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t=() Plasma Ceramides Predict Cardiovascular Death in CAD and ACS

Plasma Ceramides Predict Cardiovascular Death in Patients With Stable Coronary Artery Disease and Acute Coronary Syndromes Beyond LDL-Cholesterol

Reijo Laaksonen; Kim Ekroos; Marko Sysi-Aho; Mika Hilvo; Terhi Vihervaara; Dimple Kauhanen; Matti Suoniemi; Reini Hurme; Winfried März; Hubert Scharnagl; Tatjana Stojakovic; Efthymia Vlachopoulou; Marja-Liisa Lokki; Markku S. Nieminen; Roland Klingenberg; Christian M. Matter; Thorsten Hornemann; Peter Jüni; Nicolas Rodondi; Lorenz Räber; StephanWindecker; Baris Gencer; Eva Ringdal Pedersen; Grethe S. Tell; Ottar Nygå rd; Francois Mach; Juha Sinisalo; Thomas F. Lüscher

| Disclosures

Eur Heart J. 2016;37(25):1967-1976. 

 

Abstract and Introduction

Abstract

Aims The aim was to study the prognostic value of plasma ceramides (Cer) as cardiovascular death (CV death) markers in three independent coronary artery disease (CAD) cohorts.

Methods and results Corogene study is a prospective Finnish cohort including stable CAD patients (n = 160). Multiple lipid biomarkers and C-reactive protein were measured in addition to plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1). Subsequently, the association between high-risk ceramides and CV mortality was investigated in the prospective Special Program University Medicine—Inflammation in Acute Coronary Syndromes (SPUM-ACS) cohort (n = 1637), conducted in four Swiss university hospitals. Finally, the results were validated in Bergen Coronary Angiography Cohort (BECAC), a prospective Norwegian cohort study of stable CAD patients. Ceramides, especially when used in ratios, were significantly associated with CV death in all studies, independent of other lipid markers and C-reactive protein. Adjusted odds ratios per standard deviation for the Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio were 4.49 (95% CI, 2.24–8.98), 1.64 (1.29–2.08), and 1.77 (1.41–2.23) in the Corogene, SPUM-ACS, and BECAC studies, respectively. The Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio improved the predictive value of the GRACE score (net reclassification improvement, NRI = 0.17 and ΔAUC = 0.09) in ACS and the predictive value of the Marschner score in stable CAD (NRI = 0.15 and ΔAUC = 0.02).

Conclusions Distinct plasma ceramide ratios are significant predictors of CV death both in patients with stable CAD and ACS, over and above currently used lipid markers. This may improve the identification of high-risk patients in need of more aggressive therapeutic interventions.

Introduction

Given the high prevalence of coronary artery disease (CAD) and associated mortality, prevention of fatal and non-fatal myocardial infarctions (MI) in CAD patients remains an ongoing clinical challenge. Mortality rates among stable CAD patients range between 1% and 3%, while rates of non-fatal events are 1–2% annually.[1] In patients with acute coronary syndromes (ACS) who survive the acute event, the rate of MI and death is markedly higher, particularly during the first year.[2] However, at the individual level, the event risk may vary considerably, which makes risk estimation tools necessary to improve patient management. Expedient risk stratification should identify individuals at risk requiring more intensive therapy. Conversely, patients with a favorable prognosis should be identified to avoid drug overuse and associated side effects.[3]

Hypothesis free lipidomic analyses have revealed a handful of lipids potentially qualifying as useful prognostic markers for CAD.[4–6] In our initial lipidomic study, distinct ceramide species were significantly associated with CVD among CAD patients.[4] Molecular lipid species, particularly ceramide(d18:1/16:0), were also associated with necrotic core tissue type and lipid core burden in coronary angiography, and were predictive for 1-year clinical outcome in 581 ACS and stable CAD patients.[7] In these studies, plasma CVD risk-related ceramide molecules (Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1)), and their ratios with Cer(d18:1/24:0), emerged as potential risk stratifiers for CAD patients.[4] Ceramides are known to associate with many central processes of atherosclerosis development including lipoprotein uptake, inflammation, and apoptosis (Supplementary material online, Figure S1 ).[8] Ceramide species are produced by six fatty acyl selective ceramide synthases (CerSs; Supplementary material online, Figure S2 ), and it is becoming evident that individual ceramide species have specific physiological functions.[9–12] Thus, monitoring ratios of ceramides species may provide insight into the metabolic regulation of atherosclerotic events. In this study, we establish the suggested role of ceramides and their distinct ratios as risk predictors for CV death in patients with stable CAD and ACS.

