Jewish World Review Feb. 3, 2003 / 1 Adar I, 5763

Update on C-reactive Protein

By Robert A. Wascher, M.D., F.A.C.S. | 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.

JWR contributor Dr. Robert A. Wascher is a senior research fellow in molecular & surgical oncology at the John Wayne Cancer Institute in Santa Monica, CA. Comment by clicking here.


01/24/03: Bo-tox that BO Away!; The Super-sizing of America; Marijuana: A Gateway Drug?

01/21/03: Dietary Soy & Prostate Cancer Risks; Retention of Surgical Foreign Bodies after Surgery; Diet & hormone levels in adolescent girls

01/10/03: Can Aspirin Prevent Esophageal Cancer?; A Drink to Your Health!; Hormones & Breast Cancer; The Impact of Obesity on Lifespan

01/06/03:"The Pill" for Males?; Obesity & Diabetes Trends in the United States; Binge Drinking in the United States; One Less Reason to be Depressed; Liver Failure: Trends

12/20/02: Citrus Pectin & Cancer; Echinacea & the Common Cold; Update on High Blood Pressure Treatment

12/06/02: Calcium Intake & Prostate Cancer Risk; Alcohol Consumption & Risk of Breast Cancer; Reducing Blood Transfusions in Critically Ill Patients

12/06/02: Alcohol, Tamoxifen & Carotid Artery Wall Thickness; Coffee & Gallstones?; Irritable Bowel Syndrome Update; Statins: More Good News

11/22/02:Alcohol, HRT & the risk of breast cancer; hormone replacement therapy: more bad news; new vaccines may eliminate cervical cancer; more

11/15/02: The Effects of Diet & Exercise on Blood Pressure & Health; Growth Hormone & Sex Steroid Supplements & the Elderly; C-Reactive Protein & Cardiovascular Disease Risk

11/08/02: More Good News About Statin Drugs; Hormone replacement Therapy (HRT) & Alzheimer's Disease; A Role for Antibiotics in the Treatment of Vascular Disease?; more

11/01/02: Digoxin & gender; driving & degenerative disc disease; Coenzyme Q10 & Parkinson's Disease; Ginseng & erections; Viagra & stroke

10/25/02: Aspirin & coronary artery bypass surgery; glucosamine sulfate & progression of knee arthritis; hospital nurse staffing & patient mortality

10/18/02: Motor Vehicle Exhaust Pollution & Mortality; CT Scans, C-Reactive Protein & Heart Disease; Antiperspirant Use & the Risk of Breast Cancer; Atomic Bomb Radiation Exposure Update; more

10/04/02: Antioxidants & the Risk of Stomach Cancer; Best Way to Diagnose Appendicitis?; Coronary Artery Disease: Stent or Surgery?

09/27/02: Breast Feeding & the Risk of Asthma; HMOs & Quality of Care Scores; Red Wine & Vascular Disease

09/20/02: Dietary Folate & the Risk of Colorectal Cancer; Risks Associated with Smoking after Heart Attacks; BRCA1 Gene Mutation & the Risk of Breast & Non-breast Cancers; Breast Tissue Density & Inheritance

09/13/02: Dairy Products, Calcium, Vitamin D & the Risk of Breast Cancer; Efficacy of Nonprescription Smoking Cessation Aids; A Nutty Approach to Heart Disease Prevention; Update on Prostate Cancer

09/06/02: C-Reactive Protein & Estrogen Replacement Therapy; Walking Women & Cardiovascular Disease; Physical Activity Among Teenaged Girls

08/30/02: Babbling babies & brain function; homocysteine levels, vitamins & coronary artery disease; St. John's Wort & chemotherapy

08/16/02: A New Weapon Against Anthrax?; cataracts & motor vehicle accidents; gingko biloba takes a hit; air pollution & heart function during exercise; breast cancer genes & the estimated risk of breast cancer

08/09/02: Botulinum Toxin & Post-Stroke Spasticity; Intestinal Hormone Kills Appetite; Bone Marrow Cells Improve Blood Flow in Vascular Disease; Effectiveness of Restraining Orders on Domestic Violence

08/02/02: Mammography Saves Lives!; Obesity & the Risk of Heart Failure; High Sugar Diets & the Risk of Colon Cancer; Abuse During Childhood & Possible Effects of Genes on Antisocial Behaviors

07/26/02: Cancer: Nature vs. Nurture; Cardiorespiratory Fitness & Inflammation; Kidney Transplants from Cadaver Donors; Aircraft Cabin Air Recirculation & the Common Cold

07/19/02: PCBs & the Gender of Babies; Breastfeeding & the Risk of Breast Cancer; More Bad News About Hormone replacement Therapy

07/12/02: A cancer surgeon's perspective on hormone replacement therapy

07/08/02: Hormone replacement therapy & the risk of disease; more good news about statins; antioxidant vitamins & disease prevention; more

06/28/02: Antioxidants & the Risk of Alzheimer's Disease; Effects of Exercise on the Hearts of Patients with Mild Hypertension; Statins reduce cardiac events following angioplasty; more

06/21/02: Sex & violence and Advertising: Do Advertisers Get What they Pay For?; Don't Drink the Water (or the Salsa Either!); Vasectomy & Prostate Cancer Risk; Update on Smoking & Disease

06/14/02: Young Men, Obesity & Heart Disease; Breastfeeding & Obesity; Irritable Bowel Syndrome & rectal pain threshold; more data on cox-2 inhibitors & cancer; more

06/07/02: New coronary artery stent reduces risk of restenosis; possible cause of Parkinson's Disease identified; more

05/31/02: New biological insights into obesity & weight loss; broccoli kills cancer-causing stomach bug; anti-inflammatory drugs and the risk of heart attack

05/24/02: Molecular detection of tumor cells in the blood & prognosis; Cox-2 & breast/lung cancers; BRCA2 gene mutations & the risk of breast cancer; breast density & the risk of breast cancer

05/19/02: Moderate alcohol intake and blood sugar levels; more good news for tea drinkers; blood potassium levels & the risk of cardiovascular disease; ethnic differences in diabetic complications

05/10/02: Tea drinkers and the risk of death following heart attack; duration of breastfeeding & adult intelligence; abdominal aortic aneurysms: surgery or observation?

