Timing Matters: Why Anti-Inflammatory Therapy Must Match the Phase of Atherosclerosis

The ZEUS trial delivered an uncomfortable message: ziltivekimab, a monoclonal antibody against interleukin-6 (IL-6), substantially lowered high-sensitivity C-reactive protein (hs-CRP) but did not reduce major cardiovascular events in high-risk patients with atherosclerotic cardiovascular disease and chronic kidney disease. To many, this looked like a blow to the inflammatory hypothesis of atherosclerosis. To others, it was a refinement. The real lesson is not that inflammation is irrelevant—it is that anti-inflammatory interventions must be matched to the phase state of atherosclerotic progression.

Inflammation is not the enemy—it is the response

Atherosclerosis begins with disturbed lipid homeokinesis: atherogenic lipoproteins enter the arterial wall, become retained, and undergo modification. Inflammation does not start this process. It arises in response to it. The immune system is attempting to contain, clear, and wall off lipid deposits that the artery cannot safely eliminate. In this sense, inflammation is initially compensatory and protective—a physiological effort to isolate and manage a persistent metabolic burden.

Only when this response becomes excessive, prolonged, or poorly resolved does it shift from protective to destructive. Repeated cycles of activation and incomplete resolution leave structural residue: a larger necrotic core, a thinner fibrous cap, more matrix damage. Over time, these changes lower the threshold for plaque failure. Clinical events occur when a vulnerable plaque crosses a structural threshold, often during a short-lived surge in inflammatory or hemodynamic stress.

The wave-like nature of plaque inflammation—and why individual plaques cannot be timed

Inflammation in atherosclerosis is not a steady-state process. It is cyclic and wave-like, shaped by seasonal, circadian, infectious, and metabolic influences. Each inflammatory wave can either resolve cleanly—leaving plaques stable—or resolve incompletely, adding to cumulative structural damage. This ratchet effect explains why vulnerability is not proportional to lipid burden alone and cannot be inferred from a single cross-sectional measurement.

But here is a critical point: you cannot recognize when inflammation activates in any single plaque. Plaques are small—often only 5–10 mm or less along the vessel—embedded in the arterial wall, and clinically silent until they fail. By the time symptoms or biomarkers change, the decisive inflammatory event has already occurred. Talking about the wave-like nature of inflammation, therefore, is not about timing individual lesions. It is about recognizing that entire fields of plaques across the arterial tree are exposed to the same systemic inflammatory surges.

When systemic inflammation rises—during infection, seasonal peaks, metabolic stress—multiple plaques simultaneously experience heightened inflammatory tone. Some may resolve; others may not. The risk is not that one plaque suddenly becomes dangerous, but that a real field of plaques is pushed closer to its failure threshold at the same time. This field effect is what drives the observed clustering of events during high-inflammatory periods.

This temporal architecture implies two distinct considerations for anti-inflammatory therapy:

• Recognize the compensatory role: Inflammation is the organism's way of isolating lipid deposits in the arterial wall. At moderate levels, it serves a protective function. Blanket suppression risks impairing containment and clearance mechanisms.
• Target the destabilizing phase at the field level: The danger arises when systemic inflammatory waves push multiple plaques toward destructive escalation. Therapy should aim to blunt these systemic surges and support resolution across the plaque field, not suppress inflammation indiscriminately in individual lesions.

Why "cold case" expectations fail

Expecting large event reductions from chronic anti-inflammatory monotherapy in stable, "cold" atherosclerosis is mismatched to the disease's layered dynamics for several reasons:

• Inflammation is wave-like, not constant. Seasonal and circadian patterns, infections, and metabolic stressors create peaks and troughs in inflammatory tone. A therapy that lowers average hs-CRP may not prevent the short, intense surges that tip a vulnerable plaque into rupture.
• Events are threshold phenomena. A plaque can remain clinically silent for years, then fail during a brief inflammatory or hemodynamic surge. The trigger sets the timing; the vulnerability was built long before.
• hs-CRP must be interpreted in context. At the population level, hs-CRP is a risk marker—it enriches cohorts for event rates but does not identify which plaque will fail. But in an individual patient, changes in hs-CRP from that person's baseline (cold period) to an acute-phase surge reflect the magnitude of systemic inflammatory activation. A rise from a personal baseline of 0.8 mg/L to 6 mg/L signals a high-inflammatory state that may reflect destabilization across a real field of plaques involved in the process. This elevation can arise from amplifying processes—metabolic stress, endothelial activation, thrombogenic shifts, concomitant infection, and others—that together push vulnerable plaques toward failure, even if the absolute value remains "moderate" by population standards. Thus, hs-CRP is most informative when tracked longitudinally within a person, not as a one-time cross-sectional number. Here, inflammation expresses the dual nature of atherosclerosis: lipid burden, inflammatory tone, hemodynamic stress, and thrombogenic tendency amplify one another, and a given hs-CRP rise may be the visible marker of this broader, multi-factorial destabilization process.
• You cannot time individual plaques. The wave-like nature of inflammation operates at the level of plaque fields, not single lesions. Systemic surges affect many plaques simultaneously, and the clinical event is the first visible sign that one of them has failed.