 
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Table 1.  Baseline characteristics of the subjects in Corogene, SPUM-ACS and BECAC studies
Characteristic COROGENE SPUM-ACS BECAC
Cases Controls Cases Controls Cases Controls
No of subjects 80 80 51 1586 81 1506
Gender
   Male, n (%) 60 (75%) 60 (75%) 42 (82%) 1223 (77%) 55 (68%) 889 (59%)
Age (years) 70.2 (62.6–77.1) 70 (63.4–76.9) 77.1 (69–83) 62.8 (53.9–72.9) 71 (64–78) 61 (54–70)
Body mass index 27.5 (23.6–30.9) 26 (24.1–29.5) 25.1 (23.1–28.3) 26.6 (24.3–29.4) 24 (22–28) 26 (23–28)
Time to death/follow-up time (days) 528 (134–739) 1955 (1669–2173) 25 (7–216) 365 (359–365) 626 (196–1332) 1720 (1368–2111)
Creatinine (μmol/L) 98 (84–134) 79 (69–90) 100 (79–134) 75 (65–88) 98 (87–115) 87 (79–97)
Current smoker
   Yes, n (%) 37 (46%) 37 (46%) 16 (31%) 663 (42%) 29 (36%) 355 (24%)
   No, n (%) 43 (54%) 43 (54%) 33 (65%) 897 (57%) 50 (62%) 1146 (76%)
   NA     2 (4%) 26 (2%) 2 (2%) 5 (0%)
Diabetes
   Yes, n (%) 32 (40%) 32 (40%) 11 (22%) 266 (17%) 16 (20%) 159 (11%)
   No, n (%) 48 (60%) 48 (60%) 40 (78%) 1320 (83%) 64 (79%) 1333 (89%)
   NA         1 (1%) 14 (1%)
Hypertension
   Yes, n (%) 60 (75%) 60 (75%) 36 (71%) 912 (58%) 55 (68%) 674 (45%)
   No, n (%) 20 (25%) 20 (25%) 15 (29%) 674 (42%) 26 (32%) 832 (55%)
Lipid-lowering treatment
   Yes, n (%) 61 (76%) 61 (76%) 14 (27%) 432 (27%) 61 (75%) 933 (62%)
   No, n (%) 19 (24%) 19 (24%) 34 (67%) 1146 (72%) 20 (25%) 573 (38%)
   NA     3 (6%)      
Previous AMI
   Yes, n (%) 67 (84%) 0 (0%) 8 (16%) 210 (13%) 54 (67%) 482 (32%)
   No, n (%) 13 (16%) 80 (100%) 43 (84%) 1374 (87%) 27 (33%) 1024 (68%)
   NA       2 (0%)    
Previous stroke
   Yes, n (%) 17 (21%) 10 (12%) 2 (4%) 37 (2%) 15 (19%) 108 (7%)
   No, n (%) 63 (79%) 70 (88%) 49 (96%) 1549 (98%) 66 (81%) 1398 (93%)
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Table 2.  Medians and inter quartile ranges of established lipid markers and ceramides in case and control groups a
  BECAC SPUM-ACS
Cases (n = 81) Controls (n = 1499) P-value Cases (n = 51) Controls (n = 1586) P-value
Cer(d18:1/16:0)/Cer(d18:1/24:0) 0.121 (0.101–0.145) 0.100 (0.085–0.119) <0.001 0.116 (0.099–0.170) 0.093 (0.079–0.113) <0.001
Cer(d18:1/18:0)/Cer(d18:1/24:0) 0.046 (0.036–0.059) 0.038 (0.031–0.049) <0.001 0.064 (0.044–0.084) 0.047 (0.037–0.060) <0.001
