Fullscript Academy

Advanced lipid testing represents a significant evolution in the field of cardiovascular diagnostics, moving beyond traditional cholesterol measurements to offer a more comprehensive view of lipid-related health risks. While conventional lipid panels primarily focus on total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides, advanced lipid testing delves deeper into the nuances of lipid profiles by examining various subclasses of lipoproteins and their associated biomarkers.

These measures can help clinicians assess the specific types of lipoproteins that contribute to atherosclerosis and can help provide a more detailed assessment of cardiovascular risk. Furthermore, advanced lipid testing can help tailor personalized treatment strategies. By better categorizing risk, healthcare providers can design treatment plans that better correspond to the level of disease severity and enhance the overall management of cardiovascular risk.

Limitations of traditional lipid panels

During the last several decades, the primary focus has been on lowering lipid levels to reduce the risk of coronary heart disease (CHD). In standard lipid panels, higher levels of LDL and non-HDL (which includes LDL and other cholesterol types like VLDL) are linked to a greater risk of atherosclerotic cardiovascular disease (ASCVD). (Feingold 2023) As a result, guidelines such as the NCEP-ATP III have established LDL as the primary lipid target to lower and non-HDL-C as a secondary lipid target for patients with triglyceride levels above 200 mg/dL. (Chandra 2014)

Unfortunately, a significant number of patients—especially those with diabetes, insulin resistance, or cardiovascular disease (CVD)—continue to have progression of cardiovascular disease even when their LDL cholesterol target has been reached. (National Lipid Association n.d)(Chandra 2014) The occurrence of CHD events in such individuals suggests a significant residual risk that may not be captured by standard lipid measurements. (Chandra 2014) This highlights the added value of advanced lipid tests, as standard lipid panels may not fully capture cholesterol-related risks for heart attacks and strokes. (National Lipid Association n.d)

Advanced lipid tests

Emerging evidence has identified qualitative markers and lipoprotein specifications that contribute to the development of heart disease and predict increased CVD risk. Elevated levels of these markers may indicate more significant risk, and some of these markers may have better prognostic potential than standard lipid levels.

Advanced lipid markers that may have better prognostic potential

Several lipid markers have been identified as potentially having better prognostic value than standard lipid tests. These advanced markers can be highly valuable as they may be able to provide further insight into cardiovascular risk.

Unlike standard lipid tests, advanced lipid testing offers deeper insights into cardiovascular risk by evaluating qualitative factors such as lipid particle size and number, which contribute to atherogenicity.

LDL particle number

LDL particle number or the actual number of LDL particles may offer additional insight for assessing LDL burden than standard LDL cholesterol measurements, which assess the total cholesterol content within LDL particles. This is because a greater number of particles increases the likelihood of initiating processes that contribute to plaque formation. (Allaire 2017) Some individuals may have low levels of LDL cholesterol but a high number of LDL particles, which can arise if the LDL particles are predominantly small in size. Research suggests that LDL particle number is more strongly associated with ASCVD risk than traditional metrics such as LDL or non-HDL cholesterol levels. (Feingold 2023) Therefore, assessing LDL particle number may be valuable to assess regardless of a patient’s LDL status.

Apolipoprotein B (ApoB)

The ApoB test is a marker that represents the quantity of pro-atherogenic lipoproteins (i.e., chylomicron remnants, VLDL remnants, IDL, LDL, and Lp(a)), as they all contain an apolipoprotein B molecule on their surface. Compared to non-HDL levels, ApoB levels are a more sensitive risk predictor. Research shows that individuals with high ApoB and low or normal non-HDL are at greater risk of ASCVD, whereas those with low ApoB and high non-HDL are at lower risk. (Feingold 2023) This highlights ApoB's role as a valuable predictor of cardiovascular risk, providing additional insights beyond what's available from a standard lipid panel.

Low apolipoprotein A1 (ApoA1)

ApoA1 is a component of HDL particles and is considered anti-atherogenic. Research shows that low levels of ApoA1 are linked to a higher risk of cardiovascular disease. (Riediger 2011) Additionally, one study found that ApoA1 was the best predictor of ischemic heart disease mortality in elderly men compared to HDL, LDL, and ApoB alone. (Florvall 2006)

Apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio

ApoB and ApoA1 can be used to determine the ApoB/ApoA1 ratio, which can provide further insight into cardiovascular risk. Higher ApoB/ApoA1 ratios were found to be an effective predictor of coronary heart disease (CHD) in overweight and obese patients as well as patients with type two diabetes (T2D). (Lu 2011)(Paunica 2023) In patients with T2D, the ApoB/ApoA1 ratio showed the most significant correlation with CHD risk, surpassing traditional measures like LDL and the non-HDL/HDL ratio. This suggests that the ApoB/ApoA1 ratio could be a more reliable marker for assessing cardiovascular risk in individuals with T2D. (Paunica 2023)

Particle size markers associated with increased CVD risk

Lipid particle size is an important factor in cardiovascular risk assessment, as certain sizes have been associated with greater atherogenic potential. By considering lipid particle size, clinicians can gain a more detailed understanding of an individual’s cardiovascular risk.

