Seasonality of Atherosclerotic Events and Personalized Inflammatory Phenotyping: Lessons From the ZEUS Trial

 

The ZEUS trial found that IL-6 inhibition with ziltivekimab lowered IL-6 and hsCRP but did not reduce cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with established ASCVD, chronic kidney disease (CKD), and elevated hsCRP. The result correctly confirms that surrogate-marker improvement cannot substitute for clinical-outcome benefit. 

However, the trial should not be interpreted as disproving the causal role of inflammation in atherosclerosis. Atherosclerosis is a dynamic metabolic–inflammatory disease in which inflammatory activity varies over time, interacts with seasonal and systemic conditions, and may have both destructive and reparative functions. The central challenge for future trials is to identify which inflammatory state is present in each patient and whether it is appropriate for cytokine-directed intervention.

A Dynamic Disease

Atherosclerosis is neither a disease of lipid accumulation alone nor a disease of inflammation alone. Disturbed lipid homeokinesis generates an atherogenic burden of apoB-containing particles. Their retention and modification within the arterial wall initiate immune recognition, inflammatory recruitment, foam-cell formation, and tissue remodeling. 

Inflammation is therefore not an irrelevant by-product. It is the process through which retained lipid becomes structurally meaningful. Yet inflammation also has a necessary protective function: it participates in the recognition, containment, clearance, and repair of arterial injury. The arterial wall attempts to isolate lipid material, remove damaged cells, maintain matrix integrity, and preserve endothelial function.

The pathological condition is not simply “inflammation.” It is persistent, excessive, poorly coordinated, or incompletely resolved inflammation. When efferocytosis fails, apoptotic cells accumulate; when matrix degradation exceeds repair, the fibrous cap weakens; when inflammatory activation outlasts resolution, the necrotic core expands and the plaque becomes vulnerable. 

The therapeutic goal should therefore be modulation, not indiscriminate suppression: reduction of destructive inflammatory amplification while preserving host defense, lesion containment, repair, and resolution.

Seasonality and Inflammatory Stage

Clinical cardiovascular events exhibit seasonal variation. Reviews have documented winter peaks in multiple cardiovascular conditions and clustering of events after cold snaps, while a meta-analysis of more than 4 million myocardial infarction cases found higher occurrence in winter than in summer or autumn. 

Seasonality should not be viewed as a simple calendar effect. Colder periods may alter infection burden, sympathetic activation, blood pressure, endothelial function, platelet reactivity, thrombogenicity, physical activity, sleep, metabolic control, and systemic inflammation. These influences do not create atherosclerosis de novo. They act on pre-existing plaques and may help determine when a vulnerable lesion crosses its threshold into rupture, erosion, thrombosis, myocardial infarction, or stroke.   

This has implications for inflammatory trials. A single hsCRP measurement at enrollment may identify a real inflammatory signal, but it cannot determine whether a patient has:

• Persistent, plaque-relevant inflammatory activation

• A short-lived inflammatory increase caused by infection or another systemic stressor

• A resolving inflammatory episode

• Advanced plaque disease dominated by structural damage and failed resolution

• Modest systemic inflammation but high local plaque inflammatory activity

Thus:

$$\text{same hsCRP value}\mathrm{\ne }\text{same inflammatory stage}\mathrm{\ne }\text{same plaque biology}\mathrm{\ne }\text{same response to IL-6 }\text{inhibition}$$

 Reinterpreting ZEUS

ZEUS was appropriately designed to assess the average effect of ziltivekimab in a randomized high-risk ASCVD–CKD population with elevated hsCRP. Its neutral primary result is valid and clinically consequential: ziltivekimab should not be assumed to prevent cardiovascular events in this population on the basis of biomarker reduction alone.  

But a population-average result does not establish biological uniformity. Randomization balances treatment allocation; it does not define each participant’s inflammatory trajectory, degree of plaque vulnerability, capacity for resolution, cumulative apoB or Lp(a) burden, or CKD-related vascular phenotype.

A neutral average hazard ratio may represent true absence of benefit in every patient. Alternatively, it may reflect divergent effects that become averaged together: benefit in a subgroup with persistent destructive IL-6-dependent inflammation, no effect in patients with advanced structurally autonomous plaque disease, and unfavorable net effects in patients vulnerable to infection or dependent on preserved inflammatory repair. This possibility is a hypothesis—not a conclusion that can be drawn from ZEUS alone.

The reported increase in serious infections is particularly important. It reminds us that systemic IL-6 inhibition may entail biological costs even when inflammatory markers improve. 

Implications for Future Trials

Future studies should not abandon randomization; they should make it more biologically informative.

First, patients should be phenotyped before randomization with repeated, rather than single, hsCRP and IL-6 assessments. This would distinguish persistent inflammatory activation from intermittent, transient, or resolving states.

Second, randomization can be stratified or covariate-adaptive according to variables likely to influence treatment response: inflammatory trajectory, CKD stage and albuminuria, diabetes, obesity, apoB, Lp(a), prior clinical presentation, geographic region, and seasonal context. Mechanistic substudi​es should add plaque burden and phenotype where feasible.

Third, protocols should prespecify interaction analyses. The question is not only whether a drug lowers hsCRP, but whether it changes outcomes differently in patients with persistent inflammatory activation, transient inflammatory elevation, advanced failed-resolution states, or distinct plaque phenotypes.

Finally, future research should measure both inflammatory activation and the biology of repair. Resolution is an active process involving macrophage reprogramming, efferocytosis, removal of cellular debris, restoration of endothelial function, and matrix stabilization. In advanced plaque, these processes may fail; restoring resolution may prove more appropriate than simply blocking initiation of inflammation. 

Conclusion

ZEUS demonstrates that lower IL-6 and hsCRP do not necessarily translate into fewer cardiovascular events. It does not demonstrate that inflammation is irrelevant to ASCVD.

Atherosclerosis is a seasonally modulated, wave-like metabolic–inflammatory process. Lipoprotein retention establishes the substrate; inflammation can promote containment and repair but, when persistent and unresolved, drives plaque destabilization; systemic and seasonal stresses influence when clinical thresholds are crossed. Future anti-inflammatory trials should therefore identify not merely patients with “high inflammation,” but patients with a defined, persistent, destructive, and potentially reversible inflammatory phenotype—while preserving the reparative functions that inflammation normally serves.

These recommendations are not limited to ZEUS or to IL-6 inhibition. They should inform the design, interpretation, and personalization of all future studies of atherosclerosis treatment that address its metabolic–inflammatory nature. The same principle may also apply across chronic inflammatory connective-tissue diseases: inflammatory biomarkers should not be treated as isolated therapeutic targets, but interpreted within the patient’s underlying disease substrate, inflammatory stage, repair capacity, comorbid metabolic context, and time-dependent biological trajectory. The central therapeutic objective is not indiscriminate suppression of inflammation, but restoration of regulated inflammation—sufficient to preserve defense, clearance, containment, and repair, while preventing chronic destructive activation and failed resolution.

You can learn more by reading our e-book 

Mykola Iabluchanskyi together with Andriy Yabluchanskiy