Understanding Atherosclerosis through the Lens of Chronic Inflammation: When Aging Becomes Disease

 

Atherosclerosis is, in a very real sense, as old as humanity itself. Archaeological studies of ancient mummies have found arterial plaques in people who lived thousands of years ago, long before fast food or sedentary lifestyles. This tells us something important: the early stages of atherosclerosis are not a disease. They are a normal part of biological aging, as universal and inevitable as greying hair or slowing reflexes.

From the first decade of life, small lipid deposits — fatty streaks — begin forming quietly beneath the inner lining of our arteries. These are not inert accumulations. When these deposits begin to damage the vascular intima, the body recognizes the injury and mounts an inflammatory response. Since it cannot eliminate the lipid deposits, it does the next best thing: it encapsulates them in connective tissue, forming plaques. This is the body's compensatory mechanism — isolating what it cannot remove, much like a bee colony encasing an intruding mouse in wax when it cannot carry the carcass out.

The boundary between normal aging and disease

In many people, this process remains quiet and contained throughout life. Autopsies of individuals who died of unrelated causes at advanced age often reveal arteries full of plaques — yet these same people lived full, healthy lives. Their plaques grew inward into the arterial wall rather than outward into the blood channel, a pattern called endophytic growth.

The critical question, then, is not why plaques form — they always do — but when and why does this process cross into disease?

The answer lies not in cholesterol itself, but in the failure of the LDL transport system. The problem begins when the receptor-mediated uptake of LDL by cells becomes impaired, and lipoproteins cannot be properly eliminated. This failure allows LDL to accumulate within the arterial wall and in the bloodstream, triggering an inflammatory cascade. Macrophages are recruited to clear the excess lipid; overwhelmed, they become foam cells, die in place, and release pro-inflammatory signals — perpetuating the very cycle they were meant to resolve.

When the system fails: genetic and phenotypic origins

This failure of lipoprotein elimination occurs most severely and most dangerously through two main mechanisms. First, through genetic defects — mutations in genes such as LDLR, APOB, or PCSK9 that directly impair LDL receptor function, as in familial hypercholesterolemia. Second, through phenotypic disruption — including viral influences on the cells responsible for lipoprotein metabolism. Viruses such as hepatitis C, hepatitis B, HIV, herpes, and cytomegalovirus can infect stem and pluripotent cells within the proliferative pool of atherosclerotic plaques, producing defective mature cell forms that compromise the body's ability to manage and resolve the inflammatory process.

This is the core of atherosclerosis: not simply elevated cholesterol as one risk factor among many, but a disorder of lipoprotein metabolism driven by genetic and phenotypic factors that prevent the organism from doing what it is designed to do — eliminate what does not belong.

Lipoprotein(a) deserves particular attention here. Its levels are determined almost entirely by genetics, making it largely immune to lifestyle intervention. When elevated, it carries both pro-inflammatory and pro-thrombotic properties, significantly increasing the risk that plaques will destabilize.

When the plaque becomes dangerous

Problems arise when plaque stability breaks down. The fibrous cap protecting the lipid core endures constant mechanical stress from pulsating blood flow. If the renewal processes maintaining this cap are compromised — through dysfunctional immune cells, viral infection, or excessive lipid burden — the cap thins, becomes vulnerable, and may rupture. Rupture exposes the lipid core to the bloodstream, triggering rapid clot formation. This is one scenario — given here as an important example — of how atherosclerosis transitions from a chronic background process to a life-threatening event: heart attack, stroke, or sudden cardiac death. Other pathways include progressive luminal narrowing, atherothrombosis, and hemodynamic consequences of plaque ensembles — each reflecting a different failure mode of the same underlying inflammatory system.

Aging is not destiny

The distinction between physiological aging and pathological progression carries real clinical meaning. Since the pathological transformation of atherosclerosis is concentrated in genetic and phenotypic factors — including viral influences that produce genetic-like disruptions in lipoprotein-handling cells — prevention and treatment strategies should be directed first and foremost along this route. Identifying hereditary lipoprotein disorders early, screening for elevated Lp(a), and addressing phenotypic risk before clinical disease emerges is where the greatest leverage lies.

Atherosclerosis cannot be entirely prevented, but its progression into disease can be delayed. The goal is not to escape it entirely. It is to grow old with it on your own terms, rather than let it determine the outcome.

You can learn more by reading our e-book or listening to our audiobook 

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  Mykola Iabluchanskyi (Yabluchansky) together with Andriy Yabluchanskiy