| Laaksonen et al.5 European Heart Journal 2016;37, 1967-1976 |
Prospective cohort study with N = 1580 adults (62 years old; 59% male; BMI 25 kg/m2; LDL-cholesterol 2.8 mmol/l, triglycerides 1.4mmol/l; statin use 62.6%) who underwent elective coronary angiography due to stable CAD and were recruited at the Haukeland University Hospital in Bergen (BECAC study) with 4.6 years of follow-up, in addition to 1637 patients (63 years old; 78% male, BMI 26 kg/m2, LDL-cholesterol 2.6 mmol/l, triglycerides 1 mmol/l, statin use 27.2%) with an ACS diagnosis who underwent invasive treatment in 4 Swiss university hospitals (SPUM-ACS study), with 1-year follow-up |
Cardiovascular death |
Total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, age, sex, smoking habits, previous acute myocardial infarction, diabetes mellitus, hypertension, previous stroke |
Cer (d18:1/16:0) and Cer (d18:1/24:1) were associated with an increased risk of cardiovascular death in all cohorts. OR Cer (d18:1/16:0)/Cer(d18:1/24:0) was 4.49 (95% CI, 2.24–8.98), 1.64 (1.29–2.08), and 1.77 (1.41–2.23) for Corogene, SPUM-ACS, and BECAC studies, respectively |
| Havulinna et al.7 Arteriosclerer Thromb Vasc Biol 2016;36: 2424-2430 |
Populational cohort study with N = 8101 healthy patients (48 years old; 47% male, BMI 26 kg/m2, LDL-cholesterol 3.3 mmol/l, triglycerides 1.3 mmol/l) from FINRISK 2002 |
Major cardiac and cerebrovascular adverse events |
Total cholesterol, HDL-cholesterol, arterial pressure, diabetes mellitus, and smoking habits |
Cer (d18:1/16:0), Cer (d18:1/18:0), and Cer (d18:1/24:1) levels were significantly higher in patients with adverse cardiovascular progression when compared to asymptomatic individuals. Serum concentrations of high-risk ceramides predicting cardiovascular death in patients with CAD were also higher in FINRISK MACE cases when compared to asymptomatic individuals, as follows: Cer (d18:1/16:0), Cer (d18:1/18:0), and Cer (d18:1/24:1) 11.4%, 21.3%, and 17.0%, respectively (p < 0.001 for all) |
| Wang et al.4 Circulation 2017; 135: 2028-2040 |
Cohort study nested in the PREDIMED randomized study with N = 980 participants (68 years old; 45% male, BMI 30 kg/m2, LDL-cholesterol 3.4 mmol/l, triglycerides 1.6 mmol/l), including 230 cases of CVD and 767 randomly selected participants. The sub cohort included 37 overlapping CVD cases. Two participants with undetectable plasma ceramide concentrations were excluded. Follow-up: 4.5 years |
MACE |
IAge, sex, BMI, family history of premature CAD, smoking habits, history of hypertension, dyslipidemia, and type 2 diabetes. |
Among the high-risk ceramides identified, the upper quartiles of plasma Cer (d18:1/16:0), Cer (d18:1/22:0), Cer (d18:1/24:0), and Cer (d18:1/24:1) levels were associated with an adverse cardiovascular outcome. The multivariable hazard ratios comparing the extreme quartiles of plasma C:16, C22:0, C24:0, and C24:1 concentrations were 2.39 (1.49–3.83, p < 0.001), 1.91 (1.21–3.01, p = 0.003), 1.97 (1.21–3.01, p = 0.004), and 1.73 (1.09–2.74, p = 0.011), respectively. |
| De Carvalho et al.13 JACC Basic Transl Sci 2018;3:163-175 |
Prospective longitudinal study with N = 327 patients from a primary cohort (57 years old; 90% male, BMI 26 kg/m2, LDL-cholesterol 3.1 mmol/l, triglycerides 1.2 mmol/l) and 119 patients in the validation cohort (66 years old; 72% male, BMI 29 kg/m2, LDL-cholesterol 3.2 mmol/l) with ACS who underwent invasive stratification with plasma measurements performed before and after stratification; 1-year follow-up. |
Major cardiac and cerebrovascular adverse events |
GRACE |
Among the high-risk ceramides previously identified, the plasma Cer (d18:1/16:0), Cer (d18:1/18:0), and Cer (d18:1/24:1) levels were associated with adverse cardiovascular events |
