Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol

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

doi:10.1093/eurheartj/ehw148

Cited by 455 publications

(426 citation statements)

References 31 publications

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“…In FHS and in SHIP, both ceramide ratios favorably affected the C‐statistic for all‐cause mortality, providing incremental information after adjustment for standard CVD risk factors. Previous case‐control studies showed that the C24:0/C16:0 ceramide ratio is inversely related to CVD mortality among patients with CHD 7, 8. Our results demonstrate that quantification of plasma C24:0/C16:0 or C22:0/C16:0 ratios provides prognostic information in the general population that includes both men and women free of prevalent CVD and over a broad age range.…”

Section: Discussionsupporting

confidence: 51%

“…Consistent with these observations, we noted that the C24:0/C16:0 ceramide ratio correlated inversely with several known risk factors for CVD and with prevalent CVD in both FHS and SHIP. Recent lipidomic analyses in case‐control studies demonstrated that the C24:0/C16:0 ratio in individuals with CHD is inversely related to prevalent CHD and CVD death 7, 8. Our investigation provides the first demonstration that the ratio of very‐long‐chain/long‐chain ceramide molecular species in plasma is an independent predictor of CHD and all‐cause mortality risk in the general population.…”

Section: Discussionmentioning

confidence: 58%

“…In mice with altered expression of ceramide synthase 2 and ceramide synthase 6, increases in long‐chain ceramide species (eg, C16:0 ceramide) and decreases in very–long‐chain species (eg, C22:0 and C24:0 ceramides) in metabolic tissues are associated with diet‐induced glucose intolerance, nonalcoholic steatohepatitis, and insulin resistance 5, 6. In retrospective case‐control studies of patients with coronary heart disease (CHD), high plasma C16:0 ceramide, low C24:0 ceramide, and low C24:0/C16:0 ceramide ratios were directly related to cardiovascular mortality over 3 years 7, 8. To test the hypothesis that higher ratios of plasma very–long‐chain ceramides/long‐chain ceramides are inversely associated with risk of CHD and mortality in the general population , we related ratios of 3 abundant plasma ceramides9 to the risk of CHD and all‐cause mortality in 2 large community‐based samples.…”

Section: Introductionmentioning

confidence: 99%

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Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

Peterson

Xanthakis

Duncan

et al. 2018

JAHA

118

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BackgroundRecent studies suggest that circulating concentrations of specific ceramide species may be associated with coronary risk and mortality. We sought to determine the relations between the most abundant plasma ceramide species of differing acyl chain lengths and the risk of coronary heart disease (CHD) and mortality in community‐based samples.Methods and ResultsWe developed a liquid chromatography/mass spectrometry assay to quantify plasma C24:0, C22:0, and C16:0 ceramides and ratios of these very–long‐chain/long‐chain ceramides in 2642 FHS (Framingham Heart Study) participants and in 3134 SHIP (Study of Health in Pomerania) participants. Over a mean follow‐up of 6 years in FHS, there were 88 CHD and 90 heart failure (HF) events and 239 deaths. Over a median follow‐up time in SHIP of 5.75 years for CHD and HF and 8.24 years for mortality, there were 209 CHD and 146 HF events and 377 deaths. In meta‐analysis of the 2 cohorts and adjusting for standard CHD risk factors, C24:0/C16:0 ceramide ratios were inversely associated with incident CHD (hazard ratio per average SD increment, 0.79; 95% confidence interval, 0.71–0.89; P<0.0001) and inversely associated with incident HF (hazard ratio, 0.78; 95% confidence interval, 0.61–1.00; P=0.046). Moreover, the C24:0/C16:0 and C22:0/C16:0 ceramide ratios were inversely associated with all‐cause mortality (C24:0/C16:0: hazard ratio, 0.60; 95% confidence interval, 0.56–0.65; P<0.0001; C22:0/C16:0: hazard ratio, 0.65; 95% confidence interval, 0.60–0.70; P<0.0001).ConclusionsThe ratio of C24:0/C16:0 ceramides in blood may be a valuable new biomarker of CHD risk, HF risk, and all‐cause mortality in the community.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

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Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

