Approximately half of all patients who experience coronary events such as myocardial infarction do not exhibit traditional risk factors such as obesity, high blood pressure or elevated LDL cholesterol. Thus, there is great interest in developing other ways of identifying elevated CHD risk in apparently healthy individuals. These individuals may benefit from statin therapy.

Recently, some have recommended measuring hs-CRP to identify patients at high risk of CHD despite low LDL cholesterol. Some researchers believe Lp-PLA₂ may be another useful biomarker for identifying individuals at risk of CHD despite normal cholesterol. Previously, investigators described Lp-PLA₂ as a novel risk factor for cardiac events. In one major trial, patients who had the highest Lp-PLA₂ had a risk for a coronary event nearly twice as high as patients who had the lowest levels of this enzyme.

Dr. Ballantyne described the role of Lp-PLA₂ in CHD. In the intima, Lp-PLA₂ hydrolyzes oxidized LDL to generate lysophosphatidylcholine and oxidized fatty acid. These pro-inflammatory mediators cause up-regulation of adhesion molecules and cytokine production, leading to recruitment of monocytes from the lumen. Monocytes differntiate into activated macrophages, which engulf oxidized LDL. The resulting cells aggregate to form atheroscreotic plaque, which produces cytokines that degrade smooth muscle cells and the fibrous cap.

The purpose of this study was to evaluate the relationship between Lp-PLA₂, hs-CRP, traditional risk factors, and the incidence of CHD events over 6 years. The prospective, case-cohort study involved the patient population from the Atherosclerosis Risk in Communities (ARIC) Study. This ongoing study includes 12,819 apparently healthy middle aged individuals in the United States. Investigators identified 609 participants in ARIC who experienced CHD, and randomly selected 741 controls from the population.

Investigators used a specific assay to determine serum levels of Lp-PLA₂, an enzyme found in plasma and arterial plaques. The biotechnology company diaDexus manufactured and supplied the assay.

As expected, the 609 patients who experienced a CHD event had significantly higher LDL cholesterol, triglycerides and total cholesterol than in controls. They had lower HDL cholesterol and higher blood pressure than controls. In addition, they had increased levels of hs-CRP and Lp-PLA₂.

As investigators showed in previous studies, levels of Lp-PLA₂ correlated positively with LDL cholesterol and negatively with HDL cholesterol. There was no correlation with blood pressure or levels of hs-CRP.

The highest risk of CHD, associated for age, sex and race, occurred in the tertile of study subjects with the highest Lp-PLA₂ (relative risk of 1.16, versus 1.02 for the middle tertile). For only the subjects with LDL cholesterol under 130 mg/dL, risk adjusted for a variety of other risk factors was also significant (2.02 in the upper tertile versus 1.81 in the middle tertile). When investigators adjusted for hs-CRP, there was no change in the model, suggesting the two factors are independent.

Clinicians might use Lp-PLA₂ and hs-CRP together to stratify individuals for CHD risk. Dr. Ballantyne's analysis shows that individuals who had high hs-CRP and high Lp-PLA₂ had the highest risk ratio.

These results indicate a possible target population for statin therapy. Dr. Ballantyne noted that in the Heart Protection Study, statin therapy reduced CHD risk even in patients with normal levels of LDL cholesterol. Also, investigators in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) showed a similar result here at ACC. While the findings regarding Lp-PLA₂ and hs-CRP are promising, Dr. Ballantyne noted that expert panels would probably require further corroboration before they would enact a change in guidelines.