Plasma Lipidomic Profiles Improve on Traditional Risk Factors for the Prediction of Cardiovascular Events in Type 2 Diabetes Mellitus

Alshehry, Zahir H.; Mundra, Piyushkumar A.; Barlow, Christopher K.; Mellett, Natalie A.; Wong, Gerard; McConville, Malcolm J.; Simes, John; Tonkin, Andrew; Sullivan, David; Barnes, Elizabeth H; Nestel, Paul J.; Kingwell, Bronwyn A.; Marre, Michel; Neal, Bruce; Poulter, Neil; Rodgers, Anthony; Williams, Bryan; Zoungas, Sophia; Hillis, