Charles E. Keenan Jr., M.D.

Case Report

A 45-year-old male presented for periodic health assessment. The patient was physically fit and exercised aerobically four or five times a week. He was a former smoker who had quit eight years prior. A low-fat diet was being followed. Family history revealed that his father had suffered a myocardial infarction at age 51 with coronary revascularization surgery at age

53. The patient\'s grandfather died of myocardial infarction at age 58. Physical exam was remarkable for a BP of 135/83 and no carotid bruits or other vascular abnormalities. His cardiac exam was normal. Labs included a total cholesterol 212 mg/dl, HDL 39 mg/dl, and LDL 123 mg/dl, with triglycerides 156 mg/dl. Glucose was 97 mg/dl.

Based on the patient\'s family history of premature coronary heart disease, a measurement of C-reactive-protein was ordered. Reports during the past few years have pointed to the predictive value of the test for cardiac inflammation, now considered to be a part of the pathophysiology of cardiovascular disease.

The C-reactive protein was 0.89 mg/dl, which was at the highest quintile level of risk for development of future cardiovascular events. The patient was started on simvastatin and advised to increase his commitment to cardiovascular exercise, maintain ideal body weight, and take 81 mg aspirin daily. He was to adhere to a heart-healthy, low-fat, low-choles-terol diet high in fruits and vegetables with reduced sodium intake. Additionally, the patient was advised to supplement his diet with 800 mcg of folic acid along with a minimum of 2 mg of vitamin B6 and 6 mcg of vitamin B12 to control levels of homocysteine, also considered to be a risk factor for coronary heart disease.

Follow-up testing revealed improvement in total cholesterol 184 mg/dl, HDL 41 mg/dl, LDL 95 mg/dl, and triglycerides 143mg/dl. The patient is highly motivated to prevent cardiovascular disease. By recognizing his high level of risk, amplified by the finding of high C-reactive protein levels, aggressive preventive measures can be implemented.

Discussion

Despite recent insights into its prevention and treatment, cardiovascular disease remains the number one killer of both men and women in the United States. Long considered to be a multifactorial process, atherosclerosis can be predicted by a number of risk markers and risk factors.

A number of emerging coronary risk factors has been identified within only the past few years. These include size and buoyancy of LDL particles, lipoproteins (a), fibrinogen, homocysteine, and others.¹ Such factors are believed to have direct involvement in the pathophysiology of the disease process, adversely affecting the health of the epithelium of the coronary, carotid, and peripheral arteries.

Still other determinants are said to be markers of coronary heart disease, being associated with future risk although not necessarily exerting a direct, causal influence. Examples include distribution of adipose tissue in the abdominal rather than peripheral regions of the body, short body structure, snoring, and, most recently, levels of C-reactive protein as a marker of inflammation.²

Marcy and others now believe that cardiovascular disease is, indeed, initiated by an inflammatory process.² Exactly how inflammation influences atherosclerosis is not yet known. Some have postulated that infection, either viral or bacterial might be causal, but that hypothesis remains controversial and unproven.³

In a broad sense, C-reactive protein levels become elevated in the blood due to any inflammatory process including arthritis, gastritis, and infection.² However, inflammation of the cardiovascular epithelium can be specifically measured by the Dade-Behring assay for high-sensitivity C-reactive protein. In some multivariate analyses, only C-reactive protein level and total choles-terol/HDL ratio proved to be independently predictive of coronary heart disease after accounting for age, smoking, obesity, hypertension, family history, and diabetes.²

Data demonstrating the predictive value of C-reactive protein have accumulated during the past few years. Levels were significant predictors of risk even in the subgroup of women with LDL below 130 mg/dl, in the study of more than 28,000 apparently healthy postmenopausal women.⁴ It was similarly predictive of future risk of coronary events in middle-aged men.⁵ And C-reactive protein has also been linked to stroke.⁶

C-reactive protein may add to the predictive value of total and HDL cholesterol in determining the risk of first myocardial infarction.⁷ In the Physicians\' Health Study, those with elevated total cholesterol had a relative risk of

2.3. Looking at C-reactive protein alone, those in thehighest tertile had only a 1.1 relative risk. But for those

Table 1: Distribution of C-Reactive Protein Levels

with both elevated cholesterol and C-reactive protein, relative risk jumped to 5.3.⁷

Levels of C-reactive protein are correlated with several factors, principally family history of coronary heart disease. Obesity and sedentary behavior are also associated with elevated levels. Conversely, growth hormone injections reduce levels of several inflammatory markers including C-reactive protein.²

Levels of C-reactive protein increase with acute infection and trauma. Testing should be delayed for two or weeks after acute inflammation. Inflammatory conditions such as arthritis, gastritis, pancreatitis, and lupus increase general measurements of C-reactive protein. Therefore such individuals may not benefit from C-reactive protein determination.² Table 1 shows the distribution of C-reactive protein levels among apparently healthy American men and women.

While elevations of C-reactive protein have been overwhelmingly associated with risk of coronary heart disease and future cardiovascular events, a causal relationship as an active risk factor rather than as a marker has not been established. Treatment, therefore, begins with aggressive preventive measure including weight loss if necessary, control of diabetes and hypertension, normalization of lipids, and compliance with programs of smoking cessation if applicable, and increased physical activity.

It appears, however, that aspirin and other antiinflammatory agents lower C-reactive protein.⁸ That, indeed, may be part of aspirin\'s role in preventing primary and secondary cardiovascular events, beyond its anti-platelet activity.

Previous studies have shown the preventive benefits of statin therapy even in those with relatively normal cholesterol levels. HMG Co-A reductase inhibitors significantly decrease levels of C-reactive protein. The authors of that study postulate that the data support an anti-inflammatory effect of these drugs.⁹

Primary physicians should consider all possible risk factors and markers for cardiovascular disease in light of its pervasive role in U.S. morbidity and mortality. Measurements of C-reactive protein can be achieved with a relatively inexpensive blood test, and probably should be considered for every male and female patient with other risk factors for coronary heart disease.