Why Do Humans Have Lipoprotein(a)? A Patch for the Vessel Wall

Most mammals make their own vitamin C. Humans can't. Most mammals also have no lipoprotein(a) in their blood. Humans do, and for about one in five of us, the level is high enough to raise the risk of heart attack and stroke.

Linus Pauling thought those two facts were connected, and that a particle we now treat as a cholesterol problem began as an answer to a much older one: how the body holds itself together.

Lipoprotein(a), usually shortened to Lp(a), is a particle that carries cholesterol, similar to LDL, with an additional protein attached called apolipoprotein(a). How much of it you have is largely inherited. Elevated levels are associated with cardiovascular disease, and genetic research supports a causal contribution. It is more than a number that happens to appear alongside illness. Clarke and colleagues, 2009

I think Pauling was onto something bigger than Lp(a). Heart disease is, upstream, a problem with the vessel wall: its collagen, its lining, and how well it holds up under pressure over a lifetime. Lp(a) is a patch for that wall, useful when walls failed young and harmful when it stays in place for decades.

What scurvy tells us

Because we cannot make it ourselves, vitamin C has to come from food. It is necessary for normal collagen production, and collagen provides structural support throughout the body, including in blood vessels.

Scurvy is what happens when that requirement goes unmet for long enough. Gums swell and bleed. Bruises appear. Wounds heal poorly. Small blood vessels become fragile. The connection between nutrition and the physical integrity of tissue becomes difficult to miss. NIH vitamin C fact sheet

Scurvy is not heart disease in fast forward. It makes vessels leak, not clog. What it proves is that the wall is not a finished structure. It is rebuilt continuously, and when a key ingredient runs out, it comes apart.

We spend a great deal of time measuring what circulates through our blood vessels and far less measuring the vessels themselves. The tissue carrying that blood has to be maintained, day after day, for an entire lifetime. That is where I think the story starts.

The wall comes first

The standard story of heart disease starts with cholesterol in the blood. I think it should start with the wall. High blood pressure, smoking, and diabetes all damage the arterial wall. Cholesterol-containing particles accumulate there, and inflammation follows. NHLBI on coronary disease

Take blood pressure. We usually think of stiff arteries as a consequence of high blood pressure. In the Framingham Heart Study, the stiffness came first: people with stiffer aortas were more likely to go on to develop high blood pressure. Kaess and colleagues, 2012

What makes an artery stiff is largely what happens to its collagen and elastin, and sugar is a big part of it. Glucose reacts with long-lived proteins like collagen to form cross-linking compounds called advanced glycation end products, which make tissue rigid. This happens slowly with age and much faster with high blood sugar, which is why people with diabetes develop stiff arteries young. In diabetic rats, a drug that breaks these cross-links restored the flexibility of the arteries within weeks. Wolffenbuttel and colleagues, 1998 The same sugar products also bind receptors on the vessel lining and help drive atherosclerosis there. Serum AGEs and coronary disease in diabetes

Cholesterol matters, but it does its damage by getting stuck in the wall, and the wall's own molecules decide how much sticks. Experimental work points to the retention of lipoproteins beneath the artery's inner lining as an early step in atherosclerosis. Skålén and colleagues, 2002

The wall also decides how it ends. Most fatal heart attacks begin when the fibrous cap over a plaque cracks, and that cap gets its strength from collagen, just as skin and tendons do. Libby, 2013

So the chain I see runs like this. Sugar, age, and pressure stiffen and injure the wall. Cholesterol-carrying particles get trapped in it. Years later, a weakened collagen cap tears. The particles in the blood are part of the story, but the wall is where it starts and where it ends.

The skin as a window

If the wall is upstream, the skin should tell us something. Skin and arteries rely on the same kind of structural collagen, and sugar damage builds up in both to comparable levels. Skin glycation and cardiac surgery outcomes

It does. Glycation in the skin can be measured by shining light on it, and the reading predicts heart disease. A 2025 meta-analysis found it to be a strong predictor of cardiovascular disease and death in general, and especially in people with diabetes or kidney disease. Skin autofluorescence meta-analysis In a Dutch cohort of people with type 2 diabetes, the skin reading predicted future cardiovascular disease more strongly than cholesterol or blood pressure did. Lifelines type 2 diabetes study

Stretch marks are the question I most want answered. In inherited connective tissue disorders like Marfan syndrome, stretch marks and aortic tears go together. Genetics of thoracic aortic aneurysm The link shows up outside those syndromes too. Among adults with thoracic aortic aneurysms, those with stretch marks had dissections or needed preventive surgery at younger ages, and earlier work in children with aneurysms found that stretch marks tracked faster growth of the aorta. Striae and thoracic aortic dissection As far as I can tell, no one has tested whether ordinary stretch marks predict ordinary heart attacks. Someone should.

