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Standard lipid profiles that measure basic cholesterol levels, including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides, provide limited insight into the underlying mechanisms of cardiovascular disease. While widely available and cost-effective, they don't provide information on lipoprotein particle size or number.

Advanced cardiac lab tests, such as lipoprotein subfractionation, high-sensitivity C-reactive protein (hs-CRP), and lipoprotein-associated phospholipase A2 (Lp-PLA2), offer a deeper understanding by assessing factors like the size and density of lipoprotein particles, inflammatory markers, and specific enzymes associated with atherosclerosis. Many of these tests are included in advanced cardiac testing panels.

These additional tests may help to provide more accurate risk assessment, early detection of subclinical disease, and better-tailored therapeutic strategies.

Advanced cardiac lab tests

Lipoproteins transport lipids to different tissues for energy use, lipid storage, steroid hormone synthesis, and bile acid production. (Lipoprotein 2023) While standard lipid panels measure lipoprotein quantity, testing methods like nuclear magnetic resonance (NMR) and ion mobility analysis can be used to determine LDL and HDL subfractions. This method separates lipoprotein particles based on their size and density, allowing for a detailed analysis of the different subfractions of LDL and HDL. This technique provides precise and detailed information about the number and size of various lipoprotein particles, contributing to a comprehensive cardiovascular risk assessment. (Feingold 2023)

Advanced cardiac tests identifying qualitative information on LDL and HDL particles provide more information on their potential pathogenicity, which will be highlighted below. Furthermore, other tests discussed in this section—including apolipoproteins, markers of inflammation, and oxidative stress, and nutrition status—collectively contribute to a comprehensive assessment of cardiovascular disease risk.

Lipoprotein subfractionation

Lipoprotein subfractionation, a process that uses laboratory technologies NMR or ion mobility analysis, can provide detailed information on lipoprotein particle size, number, and composition, based on the behavior of nuclei in a magnetic or electric field, respectively. Both methods offer advanced insights beyond standard lipid panels but use different technologies to analyze lipoproteins.

LDL particle number

Advanced lipid tests are valuable because some individuals may have low or normal levels of LDL cholesterol but a high number of LDL particles. This can occur if the LDL particles are predominantly small or have less cholesterol per particle. A higher LDL particle count increases the likelihood of these particles penetrating arterial walls and triggering processes that lead to plaque formation. (National Lipid Association n.d.) Research indicates that LDL particle number is more strongly linked to atherosclerotic cardiovascular disease than traditional measures like LDL or non-HDL cholesterol levels. Although LDL and LDL particle number are generally correlated, there are cases where they may show discordant results. (Feingold 2023) Measuring LDL particle number provides an alternative method for assessing pathology and helps clinicians develop more personalized and effective treatment plans to improve particle size and number.

LDL subclasses

LDL particles come in varying sizes, with smaller, denser particles and medium LDL particles posing a greater risk for cardiovascular disease compared to larger, more buoyant LDL particles.

Small dense LDL

Numerous studies have found that small dense LDL particles are associated with an increased risk of atherosclerotic cardiovascular disease. Small dense LDL particles are considered more atherogenic because they can more easily penetrate the endothelial cell barrier, can enter the intima, are more prone to oxidation, can bind more readily to proteoglycans in the arterial wall, and can remain in circulation longer than larger LDL particles. (Feingold 2023)

Medium LDL

A shift in the baseline composition of LDL particles from large to medium and small particles has been linked to increased cardiovascular risk. Elevated concentrations of medium LDL particles have been associated with a higher incidence of cardiovascular disease, coronary heart disease, and stroke. (Pichler 2018)

Large LDL

A favorable measure of large LDL indicates a higher proportion of larger, less dense LDL particles, which are generally considered less atherogenic and therefore associated with a lower risk of plaque formation and cardiovascular disease. Large LDL particles have been linked to a lower risk of metabolic syndrome, suggesting that a predominance of large LDL particles may reduce the risk of cardiometabolic diseases. Though it might be assumed that a higher relative amount of large LDL particles is generally protective, the relative risk should be measured along with other risk factors including oxidative stress, endothelial health, and abundance of LDL and triglyceride particles. (Srisawasdi 2015)

HDL subclasses

HDL consists of particles with varying sizes, densities, and compositions. (Jin 2022) Although HDL cholesterol levels are inversely associated with coronary heart disease risk, merely raising total HDL cholesterol levels doesn't necessarily lower the risk of future cardiovascular events. (Lappegard 2021) Furthermore, very-high HDL (<80 mg/dL) is associated with an increased risk of cardiovascular disease. (Liu 2022) Thus, the protective effects of HDL are thought to stem from the functionality of various HDL particles rather than just the total HDL cholesterol concentration. (Lappegard 2021)

Large HDL

HDL particles consist of two major subclasses, large HDL, which are greater in size and more buoyant, and smaller HDL, which are more dense. (Degoricija 2019) Large HDL is thought to be more cardioprotective and associated with decreased coronary heart disease risk. (Benjamin 2018) Research suggests that adverse cardiac events are associated with significantly lower large HDL and higher small HDL subfractions. (Lee 2021) This may be due to the fact that low levels of large HDL can impair the effectiveness of the reverse cholesterol transport process, increasing risk of atherosclerosis. (Benjamin 2018)

Advanced cardiac testing panels can help assess risk, detect subclinical disease, and guide treatment strategies.

