Register now to R3i !
Your login
Your password
Confirm your password
Your email
I agree to receive the R3i newsletter

Focus on...

19 July 2022
Elevated lipoprotein(a) promotes progression of vulnerable plaque
Among patients with advanced coronary artery disease, elevated serum levels of lipoprotein(a) [Lp(a)] were associated with accelerated progression of the low-attenuation necrotic core of atherosclerotic plaques, as assessed by coronary computed tomography angiography.
Kaiser Y, Daghem M, Tzolos E, et al. Association of lipoprotein(a) with atherosclerotic plaque progression. J Am Coll Cardiol 2022;79:223–233.


Objective: To investigate whether Lp(a) is associated with adverse plaque progression.
Study design: Subjects were a cohort of the DIAMOND study, a double-blind, randomized, parallel-group, placebo-controlled single-centre trial. Coronary computed tomography angiography (CCTA) was performed at baseline and 12 months.
Study population: The cohort comprised 191 patients (mean age 65.9 years, 80% male, 19% with diabetes mellitus) with clinically stable multivessel coronary artery disease. Patients were categorized by serum Lp(a) level as either high (≥70 mg/dL, n=43) or low (<70 mg/dL, n=148). Most patients were on a statin (94.7%), and all were on antiplatelet therapy.
main study variable: CCTA was used to assess progression of total, calcific, non-calcific, fibro-fatty, and low- attenuation plaque (necrotic core), as well as the percentage change in the plaque volume over 12 months in each group.
Methods: The relationship of Lp(a) with plaque progression was assessed using multivariable linear regression analysis with adjustment for body mass index, segment involvement score, and ASSIGN score (a Scottish cardiovascular risk score comprised of age, sex, smoking, blood pressure, total and high-density lipoprotein [HDL]–cholesterol, diabetes, rheumatoid arthritis, and deprivation index). The segment involvement score was calculated as the total number of coronary artery segments exhibiting plaque, irrespective of the degree of luminal stenosis within each segment. Plaque measurements (total, calcific, non-calcific, low-attenuation, low-density and fibro-fatty plaque volume) were performed using validated software (AutoPlaque, version 2.5). Plaque progression was defined as the difference in plaque volumes between the baseline and the follow-up CCTA scan.
Main results:

At baseline, median (range) Lp(a) was 100 (82 to 115) mg/dL in the high Lp(a) group and 10 (5 to 24) mg/dL in the low Lp(a) group. There were no differences in body mass index, smoking status, diabetes mellitus, low-density lipoprotein cholesterol, and serum creatinine concentrations between those in the low and high Lp(a) groups. Coronary artery calcium scores, plaque volumes and plaque burden were similar in each group.  


Overall, 160 patients had a repeat CCTA at 12 months. Compared with patients in the low Lp(a) group, those in the high Lp(a) group had a larger increase in low attenuation plaque volume and fibro-fatty plaque volume (Table 1).


Univariable analysis showed that Lp(a) was associated with progression of low-attenuation plaque volume (11.6% change for each 50 mg/dL increase in Lp(a), p= 0.018), but not with progression of total, calcific, and non-calcific plaque volumes. This association persisted in multivariable regression analysis adjusting for body mass index, ASSIGN score, and segment involvement score (10.5% change for each 50 mg/dL increase in Lp(a), p=0.048). Results were similar for fibro-fatty plaque progression (7.0% change, p=0.025 on univariable analysis and 6.2% change, p=0.053 on multivariable analysis).  


Table 1. Change in plaque volume assessed by CCTA from baseline to 12 months. Data are given as mean (standard deviation).

Change in plaque volume


High Lp(a)


Low Lp(a)



Total plaque

128.2 (330.6)

88.5 (312.2)


Calcific plaque

19.7 (69.7)

1.0 (85.7)


Non-calcific plaque

108.5 (319.6)

87.5 (288.6)


Low-density plaque

26.2 (88.4)

-0.7 (50.1)


Fibro-fatty plaque

55.0 (242.8)

-25.0 (157.4)


Authors’ conclusion: Among patients with advanced stable coronary artery disease, Lp(a) is associated with accelerated progression of coronary low-attenuation plaque (necrotic core). This may explain the association between Lp(a) and the high residual risk of myocardial infarction, providing support for Lp(a) as a treatment target in atherosclerosis.


Epidemiologic and genetic studies provide strong support that Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease (1). Among acute coronary syndrome patients on statin therapy, elevated Lp(a) concentration was associated with adverse cardiovascular outcomes , prompting consideration of this as a potential biomarker for residual vascular risk (2-4). However, the mechanisms by which Lp(a) promotes atherogenesis are not fully elucidated.

In this study, CCTA was used to assess changes in plaque morphology and track atherosclerosis progression. This rationale is supported by previous studies which have demonstrated a strong association between plaque composition, in particular low-attenuation plaque, and cardiovascular events (5). The study showed for the first time an independent association between Lp(a) concentration and plaque morphology and volume among patients with multivessel disease. Elevated Lp(a) concentration was associated with progression of low-attenuation plaque volume, but not of other more stable plaque phenotypes. This adverse plaque phenotype, characterised by a large necrotic core, inflammation, microcalcification, and a thin fibrous cap, is at greater risk of plaque rupture. These findings provide insights into the possible mechanisms by which elevated Lp(a) concentration promotes cardiovascular risk. Moreover, the lack of difference in the progression of total plaque volume or more stable plaque subtypes between the groups with high or low Lp(a) concentration suggests that accumulation of Lp(a) particles within the plaque is less relevant.

The authors acknowledge the lack of heterogeneity in the patient population (predominantly male Caucasian patients) and the single-centre design of the study. Despite these limitations, the results of the study provide a basis for testing whether lowering Lp(a) concentration reduces low-attenuation plaque progression and prevents ischaemic events in large randomized trials.

References 1. Reyes-Soffer G, Ginsberg HN, Berglund L, et al. Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol. 2022 Jan;42(1):e48-e60.
2. Takahashi D, Wada H, Ogita M, et al. Impact of lipoprotein(a) as a residual risk factor in long-term cardiovascular outcomes in patients with acute coronary syndrome treated with statins. Am J Cardiol 2022;168:11-16.
3. Schwartz GG, Ballantyne CM, Barter PJ, et al. Association of lipoprotein(a) with risk of recurrent ischemic events following acute coronary syndrome: analysis of the dal-Outcomes randomized clinical trial. JAMA Cardiol 2018;3:164-168.
4. Shah NP, Pajidipati NJ, McGarrah RW, et al. Lipoprotein (a): an update on a marker of residual risk and associated clinical manifestations. Am J Cardiol 2020;126:94–102.
5. Williams MC, Moss AJ, Dweck M, et al. Coronary artery plaque characteristics associated with adverse outcomes in the SCOT-HEART study. J Am Coll Cardiol 2019;73:291–301.
Key words residual risk; lipoprotein(a); treatment target; atherosclerosis progression; plaque composition