Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

Peterson, Linda R.; Xanthakis, Vanessa; Duncan, Meredith S.; Groß, Stefan; Friedrich, Nele; Völzke, Henry; Felix, Stephan B.; Jiang, Hui; Sidhu, Rohini; Nauck, Matthias; Jiang, Xuntian; Ory, Daniel S.; Dörr, Marcus; Vasan, Ramachandran S.; Schaffer, Jean E.

doi:10.1161/jaha.117.007931

Cited by 120 publications

(111 citation statements)

References 22 publications

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“…A modified and fully validated two-dimensional liquid chromatography-tandem mass spectrometry (LC-MS) assay was used to quantify plasma levels of ceramides C24:0, C22:0, and C16:0 according to previous published methods. 17 Linear dynamic ranges for ceramides C16:0, C22:0, and C24:0 in this assay were 0.01 to 2, 0.04 to 8, and 0.1 to 20 µg/mL, respectively. The intraassay and interassay precisions were within 6.9%, 7.6% and 7.8% coefficient of variation for C24:0, C22:0 and C16:0, respectively.…”

Section: Measurement Of Plasma Ceramidesmentioning

confidence: 66%

“…Linear dynamic ranges for ceramides C16:0, C22:0, and C24:0 in this assay were 0.01 to 2, 0.04 to 8, and 0.1 to 20 µg/mL, respectively. The intraassay and interassay precisions were within 6.9%, 7.6% and 7.8% coefficient of variation for C24:0, C22:0 and C16:0, respectively …”

Section: Methodsmentioning

confidence: 78%

“…Fasting blood samples were drawn from participants in the early morning, centrifuged and stored at −80°C until assays were performed. A modified and fully validated two‐dimensional liquid chromatography‐tandem mass spectrometry (LC–MS) assay was used to quantify plasma levels of ceramides C24:0, C22:0, and C16:0 according to previous published methods . Linear dynamic ranges for ceramides C16:0, C22:0, and C24:0 in this assay were 0.01 to 2, 0.04 to 8, and 0.1 to 20 µg/mL, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, attention has focused on the role of circulating ratios of a very‐long‐chain to long‐chain ceramides as biomarkers for major vascular events and the possibility that these ratios may be of greater diagnostic and prognostic value for cardiovascular outcomes compared to total ceramide levels or concentrations of individual ceramide species. It has been contended, but is unproven, that the adverse cognitive effects of ceramides may be related to the relative proportions of circulating very long‐chain to long‐chain fatty acyl chains rather than simply due to elevated total ceramide levels .…”

Section: Introductionmentioning

confidence: 99%

“…It has been contended, but is unproven, that the adverse cognitive effects of ceramides may be related to the relative proportions of circulating very long-chain to long-chain fatty acyl chains rather than simply due to elevated total ceramide levels. 18,19 In the present investigation, we related circulating ratios of previously measured very long-chain to long-chain ceramides 17 to MRI structural brain measures (cross-sectionally) and amyloid burden on brain-PET (longitudinally), and to the incidence of clinically confirmed dementia and AD dementia prospectively in a large, community-based, sample of relatively healthy adults.…”

Section: Introductionmentioning

confidence: 99%

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Circulating ceramide ratios and risk of vascular brain aging and dementia

McGrath

Himali

Xanthakis

et al. 2020

Ann Clin Transl Neurol

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Background We determined the association between ratios of plasma ceramide species of differing fatty‐acyl chain lengths and incident dementia and Alzheimer’s disease (AD) dementia in a large, community‐based sample. Methods We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia‐free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long‐chain (C24:0, C22:0) to long‐chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes. Results During a median 6.5 year follow‐up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox‐proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56–0.96) and AD dementia (HR 0.73, 95% CI 0.53–1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57–0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53–1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross‐sectionally associated with lower white matter hyperintensity burden on MRI (−0.05 ± 0.02, P = 0.02; −0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures. Conclusions Higher plasma ratios of very long‐chain to long‐chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community‐based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults.