Apolipoproteins

Apolipoproteins are proteins that bind to lipids to form lipoproteins, which are essential for transporting lipids through the bloodstream. They play a crucial role in lipid metabolism by helping to stabilize lipoprotein particles and facilitate their uptake into cells. Key types of apolipoproteins described below include apolipoprotein A (ApoA1), which are part of HDL particles, and apolipoprotein B (ApoB), which is a major component of LDL and very-low-density lipoprotein (VLDL).

ApoA1

ApoA1 is a protein component of HDL particles and is considered anti-atherogenic. (Chandra 2014)(Greenland 2010) Research demonstrates that low ApoA1 levels are correlated with increased cardiovascular risk. (Riediger 2011) Another study demonstrated that ApoA1 is a better predictor for ischemic heart disease mortality in elderly men, when compared to HDL, LDL, and ApoB. (Florvall 2006)

ApoB

The ApoB test measures the amount of lipoprotein particles that contain ApoB on their surface. All pro-atherogenic lipoproteins, including chylomicron remnants, VLDL remnants, intermediate-density lipoprotein (IDL), LDL, and lipoprotein(a) (Lp(a)), carry one ApoB molecule. Therefore, ApoB levels indicate the total number of atherogenic particles present. Most circulating ApoB is linked to LDL particles. (Feingold 2023)

ApoB levels have a stronger association with atherosclerotic cardiovascular disease compared to LDL levels. While ApoB levels are similar to non-HDL levels in predicting atherosclerotic cardiovascular disease, ApoB levels provide a more accurate prediction when there's a discrepancy between these values. For example, some individuals will have a relatively high ApoB level but a relatively low non-HDL, or vice versa. Research demonstrated that subjects with a high ApoB and a low non-HDL are at a high risk of cardiovascular disease, while those with a low ApoB and a high non-HDL are at low risk. (Feingold 2023) This highlights how ApoB can serve as an excellent predictor of cardiovascular risk, offering additional insights beyond what's provided by a standard lipid panel.

ApoB/ApoA1 ratio

The ApoB/ApoA1 ratio is a marker that compares ApoB and ApoA1. A higher ApoB/ApoA1 ratio indicates a higher level of potentially more atherogenic lipoproteins relative to protective HDL particles, suggesting an increased risk of cardiovascular disease. Research showed that higher ApoB/ApoA1 ratios were effective predictors of coronary heart disease in both overweight and obese individuals, as well as those with type 2 diabetes. (Lu 2011)(Paunica 2023)

Lp(a)

Lp(a) is an LDL particle that is structurally similar to LDL, but it has an ApoA1 in addition to a single ApoB and is atherogenic. (Schmidt 2016) Numerous large studies have demonstrated an association between Lp(a) levels and atherosclerotic cardiovascular disease. Lp(a) is primarily genetically determined and not significantly affected by other established risk factors. Elevated levels of Lp(a) contribute significantly to the increased risk of cardiovascular disease associated with a family history of the condition. Given that Lp(a) is an independent risk factor and can play a significant role in pathogenesis, it's worth testing alongside standard lipid panels to help improve risk assessment. (Feingold 2023)

Inflammatory and oxidative stress markers

Inflammatory processes play a central role in the pathogenesis of atherosclerosis, and several markers of inflammation have been identified as predictors of future cardiovascular risk. (Blake 2002) Many of these markers promote a pro-inflammatory state and have been associated with stages of atherosclerosis and various cardiovascular diseases. Therefore, assessing inflammatory markers can enhance risk evaluation and assist in monitoring treatment outcomes.

hs-CRP

hs-CRP is a blood marker used to assess inflammation in the body. Elevated levels of hs-CRP can indicate chronic inflammation, which is associated with various conditions, including cardiovascular disease. It's particularly useful as it's a strong predictor for cardiovascular events. Elevated levels of CRP have been associated with an increased risk of myocardial infarction and stroke. (Poredos n.d.)

