Update on C-reactive Protein

Over the past year, there have been a number of studies published looking at the role of C-reactive protein (CRP) in the pathogenesis of heart disease.  A study in the New England Journal of Medicine last year revealed that CRP levels in the blood were more predictive of future heart disease than the standard cholesterol blood tests currently in use, and LDL (the “bad” cholesterol) in particular. 

Two studies appearing in the current issue of the American Heart Association’s journal Circulation add to the evidence that this inflammatory protein may play a critical role in the development of cardiovascular disease.

The first study looked at CRP levels in more than 14,000 clinically healthy women, and followed the women for a minimum of 8 years.  The women were assessed for the presence of upper body obesity, elevated triglycerides in the blood, low levels of HDL (the “good” cholesterol), high blood pressure, and elevated blood glucose levels, both at the beginning of the study and at regular intervals during the course of the study.  The presence of 3 or more of these findings in a patient has been termed the “metabolic syndrome,” and is associated with an increased risk of premature death. Other studies have linked high levels of CRP in the blood, in turn, with an increased risk of developing the metabolic syndrome.  The study volunteers were also assessed for the development of heart attack, stroke, surgery to correct narrowed coronary arteries, and death due to cardiovascular causes. 

At the beginning of the study, 24% of the volunteers already met the criteria for the metabolic syndrome. 

The study determined that CRP levels in the blood were significantly and proportionately related to the number of existing metabolic syndrome risk factors in the study volunteers.  During the 8-year course of the study, patients with the metabolic syndrome and CRP levels higher than 3.0 mg/L had a much higher incidence of cardiovascular disease events than did metabolic syndrome patients with a CRP less than 3.0 mg/L.  Thus, it appeared that elevated CRP levels were associated with the presence of an increased number of risk factors associated with the metabolic syndrome, and also portended a worse prognosis among patients already diagnosed with the metabolic syndrome. 

Also published in Circulation is an interesting study that assessed the relationship between alcohol and CRP levels in the blood.  We already know that elevated CRP levels are associated with an increased risk of cardiovascular disease, while many studies have shown that moderate alcohol intake can reduce the risk of cardiovascular disease.  More than 2,800 men and women participated in this study as part of a larger study that looked at the effects of statin drugs on CRP levels.  CRP levels were measured, and dietary surveys were utilized to assess alcohol intake. 

After controlling for other factors, the study found that the moderate consumption of alcohol was associated with a significantly lower level of CRP in the blood when compared to only occasional alcohol intake.  CRP levels in people who consumed less than 1 drink per month averaged 2.60 mg/L.  CRP levels following 1 to 3 drinks per month averaged 2.20 mg/L, 1 to 4 drinks per week was associated with average CRP levels of 1.70 mg/L, while 5 to 7 drinks per week resulted in CRP levels of 1.60 mg/L, and CRP levels in people who consumed 2 or more drinks per day averaged 1.80 mg/L.  These results held up irrespective of gender, smoking status, use of hormone replacement therapy (in women), the use of statins, and cardiovascular disease status. 

Previously, the moderate reduction in the risk for cardiovascular disease associated with alcohol use was thought to primarily result from alcohol’s ability to “thin” the blood, thus reducing the risk of occlusion of already narrowed coronary arteries by blood clot formation.  This new study suggests that an additional therapeutic effect of alcohol on cardiovascular health may be mediated by an antiinflammatory effect through a reduction in CRP levels.  

Both of these studies add to the growing evidence that even mild elevations in CRP levels may be associated with a significantly increased risk of cardiovascular disease, and that measuring CRP blood levels is a powerful prognostic test for risk of cardiovascular disease.  At the same time, relatively modest reductions in CRP levels may have a beneficial effect on the risk of cardiovascular disease. 

Based upon these findings, many cardiologists are now beginning to recommend that measurement of CRP levels be incorporated into routine cardiovascular disease screening tests.