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Section: Measurement Of Plasma Ceramidesmentioning

confidence: 66%

Section: Methodsmentioning

confidence: 78%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Circulating ceramide ratios and risk of vascular brain aging and dementia

McGrath

Himali

Xanthakis

et al. 2020

Ann Clin Transl Neurol

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The Association Between C24:0/C16:0 Ceramide Ratio and Cardiorespiratory Fitness is Robust to Effect Modifications by Age and Sex

Zatloukal,

Zylla,

Markus

et al. 2024

Advanced Biology

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Ceramides and cardiorespiratory (CR) fitness are both related to cardiovascular diseases. The associations of three blood plasma ceramides (C16:0, C22:0, and C24:0) with CR fitness in the population‐based Study of Health in Pomerania (SHIP‐START‐1; n = 1,102; mean age 50.3 years, 51.5% women) are investigated. In addition, subgroup analysis according to age (</≥54 years) and sex (female/male) is performed. Ceramides are quantified by liquid chromatography/mass spectrometry (LC/MS). CR fitness is assessed by a cardiopulmonary exercise test. Sex and age independent associations are found for higher levels of C24:0 and C24:0/C16:0 ratio with higher maximal oxygen consumption (VO2peak) kg−1 and oxygen consumption at the anaerobic threshold (VO2@AT1) as well as for the relation of C24:0/C16:0 with maximum workload (Wattmax kg−1). In contrast, age/sex subgroup specific inverse associations with Wattmax kg−1 are found in women <54 years for C22:0, while a positive association in men ≥54 years. Higher levels of C24:0 are associated with higher Wattmax kg−1, except for women <54 years, where no significant association can be found. The findings suggest that the use of single ceramides as cardiovascular biomarkers may be inferior, compared to ceramide ratio C24:0/C16:0. Therefore C24:0/C16:0 ratio may be a more suitable and robust cardiovascular biomarker and should be preferred over single ceramides.

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Relation between plasma ceramides and cardiovascular death in chronic heart failure: A subset analysis of the GISSI‐HF trial

et al. 2020

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Aims Ceramides exert several biological activities that may contribute to the pathophysiology of cardiovascular disease and heart failure (HF). The association between plasma levels of distinct ceramides (that have been previously associated with increased cardiovascular risk) and cardiovascular mortality in patients with chronic HF has received little attention. Methods and results In a post hoc ancillary analysis of the Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure (GISSI-HF; NCT00336336) trial, we randomly selected a sample of 200 ambulatory patients with chronic HF who died due to cardiovascular causes and 200 patients who were alive at the end of the trial (after a median follow-up period of 3.9 years). We measured baseline plasma concentrations of six previously identified high-risk ceramide species [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1) and their individual plasma ratios with Cer(d18:1/24:0)]. Patients who died due to cardiovascular causes had significantly (P < 0.05 or less) higher levels of plasma Cer(d18:1/16:0) and Cer(d18:1/24:1), but lower levels of plasma Cer(d18:1/22:0) and Cer (d18:1/24:0) than had those who did not. All plasma ratios of each ceramide with Cer(d18:1/24:0) were significantly higher in patients who died due to cardiovascular causes. In Cox regression analyses, all five plasma ratios of each ceramide with Cer(d18:1/24:0) were significantly associated with a greater risk of cardiovascular mortality (with unadjusted hazard ratios ranging from 1.23 to 1.59; P < 0.001 or less). These significant associations were attenuated after adjustment for multiple established risk factors, New York Heart Association functional class, left ventricular ejection fraction, use of medications, plasma pentraxin-3 levels, and, especially, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. When we applied a Bonferroni correction for multiple comparisons (using a P-threshold 0.05/5 ceramide ratios = 0.01), none of the five plasma ratios of each ceramide with Cer(d18:1/24:0) remained statistically associated with the risk of cardiovascular mortality (with adjusted hazard ratios ranging from 1.10 to 1.23). Conclusions Higher levels of specific plasma ceramides [especially when used in ratios with Cer(d18:1/24:0)] are associated with increased cardiovascular mortality in ambulatory patients with chronic HF. However, these associations are weakened after adjustment for established cardiovascular risk factors, medication use, and plasma NT-proBNP concentrations.

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Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

Cited by 120 publications

References 22 publications

Circulating ceramide ratios and risk of vascular brain aging and dementia

Circulating ceramide ratios and risk of vascular brain aging and dementia

The Association Between C24:0/C16:0 Ceramide Ratio and Cardiorespiratory Fitness is Robust to Effect Modifications by Age and Sex

Relation between plasma ceramides and cardiovascular death in chronic heart failure: A subset analysis of the GISSI‐HF trial

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