Prediction of Residual Risk by Ceramide-Phospholipid Score in Patients With Stable Coronary Heart Disease on Optimal Medical Therapy

Abstract

Background Identification of patients with stable coronary heart disease who are at significant residual risk could be helpful for targeted prevention. Our aim was to determine the prognostic value of the recently introduced ceramide- and phospholipid-based risk score, the Cardiovascular Event Risk Test (CERT2), in patients with stable coronary heart disease on optimal medical therapy and to identify biological processes that contribute to the CERT2 score. Methods and Results Plasma samples (n=11 222) obtained from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were analyzed using a tandem liquid chromatography-mass spectrometry method. STABILITY was a trial in patients with stable coronary heart disease randomized to the lipoprotein-associated phospholipase A2 inhibitor darapladib or placebo on optimized medical therapy at baseline, with a median follow-up of 3.7 years. Hazard ratios per SD for the CERT2 risk score were 1.32 (95% CI, 1.25-1.39) for major adverse cardiovascular event, 1.47 (95% CI, 1.35-1.59) for cardiovascular death, 1.32 (95% CI, 1.16-1.49) for stroke, 1.23 (95% CI, 1.14-1.33) for myocardial infarction, and 1.56 (95% CI, 1.39-1.76) for hospitalization due to heart failure, when adjusted for traditional cardiovascular risk factors. CERT2 showed correlation (P<0.001, r>0.2) with inflammatory markers high-sensitivity C-reactive protein, interleukin 6, the heart failure marker N-terminal pro-B-type natriuretic peptide, and low-density lipoprotein cholesterol. After also adjusting for levels of other prognostic biomarkers, the CERT2 score was still independently related to the risk of cardiovascular death but not to nonfatal events. Conclusions The CERT2 risk score can detect residual risk in patients with stable coronary heart disease and is associated with biomarkers indicating inflammation, myocardial necrosis, myocardial dysfunction, renal dysfunction, and dyslipidemia. REGISTRATION URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT00799903.

Keywords: CERT2; biomarker; cardiovascular; inflammation; lipid; risk.

Figures

Figure 1. CERT2 is associated with the risk of future cardiovascular events.

Kaplan–Meier curves of the cumulative event rate by the Cardiovascular Event Risk Test (CERT2) risk groups for (A) major adverse cardiovascular event (MACE)/hospitalization for heart failure (HHF), (B) MACE, (C) cardiovascular (CV) death, and (D) HHF.

Figure 2. CERT2 is associated with lipid and inflammatory biomarkers.

The figure presents Spearman correlations of the Cardiovascular Event Risk Test (CERT2) and its components with other biomarkers. eGFR indicates estimated glomerular filtration rate; GDF15, growth differentiation factor‐15; HDL‐C, high‐density lipoprotein cholesterol; hs‐CRP, high‐sensitivity C‐reactive protein; hs‐TnT, high‐sensitivity troponin T; IL‐6, interleukin 6; LDL‐C, low‐density lipoprotein cholesterol; Lp‐PLA2, lipoprotein‐associated phospholipase A2; and proBNP, N‐terminal pro‐B‐type natriuretic peptide.