Thus, a neutral trial in a stable, metabolically complex cohort does not refute inflammation's causal role; it highlights the importance of phase-specific targeting at the field level. And this critique applies not only to ZEUS but to any anti-inflammatory study that ignores the wave-like, phase-dependent nature of atherosclerotic inflammation.

A phase-matched strategy for anti-inflammatory therapy

A more coherent approach aligns intervention with the phase state of atherosclerotic progression:

1. Substrate control first

Disturbed lipid homeokinesis is the causal substrate. Without retained and modified lipoproteins in the wall, there is no inflammatory amplifier to drive ordinary atherosclerosis. Aggressive lowering of apoB-containing lipoproteins (statins, ezetimibe, PCSK9 inhibitors, Lp(a)-targeted RNA therapies) remains the foundation. Anti-inflammatory therapy is an adjunct, not a substitute.

2. Preserve compensatory inflammation, prevent destructive escalation

The goal is not to abolish inflammation but to prevent its shift from compensatory to destructive. This means supporting resolution pathways—efficient efferocytosis, pro-resolving mediators, macrophage phenotype shifts—rather than broadly silencing cytokine signaling. Therapies should aim to reduce the frequency of poorly resolved cycles, not eliminate the immune response that contains lipid burden.

3. Acute-phase coverage during vulnerable windows—at the field level

The highest yield for event reduction may come from covering high-risk windows when systemic inflammatory surges push entire plaque fields toward failure. In these windows, short-term or intensified anti-inflammatory coverage could blunt the systemic surge that increases the probability that one or more plaques in the field will fail.

4. Better biomarkers and enrichment

hs-CRP is useful for risk enrichment but insufficient when used as a one-time population-level marker. Future trials should:

• Track individual baselines (cold-period hs-CRP) and measure deviations during acute-phase surges to capture personal inflammatory load.
• Pair hs-CRP with proteomic signatures, immune cell phenotyping, and plaque imaging (e.g., PET-CT for vascular inflammation, OCT for cap thickness) to better reflect acute-phase modulation and resolution capacity across the arterial tree.

Implications for trial design and clinical practice

The ZEUS experience—and the broader lesson for the field—suggests several design principles for future anti-inflammatory trials:

• Enrich for acute-phase risk: Prioritize high innate immune tone or evidence of recent inflammatory surges over stable cohorts where nonvascular CRP drivers and pathway redundancies dominate.
• Combine layers: Pair potent apoB/Lp(a) lowering (substrate removal) with therapies that support resolution and prevent destructive escalation, and consider time-limited intensification during vulnerable windows.
• Measure the right things: Move beyond single cross-sectional hs-CRP values to longitudinal, person-specific tracking that captures the shift from baseline to acute-phase surge, combined with multimodal biomarkers and imaging that reflect destabilization risk and resolution capacity.
• Think in terms of plaque fields, not single lesions: Trials should be designed to detect reductions in the probability that any plaque in the field fails during high-inflammatory periods, not to time individual plaque events.

For clinicians, the message is pragmatic: do not abandon anti-inflammatory thinking, but do not expect chronic monotherapy to deliver large event reductions in stable patients without addressing the metabolic substrate and the acute-phase triggers. As new agents emerge, their use should be guided by phase-matched logic: substrate control, preservation of compensatory inflammation, prevention of destructive escalation, and acute-phase coverage when systemic surges increase the risk that multiple plaques will approach failure thresholds.

Conclusion

Atherosclerosis is not a static inflammatory state; it is a dynamic, wave-like process in which chronic burden and acute surges interact to produce events. Inflammation begins as a compensatory response to retained lipid—protective, necessary, and often beneficial. It becomes dangerous only when cycles become excessive or fail to resolve, pushing plaques from stable containment toward rupture. The ZEUS trial does not end the inflammatory hypothesis; it refines it. Anti-inflammatory interventions will likely succeed when they are tied to the phase state of atherosclerotic progression—preserving compensatory function, preventing destructive escalation, and covering acute-phase windows when systemic inflammatory waves increase the probability that one or more plaques in the arterial field will fail. In this view, inflammation remains central, but timing, breadth, and context determine whether modulation translates into fewer heart attacks and strokes. And this principle applies to all anti-inflammatory studies in atherosclerosis, not ZEUS alone: ignore the wave nature of the disease and the field-level behavior of plaques at your peril.

More about this topic can be found in our book "The Uncharted Architecture of Atherosclerosis: Beyond Lipid Panels — Functional Subspecies, Risk Stratification, and Targeted Therapy" on Our Books on Google Play.

Mykola Iabluchanskyi together with Andriy Yabluchanskiy