05/03/02: Risk of adverse drug reactions from newly released medications; preoperative beta-blockers may reduce heart bypass deaths; shape-shifting plastics may alter surgical practice; weight loss supplement may cause liver damage
04/26/02: Angry young men & risk of premature cardiovascular disease; stay-at-home dads & risk of cardiovascular disease; more on the effects of statins; dairy consumption and the risk of pre-diabetes; smallpox vaccine: good to the last drop?
04/19/02: Change your sex by drinking water?; Anti-inflammatory RXs may reduce growth of breast cancer cells; radiation treatment reduces repeat narrowing of bypass grafts
04/05/02: Fish & Omega-3 fatty acid consumption and cardiac health; news briefs
04/05/02: Can coffee reduce your risk of tooth decay?; exercise & blood pressure; a single high-fat meal reduces coronary artery function
04/01/02: Pre-diabetes: a newly defined category of health risk; teen television viewing and subsequent aggressive behavior; the benefits of strength training in the elderly; more ...
03/22/02: Bacteria, antibiotics & heart disease; mammograms: the debate continues; calcium & the risk of colon cancer ... and more
03/15/02: Mammography debate continues; statins & fracture risk; physical fitness & the risk of death; other intriguing findings
03/08/02: Blows to the chest & sudden cardiac death; air quality & the risk of lung cancer; tomatoes and your prostate
03/01/02: Diet & the risk of ovarian cancer; lifetime risk of developing high blood pressure; Osteoporosis prevention with a once-a-year injection?
02/26/02: The continuing controversy regarding screening mammography
02/22/02: Lowering body temperature after heart attack improves outcome; A silver lining for the chronically sleep-deprived?
02/15/02: Hormone replacement therapy & the risk of breast cancer; use it or lose it: Alzheimer's disease & cognitive stimulation; stress, divorce & death; child daycare, infections & parental guilt
02/08/02: Possible breakthrough in early cancer diagnosis; mammography: the controversy continues; CPR techniques revisited
02/01/02: Antibiotics in livestock feed & human disease; genetic detection of early colon cancer in the stool; genetic analysis of breast cancers may help decide treatment
01/25/02: Drug increases lifespan (if you're a fly...); workplace attitudes and smoking cessation; effects of inadequate sleep on surgeons
01/18/02: Lifelong effects of premature birth; smokers under the knife; aspirin and cardiovascular health
01/11/02: Estrogen levels in the blood & breast cancer risk; Heart attack: sex and survival; dangerous lettuce invaders
01/09/02: Cancer & aging: Two sides of the same coin?
01/04/02: Vitamin a & the risk of hip fracture in postmenopausal women; ovarian cancer risk and oral contraceptives
12/28/01: Magnetic Resonance Imaging (MRI) detects coronary artery disease; new development in obesity research; adverse childhood experiences & the risk of suicide attempts
12/21/01: Vaccination of children controls hepatitis a in the community; a possible cure for sickle cell disease; leptin and the risk of heart attacks
12/14/01: Chernobyl and the Risk of Thyroid Cancer in hildren; children & obesity; gastroesophageal reflux disease update
12/07/01: Update on school shootings; new implantable heart-assist device approved for further evaluation; prevention of fungal infections in pre-term babies
11/30/01: Flu vaccination in asthmatics; low-tar cigarettes are not less harmful; beans and your heart
11/21/01: Modified smallpox vaccine may reduce risk of cervical cancer; New approach to breast cancer diagnosis; New non-invasive prenatal diagnostic test for down's syndrome
11/16/01: Cholesterol-lowering drugs reduce risk of heart attack; supplemental radiation therapy reduces risk of breast cancer recurrence; brains of women may answer age-old questions
11/09/01: Bio-warfare (redux); my gray matter is bigger than yours; mad elk disease?
11/02/01: Making sense of bio-warfare
10/26/01: The impact of mammography on deaths due to breast cancer; diet & exercise may slow cancer cell growth; antidepressants and the risk of heart disease
10/19/01: New insights into autism; the wiley appendix
10/12/01: More bad news about obesity links to other diseases…Hey dad, can I borrow the car keys?
10/05/01: California leads nation in reduction of tobacco-related disease; exercise as an antidepressant?
09/25/01: Advances in the detection of breast cancer; primary care physician awareness of peripheral arterial disease; arsenic in the water
09/17/01: In perspective
09/12/01: Genes may hold secret to long life; men and women: cognitive function in the elderly; physical activity, obesity and the risk of pancreatic cancer
09/05/01: English milk cows prefer Beethoven and Simon & Garfunkel over Bananarama; new prostate cancer prevention study: looking for a few good men; exercise & diet can help prevent diabetes
08/28/01: Arthritis drugs may be linked with increased risk of heart disease; errors in blood clotting tests can be fatal; infant soy formula not associated with reproductive side effects

© 2002, Dr. Robert A. Wascher