Understanding C-Reactive Protein: Risk Marker vs. Cause in Heart Disease

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• CRP as a Risk Marker, Not a Cause
• Flaws in Early CRP Research
• Genetic Evidence Against Causality
• The True Biological Role of CRP
• CRP Worsens Heart Attack Damage
• Therapeutic Target and Drug Development
• Full Transcript

CRP as a Risk Marker, Not a Cause

Dr. Mark Pepys, MD, makes a critical distinction between a risk marker and a risk factor in cardiovascular disease. A risk factor, like cholesterol, directly contributes to the disease process. Lowering cholesterol protects against atherosclerosis. In contrast, C-reactive protein is merely a modestly significant risk marker. Dr. Mark Pepys, MD, emphasizes that this distinction is a serious scientific issue, not just semantics. The conflation of association with causality led to widespread misunderstanding about CRP's role in heart health.

Flaws in Early CRP Research

Dr. Mark Pepys, MD, explains how initial epidemiological studies produced misleading results. These trials involved thousands of people but had a very small number of actual heart attack events. This allowed for statistical anomalies that suggested an incredibly high association between baseline CRP and future heart attacks. When research scaled up to include hundreds of thousands of participants in meta-analyses, the association was shown to be much weaker. Dr. Mark Pepys, MD, notes that similar weak associations are found with other inflammatory markers like low albumin or ESR, indicating nothing specific to CRP.

Further confusion arose from flawed in vitro experiments. Commercially sourced CRP was often impure and contaminated with bacterial lipopolysaccharide, a potent pro-inflammatory agent. When this contaminated CRP was applied to cells, it caused a strong inflammatory response. Researchers incorrectly attributed this effect to CRP itself. Dr. Anton Titov, MD, discusses these findings with Dr. Pepys, who highlights the importance of pure reagents in medical research.

Genetic Evidence Against Causality

The most definitive evidence against CRP causing heart disease comes from genetic epidemiology, specifically Mendelian randomization. Dr. Mark Pepys, MD, describes how certain genes control an individual's baseline CRP level. Some people naturally have low CRP around 0.1 mg/L, while others have a baseline near 5 mg/L. If CRP were a causal factor, people with genes for higher CRP would have a significantly higher incidence of cardiovascular disease. However, large genetic studies show no relationship whatsoever between these CRP-controlling genes and the risk of heart attacks or strokes. This provides unequivocal proof that CRP does not cause cardiovascular events.

The True Biological Role of CRP

Dr. Mark Pepys, MD, clarifies the actual biological function of C-reactive protein. CRP is a binding protein, closely related to serum amyloid P component (SAP). It recognizes and binds to phosphocholine residues exposed on the membranes of dead or damaged cells. This binding activates the complement system, a part of the immune system responsible for clearing cellular debris and pathogens. In this capacity, CRP acts as a helpful scavenger, aiding the body in cleaning up after injury or cell death. This process is a natural part of the body's defense and repair mechanisms.

CRP Worsens Heart Attack Damage

Despite its helpful role in debris clearance, Dr. Mark Pepys, MD, and his team made a pivotal discovery in 1999. In the context of an acute event like a heart attack, CRP's activity becomes harmful. During a myocardial infarction, a blocked coronary artery causes heart muscle cells to die from lack of oxygen. CRP binds to these dying cells and activates the complement system. This activation significantly amplifies the inflammatory response, greatly increasing the size of the infarct and the resulting damage. Dr. Pepys' team validated this mechanism in animal models, showing that infusing human CRP into rats with induced heart attacks made the damage much worse in a complement-dependent manner.

Therapeutic Target and Drug Development

This discovery validated CRP as a promising therapeutic target for acute conditions. Dr. Mark Pepys, MD, explains that his team set out to develop a medication that could block CRP from binding to damaged cells. The goal was to reduce the complement-mediated damage during a heart attack or stroke. They successfully created a family of candidate compounds that worked very effectively in animal models. These drugs were designed for intravenous infusion, making them suitable for hospitalized patients experiencing acute events.

However, the journey of drug development is notoriously difficult. Dr. Anton Titov, MD, and Dr. Pepys discuss the immense challenges. The initial compounds were extremely difficult to purify on the large scale required for pharmaceutical manufacturing. This halted their development. Dr. Mark Pepys, MD, notes that his team is now deep in the process of trying to invent new, more developable molecules that can achieve the same therapeutic effect—blocking CRP to limit tissue damage—but can be manufactured as stable, cost-effective medications.

Full Transcript

Dr. Anton Titov, MD: Is CRP [C-Reactive Protein] a "risk factor" for heart disease?

Dr. Mark Pepys, MD: C-reactive Protein is indeed a very modestly significant risk marker for cardiovascular disease. But that story was greatly overhyped. People started talking about CRP as a "risk factor". A "risk factor" is something that actually contributes to the disease. Cholesterol is a risk factor. We know that cholesterol causes atherosclerosis. You've got too much cholesterol, then you get atherosclerosis. You lower cholesterol, then you protect against atherosclerosis.

Again, playing loose with the words! It is not only playing with the words. It is also a serious scientific error: the conflation of association with causality. People did epidemiological clinical trials that seemed to be large because there were thousands of people involved. But the number of events, number of heart attacks in them, for example, was very small.

Now, it doesn't matter if you've got 10,000 people in a clinical trial. If you have only got a hundred heart attacks in a clinical trial, then you can divide them into quintiles of what their CRP was a year before or 10 years before. You can get all sorts of funny results.