Cer(d18:1/24:1)/Cer(d18:1/24:0) 0.498 (0.408–0.624) 0.413 (0.337–0.508) <0.001 0.489 (0.415–0.675) 0.394 (0.337–0.474) <0.001
Cer(d18:1/16:0) (μmol/L) 0.271 (0.235–0.326) 0.253 (0.213–0.300) 0.010 0.313 (0.255–0.385) 0.292 (0.247–0.346) 0.090
Cer(d18:1/18:0) (μmol/L) 0.108 (0.077–0.143) 0.096 (0.076–0.123) 0.097 0.161 (0.109–0.234) 0.146 (0.112–0.189) 0.163
Cer(d18:1/24:0) (μmol/L) 2.335 (1.843–2.866) 2.548 (2.030–3.098) 0.035 2.366 (2.112–3.084) 3.107 (2.490–3.826) <0.001
Cer(d18:1/24:1) (μmol/L) 1.056 (0.927–1.344) 1.028 (0.844–1.257) 0.026 1.421 (1.012–1.628) 1.229 (1.004–1.484) 0.175
LDL-C (mg/dL) 110 (89–133) 116 (93–147) 0.087 101 (81–128) 121 (93–150) 0.001
HDL-C (mg/dL) 46 (35–58) 50 (41–62) 0.036 48 (36–58) 44 (36–53) 0.266
TC (mg/dL) 185 (158–212) 193 (166–224) 0.081 159 (147–189) 189 (161–221) <0.001
TG (mg/dL) 135 (100–169) 126 (92–182) 0.738 76 (54–108) 92 (61–142) 0.014
  COROGENE      
Cases (n = 80) Controls (n = 80) P-value
Cer(d18:1/16:0)/Cer(d18:1/24:0) 0.132 (0.105–0.175) 0.105 (0.090–0.128) <0.001      
Cer(d18:1/18:0)/Cer(d18:1/24:0) 0.062 (0.047–0.077) 0.046 (0.037–0.062) <0.001      
Cer(d18:1/24:1)/Cer(d18:1/24:0) 0.703 (0.582–0.846) 0.556 (0.483–0.665) <0.001      
Cer(d18:1/16:0) (μmol/L) 0.275 (0.222–0.326) 0.235 (0.212–0.282) 0.007      
Cer(d18:1/18:0) (μmol/L) 0.118 (0.094–0.152) 0.107 (0.092–0.137) 0.195      
Cer(d18:1/24:0) (μmol/L) 1.923 (1.475–2.511) 2.235 (1.993–2.672) 0.008      
Cer(d18:1/24:1) (μmol/L) 1.385 (1.189–1.620) 1.245 (1.091–1.427) 0.017      
TC (mg/dL) 128 (111–165) 139 (122–163) 0.064      
TG (mg/dL) 108 (86–140) 92 (75–139) 0.110      
LDL-C (mg/dL) 69 (55–99) 75 (65–92) 0.251      
LDL-P (nmol/L) 830 (694–1110) 928 (712–1175) 0.395      
sdLDL (nmol/L) 533 (304–659) 548 (376–737) 0.265      
ApoB (mg/dL) 67 (55–82) 68.5 (57–84) 0.997      
HDL-C (mg/dL) 34 (29–40) 41 (33–51) <0.001      
HDL-P (μmol/L) 24 (21–27) 28 (24–31) <0.001      
sdHDL (μmol/L) 12.8 (9.3–15.6) 15.8 (13.1–18.2) <0.001      
ApoA1 (mg/dL) 115 (101–131) 132 (115–150) <0.001      
Lp(a) (mg/dL) 7.2 (2–35) 3.6 (1–28) 0.319      
Lp-PLA2 (nmol/min/ml) 138 (119–166) 130 (115–163) 0.354      
C-reactive protein (mg/L) 3.1 (1.6–8.7) 1.1 (0.7–2.8) <0.001      

aCer, ceramide; TC, total cholesterol; TG, triacylglycerols, LDL-C low-density lipoprotein cholesterol, HDL-C high-density lipoprotein cholesterol, sdLDL small dense low-density lipoprotein cholesterol, LDL-P low-density lipoprotein particle number, sdHDL small dense high-density lipoprotein cholesterol, HDL-P high-density lipoprotein particle number, ApoB apolipoprotein B, ApoA1 apolipoprotein A1, Lp(a) lipoprotein (a), Lp-PLA2 lipoprotein-associated phospholipase A2. SI conversion factors: To convert cholesterol to mmol/L, multiply values by 0.0259; to convert triacylglycerols to mmol/L, multiply values by 0.01129.

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Table 3.  Association between ceramides and cardiovascular death in BECAC a
  Univariate model Multivariableb model 1b Multivariablec model 2c
Hazard ratiod (95% CI) P-value Hazard ratiod (95% CI) P-value Hazard ratiod (95% CI) P-value
Cer(d18:1/16:0)/Cer(d18:1/24:0)e 1.77 (1.46–2.16) <0.001 1.79 (1.45–2.20) <0.001 1.52 (1.21–1.92) <0.001
Cer(d18:1/18:0)/Cer(d18:1/24:0)e 1.63 (1.31–2.04) <0.001 1.58 (1.25–2.00) <0.001 1.29 (1.01–1.65) 0.039
Cer(d18:1/24:1)/Cer(d18:1/24:0)e 1.61 (1.30–1.98) <0.001 1.58 (1.27–1.97) <0.001 1.31 (1.03–1.66) 0.028
Cer(d18:1/16:0)e 1.44 (1.17–1.77) <0.001 2.09 (1.61–2.73) <0.001 1.75 (1.30–2.35) <0.001
Cer(d18:1/18:0)e 1.33 (1.07–1.65) 0.011 1.54 (1.19–2.01) 0.001 1.27 (0.98–1.66) 0.076
Cer(d18:1/24:0)e 0.83 (0.67–1.02) 0.081 0.82 (0.62–1.10) 0.182 0.91 (0.69–1.21) 0.510
Cer(d18:1/24:1)e 1.39 (1.13–1.72) 0.002 1.74 (1.34–2.25) <0.001 1.38 (1.04–1.82) 0.023

Cer denotes ceramide.
aCV death denotes death from MI, stroke, and heart failure.
bThe model was adjusted for TC, TG, HDL-C, and LDL-C.
cThe model was adjusted as for model 1 with additional adjustment for the following Marschner score variables: age, gender, smoking status, previous acute MI, diabetes, hypertension, and prior stroke.
dHazard ratios are for 1 SD increase.
eNatural logarithm of the ceramides and ceramide ratio.

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Table 4.  Association between ceramides and cardiovascular death in SPUM-ACS a
  Univariate model Multivariableb model 1b Multivariablec model 2c
Hazard ratiod (95% CI) P-value Hazard ratiod (95% CI) P-value Hazard ratiod (95% CI) P-value
Cer(d18:1/16:0)/Cer(d18:1/24:0) 1.81 (1.52–2.14) <0.001 1.82 (1.51–2.21) <0.001 1.69 (1.39–2.06) <0.001
Cer(d18:1/18:0)/Cer(d18:1/24:0) 1.66 (1.43–1.96) <0.001 1.65 (1.39–1.97) <0.001 1.48 (1.24–1.76) <0.001
Cer(d18:1/24:1)/Cer(d18:1/24:0) 1.74 (1.45–2.08) <0.001 1.77 (1.44–2.17) <0.001 1.64 (1.32–2.03) <0.001
Cer(d18:1/16:0)e 1.45 (1.10–1.93) 0.010 1.96 (1.45–2.66) <0.001 1.98 (1.49–2.62) <0.001
Cer(d18:1/18:0)e 1.43 (1.07–1.90) 0.015 1.77 (1.31–2.38) <0.001 1.66 (1.26–2.20) <0.001
Cer(d18:1/24:0)e 0.66 (0.51–0.87) 0.003 0.74 (0.52–1.05) 0.090 0.91 (0.65–1.29) 0.609
Cer(d18:1/24:1)e 1.23 (0.93–1.63) 0.154 1.74 (1.25–2.42) 0.001 1.73 (1.27–2.36) <0.001

