Model used for illustrative purposes.
A previous Primary Insights post discussed the response-to-injury hypothesis in cardiovascular disease (CVD). The events leading to CVD are thought to begin with an injury to the arterial wall. Risk factors like smoking, hypertension, and diabetes can injure the arterial wall, making it more susceptible to penetration and accumulation of excess lipids. The inflammatory response to injury contributes to the progression of plaque development and can be a key factor in the formation of vulnerable plaque and plaque rupture, which can cause a heart attack or stroke. Testing for biomarkers of inflammation in addition to lipid testing—a multimarker approach to CVD risk stratification—can offer deeper insight into a patient’s true risk for progression of CVD and adverse events, especially when the patient isn’t an obvious candidate for heart disease.
This post will offer a deeper dive into the inflammatory markers that help you know more about your patient’s risk of heart attack and other adverse events, so you can treat, plan, or manage accordingly.
In the exam room: a seemingly healthy patient
Alison is a 47-year-old mother of two teenage sons. She manages a popular local coffee shop and goes to the gym regularly. She’s come in for her annual wellness visit and reports generally good health. She’s a bit discouraged that despite being on her feet much of the day and working out 3 times a week, she’s gained weight. “I feel I’m as active as I’ve always been, and I try to watch what I eat, but it’s getting harder to keep the pounds off,” she tells you. Although most of her blood work is normal, her triglycerides are mildly elevated and her blood pressure is a bit higher than it has been in the past. You know there is a family history of heart disease—both of Alison’s grandfathers died of heart attacks, although both of her parents are reasonably healthy in their late 70s.
Given her history and results, what is Alison’s risk for cardiovascular disease?
What inflammatory markers reveal
Alison may be a candidate for inflammatory marker testing. Inflammatory markers help assess “hidden” risk of CVD by identifying response to injury of the arterial wall—for example, injury caused by high levels of LDL particles that might not be identified with a standard lipid panel. Moreover, inflammatory markers allow for testing across the risk spectrum: there are individual markers indicating risk of disease, presence of disease, disease activity, and risk of adverse events. This allows for long- mid-, and near-term assessment, enabling the clinician to identify hidden risk and treat more aggressively when appropriate. A closer look at these clinically actionable markers is below.
Markers indicating risk of disease
F2-IsoPs, or F2-Isoprostanes, are prostaglandin-like compounds formed from free radical-mediated oxidation of arachidonic acid. F2-IsoPs measure oxidative stress induced by lifestyle risk factors for CVD including smoking, poor diet, high red meat intake, and a sedentary lifestyle. F2-IsoPs contribute to CVD progression through increased vasoconstriction via thromboxane production, platelet aggregation, and thrombus formation. Elevated levels of F2-IsoPs indicate a 2.6x increased risk for coronary artery disease (CAD) and a 1.8x increased risk of CVD mortality.
OxLDL, or oxidized LDL, measures damage of the apolipoprotein B (ApoB) protein subunit on the surface of LDL due to oxidative modification. Oxidation of ApoB is an initiating factor in macrophage recruitment, foam cell formation, and vascular inflammation within the arterial wall. Elevated OxLDL levels indicate a 4.3x increased risk of having a coronary heart disease (CHD) event and a 3.5x increased risk of developing metabolic syndrome (MetS).
Markers indicating presence of disease
ADMA/SDMA, or asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are derivatives of the amino acid L-arginine and are produced via protein degradation. ADMA is a competitive inhibitor of nitric oxide synthase and can reduce the production of nitric oxide. Nitric oxide deficiency is an early manifestation of endothelial dysfunction and atherosclerotic disease. Elevated ADMA indicates a 1.4x increased risk of CVD and CHD and a 1.6x increased risk of stroke. SDMA is primarily excreted in the urine and strongly correlates with reduced renal function.
hs-CRP is a highly sensitive measurement of C-reactive protein, an acute-phase reactant protein that increases in response to inflammation. In large epidemiologic studies, elevated levels of CRP have been shown to be a strong indicator of CVD. Patients with high CRP have a 1.5x-2.0x increased risk of developing subsequent atherosclerotic disease compared with patients with low CRP levels. It’s also been demonstrated that lowering hs-CRP, independent of lipid levels, results in a 15% risk reduction of recurrent cardiovascular events.
Markers indicating disease activity or risk of adverse events
Lp-PLA2 Activity, or lipoprotein-associated phospholipase A2, is an enzyme produced by macrophages and foam cells within the necrotic core of arterial plaque. Lp-PLA2 Activity measures the disease activity within the arterial wall under the calcified cap of the plaque. Elevated Lp-PLA2 Activity has been associated with a 2.0x increased risk for developing CHD independent of non-HDL cholesterol levels. Also, elevated Lp-PLA2 Activity indicates a 2.0x risk of having a CHD event (MI, coronary revascularization, or CHD-related death).
MPO, or myeloperoxidase, is an inflammatory enzyme released within the vascular lumen during white blood cell activation in response to fissures, erosions, or degradation of the fibrous cap. MPO is a specific marker of vascular inflammation and is a measure of vulnerable plaque. Elevated levels of MPO independently predict 2.0x-2.4x increased risk of future cardiovascular events (MI, coronary revascularization, or CVD-related death).
Uncover hidden risk
Given Alison’s family history of heart disease and mildly elevated triglycerides and blood pressure, as well as what is by all appearances a healthy lifestyle, inflammatory marker testing may offer clues as to her true CVD risk. For example, if Alison’s F2-IsoP levels are elevated due to her lifestyle, despite her exercising 3 times per week, this indicates risk of disease development, and cutting back on red meat intake may be advised. In this case, testing for inflammatory markers fills in the other side of the injury/response-to-injury picture for a more complete assessment of Alison’s CVD risk.
The bottom line: a multimarker approach utilizing both advanced lipid testing (for injury) and inflammatory markers (response to injury) can aid in risk stratification, so you may know better which patients you should be most concerned about and which you should monitor more frequently. Quest Diagnostics offers a broad Cardio IQ® test menu that includes these markers as well as others for metabolic disease.
Next: A closer look at what advanced lipid testing can tell you. For this and other upcoming articles on what’s new in diagnostics, subscribe to Primary Insights.