| Meeusen et al.32 Arterioscler Thromb Vasc Biol. 2018; 38: 1933-1939 |
Cross-sectional study: 495 participants (60 years old; 62% male, BMI 28kg/m2, LDL-cholesterol 3.1 mmol/l, triglycerides 1.7 mmol/l, statin use 28.5%) before nonurgent coronary angiography. Follow-up: 4 years |
MACE (myocardial infarction, percutaneous intervention, myocardial revascularization surgery, stroke, or death). |
Age, sex, BMI, hypertension, smoking habits, LDL-cholesterol, HDL-cholesterol, triglycerides, glycemia, family history of CAD |
Among the high-risk ceramides previously identified, plasma Cer (d18:1/16:0), Cer (d18:1/18:0), and Cer (d18:1/24:1) levels were associated with adverse cardiovascular events. Adjusted hazard ratios per standard deviation (95% CI) were 1.50 (1.16–1.93) for Cer (16:0), 1.42 (1.11–1.83) for Cer (18:0), and 1.43 (1.08–1.89) for Cer (24:1) |
| Peterson et al.28 J Am Heart Assoc. 2018;7: e007931 |
Community-based study: 2642 participants from the Framingham Heart Study (FHS; 66 years old; 46% male, BMI 28 kg/m2, LDL-cholesterol 2.7 mmol/l, triglycerides 1.3 mmol/l, statin use 42.7%) and 3134 participants from the Study of Health in Pomerania (SHIP; 54 years old, 48% male, BMI 28 kg/m2, LDL-cholesterol 5.5 mmol/l, triglycerides 1.8 mmol/l, statin use 14.5%) were followed up for 6 and 8 years, respectively |
MACE (fatal and non-fatal cardiovascular events) |
Age, sex, BMI, hypertension, diabetes mellitus, smoking habits, anti-hypertensives, total cholesterol/HDL-cholesterol ratio, triglycerides, and lipid-lowering drugs |
Among the high-risk ceramides previously identified, only Cer (d18:1/24:0) were associated with adverse cardiovascular outcomes. In the meta-analysis of both cohorts and after adjusting risk factors for CAD, C24:0/C16:0 ratios were inversely associated with CAD (hazard ratio per mean standard deviation increase, 0.79; 95% CI, 0.71–0.89; p < 0.0001) and inversely associated with HF (hazard ratio, 0.78; 95% CI, 0.61–1,00; p = 0.046). |
| Hilvo et al.33 European Heart Journal 2019, in press |
Longitudinal study; 3 large cohort studies: 3789 patients (62 years old; 72% male, LDL-cholesterol 2.9 mmol/l, triglycerides 1.5 mmol/l, statin use 72.6%) from the Western Norway Coronary Angiography Cohort (WECAC); 5991 patients (65 years old; 83% male, LDL-cholesterol 3.9 mmol/l, triglycerides 1.6 mmol/l, statin use 49.9%) from the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study; and 1023 patients (62 years old; 84% male, LDL-cholesterol 3 mmol/l, triglycerides 1.6 mmol/l, statin use 75.6%) from the Langzeiterfolge der Kardiologischen Anschlussheilbehandlung (KAROLA) study. Follow-up: 6 years |
MACE (composite endpoint including death due to CV events, MI, and stroke ) |
IAge, sex, treatment with statins (WECAC, KAROLA), diabetes mellitus, hypertension, current smoking habit, previous MI, previous stroke, stratified according to vitamin B intervention (WECAC) and treatment group (LIPID). |
A simple risk score, based on ceramides and phosphatidylcholines with the best prognostic characteristics, was developed by the WECAC study and validated in the other 2 cohorts. This score was highly significant for predicting mortality due to CVD (multi-adjusted hazard ratios [95% CI] per standard deviation were 1.44 [1.28–1.63] at the WECAC, 1.47 [1.34–1.61] at the LIPID study, and 1.69 [1.31– 2.17] at the KAROLA study). Moreover, a combination of the risk score with high-sensitivity troponin T increased hazard ratios to 1.63 (1.44–1.85) and 2.04 (1.57–2.64) in the WECAC and KAROLA cohorts, respectively. |
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