Cer denotes ceramide.
aCV death denotes death from MI, stroke, and heart failure.
bThe model was adjusted for TC, TG, HDL-C, and LDL-C.
cThe model was adjusted as for model 1 with additional adjustment for the Grace score (Killip class, systolic blood pressure, heart rate, age, creatinine, cardiac arrest at admission, ST-segment deviation, and elevated cardiac enzyme levels).
dHazard ratios are for one standard deviation increase.
eNatural logarithm of the ceramides.

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Table 5.  Ceramide score and risk for cardiovascular death
BECAC (5-year risk) SPUM-ACS (1-year risk)
Score No death Death % Relative risk Score No death Death % Relative risk
0–2 534 15 2.7% 1.0 0–2 566 9 1.6% 1.0
3–6 572 29 4.8% 1.8 3–6 595 16 2.6% 1.7
7–9 268 20 6.9% 2.5 7–9 261 9 3.3% 2.1
10–12 132 17 11.4% 4.2 10–12 164 17 9.4% 6.0
LDL-C (mg/dl) No death Death % Relative risk LDL-C (mg/dl) No death Death % Relative risk
≤100 513 36 6.6% 1.0 ≤106 532 27 4.8% 1.0
100–143 572 29 4.8% 0.7 106–145 576 17 2.9% 0.6
143–175 278 10 3.5% 0.5 145–174 260 3 1.1% 0.2
≥175 142 6 4.1% 0.6 ≥174 174 2 1.1% 0.2

See Supplementary material online, Table S11 for information on Ceramide Score calculation. To compare Ceramide Score performance with that of LDL-C study, subjects were sorted according to their LDL-C levels and split into four categories in the same proportion as for the ceramide risk score.

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[ CLOSE WINDOW ]

Authors and Disclosures

Reijo Laaksonen1,2,3*, Kim Ekroos1, Marko Sysi-Aho1, Mika Hilvo1, Terhi Vihervaara1, Dimple Kauhanen1, Matti Suoniemi1, Reini Hurme1, Winfried März4,5, Hubert Scharnagl6, Tatjana Stojakovic6, Efthymia Vlachopoulou7, Marja-Liisa Lokki7, Markku S. Nieminen7,8, Roland Klingenberg9, Christian M. Matter9, Thorsten Hornemann10, Peter Jüni11, Nicolas Rodondi12,13, Lorenz Räber14, StephanWindecker14, Baris Gencer15, Eva Ringdal Pedersen16, Grethe S. Tell17, Ottar Nygå rd16,18†, Francois Mach15†, Juha Sinisalo7,8† and Thomas F. Lüscher10†

1Zora Biosciences, Espoo, Finland; 2Medical School, Tampere University, Tampere, Finland; 3Finnish Clinical Biobank Tampere, University Hospital of Tampere, Tampere, Finland; 4Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; 5synlab Academy, synlab Holding Deutschland GmbH, Mannheim and Augsburg, Germany; 6Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria; 7Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland; 8Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland; 9Department of Cardiology, University Heart Center, University Hospital Zürich and University of Zürich, Zürich, Switzerland; 10Institute of Clinical Chemistry, University Hospital, Zürich, Switzerland; 11Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael's Hospital, and Department of Medicine, University of Toronto, Toronto, Canada; 12Department of General Internal Medicine, University Hospital Bern, Bern, Switzerland; 13Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland; 14Cardiovascular Center, Department of Cardiology, University Hospital Bern, Bern, Switzerland; 15Cardiovascular Center, Department of Cardiology, University Hospital Geneva, Geneva, Switzerland; 16Department of Clinical Science, University of Bergen, Bergen, Norway; 17Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; and 18Department of Heart Disease, Haukeland University Hospital, Bergen, Norway

*Corresponding author
Zora Biosciences Oy, Biologinkuja 1, 02150 Espoo, Finland. Tel: +358 40 724 077, Email: reijo.laaksonen@zora.fi

†Equal contribution.

