Why Atherosclerosis Must Be Rewritten

Medicine rarely fails from ignorance. It fails when it knows something well enough to stop asking questions. Nowhere is this truer than in cardiovascular medicine's relationship with atherosclerosis, a disease measured meticulously for seventy years yet still not fully explained at the level that matters most: the individual patient.

Consider two people sitting in the same clinic. Their cholesterol panels look nearly identical. Their diets are similar, their risk scores comparable. Yet one develops rupture-prone disease and suffers a heart attack in his fifties. The other reaches old age with arteries showing little more than ordinary wear. The standard framework can calculate a probability for each of them, but it cannot explain the difference between them. That gap isn't a minor anomaly — it's the central unsolved problem in the field. A tool mistaken for a theory

The story starts with the Framingham Heart Study in 1948, a genuine methodological breakthrough. Researchers needed measurable, reproducible predictors of cardiovascular risk across large populations, and serum cholesterol fit the bill perfectly. Over subsequent decades, LDL-C, HDL-C, and triglycerides joined it. Statins arrived, were tested rigorously, and reduced cardiovascular events with a consistency few drugs achieve. 

The science was sound. But somewhere along the way, a screening instrument built for population-level risk stratification got promoted into a complete causal explanation. The question "what do these numbers actually represent biologically?" got deferred for decades — and that deferral is where resolution was lost. 

Metabolism comes before inflammation

Disturbed lipid handling comes first, causally; inflammation comes second; diet comes third — not as competing explanations but as a hierarchy. Food is not the lesion; it is raw material. When a lipid-containing meal is eaten, the intestine disassembles it into fatty acids, monoacylglycerols, cholesterol, and fat-soluble compounds, then reassembles these fragments into chylomicrons for transport. Chylomicrons themselves are too large to penetrate the arterial wall efficiently; their triglyceride cargo is rapidly hydrolyzed, and what remains becomes dangerous only depending on how the body's own machinery — enzymes, receptors, feedback loops, all governed by genetics and metabolic state — handles it. 

External input modifies risk; internal machinery produces disease. Two people can eat identically and even show similar cholesterol shifts, yet one has efficient receptor-mediated clearance and low arterial retention, while the other — carrying familial hypercholesterolemia, elevated Lp(a), or insulin resistance — turns the same raw material into a far more atherogenic particle population. The gut doesn't deliver "dietary fat" to the artery; it delivers fragments the body reconstructs into its own personalized lipoproteins. This is also why dietary modification is usually necessary but rarely sufficient in patients whose risk lies mainly in inherited receptor architecture or acquired metabolic dysregulation. 

Inflammation builds the plaque — then determines its fate

A common oversimplification treats inflammation as something that merely destabilizes a plaque already built by lipids alone. The actual sequence is more precise, and more clinically useful: 

• Disturbed lipid regulation generates atherogenic particle burden beyond the body's capacity to clear it

• Particles enter and are retained in the subendothelial space

• Retained particles are oxidatively modified and become biologically provocative

• Inflammatory activation — monocyte recruitment, foam cell formation, cytokine signaling — builds the lesion itself, not just its instability

• Clinical events occur when inflammatory and structural destabilization overwhelm plaque integrity

Inflammation is therefore indispensable but secondary: lipid retention must occur first, but everything that follows — the foam cells, the necrotic core, the thin fibrous cap — is inflammatory construction, not a separate later stage. The same unresolved inflammatory cycles that build the plaque over years are what eventually determine whether it stays quietly compensated or ruptures. Instability isn't bolted onto a finished structure; it's the residue of inflammation that never fully resolved. 

Why identical panels produce opposite fates

A fifty-one-year-old man with "borderline," unremarkable lipid numbers has a major heart attack the following year; a fifty-three-year-old woman with nearly identical numbers develops diffuse coronary plaque over two decades without ever having an event. The panel measures concentration, not configuration — it cannot see particle size, oxidation state, inflammatory tone, cap thickness, or genetic substrate, all of which govern actual arterial fate. Lp(a) makes this especially vivid: it's one of the most heritable traits in human biology, largely fixed by the LPA gene and historically treated as untouchable, yet its clinical expression varies with menopausal status, inflammatory burden, and renal function, and new RNA-based therapies can now directly silence its hepatic production. 

The gene sets a tendency; physiology and modern pharmacology determine what that tendency becomes. Rewriting atherosclerosis doesn't mean discarding LDL-C or abandoning statins — both remain well-established. It means recognizing that the lipid panel captures only one layer of a system whose decisive behavior — construction, retention, and resolution of inflammation — happens deeper in the architecture than a blood draw can reach. 

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This article was written on the base of the first chapter of the book, "Why Atherosclerosis Must Be Rewritten."

Mykola Iabluchanskyi together with Andriy Yabluchanskiy