Rethink why inflammation persists before suppressing it

Inflammation is having an important moment in cardiovascular medicine. That is appropriate. Atherosclerosis is unquestionably an inflammatory disease. Chronic inflammation participates in plaque initiation and progression, plaque instability, thrombosis, and ultimately myocardial infarction and stroke.

But a recent clinical trial gives us reason to ask a question that may take us one step further: not whether inflammation matters, but why inflammation persists in the first place. Before attempting to suppress it, should we make a greater effort to identify everything that keeps provoking it?

A provocative clinical result

The recent ZEUS phase 3 trial investigated ziltivekimab, an antibody targeting interleukin-6 (IL-6), in high-risk patients with established atherosclerotic cardiovascular disease, chronic kidney disease, and systemic inflammation. The treatment produced the expected biological effect. The IL-6 pathway was inhibited, and inflammatory biomarkers, including high-sensitivity C-reactive protein (hsCRP), fell substantially.

Yet major adverse cardiovascular events were not reduced. That result should not lead us to conclude that inflammation is unimportant in atherosclerosis. An enormous body of biological and clinical evidence tells us otherwise. Other anti-inflammatory interventions have demonstrated cardiovascular benefit in selected populations.

Instead, the result should stimulate scientific curiosity. Perhaps we need to ask a question upstream from hsCRP: What keeps telling the immune system that something is wrong?

Why did evolution give us inflammation

Inflammation existed long before coronary artery disease became a major cause of human mortality. Evolution preserved inflammatory responses because organisms capable of recognizing and responding to injury and infection had an obvious survival advantage:

• A wound requires containment and repair.
• An invading microorganism requires recognition and elimination.
• Damaged cells require removal.
• Foreign material must be identified.
• Injured tissue needs increased blood flow, immune-cell recruitment, molecular communication, cleanup, and reconstruction.

Inflammation helps accomplish these tasks. The redness, warmth, swelling, pain, cytokine signaling, leukocyte recruitment, and acute-phase responses that accompany inflammation are not random biological malfunctions. They are components of an ancient defense-and-repair system.

But evolution also gave us something equally important: resolution. Once the threat has been controlled, inflammation is not supposed to continue indefinitely. Immune-cell populations change, cellular debris is removed, repair progresses, and tissues attempt to return toward homeostasis.

Therefore, chronic inflammation may represent several different biological situations:

• The original stimulus never disappeared.
• New inflammatory stimuli keep arriving.
• The mechanisms responsible for resolving inflammation have become inadequate.

Or, quite possibly, all three are occurring simultaneously.

What keeps provoking it

Consider how many different signals can potentially call inflammatory machinery into action:

• Chronic infection can do it.
• Cigarette smoke and environmental pollutants can do it.
• Visceral adiposity and metabolic dysfunction can generate persistent inflammatory signaling.
• Hyperglycemia and insulin resistance alter vascular and metabolic biology.
• Autoimmune diseases activate inflammatory pathways through entirely different mechanisms.
• Periodontal disease may provide another chronic inflammatory burden.
• Recurrent tissue injury generates local inflammatory responses.
• Sleep disruption intersects with immune, metabolic, neuroendocrine, and autonomic physiology.
• Physical inactivity contributes indirectly through multiple metabolic and vascular pathways.
• Aging itself brings cellular senescence, altered immune regulation, accumulated cellular damage, and what has appropriately been termed inflammaging.

These conditions are not biologically identical. Yet many eventually converge upon portions of the same inflammatory machinery. That raises an important possibility. Perhaps what we call chronic inflammation is sometimes less a single disease than a common biological destination reached by many different roads.

Now look inside the coronary artery

This concept becomes particularly interesting in atherosclerosis. Lipoproteins containing apolipoprotein B (ApoB) enter and become retained within susceptible regions of the arterial intima. The arterial wall responds. Endothelial activation occurs. Monocytes are recruited. They enter the arterial wall, differentiate into macrophages, and ingest modified lipoproteins.

