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HDL-cholesterol, LDL-cholesterol, and coronary atherosclerosis: observations from cardiac imaging studies

Comment by Konstantinos C. Koskinas, Population Science and Public Health Section

Preventive Cardiology

Blood cholesterol is a well-recognised risk factor for the development and progression of atherosclerosis. Consistent evidence from genetic studies, epidemiologic observations, and randomised controlled trials (RCT) has unequivocally shown that elevated plasma concentrations of atherogenic lipid, particularly low-density lipoprotein cholesterol (LDL-C), are causally linked to atherosclerotic cardiovascular disease (ASCVD).(1) Conversely, for higher-density lipoprotein cholesterol (HDL-C), higher levels are associated with a lower ASCVD risk.

In their recent article, Kim and all analyzed coronary computed tomography angiography (CCTA) data from 5,130 non-diabetic Korean patients without known coronary artery disease in relation to HDL-C and LDL-C levels.(2) Imaging outcomes included any obstructive plaque; presence of obstructive plaques in clinically most relevant locations (i.e. left-main or proximal left anterior descending artery); and multivessel obstructive lesions. The authors found that patients with low levels (< 40 mg/dL) of HDL-C, as compared with those with higher levels (≥ 40 mg/dL), had a higher prevalence of obstructive plaques (by any of the aforementioned three definitions), but only in the subgroup of patients with LDL-C levels <130 mg/dL. In contrast, there was no difference in the prevalence of obstructive plaques in relation to HDL-C in the context of higher (≥ 130 mg/dL) LDL-C levels.(2)

Some aspects of the study methodology deserve consideration in interpreting these results. First, thresholds for considering LDL-C levels as “normal” or “elevated” are not the same for all individuals, but rather depend on each individual’s cardiovascular risk: for patients with established ASCVD or at higher risk of developing ASCVD, lower LDL-C levels are generally recommenced.(3) In the study by Kim et al, about 26% had a high ASCVD risk score, whereby recommended LDL goals according to current guidelines are not <130 mg/dL but lower.(3) It would be of interest to explore whether favorable (high) HDL-C levels remain to be predictive of less advanced coronary atherosclerosis in the context of lower LDL-C levels (< 100 mg/dL) in these higher-risk primary-prevention individuals. Second, the long-established concept “the higher, the better” for HDL-C might may not apply for the entire spectrum of HDL-C levels, since extremely high HDL-C was paradoxically associated with high mortality in recent observational studies.(4) With respect to coronary atherosclerosis by CCTA, this aspect cannot be addressed by applying a dichotomous approach for HDL-C (< vs. ≥40 mg/dL). Notwithstanding these considerations, and taking into account the observational, cross-sectional study design (thus showing associations but precluding any inference on causality), Kim et al. provide interesting data that add to the evidence base of HDL-C and its relation to ASCVD risk.(2)

The inverse association between plasma HDL-C and the risk of ASCVD has been consistently shown in numerous epidemiological studies.(5) In contrast, a causal role of HDL-C in ASCVD was not confirmed in Mendelian randomisation studies (6), although the latter evidence requires cautious interpretation given that most genetic variants associated with lower HDL-C are also associated with higher LDL-C and triglyceride levels. Importantly, RCTs of medications that increase plasma HDL-C levels, e.g. cholesteryl ester transfer protein (CETP) inhibitors, failed to show a reduction in the risk of CV events.(7,8) Along the same lines, directly infused HDL mimetics that raise HDL-C plasma level did not reduce the progression of atherosclerosis as measured by intravascular ultrasound.(9)

Taken together, elevated HDL-C levels do associate with a lower risk of CVD in epidemiological studies, and consistently with fewer obstructive lesions in the CCTA study by Kim et al (2), but there is currently no RCT or genetic evidence that raising plasma levels of HDL-C effectively reduces ASCVD risk. In contrast, lowering LDL-C level by 1.0 mmol/l (38.7 mg/dL) reduces the risk of major cardiovascular event by about 20%.(10,11) Accordingly, current guidelines recommend LDL-C as the primary lipid analysis for screening, diagnosis, and management; HDL-C analysis is recommended to refine risk estimation.(3) With respect to physician-patient communication, it is essential to explain to our patients that high levels of their “good” (HDL) cholesterol may indeed be protective, but this does not compensate for the adverse, pro-atherogenic effects of elevated levels of “bad” (LDL) cholesterol.


