Most chronic disease is caused by underlying low grade chronic inflammation.
In cardiology, one of our biggest challenges in atherosclerosis (which refers to wear and tear of the blood vessels which supply our vital organs) and these blood vessels are also prone to increased wear and tear which results in progressive damage to the vessel walls and the devlopment of plaque within the vessels. This plaque (otherwise called atheroma) is also thought to result from increasing age but also from increased inflammation.
In some people, plaque in the vessel walls may rupture and lead to sudden heart arrack or strokes and it is believed that even that acute rupturing may be due to increased inflammation. Inflammation is therefore a really big deal and understanding it, learning to recognise its presence, measuring its severity and then using treatments which specifically target the inflammation may help make a substantial contribution to improving how we treat patients in the future. Scientists are always therefore on the lookout for any compound or biochemical that can easily be obtained from the patient that can give us an insight into how inflamed that patient is.
In that sense, the most extensively studied marker of inflammation is called C-reactive protein (CRP) and in this video i will discuss CRP in a bit more detail.
CRP is an acute phase protein which is produced mainly in the liver and its production is influenced by cytokines such as interleukin-6 and TNF alpha.
CRP tells us there is inflammation within the body. However it does not tell us where exactly the inflammation is and what the cause of it is.
CRP can however be used to monitor inflammation and if the CRP goes up then it means that the inflammation is increasing and if it falls, it suggests that the inflammation is falling.
In epidemiological studies, we have observed a few interesting things:
- There appears to be a significant association between elevated CRP levels and underlying atherosclerosis.
- Elevated CRP levels tend to be associated with recurrent events in patients with already established disease
- Elevated CRP levels tend to be associated with increased incidence of a first cardiovascular event among individuals at higher risk of atherosclerosis.
- CRP gives us additional information over and above traditional risk factors regarding future risk of events.
We still don’t know whether CRP is a bystander that responds to inflammation or whether it is in some way contributing to the inflammation.
There are some conflicting data regarding whether we think CRP itself is the culprit or just a witness.
In the lab there have been small studies suggesting that if you inject CRP into tissue then it can stimulate inflammation. However the current thinking based around much larger studies is that CRP is perhaps more likely a witness rather than a culprit.
CRP is measured by obtaining a simple blood sample. There are 2 different ways it can be measured.
- Traditional assays: These are done virtually in every hospital and help look for infection and inflammation. The limit of detection is 3-5 mg/L. This range is much higher than what you would see in most ‘apparently’ healthy individuals and therefore they are not ideal to look for low grade inflammation in such patients.
- High sensitivity CRP assays: These detect concentrations of less than 0.3mg/L and even lower. These are best suited to assessment of cardiovascular risk because they are able to quantitate CRP within the range seen in healthy people.
We don’t really know what the ideal values are but in general you can divide HsCRP readings into high (3 mg/L), average (1-3 mg/L) and low (<1 mg/L) values. Levels of >10 mg/L are more suggestive of some other pathology causing inflammation such as trauma, infection or a chronic inflammatory condition
In general, these values are not always the same if you measure them more than once and therefore an average of 2 values measured 2 weeks apart is a better guide for risk stratification purposes.
As mentioned earlier, CRP can be affected by other co-morbid illnesses or even medications such as hormone therapy in women. In women, between the age of 18-44 years, CRP levels tend to be highest during menses and lowest during ovulation.
A few other things to note include:
- Women in general tend to have higher CRP levels than. In men
- Ethnicity can also affect CRP levels. In general, African Americans have the highest baseline CRP levels and East Asians have the lowest CRP levels.
- Nevertheless CRP is still an independent risk factor in these subgroups.
What do we know about CRP and cardiovascular risk?
- General population without a history of heart disease – In this group, studies have shown that the baseline CRP predicts the long term risk of a 1st heart attack, stroke, high blood pressure and even sudden death and mortality from any cause. This relationship is maintained even after statistical adjustment for age, smoking, diabetes, blood pressure and cholesterol levels however the incremental predictive value is small. There was a study called the Framingham offspring study which looked at 3006 patients without known cardiovascular disease and they followed these guys up for 12 years and found that patients with a CRP of >3 mg?L had significantly higher events compared to patients with a CRP of < 1mg/L.
- In patients with stable coronary disease – In the PEACE study, 3771 patients with stable coronary disease were studied and the authors again found that the population of patients who had a higher CRP levels of >3mg?dL had significantly higher events such as heart attacks, strokes or cardiovascular disease over a mean follow-up of 4.8 years. They also found that elevated CRP levels were predictive of development of heart failure or even a future diagnosis of diabetes. We also know from small studies that patients with the highest CRP levels seem to have more rapid progression of coronary disease.
- In acute coronary syndromes, CRP levels are in general much higher suggesting that these patients are more acutely inflamed and that this inflammation clearly plays a role in plaque instability and ACS. It is however important to note that not all patients with ACS have a very high CRP level. In one study about 41% of patients had CRP levels of <2 mg/L
- Patients with a high CRP levels on admission and on discharge appear to have both a worse short-term and long-term prognosis compared to patients with the lowest CRP levels.
So it does appear that elevated CRP levels could help us detect populations at a higher risk. However there are a number of outstanding questions that remain to be answered.
How often should we measure CRP if we are going to be using it for screening?
Do treatments which lower CRP make a significant difference to outcome? Would the benefits of treatments (such as statins) outweigh the risks of side effects.
Here there is an interesting study to mention. This was called the JUPITER study and hypothesized that Statins have an antiinflammatory role and therefore if we give statins to healthy people with normal cholesterol (LDL levels) but HsCRP levels of >2 mg/L, could we reduce the likelihood of cardiac events such as heart attacks, strokes, death from cardiovascular causes. They studied almost 18000 patients and randomised them to ROsuvastatin 20mg daily versus placebo. The study was stopped early and only after a median follow-up of 1.9 years because the authors found that the patients on placebo had significantly worse outcomes. So whilst this was interesting, the results have not changed practice for a number of reasons.
- The number of events was very low and therefore based on what was seen, almost 500 patients would have to take the statin for 1 year for one patient to benefit in terms of avoiding a fatal or non fatal heart attack
- There were some conflicts of interest as the study was funded by Astra Zeneca and several of the leading investigators had ties with the phamrmaceutical company that sold rosuvastatin
If we are going to lower CRP with medications, what is the ‘normal range’ to get the CRP down to.
Perhaps the most useful thing from my perspective from all this is as follows:
- Inflammation is bad
- Where possible we should avoid inflammation and control our risk of inflammation by using the best anti-inflammatories that nature provides us – these include good sleep, reducing stress, exercise, minimising our exposure to toxins, good nutrition and being happy wherever possible.
I hope this was helpful. Please do let me know in the comments what you thought of this video and as always I am so grateful that you take time out of your daily hectic lives to watch me and listen to my ramblings.