COX-2 Inhibitors & Arterial Function

Also in the current issue of Circulation is a study that looks at the effects of the so-called COX-2-specific inhibitor celecoxib (Celebrex) on coronary artery function.  COX-2 inhibitors, which include the drugs Celebrex and Vioxx, are anti-inflammatory medications that are commonly used to treat arthritis and other causes of pain.  Unlike aspirin and other nonsteroidal antiinflammatory drugs (e.g., ibuprofen, Naprosyn, indomethacin, etc.), that block all three forms of COX (COX-1, COX-2, and COX-3), COX-2-specific inhibitors selectively block the formation of COX-2 alone.  Although there is some recent evidence to suggest otherwise, the COX-2 inhibitors were supposed to be associated with a lower incidence of gastrointestinal upset and bleeding when compared with nonspecific COX inhibitors, and they have been extensively prescribed since their approval by the FDA. 

There has been some evidence that COX-2-specific inhibitors, particularly in higher doses, may actually increase the risk of coronary artery disease (Lancet, 2002).  In this new study, 14 male patients (average age was 66 years) with severe coronary artery disease were evaluated.  All patients were already taking daily aspirin and a statin drug.  The patients were given Celebrex for 2 weeks, and then were switched to a placebo (sugar pill) drug for 2 weeks.  At each 2-week interval, the ability of the large artery in the arm to dilate, CRP and LDL levels in the blood, and prostaglandin (the inflammatory substances that the COX enzyme generates) levels were measured.  The study found that the use of Celebrex was associated with an increased ability of the brachial artery to dilate (and, hence, to carry more blood).  CRP and LDL levels also decreased significantly following a 2-week course of Celebrex (prostaglandin levels did not, however, change). 

The results of this study, therefore, challenge previous studies that have associated COX-2 inhibitors with an increased risk of developing coronary artery disease.  Almost certainly, however, the final word is not yet in on this subject.  The current study only looked at 14 patients, and then for only a relatively brief time.  A larger scale study, and one with more extensive follow-up, should be performed to further confirm the findings of this small pilot study.

COX-2 Inhibitors and Gastrointestinal Complications

While we are on the subject of COX-2-specific inhibitors and their safety profiles, a new study in this month’s journal Gastroenterology looks at the incidence of GI complications associated with this class of antiinflammatory drugs.  As I have already mentioned, recent studies have called into question the premise that COX-2-specific inhibitors reduce the risk of GI upset and bleeding.  In the new Gastroenterology study, more than 8,000 arthritis patients were randomized to receive either Naprosyn (a nonspecific COX inhibitor) or rofecoxib (a COX-2-specific inhibitor).  All patients were studied for at least one year, and the incidence of serious colon complications was assessed, including hemorrhage, perforation, obstruction, ulceration, or diverticulitis (inflammation of the colon).  In this study, the use of rofecoxib was associated with less than one-half the risk of serious colon complications that were seen among patients taking Naprosyn.  While this study looked only at the incidence of complications in the lower GI tract, it does appear to generally support the claims of the pharmaceutical industry that COX-2-specific anti-inflammatory medications are less toxic to the GI tract than the nonspecific COX blockers.  It is curious, however, that this study did not comment upon the incidence of upper GI complications among the two patient groups….

Telomere Shortening & Risk of Death

Telomeres are highly specialized structures situated at either end of every chromosome.  These chromosomal caps gradually shorten during the aging process, a process that is thought to be pivotal in the eventual age-related death of cells in our body, or senescent cell death.  In many cancer cells, elevated levels of enzymes that maintain telomere length are often found, and this process is thought to play an important role in the immortality of many types of cancer cells.

In the current issue of the journal Lancet is a very interesting study.  In this study, 143 volunteers over the age of 60 had blood drawn to assess the length of the telomeres in their blood cells.  The volunteers were then followed, clinically, for evidence of serious illness and death.  The study found that the volunteers with the shortest telomeres had a more than three-fold increase in the risk of dying during the course of the study as did the volunteers with the longest telomere length.  Interestingly, the risk of dying form an infectious disease was nearly 9 times as great among the “short telomere” volunteers when compared to those with longer telomeres. 

This is a fascinating study that directly associates telomere length with the risk of death in otherwise healthy older people.  It is particularly interesting that short telomeres were so strongly correlated with an increased susceptibility to infection, and to death from infection.  It has long been known that our immune systems deteriorate as we age, leaving us more vulnerable to infection as we grow older.  This Lancet study offers a highly specific and intriguing potential explanation for this phenomenon of age-related immune system deterioration.  Perhaps these findings may, someday, lead to the design of medications that will be capable of restoring the aging immune system to its prior youthful vigor and effectiveness.

Dr. Robert A. Wascher