Konstantinos C. Koskinas commented on this article:

2. Kim YG, Cho YR, Park GM, Won KB, Ann SH, Yang DH, Kang JW, Lim TH, Kim HK, Choe J, Lee SW, Kim YH, Yang YJ, Kim SJ, Lee SG. High-density lipoprotein cholesterol and the risk of obstructive coronary artery disease beyond low-density lipoprotein cholesterol in non-diabetic individuals. Eur J Prev Cardiol. 2020;27(7):706-714.

Other references:

1. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA, Krauss RM, Raal FJ, Schunkert H, Watts GF, Borén J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen MR, Tokgözoglu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ, Catapano AL. Low-density lipoproteins cause atherosclerotic cardiovascular disease. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38:2459-2472.

3. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111-188.

4. Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J. 2017;38(32):2478-2486.

5. Emerging Risk Factors Collaboration, Di Angelantonio E, Gao P, Pennells L, Kaptoge S, Caslake M, Thompson A, Butterworth AS, Sarwar N, Wormser D, Saleheen D, Ballantyne CM, Psaty BM, Sundstrom J, Ridker PM, Nagel D, Gillum RF, Ford I, Ducimetiere P, Kiechl S, Koenig W, Dullaart RP, Assmann G, D’Agostino RB Sr, Dagenais GR, Cooper JA, Kromhout D, Onat A, Tipping RW, Gomez-de-la-Camara A, Rosengren A, Sutherland SE, Gallacher J, Fowkes FG, Casiglia E, Hofman A, Salomaa V, Barrett-Connor E, Clarke R, Brunner E, Jukema JW, Simons LA, Sandhu M, Wareham NJ, Khaw KT, Kauhanen J, Salonen JT, Howard WJ, Nordestgaard BG, Wood AM, Thompson SG, Boekholdt SM, Sattar N, Packard C, Gudnason V, Danesh J. Lipid-related markers and cardiovascular disease prediction. JAMA. 2012;307:2499-2506.

6. Holmes MV, Asselbergs FW, Palmer TM, Drenos F, Lanktree MB, Nelson CP, Dale CE, Padmanabhan S, Finan C, Swerdlow DI, Tragante V, van Iperen EP, Sivapalaratnam S, Shah S, Elbers CC, Shah T, Engmann J, Giambartolomei C, White J, Zabaneh D, Sofat R, McLachlan S, consortium U, Doevendans PA, Balmforth AJ, Hall AS, North KE, Almoguera B, Hoogeveen RC, Cushman M, Fornage M, Patel SR, Redline S, Siscovick DS, Tsai MY, Karczewski KJ, Hofker MH, Verschuren WM, Bots ML, van der Schouw YT, Melander O, Dominiczak AF, Morris R, Ben-Shlomo Y, Price J, Kumari M, Baumert J, Peters A, Thorand B, Koenig W, Gaunt TR, Humphries SE, Clarke R, Watkins H, Farrall M, Wilson JG, Rich SS, de Bakker PI, Lange LA, Davey Smith G, Reiner AP, Talmud PJ, Kivimaki M, Lawlor DA, Dudbridge F, Samani NJ, Keating BJ, Hingorani AD, Casas JP. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J. 2015;36:539-550.

7. Lincoff AM, Nicholls SJ, Riesmeyer JS, Barter PJ, Brewer HB, Fox KAA, Gibson CM, Granger C, Menon V, Montalescot G, Rader D, Tall AR, McErlean E, Wolski K, Ruotolo G, Vangerow B, Weerakkody G, Goodman SG, Conde D, McGuire DK, Nicolau JC, Leiva-Pons JL, Pesant Y, Li W, Kandath D, Kouz S, Tahirkheli N, Mason D, Nissen SE; ACCELERATE Investigators. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376:1933-1942.

8. HPS/TIMI/REVEAL Collaborative Group, Bowman L, Hopewell JC, Chen F, Wallendszus K, Stevens W, Collins R, Wiviott SD, Cannon CP, Braunwald E, Sammons E, Landray MJ. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017;377:1217-1227.

9. Tardif JC, Ballantyne CM, Barter P, Dasseux JL, Fayad ZA, Guertin MC, Kastelein JJ, Keyserling C, Klepp H, Koenig W, L’Allier PL, Lesperance J, Luscher TF, Paolini JF, Tawakol A, Waters DD; Can HDL Infusions Significantly QUicken Atherosclerosis REgression (CHI-SQUARE) Investigators. Effects of the highdensity lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial. Eur Heart J. 2014;35:3277-3286.

10. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681.

11. Koskinas KC, Siontis GCM, Piccolo R, Mavridis D, Räber L, Mach F, Windecker S. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur Heart J. 2018;39:1172-1180.

Notes to editor

Note: The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology