% in baseline grade I to 51.2%, 80.0%, and 100% in grades II, III, and IV, respectively. Patients with MR improvement had greater increases in LVEF (9.0 vs. 7.0 percentage points, p = 0.006) and larger reductions in LVEDV (−45.7 vs. −28.6 mL, p = 0.004) and LAV (−20.4 vs. −4.2 mL, p < 0.001). The correlation between changes in LVEDV and MR grade was statistically significant but modest (r = 0.22, p = 0.002). Non-ischemic etiology and greater baseline LVEDV were independently associated with MR improvement, whereas baseline LVEF was not. The strong association with baseline MR grade partly reflects the endpoint’s inherent dependence on initial severity. Conclusions: In patients with HFrEF treated with CRT who also received sacubitril/valsartan, lower MR grades were observed at follow-up and were associated with greater longitudinal changes in LVEF, LVEDV, and LAV. These findings describe parallel longitudinal changes in MR severity and cardiac structure within a combined device- and pharmacological-treatment setting. The observed changes cannot be disentangled from ongoing CRT-mediated remodeling, concomitant GDMT, changes in loading conditions, or other time-dependent factors and cannot be attributed specifically to sacubitril/valsartan.