Is CRP [C-Reactive Protein] a “risk factor” for heart disease? Prof. Mark Pepys is an eminent expert in immunology and CRP research. He discusses real evidence for CRP as a cardiovascular risk marker and correct use of CRP as a signal for a presence of pathological processes in the body. That is the good news about C-reactive Protein. The bad news is this. C-reactive Protein test is so easy to do. Dr. Anton Titov, MD. People have done it in all sorts of other investigations and produced wildly misleading results. You mentioned "C-reactive Protein is a risk marker”. C-reactive Professor Dr. Mark Pepys, MD. 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 this 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. Professor Dr. Mark Pepys, MD. Again, playing loose with the 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 seem to be large, because there were thousands of people involved. Dr. Anton Titov, MD. 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. 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. Professor Dr. Mark Pepys, MD. 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 in 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. Professor Dr. Mark Pepys, MD. 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. It 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. Dr. Anton Titov, MD. 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 being able to reproduce them in vitro or in an animal models. We made pharmaceutical-grade human CRP from human donor blood It was very laborious, very expensive process. We infused C-reactive Protein into healthy volunteers. Guess what happened to them? Professor Dr. Mark Pepys, MD. 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”. Mendelian randomization. Sometimes you find the genes this encode different levels of C-reactive protein [CRP] at baseline. At different acute-phase responses. There are such genes. There are various polymorphisms in the human population. Some people have genes this give them a low baseline CRP, 0.1 mg per liter. Dr. Anton Titov, MD. Other people go around with a CRP baseline 5 mg per liter. Sometimes they have an acute phase response. Correspondingly the one goes up more than the other. Professor Dr. Mark Pepys, MD. 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. Dr. Anton Titov, MD. They can argue about experiments, infusions and so on. It is unequivocal that CRP does not cause heart attacks and strokes. Professor Dr. Mark Pepys, MD. 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. 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. Dr. Anton Titov, MD. 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. It is used for clearing up debris. Professor Dr. Mark Pepys, MD. 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 show CRP actually makes the damage in a heart attack worse than it would otherwise be. Duringt 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. Sometimes you put human CRP into such an experiment in rats. Professor Dr. Mark Pepys, MD. 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. We showed that in 1999. Dr. Anton Titov, MD. That is the validation of CRP as a therapeutic target. 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. Professor Dr. Mark Pepys, MD. 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. 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. Professor Dr. Mark Pepys, MD. There is nothing that the human race does this is so difficult, so slow and so expensive. 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. Then 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. We are currently trying with considerable difficulty to invent other molecules that will do the same thing. This will be nice solids that can be made in large amounts at a cost that is acceptable. Professor Dr. Mark Pepys, MD. 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!