Peterson

Xanthakis

Duncan

et al. 2018

JAHA

118

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“…5,14 With this in mind, we separately analyzed subjects who already had experienced MACE before the baseline measurement (n=396) and as the end point those who had a recurrent MACE (n=226) or fatal recurrent MACE (n=70) during follow-up. For recurrent MACE, Cer(d18:1/16:0) and Cer(d18:1/24:1) showed significant univariate associations, with Cer(d18:1/16:0) having the highest univariate HR at 1.28 (1.10-1.49), which remained significant at HR=1.50 (1.22-1.83) also after adjusting for the Framingham Risk Score factors (Figure 1).…”

Section: Ceramide (D18:1/16:0) and (D18:1/24:1) Associate With Recurrmentioning

confidence: 99%

Circulating Ceramides Predict Cardiovascular Outcomes in the Population-Based FINRISK 2002 Cohort

Havulinna

Sysi-Aho

Hilvo

et al. 2016

ATVB

Self Cite

263

181

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Objective-Ceramides are molecular lipids implicated in apoptosis, inflammation, obesity, and insulin resistance. An earlier study reported that ceramides were associated with fatal outcome among patients with coronary heart disease. Here, we examined whether ceramides are associated with major adverse cardiovascular events (MACEs) among apparently healthy individuals. Approach and Results-FINRISK 2002 is a population-based risk factor survey, which recruited men and women aged 25 to 74 years. The cohort was followed up until the end of 2014. We quantified 4 circulating ceramides, Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1), in 8101 serum samples by a targeted liquid chromatographytandem mass spectrometry assay. Primary outcome of interest was incident MACE (n=813). Secondary analyses were performed for MACE death (n=116) without previous nonfatal MACE and for recurrent MACE (n=226) among survivors of a previous incident MACE. We used Cox proportional hazard models adjusted for the Framingham covariates to determine the association of ceramides with the outcomes. Of the ceramide species, Cer(d18:1/18:0) had the strongest association with incident MACE and the highest unadjusted hazard ratio of 1.31 (95% confidence interval, 1.21-1.41), which remained significant at 1.21 (95% confidence interval, 1.11-1.33) after Framingham risk factor adjustments. The hazard ratios were generally stronger for recurrent and fatal events than for first events. Clinical net reclassification improvement was 7.5% (P=6.9×10 −5 ) for Cer(d18:1/18:0). Conclusions-Distinct serum ceramides are associated with the risk of incident MACE in apparently healthy individuals. These results should encourage more detailed analyses of ceramides in cardiovascular pathobiology and suggest new biomarkers of MACE risk.

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“…Lipid families in the sphingolipid class include sphingomyelins, ceramides, sphingosines, cerebrosides, and gangliosides (Merrill et al., 2005). Aberrations in sphingolipid concentrations have been reported in individuals with CAD (Huynh, 2016; Laaksonen et al., 2016; Park, Lee, Shin, & Hwang, 2015). For example, Sattler et al.…”

Section: Introductionmentioning

confidence: 99%

Plasma sphingolipids and depressive symptoms in coronary artery disease

et al. 2017

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BackgroundDepression is highly prevalent in individuals with coronary artery disease (CAD) and increases the risk of future cardiac events and mortality. Sphingolipids have been implicated in the pathophysiology of both CAD and depression. This study assessed the association between plasma sphingolipid concentrations and depressive symptoms in CAD subjects.MethodsDepressive symptoms were measured using the depression subscale of the self‐reported Hospital Anxiety and Depression Scale (HADS). Sphingolipid concentrations were measured from fasting plasma samples using high‐performance liquid chromatography‐coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Linear regression models were used to assess associations between log‐transformed concentrations of plasma sphingolipids and depressive symptoms.ResultsA total of 111 CAD patients (mean (SD) age = 63.6 ± 6.4, 84.7% male) were included. In linear regression analyses, higher plasma concentrations of ceramides C16:0 (β = 0.204, p = .026) and C18:0 (β = 0.209, p = .023) and sphingomyelin SM18:1 (β = 0.210, p = .024) were significantly associated with higher HADS depression subscale score after adjusting for covariates.ConclusionSphingolipids, in particular the ceramide species C16:0 and C18:0 and the sphingomyelin species SM18:1, may be implicated in the pathophysiology of depression in CAD. The association between plasma sphingolipid concentrations and depression should be further examined in CAD patients and in other populations.

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Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol

Cited by 455 publications

References 31 publications

Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

Circulating Ceramides Predict Cardiovascular Outcomes in the Population-Based FINRISK 2002 Cohort

Plasma sphingolipids and depressive symptoms in coronary artery disease

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