https://orcid.org/0000-0001-6441-3339
This editorial refers to ‘Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial’†, by M.J. Budoff et al., on page .
Atherosclerotic plaque imaging can help us unravel some of the features leading to cardiovascular (CV) events and contribute to risk prediction. Recent advances in imaging have enabled us to detect and quantify the plaque burden and characteristics by non-invasive and invasive technology. These characteristics, such as inflammation, microcalcification, angiogenesis, positive remodelling, presence of a thin fibrous cap, and a large necrotic core, can now be visualized by morphological or biological imaging. Coronary computed tomographic angiography (CCTA) has emerged as a promising tool to non-invasively provide information on the degree of luminal stenosis, plaque presence, and composition.The CONFIRM study was one of the earlier studies showing that CCTA findings of plaque location, composition, and stenosis severity improved risk prediction over traditional risk factors.1 A meta-analysis of 13 studies reporting plaque characterization by CCTA and the incidence of major cardiovascular events (MACE) showed that, in addition to plaque burden, the presence of low-attenuation plaques (LAPs), spotty calcium, positive remodelling, and napkin-ring sign identifies high risk plaques and are strongly associated with MACE.2 In this meta-analysis, the strongest predictor of events was the presence of non-calcified plaque.2 More recently, the SCOT-HEART trial showed that, in 1769 patient with stable chest pain, LAP burden was the strongest predictor of fatal or non-fatal myocardial infarction.3 Although CT cannot analyse the plaque in detail because of its spatial resolution, lower plaque attenuation values have been correlated with necrotic core and fibrofatty tissue on virtual histology intravascular ultrasound (IVUS) imaging.4
There is extensive evidence from Mendelian randomization studies, clinical trials, and epidemiology that apoprotein B-containing lipoproteins, mainly LDL-cholesterol (LDL-C), are causal for cardiovascular disease (CVD).5LDL-C lowering with high intensity statins, ezetimibe, and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors affects plaque composition, and decreases percent atheroma volume (PAV) as well as CV events.6–8 In addition to decreasing the necrotic core, PAV, and thickening the fibrous cap, statins also increase plaque calcification (Figure 1).9
The effects of statins and EPA on atherosclerosis.
Can mechanisms other than LDL-C lowering affect plaque characteristics?
Remnant cholesterol, that is the cholesterol content of triglyceride (TG)-rich lipoproteins, which is increased especially in insulin-resistant states, is also causal for CVD and has been related to coronary atheroma progression by IVUS studies.10 The association between remnant cholesterol levels and coronary atherosclerotic burden is also significant in patients with optimal LDL-C levels,11 moving the attention on the treatment of the residual CV risk in statin-treated patients. The omega-3 eicosapentaenoic acid (EPA) possesses TG-lowering properties, but also presents potential beneficial effects on atherosclerotic plaques, as it was shown to decrease characteristics associated with vulnerable plaque by increasing the thickness of the fibrous cap in patients treated with statins, and also to reduce atheroma-associated inflammation.12 In agreement with these observations, the CHERRY study randomized coronary heart disease patients to EPA + pitavastatin or pitavastatin alone and evaluated coronary plaque volume and composition by integrated backscatter (IB)-IVUS.13 Although follow-up was only 6–8 months, and the dose of EPA was 1.8 g/day, the EPA + pitavastatin group had a greater reduction in total atheroma volume and lipid volume of coronary plaque.13 Atherosclerotic plaques rapidly incorporate EPA, and a higher content of EPA within the atheroma is associated with decreased plaque inflammation and increased stability.14 Other clinical trials have reported beneficial effects on inflammation during the treatment with purified EPA.15
In this issue of the European Heart Journal, the EVAPORATE trial sought to determine whether adding 4 g/day of icosapent ethyl (IPE), a highly purified form of EPA ethyl ester, to statin therapy would change plaque volume and characteristics measured by serial multidetector computed tomography (MDCT) in middle-aged hypertriglyceridaemic patients with coronary artery disease.16 The primary endpoint was change in LAP volume at 18 months. IPE + statin treatment was associated with a significant reduction in LAP volume compared with statin plus placebo (which was mineral oil); significant differences between IPE and placebo treatment were observed also when other plaque characteristics were evaluated, including total plaque, total non-calcified plaque, and fibrofatty and fibrous plaque.16 The authors also addressed the question of whether the mineral oil used as a placebo might have harmful effects; however, any significant relationship between mineral oil placebo consumption and progression of coronary plaque volumes was not observed.17 Surprisingly, TGs were decreased similarly in IPE- or placebo-treated patients; LDL-C and HDL-C levels were not affected by any of the treatments. Based on this last observation, the authors attribute the favourable results reported in this trial to pleiotropic, non-lipid-related effects of IPE, which may include antithrombotic, antiplatelet, anti-inflammatory, antioxidant, and proresolving effects. The results reported in the EVAPORATE trial further establish a role for EPA-based formulations and provide further insights into the mechanisms by which EPA reduces CVD beyond its TG-lowering properties. Previously in the REDUCE-IT trial, IPE added to a statin was shown to reduce first CV events by 25% and total (first and subsequent) CV events by 30%.18 , 19 Although the mechanisms of benefit were not fully explained, there was a significant decrease in TGs, a decrease in high sensitivity C-reactive protein (hs-CRP) levels, and benefit was proportional to EPA levels.18 , 20Hs-CRP levels, however, were not reported in the EVAPORATE trial.
Clinical trials testing combinations of EPA and DHA failed to observe any benefits, probably due to the distinct effects of these two omega-3 fatty acids.15 EPA associates with atherosclerotic plaque membranes in blood vessels where it modulates lipid oxidation and inflammation-related pathways, thus resulting in the improvement of endothelial function, and the reduction of inflammatory cell recruitment and proinflammatory mediator production.15 , 21 EPA also inhibits the formation of cholesterol crystals, which activate Nod-Like Receptor Protein 3 (NLRP3) inflammasomes and can destabilize the plaque fibrous cap;15 this effect could not be reproduced by other TG-lowering agents or docosahexaenoic acid. Finally, EPA modulates atherosclerotic plaque features, leading to an overall higher atherosclerotic plaque stability.21 Of note, some beneficial effects of EPA appear to be enhanced when given in combination with a statin, which may suggest a role for EPA in the treatment of residual CV risk in hypertriglyceridaemic patients with well controlled LDL-C levels. The findings of the EVAPORATE trial shed some light on the mechanism of action of EPA on the plaque, although much remains to be explained, especially since the TG-lowering effect seen in REDUCE-IT was not reproduced. Newer imaging techniques such as radiomic imaging will redefine our understanding of unstable plaques and provide more insight into mechanistic action of therapies.
Conflict of interest: L.T. has received consulting fees/honoraria from Abbott, Actelion, Amgen, Servier, Pfizer, Bayer, Daiichi-Sankyo Sanofi Aventis, Merck Sharp & Dohme, Mylan, Novartis, and Recordati. She is currently the President of the European Atherosclerosis Society. A.L.C. reports receiving grants from Mediolanum; grants and personal fees from Amgen, Pfizer, Merck, Regeneron, and Sanofi; non-financial support and personal fees from Menarini, Eli Lilly, Recordati, Sigma-Tau Pharmaceuticals, and Kowa; and personal fees from AstraZeneca, Aegerion, Amaryt, Medco, and Genzyme outside the submitted work.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
Footnotes
† doi:10.1093/eurheartj/ehaa652.
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