Foam cells appear, and inflammatory signaling increases. The macrophage is not there accidentally. It has been recruited because biology has detected something requiring attention. Initially, the response can therefore be viewed partly as an attempt at containment and cleanup.

But the provoking material continues arriving. More ApoB-containing particles become retained. Macrophages accumulate lipid. Some eventually die. When cellular debris is inadequately cleared, a necrotic core develops. Smooth muscle cells migrate and proliferate, extracellular matrix is produced, and a fibrous cap develops around the lesion.

The remarkable biological paradox is that the arterial wall may now be experiencing injury, inflammation, containment, and repair simultaneously. Over time, inflammatory mechanisms can contribute to weakening of some plaques. If the fibrous cap ruptures or the endothelial surface erodes, thrombogenic material encounters circulating blood. Platelets respond, coagulation follows, and a thrombus forms. Within minutes, a biological process developing silently over decades can become an acute myocardial infarction.

Inflammation is unquestionably part of this story. But what continually summons it?

Perhaps there is more than one fire

Imagine a patient with established coronary disease. The patient has:

• Elevated ApoB.
• Visceral adiposity.
• Insulin resistance.
• Hypertension.
• Periodontal disease.
• Inadequate physical activity.
• Poor sleep.
• Continued exposure to cigarette smoke.

We measure an elevated hsCRP. We now have an important biomarker. But have we identified the disease, or have we measured the smoke rising from several biological fires?

Suppose a medication successfully suppresses one inflammatory pathway and substantially lowers C-reactive protein (CRP). Several upstream provocations may still be operating:

• The retained ApoB particles have not necessarily disappeared.
• The metabolic dysfunction has not necessarily disappeared.
• The tobacco exposure has not disappeared.
• The periodontal inflammation has not disappeared.
• The visceral adiposity has not disappeared.
• The sleep disturbance has not disappeared.

This does not make targeted anti-inflammatory treatment irrational. It tells us that suppressing one component of the inflammatory response may not be equivalent to removing the network of biological signals that generated it.

Biomarker improvement and biological improvement are not synonymous

Modern medicine understandably loves measurable endpoints:

• Blood pressure
• LDL cholesterol
• Hemoglobin A1C
• CRP
• IL-6

Numbers allow us to quantify disease, stratify risk, evaluate treatment, and conduct rigorous clinical trials. But biomarkers are maps of biology. They are not biology itself.

A treatment that changes a biomarker may be extraordinarily beneficial when that biomarker represents a causal pathway and modification of that pathway improves clinical outcomes. But changing a number cannot itself be the final objective. Patients do not seek lower laboratory values. They seek longer lives with fewer heart attacks, strokes, disabilities, hospitalizations, and adverse effects. Clinical outcomes remain the ultimate test.

We should not make the opposite mistake

The ZEUS result should not be interpreted as evidence that anti-inflammatory cardiovascular therapy has failed as a concept. That would be scientifically unjustified. Other trials targeting inflammatory pathways have produced cardiovascular benefits. Low-dose colchicine, for example, has reduced cardiovascular events in selected patients with established coronary disease. Previous targeting of the interleukin-1 beta (IL-1β) pathway also demonstrated that modifying inflammation can alter cardiovascular outcomes.

Inflammation therefore can be both a response to injury and a contributor to further injury. Once activated, inflammatory pathways can become pathogenic themselves. The therapeutic challenge is not choosing between treating inflammation and treating its causes. It is understanding where in the biological chain intervention will produce the greatest net benefit with the least harm.

The forgotten biology of resolution

There is another possibility that deserves much more attention. Perhaps some chronic inflammatory diseases are not caused only by excessive activation. They may also involve inadequate resolution. Resolution of inflammation is not simply the passive disappearance of inflammatory chemicals. It is an active biological process:

• Cells must change their behavior.
• Neutrophils must disappear from tissues.
• Macrophages must clear dead cells and debris.
• Repair mechanisms must replace destructive ones.
• Specialized pro-resolving molecular pathways participate in restoring homeostasis.

