PLASMA CERAMIDE CONCENTRATIONS PREDICT RISK OF CARDIOVASCULAR EVENTS

1824 JACC March 21, 2017 Volume 69, Issue 11

Prevention PLASMA CERAMIDE CONCENTRATIONS PREDICT RISK OF CARDIOVASCULAR EVENTS Poster Contributions Poster Hall, Hall C Saturday, March 18, 2017, 3:45 p.m.-4:30 p.m. Session Title: Innovations in Cardiovascular Risk Assessment and Reduction Abstract Category: 32. Prevention: Clinical Presentation Number: 1235-057 Authors: Jeffrey Meeusen, Leslie Donato, Sandra Bryant, Grant Spears, Linnea Baudhuin, Allan Jaffe, Mayo Clinic, Rochester, MN, USA

Background: Ceramides are lipids that accumulate in tissues during hyperlipidemia and inflammation. Plasma concentrations of ceramides predict cardiovascular death in patients with CAD. Risk conferred is independent of age, sex, hypertension, smoking, LDL-C and HDL-C. Our objective was to validate ceramide risk in an independent set of patients with clinically ordered angiography. Methods: A validation cohort of 499 patients referred for coronary angiography was followed for MI, revascularization, stroke or mortality for a median of 5.9 years (IQR 3.0 - 13.0). CAD was defined as 50% stenosis in ≥1 coronary artery. A ceramide risk score based on Cer(16:0), Cer(18:0) and Cer(24:1); and their ratio to Cer(24:0) was calculated. One or two points were allotted for each value in the third or fourth quartile.

Results: Ceramides were significantly associated with cholesterol, LDL-C, triglycerides, hsCRP and Lp-PLA2. There were 191 events during 3,763 person years for an incidence of 5.1%. Total events and incidence were significantly higher among patients with an elevated ceramide score. Risk remained significantly higher in those with a score of 10-12 after adjusting for age, sex, hypertension, smoking, total cholesterol, HDL-C, hsCRP and LpPLA2; and in subgroup analyses of patients with LDL-C <100 mg/dL (n= 124) and those without CAD (n = 231). Conclusions: Our data expand the utility of ceramides to predictors of cardiovascular events among patients with low LDL-C and those without significant coronary stenosis. Ceramide Risk Score Subjects, N (%) Age, mean(SD) Female, N (%) Hypertension, N (%) Smoking, N (%) CAD, N (%) Biomarkers, median (IQR) Total cholesterol, mg/dL Triglycerides, mg/dL HDL cholesterol, mg/dL LDL cholesterol, mg/dL hsCRP, mg/L Lp-PLA2, ng/mL Outcomes Overall Events, N (%) MACE Incidence, per person year (95CI) Odds Ratio (95CI) Adjusted OR (95CI) LDL-C <100 mg/dL Events (Subjects) MACE Incidence Adjusted OR No CAD Events, N (subjects) MACE Incidence Adjusted OR

0 to 2 87 (17.4) 60±11 24 (27.6) 32 (36.8) 7 (8.0) 44 (50.6)

3 to 6 206 (41.3) 59±11 80 (38.8) 98 (47.6) 18 (8.7) 108 (52.4)

7 to 9 122 (24.5) 61±11 46 (37.7) 57 (46.7) 8 (6.6) 66 (54.1)

10 to 12 84 (16.8) 62±11 41 (48.8) 43 (51.2) 6 (7.1) 50 (59.5)

p-value 0.29 0.04 0.24 0.90 0.65

189 (173 - 222) 123 (88 - 180) 49 (39 - 59) 115 (96 - 138) 1.7 (0.7 - 2.9) 211 (182 - 270)

203 (180 - 227) 157 (117 - 205) 46 (38 - 56) 120 (98 - 145) 2.4 (1.0 - 5.0) 227 (180 - 278)

205 (174 - 236) 146 (112 - 210) 44 (37 - 54) 120 (99 - 150) 4.0 (1.5 - 9.3) 237 (195 - 298)

223 (200 - 254) 176 (134 - 255) 46 (36 - 52) 137 (110 - 161) 5.5 (3.0 - 18.7) 264 (209 - 309)

<0.01 <0.01 0.25 0.01 <0.01 <0.01

27 (31) 4.1% (2.8 - 6.0) Ref Ref

68 (33) 4.2% (3.3 - 5.2) 1.10 (0.64 - 1.90) 1.11 (0.63 - 1.98)

51 (41.8) 5.6% (4.2 - 7.3) 1.60 (0.90 - 2.87) 1.50 (0.81 - 2.80)

45 (53.6) 8.1% (6.1 - 10.7) 2.56 (1.38 - 4.84) 2.10 (1.05 - 4.39)

<0.01 <0.01 <0.01 0.03

7 (26) 3.7% (1.6 - 7.5) Ref

13 (53) 12 (32) 10 (13) <0.01 3.0% (1.7 - 5.2) 5.0% (2.8 - 8.6) 16.4% (9.0 - 27.8) <0.01 1.26 (0.38 - 4.40) 1.59 (0.47 - 5.71) 13.1 (1.97 - 117) <0.01

7 (43) 2.2% (1.0 - 4.7) Ref

23 (94) 19 (56) 16 (34) 2.9% (2.0 - 4.4) 3.9% (2.5 - 6.0) 7.8% (4.8 - 12.3) 1.81 (0.69 - 5.24) 2.53 (0.91 - 7.71) 3.94 (1.18 - 14.2)

0.02 0.01 <0.01