The original epidemiological results suggested a fantastically, incredibly, unbelievably high association between a raised baseline CRP and patient's risk of having a heart attack later on. But then the epidemiology went up to proper epidemiological scale. Hundreds of thousands of people were tested. Meta-analyses or very big clinical trials were done on C-reactive Protein and heart attacks. It turned out that the association was much, much weaker. It is still there, but it is pretty modest.

All it really means is nothing much. You find the same association with many other inflammatory markers. It is nothing specific to CRP. You find low association with low albumin; when the CRP goes up, albumin goes down. Sedimentation rate [ESR], or the cytokines, all sorts of things like that.

So this was a complete conflation, wrong conflation of association and causality. It got exacerbated because people did experiments in vitro with commercial sourced CRP. C-reactive Protein was impure. It was contaminated with bacterial lipopolysaccharide, which is very pro-inflammatory. They put that onto cells and the cells went "whoa!". Researchers said "this is the CRP causes atherosclerosis!”.

They even did in vivo experiments where they infused this dirty stuff into people. They got lots of inflammation going on. The body has strong response to bacterial polysaccharides. Yes, CRP was claimed to be pro-inflammatory. It turned out that C-reactive Protein is not pro-inflammatory.

Eventually we were very concerned by these reports. We were not able to reproduce them in vitro or in animal models. We made pharmaceutical-grade human CRP from human donor blood. It was a very laborious, very expensive process. We infused C-reactive Protein into healthy volunteers. Guess what happened to them? Absolutely nothing!

We showed that CRP is not pro-inflammatory if you're healthy. The whole story of CRP as a risk marker for atherosclerosis and for cardiovascular risk is false. That has evaporated.

The final nail in the coffin was what's called "genetic epidemiology” or Mendelian randomization. Sometimes you find the genes that encode different levels of C-reactive protein [CRP] at baseline or different acute-phase responses. There are such genes. There are various polymorphisms in the human population. Some people have genes that give them a low baseline CRP, 0.1 mg per liter. Other people go around with a CRP baseline of 5 mg per liter. Sometimes they have an acute phase response; correspondingly the one goes up more than the other.

Now imagine that CRP was causing cardiovascular disease. Then the people who have the genes encoding more CRP would have more cardiovascular disease. People with lower levels of C-reactive Protein would have lower cardiovascular disease. It turns out that there is no relationship between C-reactive Protein and heart disease. Genes that control CRP production and whether you get heart attacks or strokes—there is no relationship. Completely "no".

It doesn't matter what people found in in vitro experiments. They can argue about experiments, infusions and so on. It is unequivocal that CRP does not cause heart attacks and strokes.

That is one side of the story. The other side of the story is that CRP is a binding protein. CRP is actually very closely related to SAP, which we talked about in regard to amyloidosis. SAP binds to amyloid fibrils. What does CRP bind to? CRP binds to dead or damaged cells. It recognizes phosphocholine residues.

These chemical residues are ubiquitous in plasma membranes, phospholipids. These residues are exposed when cells are sick or dying or dead. CRP binds to dead and dying cells. Human CRP also activates a protein system in the blood that is called the Complement System. This is a pro-inflammatory and host defense system. It is used by the body for getting rid of bacteria and for clearing up debris.

We use it in our amyloid treatment to get rid of the amyloid deposits. The antibody activates complement; that is what gets rid of amyloid deposits. The body uses CRP to bind to dead cells to activate complement. That helps to get rid of dead cells.

But we showed first of all in 1999—many people had been "hinting" about this, making "observations", "suggesting it”—we did the first definitive experiments. We showed CRP actually makes the damage in a heart attack worse than it would otherwise be.

During a heart attack your coronary artery is blocked. There is no arterial blood going to part of the myocardium. The cells die from anoxia. A chunk of your heart muscle dies. If you put human CRP into such an experiment in rats, human CRP activates rat complement. You greatly increase the size of the infarct. That is complement-dependent. We know the mechanism; we showed all the molecules there.

Dr. Anton Titov, MD: That is the validation of CRP as a therapeutic target.

Dr. Mark Pepys, MD: Because you can look at anybody who has died of a heart attack. You can always find CRP and complement in and around the infarct. The dead muscle is there. C-reactive Protein is always there. These are the molecules that make things worse. We set out to make a medication that would prevent CRP binding there.

We showed the same thing in a rat model of stroke. We can make rat strokes bigger by adding human CRP. We set out to make molecules that would block CRP binding to dead and damaged cells. Such medications could reduce the damage in a heart attack. We made a successful candidate compound and family of compounds.

Dr. Anton Titov, MD: This actually in the animal model worked very, very well.

Dr. Mark Pepys, MD: But they turned out not to be developable as medications, at least so far. We've talked before about the nightmare journey of medication development. It really is a nightmare journey. There is nothing that the human race does that is so difficult, so slow and so expensive as trying to develop a new medicine. It can take decades and cost billions of pounds. So it is an indescribable nightmare journey.

These particular molecules looked very favorable at least for use as infusion medications. They couldn't be taken by mouth but could be infused into a vein. This is fine if you've got a patient in a hospital with a heart attack, or a stroke, or burn, for example, where CRP also contributes to the damage, or trauma, and other things. But they were very difficult to purify on a scale that would be necessary for medication development.

Dr. Anton Titov, MD: Those molecules have stopped development.

Dr. Mark Pepys, MD: We are currently trying, with considerable difficulty, to invent other molecules that will do the same thing. These will be nice solids that can be made in large amounts at a cost that is acceptable. We are deep in the bowels of developing these medications. Someone maybe wants to come and give us a few million pounds to help that journey along. It will be very gratefully received!