The role of C-reactive Protein (CRP) in cardiometabolic risk assessment remains controversial. Despite considerable research in the last few years, several interrelated questions remain unresolved.
In the Winter 2005 issue of Holistic Primary Care, I asked in this column “Is Homocysteine Dead?” (visit www.holisticprimarycare.net to read this and other past installments of Naturopathic Perspective). I believe we can now ask a similar question: “Is CRP Dead?” Again, my answer is, “I think not.”
Prospective studies show clearly that higher CRP levels are associated with higher coronary heart disease (CHD) incidence and mortality, but the cardiology community has largely de-emphasized this association in recent years. To some extent, this may reflect a commercial rather than a scientific imperative: there may be an attempt by some to discourage the use of other risk markers in favor of lipid markers and the subsequent prescription of statin drugs. This may change in the near future. Pharmaceutical companies are now rushing to seek approval of drugs designed to raise HDL and lower CRP; their revenue from statins will soon be declining when the patents run out.
On the other hand, the unwillingness of many cardiologists to embrace CRP as a fully-fledged risk factor may be due to uncertainty as to whether CRP is a passive marker of risk, an active participant in the disease process, or both. Is a high CRP level an actual driver of heart disease or merely a hapless passenger on the road to MI? Is there a causal connection or merely an association?
Like many other things in medicine, confusion about CRP may reflect our desire for simple “yes or no” answers, and “one size fits all” solutions. In truth, CRP elevation may mean different things in different people.
A patient’s specific CRP genotype may influence CRP synthesis, which could mediate the onset of subclinical and clinical CV events. Alternatively, CRP may increase the propensity toward acute ischemic events through indirect effects, such as a procoagulant phenotype that induces tissue factor and expression of plasminogen activator inhibitor (PAI)-1 by endothelial cells or monocytes.
Attempts to add CRP to traditional CV risk modeling protocols, with the ultimate objective of improving targeted therapy, have led to widely divergent conclusions (Cook NR, et al. Ann Intern Med. 2006; 145: 21–29; Lloyd-Jones DM, et al. Ann Intern Med. 2006; 145: 35–42).
The burning question is whether CRP truly has a causal role in heart disease. Principles of Mendelian randomization have been applied to try and tease out an answer. We know there are polymorphisms in the CRP gene that influence CRP levels. These genetic variations, however, are not related to any of the factors that confound observational studies, such as smoking, obesity, or socioeconomic status.
Groups defined on the basis of CRP genotype have long-term differences in CRP levels. If CRP is causally related to CHD, the genotypic variations should be reflected as variations in CHD risk. New data from studies in elders suggest that certain CRP gene variants are, in fact, linked with increased incidence of CV events (Lange LA, et al. JAMA. 2006; 296: 2703–2711). The data also suggest that CRP polymorphisms better reflect lifetime exposure to CRP than CRP serum levels measured at a single point in time. When it comes to the negative impact of CRP, lifetime exposure means more than isolated, short-term elevations.
Randomized, controlled trials of CRP-lowering would provide a more definitive answer to the question of whether CRP causes CHD. To date no such trials are under way, though clinically it is possible to lower a patient’s CRP with a combination of vitamin C, bromelain, curcumin, quercetin, and the herbal anti-inflammatory combination, Zyflamend.
Even if studies show no direct causal connection between CRP and CHD, we cannot ignore the fact that inflammation plays a role in atherosclerosis. Keep in mind, also, that inflammation is strongly reflective of psychosocial risk factors, as evidenced in a recent large cross-sectional study.
Rangit and colleagues found that depression, cynical distrust, and chronic stress all correlated with elevated inflammatory markers (Rangit N, et al. Arch Intern Med. 2007; 167: 174–181). They also looked at impact of physical activity, smoking, alcohol use, and other factors (diabetes, BMI, recent infection, medication use). Elevated inflammatory markers were partially attributable to BMI and diabetes, not surprising given that abdominal adiposity and adipokines such as TNF-alpha, IL-6, leptin, and adiponectin engender inflammation and thrombosis. However, elevations of CRP and IL-6 showed the strongest links to psychosocial factors.
Whether or not CRP proves to be a bona fide CVD risk factor, reducing systemic inflammation is a good idea, and it begins with a dietary approach. An anti-inflammatory diet includes “good fats” such as oils from cold water fish (wild salmon, herring, sardines, mackerel, trout, and [small] halibut); ginger, garlic, onions, nuts, seeds, avocado, and extra virgin olive oil. “Bad fats” are pro-inflammatory and should be avoided. It is wise to eliminate or reduce red meat and whole milk dairy, fried foods, hydrogenated oils, poor quality oils such as cottonseed and peanut oil, sugar and caffeine.
Nutritional supplements to reduce inflammation include curcumin, fish oil, garlic, ginger, quercetin, and pancreatic enzymes. As can be deduced from the above study, effective stress management such as exercise, meditation, breathing techniques, cognitive behavioral therapy, progressive relaxation, therapeutic imagery and time management will positively impact the inflammatory process as well. Smoking cessation and moderation in alcohol use are other essential therapeutic lifestyle changes.
Keep in mind that over half of all heart attacks and strokes in the US occur in people with normal cholesterol levels; 20% of all events occur in people with no major risk factors. Several studies show that high CRP levels, when added to traditional ways of measuring risk, enhances detection of high-risk individuals and affords the opportunity to lower risk through diet, supplements, exercise, stress reduction, smoking cessation. I am in favor of anything that improves our abilitiy to not only predict but prevent thrombotic occlusion.
Until we have definitive evidence showing that CRP has no real bearing on risk of MI, I believe the evidence still weighs in favor of comprehensive cardiometabolic risk assessment that includes both homocysteine and CRP. To learn more about C-reactive Protein, visit www.holisticprimarycare.net and search CRP.
Michael Traub, ND, past-president of the American Association of Naturopathic Physicians, recently contributed a chapter on naturopathic medicine for the textbook Integrative Cardiology, to be published soon by McGraw-Hill. He practices in Kailua-Kona, Hawaii.