Small dense LDL

The size of LDL particles can influence the atherogenicity of LDL particles. Numerous studies have shown that small, dense LDL particles are linked to a higher risk of ASCVD. (Feingold 2023) These small, dense LDL particles are deemed more atherogenic due to their greater ability to penetrate the endothelial cell barrier, enter the intima, become oxidized more easily, bind more readily to proteoglycans in the arterial wall, and persist in circulation longer than larger LDL particles. (Feingold 2023)

LDL medium

Medium-sized LDL particles are also associated with a higher cardiovascular risk compared to large-size LDL particles. (Pichler 2018) Elevated levels of medium LDL particles have been linked to a greater incidence of cardiovascular disease, coronary heart disease, and stroke. (Pichler 2018)

Large VLDL

Very-low-density lipoprotein (VLDL) is a precursor to LDL and is the only lipoprotein containing apolipoprotein B secreted from the liver. VLDL contributes to atherosclerotic disease, with larger, less dense VLDL particles more strongly associated with atherosclerosis as well as with insulin resistance and diabetes incidence. (Lee 2022)

Additional markers for CVD

Research has identified additional markers related to genetics and nutritional status that are associated with increased cardiovascular risk. Elevations in these markers not only signal a greater risk but can also assist in determining specific treatment goals.

Lipoprotein (a) (Lp(a))

Lipoprotein(a) or Lp(a) is a type of lipoprotein consisting of an LDL core and an additional ApoA protein and was found to be causative in the development of atherosclerosis. (Koschinsky 2014)(Lamon-Fava 2014)(Clarke 2009)(Hobbs 1994)(Liu 1994) Lp(a) levels are largely determined by genetics and serve as an independent risk factor for cardiovascular disease, with elevated levels marking increased risk of cardiovascular disease. (Feingold 2023) Increased Lp(a) levels significantly contribute to the elevated cardiovascular disease risk associated with a family history of the condition. (Feingold 2023) Many experts recommend measuring Lp(a) in all patients at least once, while others recommend measuring Lp(a) more selectively in patients with a family history of heart disease, unexplained cardiovascular events, or resistance to LDL lowering with statins. (Feingold 2023)

Homocysteine

Homocysteine is an amino acid found in the blood that's a byproduct of the metabolism of methionine, another amino acid obtained from dietary protein. It is normally converted into other substances by the body with the help of nutrients such as B6, B12, and most notably folate. A common single gene polymorphism (SNP) that reduces the activity of an enzyme involved in folate metabolism (MTHFR) is associated with an increase in serum homocysteine. High homocysteine is a risk factor for CVD complications, including stroke and myocardial infarction. (Paganelli 2021) Identifying hyperhomocysteinemia is valuable as replenishing nutritional deficiencies can lower homocysteine levels and improve cardiovascular risk. (High 2024)

Trimethylamine N-oxide (TMAO)

Trimethylamine N-oxide (TMAO) is a metabolite produced by gut microbiota’s metabolism of dietary choline and carnitine found in foods such as red meat, egg yolk, and dairy products. (Naghipour 2021) Elevated levels of TMAO are linked to a higher risk of major adverse coronary events and mortality, independent of other risk factors. (Schiattarella 2017)(Nam 2019) The microbiome and gut environment contributes to production of TMAO, so along with evaluating microbiome status, identifying high levels of this marker is useful. This can help tailor specific interventions such as probiotic supplementation which has been shown to decrease TMAO levels. (Hage 2023)

Other related markers

Several lines of evidence have shown that lipids explain less than 50% of the variability in cardiovascular risk in the United States. (Reddy 2009) This highlights the need to consider additional risk factors for cardiometabolic diseases, such as inflammation, which can facilitate the entry of cholesterol into the arterial wall and contribute to the pathogenesis of CVD. Inflammatory markers are valuable to assess as they can serve as treatment targets to help reduce cardiovascular risk. These markers encompass proteins like C-reactive protein (CRP) and fibrinogen, pro-atherogenic enzymes such as myeloperoxidase (MPO) and lipoprotein-associated phospholipase A2 (Lp-PLA2), cytokines including interleukin-6 (IL-6) and tumor necrosis factor (TNF)α, as well as other indicators like 8-hydroxy-2'-deoxyguanosine (8-OHdG) and oxidized LDL (oxLDL). (Blake 2002)

Other markers that would be useful to investigate are those that reflect nutritional status, such as omega-3 index, AA/EPA ratio, and RBC magnesium, as healthy fatty acid balance and adequate magnesium are crucial for optimal cardiovascular health.

Clinical applications of advanced lipid tests

Advanced lipid testing is a valuable addition to standard lipid panels and risk assessment tools like the Framingham Risk Score, New Zealand Risk Calculator, or Atherosclerotic Cardiovascular Disease Risk Calculator, as it can help provide a more detailed insight into cardiovascular risk. Advanced lipid testing can help improve risk prediction for all patients—whether they have a family history of cardiovascular disease, have been categorized as having medium risk, or even have standard lipid panels that appear to be normal. Furthermore, advanced lipid tests can help monitor response to treatment and assess treatment outcomes. (Chandra 2014) The combination of advanced lipid testing with other markers of inflammation and nutritional status may improve risk stratification, as opposed to lipid testing alone. This approach can assist healthcare providers in developing more tailored and effective treatment plans to reduce cardiovascular risk.