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8 October 2013
Triglyceride-rich lipoproteins associate with unstable carotid plaque
This study highlights the relevance of triglyceride-rich lipoprotein and their remnants, together with small dense low-density lipoprotein (LDL), in modulating carotid plaque cellular composition. Non-high-density lipoprotein cholesterol (non-HDL-C), which reflects the sum of cholesterol carried in these lipoproteins, should be a priority target for reducing residual cardiovascular risk beyond LDL cholesterol (LDL-C).
Zambon A, Puato M, Faggin E, Grego F, Rattazzi M, Pauletto P. Lipoprotein remnants and dense LDL are associated with features of unstable carotid plaque: A flag for non-HDL-C. Atherosclerosis 2013;230:106-9.
Objective Although LDL-C is strongly associated with coronary heart disease, the association with stroke is weaker and inconsistent. The current study investigated the potential contribution of each lipoprotein class, including dense LDL, triglyceride-rich lipoproteins (very low-density lipoproteins [VLDL] and their remnants and intermediate-density lipoproteins [IDL]), on the cellular composition of carotid plaques.
Study design Open study
Study population

45 consecutive patients (35 males and 10 females, mean age 68 years) undergoing endarterectomy for significant narrowing (>70%) of the internal carotid artery. All patients were on antiplatelet therapy and 9 (20%) were on a statin. Mean fasting lipid levels were 153 mg/dl (3.96 mmol/L) for LDL-C, 53 mg/dL (1.37 mmol/L) for high-density lipoprotein cholesterol (HDL-C), 144 mg/dL (1.63 mmol/L) for triglycerides and 180 mg/dL (4.65 mmol/L) for non-HDL-C.

Primary variable • Carotid plaque macrophage content, a marker of unstable plaque

Plaque samples were analysed for cellular composition (macrophages, smooth muscle cells and lymphocytes) by immunocytochemistry using monoclonal antibodies. Lipoprotein subclasses were separated by gradient ultracentrifugation and cholesterol measured in each fraction.

Main results

Carotid plaque macrophage content was significantly associated (p<0.01) with cholesterol in triglyceride-rich lipoprotein remnants and dense LDL, but not with cholesterol in HDL subclasses. Multiple regression analyses showed that non-HDL-C was the only lipid parameter (other than LDL density) that was significantly associated with plaque macrophage accumulation (p=0.021).

Author's conclusion This study provides evidence that cholesterol carried in dense LDL and triglyceride-rich lipoproteins significantly affects carotid plaque cellular content, in particular macrophage content, a marker of unstable plaque. The study also highlights the relevance of targeting non-HDL-C in patients at high residual cardiovascular risk, given that it was the only modifiable lipid parameter (other than LDL density) that was associated with macrophage plaque content.


Stroke is the second most common cause of death in developed countries. In Europe, more than one in seven women and one in ten men die from stroke.(1) However, while there is a strong causal association between cholesterol and LDL-C and risk for coronary events, their individual association with stroke risk is weaker.(2) Statin therapy, the mainstay of LDL-C lowering therapy, has been shown to reduce the risk of stroke by 18%, with post hoc analysis from the SPARCL (Stroke Prevention by Aggressive Reduction of Cholesterol Levels) trial suggesting that intensive LDL-C lowering (<1.8 mmol/L) is associated with greater benefit.(2,3) Yet even with potent statin therapy, patients remain at high residual risk of stroke.

The Residual Risk Reduction Initiative (R3i) has consistently highlighted atherogenic dyslipidaemia, characterised by elevated triglyceride-rich lipoproteins and their remnants, low HDL-C and often by an increase in the preponderance of small dense LDL, as a key driver of accelerated atherosclerosis and residual cardiovascular risk in patients on LDL-C lowering therapy; this view is also supported by recent expert consensus.(4)
The failure of recent trials of interventions aimed at increasing circulating HDL-C levels to impact hard endpoints has raised the focus on triglyceride-rich lipoproteins, in particular remnant lipoproteins which represent the products of partially catabolized chylomicrons and VLDL, as a modifiable lipid contributor to residual cardiovascular risk.
In support, a recent Mendelian randomisation study showed that remnant lipoproteins are causal for ischaemic heart disease.(5) Furthermore, there is also convincing evidence for associations between the level of plasma triglycerides, a marker of triglyceride-rich lipoproteins and their remnants, and risk of ischaemic stroke.(6,7) Mechanistically, remnant lipoproteins are highly atherogenic as they are able to cross the endothelial barrier where they are taken up by scavenger receptors into the subendothelial space to promote foam cell formation.(8,9)

To provide further insight, the current study aimed to investigate the potential association of different lipoprotein subclasses with different plaque components. The macrophage is recognised as the key cellular mediator of the progression from unstable plaque to clinical event. The results of this study show that cholesterol carried in dense LDL, triglyceride-rich lipoproteins and their remnants is directly predictive of carotid macrophage content.
These data therefore provide a pathophysiological rationale for the contributory role of triglyceride-rich lipoproteins in the later stages of the atherothrombotic process, and ultimately progression to unstable plaque. As a consequence, the authors make the case for measurement of non-HDL-C, which measures the sum of cholesterol contained in LDL, IDL, triglyceride-rich lipoproteins and their remnants, together with lipoprotein(a), as a key target for treatment decisions in managing residual cardiovascular risk.
Such a view is also supported by recent international guidelines and the International Atherosclerosis Society Position statement for management of dyslipidaemia.(10,11)


1.  Nichols M, Townsend N, Luengo-Fernandez R, Leal J, Gray A, Scarborough P, Rayner M: European Cardiovascular Disease Statistics 2012. Sophia Antipolis: European Heart Network, Brussels, European Society of Cardiology;2012.
2. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009;8:453-63.
3. Amarenco P, Goldstein LB, Szarek M, et al. Eff ects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke 2007;38:3198–204.
4. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
5. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.
6. Freiberg JJ, Tybjærg-Hansen A, Jensen JS, Nordestgaard BG. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA 2008;300:2142–52.
7. Kim J-Y, Park J-H, Jeong S-W et al. High levels of remnant lipoprotein cholesterol is a risk factor for large artery atherosclerotic stroke. J Clin Neurol 2011;7:203–9.
8. Nordestgaard BG, Wootton R, Lewis B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol 1995;15:534-42.
9. Nakajima K, Nakano T, Tanaka A. The oxidative modification hypothesis of atherosclerosis: the comparison of atherogenic effects on oxidized LDL and remnant lipoproteins in plasma. Clin Chim Acta 2006;367:36–47.
Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005;96:939-49.
10. Reiner Z, Catapano AL, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011,32:1769-818.
11. The International Atherosclerosis Society. An International Atherosclerosis Society Position Paper: Global recommendations for the management of dyslipidemia. Full report [].