This changes the therapeutic question substantially. Instead of thinking only about how to turn inflammation off, perhaps we should also ask why the body hasn’t successfully completed the inflammatory response. Those are different questions, and they may eventually lead to different treatments.

Prevention should search upstream

None of this diminishes the importance of established cardiovascular therapy. Quite the opposite:

• Lowering LDL and ApoB reduces an important causal driver of atherosclerosis.
• Controlling hypertension reduces vascular stress.
• Treating diabetes and metabolic dysfunction matters.
• Smoking cessation removes a powerful source of vascular injury.
• Regular physical activity improves numerous interconnected physiological systems.
• Sound nutrition, healthy body composition, adequate sleep, and treatment of appropriate chronic inflammatory conditions may reduce additional contributors to the biological environment in which vascular disease develops.
• Pharmacologic anti-inflammatory therapy may also have an important role when particular inflammatory pathways themselves have become clinically consequential and randomized evidence demonstrates benefit.

These strategies should not compete with one another. They operate at different points along the biological chain.

A different question for preventive medicine

Medicine has become extraordinarily sophisticated at identifying molecules and designing drugs capable of modifying them. That achievement deserves admiration. But increasingly sophisticated therapeutics should be accompanied by equally sophisticated questions about causation.

When we encounter persistent inflammation, perhaps our first question should not always be how to suppress this inflammatory pathway. We should also ask why this patient’s biology is repeatedly activating it.

• What is entering the body?
• What is accumulating within tissues?
• What tissue is repeatedly being injured?
• What metabolic signals remain abnormal?
• Is infection present?
• Is autoimmunity involved?
• Is visceral adiposity contributing?
• Is sleep chronically disturbed?
• Is normal inflammatory resolution impaired?
• Which provocations can we safely remove?
• Which inflammatory pathways have themselves become sufficiently pathogenic that they require direct treatment?

This is not an argument against anti-inflammatory therapy. It is an argument for following biology farther upstream. Inflammation evolved as one of our most important mechanisms of survival. In chronic disease, that protective response can become persistent, dysregulated, and ultimately destructive.

Our challenge is therefore not simply to silence inflammation. It is to understand it. Before asking how aggressively we can suppress inflammation, perhaps we should first ask why the immune system keeps receiving the message that something is wrong.

That question may lead us beyond CRP and closer to the origins of chronic disease.

Narinder Singh Parhar is a physician with more than three decades of experience in internal medicine, hospital medicine, and intensive care medicine. Over the course of his career, he cared for a broad spectrum of medically complex and critically ill patients while developing a growing interest in health care systems improvement, prevention, biomechanics, and population health.

Dr. Parhar previously served as an associate clinical professor affiliated with the University of California, Davis, and on the executive board of Sutter Independent Physicians IPA in California. His professional experience spans outpatient medicine, inpatient care, intensive care medicine, and health care leadership, including past affiliations with Sutter Health and Sutter Roseville in California.

Throughout his career, he became increasingly concerned about several structural challenges within the current health care model, including affordability, accessibility, polypharmacy, health care fragmentation, microbial resistance, physician burnout, and the progressive underemphasis of prevention and functional preservation. These observations led him to develop the Health Enhancement Organization (HEO) Framework, a prevention-oriented and biomechanics-aware health care enhancement model designed to complement scientific medicine through earlier biological support, movement preservation, patient empowerment, and health care team well-being.

Dr. Parhar’s current work focuses on health care course correction, scalable prevention strategies, biomechanics education, healthier aging, and improving long-term population health resilience in practical, affordable, and biologically grounded ways. He is the founder of Jeeva Health Systems, and his research includes “Impact of a Novel Plant-Based Treatment Option in Improving Pulmonary Function Markers,” published in Alternative and Integrative Medicine.