Pauling's idea

In 1990, Matthias Rath and Linus Pauling proposed that Lp(a) helped compensate for the loss of vitamin C synthesis in our evolutionary history. During periods of scarcity, a mechanism that reinforced damaged tissue would have helped an animal survive, even if it carried a cost later in life. Rath and Pauling, 1990

The way I picture it is duct tape. When the material underneath weakens, a patch holds it together long enough to get through a hard stretch. Lp(a) is that patch.

I admire Pauling's willingness to approach a medical question through chemistry. His broader concept of orthomolecular medicine concerned changing the concentrations of substances normally present in the body. The term appears in his 1968 paper on orthomolecular psychiatry. Pauling, 1968

The chemistry behind the duct tape

The protein attached to Lp(a) resembles plasminogen, a component of the system that breaks down blood clots. In laboratory experiments, Lp(a) interferes with plasminogen binding and activation on fibrin, the protein mesh of a clot, which slows clot breakdown. It grips fibrin through lysine-binding sites, the same sites Rath and Pauling proposed blocking with lysine. Experiments on fibrin and plasminogen activation

Holding a clot in place is exactly what you want when a vessel is leaking and the tissue underneath needs time to rebuild. It is exactly what you do not want inside a narrowed coronary artery. Same mechanism, different setting. That, in short, is the story of Lp(a).

What other animals tell us

If Lp(a) stood in for vitamin C, the animals that lost the ability to make vitamin C should be the ones that carry it. That was the core of Rath and Pauling's case. They noted that Lp(a) appears in higher primates and guinea pigs, both unable to make their own vitamin C, and only rarely in other animals. Rath and Pauling, 1990

Genetic work since then has made that pattern harder to see. Apolipoprotein(a) turns out to be limited to a subset of primates and, unexpectedly, the hedgehog. Many bats cannot make vitamin C either, yet bats are not among the animals known to carry Lp(a). Genomic comparison of apo(a) across species Vitamin C synthesis in bats

The guinea pig, the main example outside the primates, is also in doubt. Rath and Pauling reported detecting apolipoprotein(a) in guinea pig blood using antibodies, but a later review of Lp(a) biology lists the guinea pig among research animals that do not express it. Rath and Pauling's guinea pig study Review of Lp(a) biology

The hedgehog is the strangest part of the story. Its Lp(a)-like particle was not inherited from an ancestor we share. It came from a separate copy of the plasminogen gene, roughly 80 million years ago, built from repeats of a different section of that gene. Like ours, it binds fibrin. Lawn and colleagues, 1997

The animals do not support the narrow version of Pauling's idea, in which Lp(a) exists specifically because we lost vitamin C. They do support the broader one. Evolution built a fibrin-binding particle twice, by separate routes, which tells me it was doing something useful. Vitamin C was one pressure on the wall. It was not the only one.

The test I would want run next is whether hedgehogs make their own vitamin C. If they do, the hedgehog evolved its patch without any vitamin C problem to solve, which is exactly what the broader version predicts.

Why the patch survived

Here is what I think happened. For most of human history, vessel walls failed for many reasons: scurvy in lean seasons, injuries, and inherited connective tissue weaknesses like Marfan syndrome, in which the aorta can tear in early adulthood. A particle that held clots in place and patched leaks would have kept some of those people alive long enough to have children. Its cost, plaque in the arteries decades later, arrived mostly after the reproductive years, where natural selection barely sees it.

That is why a harmful particle is so common. It is also why people with little or no Lp(a) show no disease from lacking it. Lp(a) in vascular disease, cancer and longevity With enough vitamin C and modern medicine, most of us no longer need the patch, and we still pay for it.

Lowering a number

The pelacarsen result is where this stops being theoretical, so it is worth being clear about what the drug does.

