A Biological Alignment Framework for Interpreting Anti-Inflammatory Cardiovascular Trials in Atherosclerosis

The inflammatory hypothesis of atherosclerosis has generated large-scale clinical trials with heterogeneous outcomes-from landmark success (CANTOS) to informative neutral results (CIRT). Understanding why anti-inflammatory therapies produce inconsistent outcomes requires a structured translational framework. We conducted a narrative review of randomized controlled trials, Mendelian randomization studies, and mechanistic investigations in anti-inflammatory cardiovascular therapy, searching PubMed, EMBASE, and the Cochrane database through December 2024. Trial outcomes were analyzed through four alignment domains: pathway specificity, target engagement, patient selection, and endpoint matching. Clinical trial outcomes can be systematically characterized by the degree of coherence-or biological alignment-across these four domains. High alignment (CANTOS, Total Alignment Score [TAS] 8/8) is associated with robust clinical benefit; partial alignment (COLCOT, LoDoCo2, TAS 6/8) yields consistent but modest effects; and low alignment (CIRT, TAS 4/8) is associated with neutral results. TAS is calculated as the additive sum of four domain scores (0-8); the "multiplicative" characterization in prior descriptions refers to a conceptual metaphor for rate-limiting failure, not a formal mathematical model. Aging-related processes (inflammaging, immunosenescence, clonal hematopoiesis of indeterminate potential [CHIP]) modify each alignment domain and require explicit incorporation into trial design. The Biological Alignment Model provides a mechanistically grounded, extensible framework for interpreting divergent anti-inflammatory cardiovascular trial outcomes. It enables iterative trial refinement and supports the design of precision immunotherapy strategies in atherosclerosis.