Myeloperoxidase

Myeloperoxidase (MPO) is an enzyme produced by leukocytes that drives the generation of several reactive oxidant species (ROS) and therefore contributes to inflammation and tissue damage. (Nicholls 2005) Elevated MPO levels lead to dysfunctional lipoproteins with greater atherogenic potential, reduced availability of nitric oxide (NO), endothelial dysfunction, impaired vasoreactivity, and increased plaque instability. (Ndrepepa 2019) Elevated levels of MPO are a marker for plaque instability and increased cardiovascular risk. (Lubrano 2015)(Ndrepepa 2019)

Fibrinogen

Fibrinogen is a protein produced by the liver that plays a crucial role in blood clotting. Measuring fibrinogen levels can help assess clotting function and inflammation status. One study demonstrated that patients with levels of fibrinogen have a significantly higher risk of cardiovascular disease by 102%. (Yang 2017)

Lp-PLA2

Lp-PLA2 is an enzyme associated with lipoproteins in the blood, particularly LDL. It plays a role in inflammation and atherosclerosis by hydrolyzing oxidized phospholipids in LDL, thereby leading to the production of pro-inflammatory products that can contribute to atherosclerosis. (Huang 2019)(Santoso 2020) Elevated levels of Lp-PLA2 are significantly associated with an increased risk of coronary heart disease and cerebrovascular disease. (Sheinberg 2024)

8-hydroxy-2'-deoxyguanosine

8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative damage caused by reactive oxygen species, has been associated with cardiovascular events, including stroke and heart failure, as well as all-cause mortality. (Thomas 2018)

Oxidized LDL

Oxidized LDL (oxLDL) refers to LDL particles that have been oxidized by reactive oxygen species, leading to the formation of oxidized lipids and proteins. OxLDL is particularly significant in the context of atherosclerosis; it's more likely to contribute to the formation of arterial plaques compared to non-oxidized LDL because it promotes inflammation and lipid deposition in the arterial wall. Increased oxLDL was found to be predictive of future coronary heart disease events in apparently healthy individuals. (Meisinger 2005)(Trpkovic 2015)

Cytokines

Certain cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor (TNF), can serve as markers for cardiovascular risk. Elevated levels of these pro-inflammatory cytokines are associated with increased inflammation, which can contribute to the development and progression of atherosclerosis and other cardiovascular conditions. Many prospective studies indicate that inflammatory cytokines are strong predictors of coronary artery disease, myocardial infarction, heart failure, and other adverse cardiac events. (Amin 2020) Cytokine levels can therefore be used to help predict cardiovascular risk and monitor disease progression.

Nutrition markers implicated in cardiovascular health

Nutrition is critical for cardiovascular health, and several nutritional markers can be used to identify nutrient deficiencies that may be affecting cardiovascular health. Identifying nutritional deficiencies and associated markers can help establish treatment goals that can help improve cardiovascular health.

Advanced testing that evaluates the status of key nutrients related to cardiovascular health can help identify nutritional deficiencies and guide targeted interventions to improve cardiovascular health.

Homocysteine

Homocysteine is an amino acid in the blood that results from the metabolism of methionine, an amino acid derived from dietary protein. Normally, the body prevents its accumulation by converting it into other substances with the help of nutrients like vitamin B6, vitamin B12, and particularly folate. Elevated homocysteine is linked to inflammation and atherosclerosis and is an independent risk factor for cardiovascular disease, stroke, and myocardial infarction. (Paganelli 2021)

Vitamin D

Testing vitamin D levels is valuable for assessing cardiovascular risk because low vitamin D has been associated with an increased likelihood of cardiovascular diseases including hypertension, heart failure, and ischemic heart disease. (Judd 2009) Vitamin D plays a role in reducing inflammation and supporting endothelial function, both of which are important for maintaining vascular health. (Kim 2020)(Krajewska 2022)

Omega-3 index

The omega-3 index is a measurement that reflects the levels of omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are important for promoting an anti-inflammatory environment. Omega-3 index is expressed as a percentage of total fatty acids and provides an indication of if an individual is getting enough omega-3s in their diet. Omega-3 intake is associated with a decreased risk of cardiovascular events. (Aung 2018)

Other related markers

Metabolic markers can help provide insight into insulin glycemic control, a factor that can influence cardiometabolic risk.

HbA1c and fasting insulin

Assessing HbA1c and fasting insulin levels in addition to fasting blood sugar is valuable for evaluating cardiovascular risk due to their roles in reflecting potential glucose metabolism and insulin sensitivity. HbA1c measures the average blood glucose levels over the previous 2–3 months, providing insight into long-term glucose control. Fasting insulin levels help to assess insulin resistance, which provides insight into insulin function.

Elevated HbA1c and fasting insulin levels can lead to type 2 diabetes, which is associated with an increased risk of cardiovascular disease, as elevated blood sugar can cause damage to blood vessels. (Raghavan 2019) Together, these tests offer a comprehensive view of glycemic control and can help guide appropriate preventive or therapeutic measures.

The bottom line

Advanced cardiac lab tests provide a more detailed and nuanced understanding of cardiovascular health compared to standard tests. By identifying risk factors that standard lipid profiles might miss, advanced tests may lead to more accurate risk stratification, precise monitoring, and intervention, leading to better management of cardiovascular risk and improved patient outcomes.