Background: Digitalis has been widely utilized for heart failure therapy and several studies have demonstrated an association of digitalis and adverse outcome events in patients receiving implantable cardioverter defibrillators (ICDs) or cardiac resynchronization therapy defibrillators (CRT-Ds). Hence, we conducted this meta-analysis to assess the effect of digitalis on ICD or CRT-D recipients. Methods: We systematically retrieved relevant studies using the Cochrane Library, PubMed, and Embase database. A random effect model was used to pool the effect estimates (hazard ratios (HRs) and 95% confidence intervals (CIs)) when the studies were of high heterogeneity, otherwise a fixed effect model was used. Results: Twenty-one articles containing 44,761 ICD or CRT-D recipients were included. Digitalis was associated with an increased rate of appropriate shocks (HR = 1.65, 95% CI: 1.46–1.86, p < 0.001) and a shortened time to first appropriate shock (HR = 1.76, 95% CI: 1.17–2.65, p = 0.007) in ICD or CRT-D recipients. Furthermore, the all-cause mortality increased in ICD recipients with digitalis therapy (HR = 1.70, 95% CI: 1.34–2.16, p < 0.01), but the all-cause mortality was unchanged in CRT-D recipients (HR = 1.55, 95% CI: 0.92–2.60, p = 0.10) or patients who received ICD or CRT-D therapy (HR = 1.09, 95% CI: 0.80–1.48, p = 0.20). The sensitivity analyses confirmed the robustness of the results. Conclusion: ICD recipients with digitalis therapy may tend to have higher mortality rates, but digitalis may not be associated with the mortality rate of CRT-D recipients. Further studies are required to confirm the effects of digitalis on ICD or CRT-D recipients.

The PD-1/PD-L1 pathway is a pivotal regulator of peripheral immune tolerance and a key modulator of pancreatic islet immunity. Paradoxically, both inhibition and overexpression of PD-1/PD-L1 have been associated with either protection or exacerbation of type 1 diabetes (T1D), complicating the development of targeted therapies. Here, we integrate preclinical and clinical evidence to propose the “PD-1/PD-L1 U-Curve Equilibrium Hypothesis,” which posits that immune outcomes are determined by the stoichiometric balance between PD-1 and PD-L1 at the cellular interface. At the nadir of this curve, balanced PD-1/PD-L1 engagement maintains tolerance, whereas deviations toward either extreme-excessive ligand or receptor expression, or disruption by soluble isoforms and checkpoint inhibitors-lead to dysregulated and potentially stimulatory signaling. We review evidence from animal models, immune checkpoint inhibitor–induced diabetes, and emerging PD-1/PD-L1–modulating therapies that illustrate the explanatory and predictive power of this framework. Finally, we outline translational priorities, including biomarker development, spatial and single-cell profiling, precision immune endotyping, and the design of localized PD-1/PD-L1 agonists to restore islet tolerance without systemic immunosuppression. The U-curve hypothesis provides a unified model that reconciles previously conflicting findings and guides the rational design of context-specific PD-1/PD-L1–based immunotherapies aimed at preserving β -cell function in T1D.