Assessing residual cardiovascular risk and vulnerable plaques via non-traditional lipids: From biomarkers to novel targets for precision therapy

Table 2 Clinical applicability, measurement characteristics, and evidence status of major non-traditional lipid-related parameters

Parameters	Definition/composition	Main biological characteristics	Atherosclerotic mechanism/potential	Clinical significance
Lp(a)	Lipoproteins containing apoB100 and Apo(a)	The structure is stable and not easily affected by lifestyle	Promote atherosclerosis, inflammation and thrombosis; even a low LDL-C level remains a risk factor[9,13]	Independent and causal ASCVD risk factors; a powerful marker of residual cardiovascular risk[9,56]
LDL-P, sdLDL-C	The total number and diameter of LDL particles; sdLDL-C refers to small and dense LDL-C	Cholesterol transport binds to receptors through apoB100	SdLDL particles are more likely to be filtered into the subendothelial space; more sensitive to oxidation, it promotes the formation of foam cells[57]	When LDL-C and LDL-P are inconsistent, LDL-P is superior to LDL-C in predicting the risk of ASCVD[58,59]
Non-HDL-C	The total amount of cholesterol in all atherosclerotic lipoproteins except HDL	Reflect the cholesterol load of all atherogenic lipoproteins	Better represents the overall atherosclerotic burden; related to coronary artery calcification and necrotic core volume[7,32]	Useful marker for assessing the risk of CVD, especially in patients with diabetes or high triglycerides; residual risks can be identified[7]
ApoE	The primary determinants in lipoprotein metabolism include three isomers: Ε2, ε3, and ε4	Mediate the clearance of plasma lipoproteins; regulate cellular cholesterol homeostasis; affect inflammation and cellular signaling	ApoE4 is associated with an increased risk of hyperlipidemia and atherosclerosis. It affects the inflammation and stability of plaques[60]	Genetic determinants of the risk of atherosclerosis; affecting the vulnerability of plaques[60]
ApoA1	Main structural protein of HDL	Key components involved in reverse cholesterol transport; facilitating cholesterol efflux from peripheral cells	Promote the outflow of cholesterol from lesions and reduce cholesterol accumulation; protect plaques from the development of necrotic cores[40]	Low levels are associated with unstable plaques; reverse cholesterol transport dysfunction is a cardiovascular risk factor[41]
RC	Cholesterol in triglyceride-rich lipoprotein metabolites	Metabolic residues of triglyceride-rich lipoproteins; high content in a non-fasting state	It penetrates and is retained within the arterial intima, leading to endothelial dysfunction, inflammation and atherosclerosis[12,61]	An important indicator for predicting the incidence of ASCVD; independently associated with unstable plaques; explaining the residual risk after good control of LDL-C[45,62]
PUFAs	Fatty acids containing two or more double bonds in their hydrocarbon chains, such as ω-3 PUFAs (e.g. EPA, docosahexaenoic acid)	Regulation of cell membrane fluidity lipid medium precursors; anti-inflammatory effect	ω-3 PUFAs can lower triglycerides, reduce inflammation, stabilize plaques and prevent plaque progression[63]	Potential adjunctive interventions; EPA may improve plaque characteristics in selected populations, but routine PUFA supplementation remains unsupported for plaque stabilization[63]

Lp(a): Lipoprotein(a); LDL-P: Low-density lipoprotein particle number; sdLDL-C: Small dense low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; ApoE: Apolipoprotein E; ApoA1: Apolipoprotein A1; RC: Remnant cholesterol; PUFAs: Polyunsaturated fatty acids; Apo(a): Apolipoprotein(a); EPA: Eicosapentaenoic acid; ASCVD: Atherosclerotic cardiovascular disease; CVD: Cardiovascular disease.