Authors' contributions
M. S.-A., M. H., M. S. performed statistical analysis; R. L., R. H., M. N., J. S., O. N., T. L., W. M. handled funding and supervision; K. E., D. K., H. S., T. S., E. V., M.-L. L., R. K., C. M., T. H., P. J., N. R., L. R., S. W., B. G., E. R. P., G. S. T., F. M. acquired the data; R. L., R. H., J. S., T. L., F. M., O. N. conceived and designed the research; R. L., T. V. drafted the manuscript; K. E., M. S.-A., M. H., R. H., D. K., W. M., H. S., T. S., E. V., M. L. L., M. N., R. K., C. M., T. H., P. J., N. R., L. R., S. W., E. P., G. T., B. G., F. M., J. S., O. N., T. L. made critical revision of the manuscript for key intellectual content.

Funding
This work was supported by the European Union's Seventh Framework Programme FP7/2007-2013 RiskyCAD Project (3057392) and further by research grants of the Swiss National Research Foundation (SPUM 33CM30-124112), the Swiss Heart Foundation, both Bern Switzerland, the Foundation for Cardiovascular Research—Zürich Heart House, Zürich, Switzerland as well as AstraZeneca, Zug; Eli Lilly Indianapolis, USA; and Vernier, Medtronic, Tolochenaz; Merck Sharpe and Dohme, Glattbrugg; Sanofi, Vernier; and St. Jude Medical, Zürich (all Switzerland). The Corogene study was supported by grants from Aarno Koskelo Foundation, Helsinki University Central Hospital Special Government Funds (EVO #TYH7215, #TKK2012005, #TYH2012209, and #TYH2014312), and Finnish Foundation for Cardiovascular research. The BECAC study was supported by a grant from the Western Norway Regional Health Authority (911570). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Funding to pay the Open Access publication charges for this article was provided by Zora Biosciences.

Conflict of interest
F.M. has received research grants to the institution from Amgen, AstraZeneca, Boston Scientific, Biotronik, Medtronic, MSD, Eli Lilly, and St. Jude Medical including speaker or consultant fees. S.W. has received research grants to the institution from Abbott, AstraZeneca, Boston Scientific, Biosensors, Biotronik, Cordis, Eli Lilly, Medtronic, and St. Jude Medical. T.F.L. received research grants to the institution from AstraZeneca, Bayer Health Care, Biosensors, Biotronik, Boston Scientific, Medtronic, Merck, Sharpe and Dohme, Merck, Inc., Roche, and Servier, including lecture fees. C.M.M. received research grants to the institution from Eli Lilly, AstraZeneca, Roche and MSD and speaker or consultant fees from Eli Lilly, Daiichi Sankyo, AstraZeneca, Roche and MSD. W.M. is employed with Synlab Holding Germany GmbH, has ownership interest in Synlab Holding International GmbH and has received research grants to the institution from Aegerion Pharmaceuticals, Amgen, Astrazeneca, Danone Research, Sanofi/Genzyme, Hoffmann LaRoche, Numares, Unilever, and BASF and speaker and consultancy fees from Aegerion Pharmaceuticals, Amgen, Astrazeneca, Danone Research, Sanofi/Genzyme, Hoffmann LaRoche, Merck Sharp and Dohme, Pfizer, Sanofi, Synageva, Numares, Unilever, and BASF. Zora Biosciences holds patents for the diagnostic use of ceramides and R.H. and R.L. are shareholders of Zora Biosciences.

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