Your liver builds apolipoprotein(a), the protein that turns an ordinary cholesterol particle into Lp(a). To make it, liver cells first copy the gene's instructions into a messenger molecule, a working copy the cell reads from. Pelacarsen is a short, synthetic strand of genetic material designed to stick to that working copy. Once it sticks, the cell destroys the copy, so less of the protein gets made and less Lp(a) reaches the blood. In kitchen terms, the gene is the cookbook, the messenger molecule is a photocopied recipe on the counter, and pelacarsen shreds the photocopy before anyone cooks. It is given as a shot under the skin, and in earlier trials it cut Lp(a) by up to 80%. HCPLive on pelacarsen

HORIZON was the test that matters: does lowering Lp(a) actually prevent heart attacks and strokes? It enrolled 8,323 people who already had cardiovascular disease, meaning a past heart attack, stroke, or blocked arteries in the legs, and Lp(a) of at least 70 mg/dL. Half got a monthly pelacarsen shot and half got a placebo shot, on top of their usual treatment, and neither they nor their doctors knew which. Then the researchers waited years and counted cardiovascular deaths, heart attacks, strokes, and urgent procedures to reopen coronary arteries. Design of the Lp(a)HORIZON trial

On September 4, 2026, Novartis reported the answer. Pelacarsen lowered Lp(a) substantially, but the people taking it did not have significantly fewer of those events than the people on placebo. Novartis trial announcement

You can argue that the drug came too late or did not lower Lp(a) enough. I think the problem is more basic. If Lp(a) is a patch, lowering it treats the patch and leaves the wall alone. The people in HORIZON already had diseased arteries. Whatever made their walls fail, whether glycation, pressure, inherited connective tissue weakness, or all three, was still there after the drug did its job.

The strongest objection is genetic. People who inherit high Lp(a) have more heart disease, and because genes are dealt at conception, independent of diet and lifestyle, that is good evidence that Lp(a) itself does harm. Clarke and colleagues, 2009 I agree that it does. A particle that holds clots in place will make a failing artery more dangerous. But making a failing artery more dangerous is different from being the reason it fails. Read together, the genetics and HORIZON tell me that Lp(a) raises the stakes of wall damage, and that removing it late does not undo the damage.

The National Lipid Association still recommends measuring Lp(a) after HORIZON, and so do I. A high level tells you something real about your risk. National Lipid Association statement What HORIZON shows is that lowering the number is not the same as fixing what it warns you about. I cover the trial, the market reaction, and the other Lp(a) drugs in development in a separate essay.

Following the question upstream

I am skeptical of the financial incentives in medicine. A business can earn recurring revenue by managing a condition indefinitely. Preventing that condition may have enormous human value without offering the same return to the business. There are perverse and conflicting incentives here, and they shape which questions receive attention and funding. A drug that lowers a number in the blood is a product. A healthy vessel wall is not.

The same standard applies to vitamins, and the vitamin side of this story had money in it too. Rath and Pauling patented vitamin C combined with lysine and similar compounds as a treatment for cardiovascular disease. Rath later promoted his own vitamin formulas as a cure for AIDS in South Africa while calling antiretroviral drugs toxic, until a court effectively ordered him to halt his operations there in 2008. A 2015 mouse study supporting the hypothesis came out of his own research institute. None of that makes the hypothesis wrong, but it deserves the same scrutiny I would give a drug company. Rath and Pauling's patent The Lancet on the 2008 ruling Cha, Niedzwiecki, and Rath, 2015

In the Physicians' Health Study II, 500 mg of vitamin C daily did not reduce major cardiovascular events over an average of eight years among 14,641 male physicians aged 50 or older. Physicians' Health Study II That fits the wall argument rather than undercutting it. Most well-fed adults are not short on vitamin C, so extra pills had little to fix. Vitamin C is one input to the wall. Sugar, pressure, and inherited connective tissue quality are others, and no vitamin covers those.

Pauling asked the right question: why would the body make something that hurts it? My answer is that for most of our history, the wall failed first, and Lp(a) held it together. We have spent decades going after the patch. The next step is to measure and protect the wall itself: its collagen, its lining, its stiffness, and the sugar slowly hardening it.

I would like to see those tested together: vitamin C status, skin glycation, arterial stiffness, stretch marks, inherited Lp(a), and actual cardiovascular outcomes. None of this is a reason to drop proven treatment. It is a reason to ask what that treatment is missing.

Thinking from first principles means being willing to follow an idea far enough to test it, including the parts we most want to be true.