Cardiovascular disease (CVD) originates from atherosclerosis, a disease in which low-density lipoprotein (LDL) particles build up in the arterial wall. LDL particles are oxidized and combine with macrophages, T-lymphocytes, and other inflammatory cells to induce chronic inflammation within the artery. A growing plaque causes progressive arterial narrowing. Rupture-prone plaque contains considerable amounts of inflammatory cells, such as macrophages and T-lymphocytes.
CVD leads to acute coronary syndromes (myocardial infarction, unstable angina, or sudden cardiac death) and most strokes. Most of these events are caused by plaque rupture.
Beyond traditional risk factors
When evaluating patients with known CVD, clinicians typically look for traditional risk factors—hypercholesterolemia and other lipid disorders, hypertension, smoking, obesity, diabetes, physical inactivity, and family history. A global risk score can be calculated using the Framingham assessment tools for coronary heart disease (CHD) and stroke. A patient’s 10-year risk for CHD and stroke can be estimated by assigning points to certain risk factors.
But some patients with traditional risk factors experience CHD events and strokes despite treatment. Does this mean we’re not treating patients aggressively enough? What are we missing in risk assessment to guide this decision?
Knowledge that atherosclerosis is an inflammatory disease has led many clinicians to include inflammatory-marker testing in comprehensive risk assessment for selected patients. The most commonly measured inflammatory markers are high-sensitivity C-reactive protein (hs-CRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2). The latter is an especially appealing marker as it seems to be directly involved in atherosclerosis.
Evidence supporting Lp-PLA2 measurement
An enzyme secreted by macrophages and other inflammatory cells, Lp-PLA2 binds primarily to LDL in the bloodstream, where it stays inactive until LDL particles penetrate the arterial wall and are oxidized. Then Lp-PLA2 releases two toxic products—lysophosphatidylcholine and oxidized fatty acid. These proinflammatory substances trigger a cascade of events that promotes athero-sclerosis. Thus, Lp-PLA2 is considered a risk marker specific for vascular inflammation.
Clinical trials have explored the link between Lp-PLA2 and the risk of CHD events and stroke. Generally, results show a consistent and statistically significant correlation between elevated Lp-PLA2 levels and a twofold increase in risk. In their analyses, investigators statistically adjusted for traditional risk factors; thus, the risk associated with Lp-PLA2 was considered independent of other risk factors. With the strong evidence supporting Lp-PLA2 as a risk marker, the Food and Drug Administration approved the Lp-PLA2 blood test in 2005 for assessing the risk of ischemic stroke and coronary artery disease. (See Interpreting Lp-PLA2 results by clicking on the pdf icon above.)
When should Lp-PLA2 be measured?
The 2001 Adult Treatment Panel (ATP) III Cholesterol Guidelines from the National Cholesterol Education Program recommends that clinicians assess traditional risk factors for CHD and calculate 10-year CHD risk using the Framingham Risk Score (FRS) in patients with two or more risk factors. For patients with a 10-year risk of 10% to 20% (intermediate or moderate risk), ATP III recommends interventions to reduce LDL levels below 130 mg/dL. However, updated ATP guidelines in 2004 set an optional LDL goal of below 70 mg/dL for patients at very high risk.
Recently, a consensus panel of experts met to discuss how Lp-PLA2 testing could be used in conjunction with traditional risk factor assessment to determine if certain intermediate- or high-risk patients may be at even higher CVD risk and therefore require even more aggressive risk-reducing therapies. The panel’s guidelines stated that inflammatory-marker testing might be used to assess the risk status of intermediate- or moderate-risk patients, and recommended such testing for patients with known CHD or a CVD risk equivalent, such as diabetes or ischemic stroke. An elevated Lp-PLA2 level would place these patients in the very high risk category with an LDL goal below 70 mg/dL. A moderate-risk patient with a high inflammatory-marker level would be reclassified as high risk, with an LDL goal adjusted to below 100 mg/dL. (See the “ATP III guidelines and risk assessment” algorithm at www.plactest.com/pdf/literature/Decision_Algorithm.pdf).
The consensus panel endorsed testing of Lp-PLA2 to assess CHD event and stroke risk in moderate-risk populations. To help eliminate the need to calculate the FRS, they provided a simplified framework based on counting traditional Framingham risk factors. Lp-PLA2 testing is recommended for any patient with two or more risk factors. Given that CHD events and strokes increase with age, patients age 65 or older with one additional risk factor should be tested. Also, most smokers and persons with elevated fasting glucose levels have at least a moderate risk and should be tested.
Patients who meet the diagnostic criteria for metabolic syndrome generally are at moderate risk. In these patients, an elevated Lp-PLA2 level further increases CVD risk; therefore, Lp-PLA2 levels should be measured.
Can therapy lower elevated inflammatory markers?
Levels of inflammatory markers decrease with weight loss (probably because excess visceral fat boosts production of inflammatory cytokines). Studies show a whole grain–enriched hypocaloric diet and increased fruit and vegetable intake can lower hs-CRP levels. In healthy adults, regular exercise is linked to lower hs-CRP levels if baseline hs-CRP is elevated. (Few studies have explored the effects of diet, exercise, and weight loss on Lp-PLA2.)
Statin medications lower not just LDL levels but hs-CRP and Lp-PLA2 levels as well. Other lipid-altering drugs, such as niacin and omega-3 fatty acids, further lower Lp-PLA2 when added to a statin.
Case study: Jasmine Carmichael
Jasmine Carmichael, age 57, is an African-American female with a family history of CHD and stroke. She has these additional CVD risk factors:
- hypertension at 144/82 mm Hg on treatment with hydrochlorothiazide 25 mg daily
- total cholesterol level 220 mg/dL, triglycerides 200 mg/dL, high-density lipoprotein (HDL) level 41 mg/dL, and LDL level 139 mg/dL
- body mass index of 31 kg/m2 (indicating obesity)
- waist circumference of 41 inches
- fasting glucose level slightly elevated at 101 mg/dL
- left ventricular hypertrophy on resting electrocardiogram
- smokes cigarettes.
Knowing Ms. Carmichael has multiple CHD and stroke risk factors, the author and colleagues used the FRS to identify her 10-year risk for CHD events and stroke. Based on these calculations, we found she has a 10-year risk for a CHD event of 14% and a 10-year stroke risk of 13%, placing her in the intermediate-risk category. Using the simplified Lp-PLA2 criteria developed by the consensus panel, we took into account that she smokes, has several other traditional risk factors (low HDL level, hypertension, family history of premature CVD), has an elevated fasting glucose level, and meets the criteria for metabolic syndrome.
We informed Ms. Carmichael that the PLAC Test can measure her Lp-PLA2 level and help determine the best way to treat her risk factors. She agreed to the PLAC Test to determine if she is high risk and might require more aggressive risk-reduction therapies. The test showed her Lp-PLA2 level was elevated at 278 ng/mL, placing her in the high-risk category. We partnered with her to develop the following management plan:
- Begin statin therapy to lower the LDL level below 100 mg/dL.
- Intensify the antihypertensive drug regimen to target optimal blood pressure below 120/80 mm Hg.
- Stop smoking.
- Lose weight.
- Monitor fasting glucose levels.
- Eat a heart-healthy diet with 500 fewer calories per day than normal, and limit sodium intake to no more than 2 g daily.
- Maintain a regular exercise routine.
As Ms. Carmichael’s case shows, traditional atherosclerosis risk factors don’t entirely account for a person’s risk of a CHD event or stroke. Lp-PLA2 testing should be used to refine absolute risk status and identify patients who would benefit most from amplified lifestyle changes and lipid-lowering therapies.