Elsevier

Atherosclerosis

Volume 243, Issue 2, December 2015, Pages 560-566
Atherosclerosis

Plasma concentrations of molecular lipid species in relation to coronary plaque characteristics and cardiovascular outcome: Results of the ATHEROREMO-IVUS study

https://doi.org/10.1016/j.atherosclerosis.2015.10.022Get rights and content

Highlights

  • Several molecular lipid species are associated with coronary plaque characteristics.

  • Several molecular lipid species are associated with 1-year MACE in CAD patients.

  • Plasma ceramide (d18:1/16:0) is associated with vulnerable plaque and 1-year MACE.

Abstract

Background and Aims

Previous lipidomics analyses have demonstrated that several lipid molecules in plasma are associated with fatal outcome in patients with coronary artery disease (CAD). This study aims to investigate the associations of previously identified high risk lipid molecules in plasma with coronary plaque characteristics derived from intravascular ultrasound virtual histology (IVUS-VH) imaging, with coronary lipid core burden index (LCBI) on near-infrared spectroscopy (NIRS), and with one year cardiovascular outcome in patients with CAD.

Methods

Between 2008 and 2011, IVUS-VH imaging of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography for acute coronary syndrome (ACS) or stable CAD. NIRS imaging was additionally performed in 191 patients. Plasma concentrations of molecular lipids were measured with mass spectrometry.

Results

Several cholesteryl ester, ceramide and lactosylceramide species and ceramide ratios were associated with vulnerable plaque characteristics on IVUS-VH and NIRS imaging and with 1-year major adverse cardiac events (MACE, defined as all-cause mortality, ACS and unplanned coronary revascularization). In particular, ceramide d18:1/16:0 was consistently associated with higher necrotic core fraction on IVUS-VH (p = 0.001), higher LCBI (p = 0.024) on NIRS and higher MACE rate (adjusted HR 1.79 per standard deviation increase in log-transformed lipid concentration, 95%CI 1.24–2.59, p = 0.002).

Conclusion

Several molecular lipid species, and particularly ceramide(d18:1/16:0), are associated with the fraction of necrotic core tissue and lipid core burden in coronary atherosclerosis, and are predictive for 1-year clinical outcome after coronary angiography. These molecular lipids may improve risk stratification in CAD and may also be interesting therapeutic targets for the treatment of atherosclerotic disease.

Introduction

In current clinical practice, the concentration of low-density lipoprotein (LDL) cholesterol is often used for risk stratification in coronary artery disease (CAD). However, LDL cholesterol represents merely one aspect of lipid metabolism. Lipidomic analyses have demonstrated that hundreds of molecular lipid species are present in human plasma [1]. It is reasonable to assume that some of these molecular lipid species are also directly involved in the development of atherosclerosis [2], [3], [4]. Assessment of such 'high risk' molecular lipids may further improve our understanding of the development of atherosclerosis and may also improve CAD risk stratification. In fact, we have recently identified several molecular lipid species that are associated with fatal outcome in patients with CAD by performing lipidomic analysis in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study [5].

So far, lipidomics studies in CAD have mostly examined associations with clinical cardiovascular outcomes. Investigations using sophisticated imaging techniques may provide further insight into the pathophysiological role of lipid species in CAD. Intravascular ultrasound virtual histology (IVUS-VH) is an in-vivo imaging technique that analyzes radiofrequency backscatter [6]. IVUS-VH imaging allows for accurate measurement of the extent of coronary atherosclerosis and of the composition of atherosclerotic plaque, including necrotic core tissue [6], [7], [8], [9]. Previous studies have demonstrated that the amount of necrotic core tissue on IVUS-VH predicts cardiovascular outcome [7], [8], [9]. Near-infrared spectroscopy (NIRS) is another in-vivo imaging technique that analyzes tissue scattering and absorption of light in the near-infrared wavelength region. NIRS allows for identification of plaques with lipid cores in coronary atherosclerosis [10]. We have recently demonstrated that the lipid core burden assessed by NIRS predicts cardiovascular outcome [11].

This study aims to investigate the associations of high risk molecular lipids, previously identified in the LURIC study, with coronary plaque characteristics assessed by IVUS-VH imaging, with coronary lipid core burden assessed by NIRS imaging, and with 1 year cardiovascular outcome in patients with CAD.

Section snippets

Study population

The design of The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis – Intravascular Ultrasound (ATHEROREMO-IVUS) study has been described in detail elsewhere [7], [12]. In brief, 581 patients who underwent diagnostic coronary angiography or percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) or stable angina pectoris were included between 2008 and 2011 in the Erasmus MC, Rotterdam, the Netherlands. The ATHEROREMO-IVUS study was

Baseline characteristics

Mean age of the patients was 61.5 ± 11.3 years, 75% were men, and 55% were admitted with ACS (Table 1). ACS patients had higher concentrations of CE 14:0, CE 18:3, CE 22:5, Cer(d18:1/16:0), Cer(d18:1/24:0), LacCer(d18:1/18:0) and Cer(d18:1/16:0)/Cer(d18:1/24:0) than patients with stable CAD (Table 2). Patients who used statins at hospital admission had lower concentrations of the majority of the molecular lipids compared to patients who did not used statins (Supplemental Table 1).

Association between molecular lipids and coronary plaque characteristics

Patients whose

Discussion

This study investigated the association of eight previously identified high risk cholesteryl ester, ceramide and lactosylceramide lipids and three ceramide ratios with coronary plaque characteristics on IVUS-VH and NIRS imaging, as well as with 1-year clinical outcome in patients with established CAD undergoing coronary angiography. The main finding is that higher plasma concentrations of several of these molecular lipid species are associated with more vulnerable plaque morphology, reflected

Funding sources

The ATHEROREMO-IVUS study was funded by the European Commission, Seventh Framework Programme (grant number FP7-HEALTH-2007-2.4.2-1). Jin M. Cheng was supported by the Netherlands Heart Foundation (grant number NHS2009B091).

Disclosures

Matti Suoniemi, Terhi Vihervaara, Marko Sysi-Aho, Kim Ekroos and Reijo Laaksonen are employed by Zora Biosciences, Espoo, Finland. Other authors declare no conflict of interest.

Acknowledgments

We would like to thank the following interventional cardiologists and technical staff for their contribution to this study: Eric Duckers, MD, PhD; Jurgen M.R. Ligthart; Nicolas van Mieghem, MD; Carl Schultz, MD, PhD; Karen T. Witberg and Felix Zijlstra, MD, PhD. We are indebted to professor Willem van der Giessen, who made a valuable contribution to the design and completion of the study, but passed away before finalization of this work.

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