Pre-Implant Substrate, Peri-Implant Electrical Features, and Outcomes Across Four Echocardiographic Phenotypes After CRT-D

Background: Reverse remodeling after cardiac resynchronization therapy with defibrillator backup (CRT-D) is heterogeneous and may reflect both pre-implant substrate and post-implant electrical response, with implications for subsequent outcomes. Objectives: This study evaluated a graded echocardiographic response framework after CRT-D as an integrative phenotype linking pre-implant substrate, peri-implant electrical features, and post-landmark clinical outcomes. Methods: The analytic cohort included 334 CRT-D recipients with complete four-group classification based on relative left ventricular end-systolic volume reduction at the first eligible post-implant echocardiogram. Baseline correlates of the 4-class response phenotype were assessed using ordinal logistic regression, supported by permutation-importance analysis. A stacked peri-implant model added ΔQRS, RV1SI pattern on ECG, left ventricular lead position, and lead depth. Time-to-event analyses used a landmark design anchored at the first post-CRT echocardiogram. Results: In the pre-implantation ordinal model, female sex (p = 0.005), higher baseline left ventricular ejection fraction (p = 0.032), left bundle branch block (p = 0.038), and dilated cardiomyopathy (p = 0.048) were associated with a more favorable response class. In the stacked peri-implant model, ΔQRS was the strongest correlate of higher response class (OR: 1.41; 95% CI: 1.15–1.73; p = 0.0008). Mortality differed across response classes (log-rank p < 0.001); compared with super-responders, negative responders had higher adjusted mortality (HR: 4.41; 95% CI: 1.82–10.70). At 60 months, heart failure hospitalization ranged from 23.3% to 2.9% and first appropriate ICD shock from 29.3% to 9.0% from negative responders to super-responders. Conclusions: After CRT-D, reverse-remodeling phenotype identified clinically distinct post-landmark risk profiles. Less favorable remodeling was associated with worse mortality, heart failure hospitalization, and appropriate ICD shock.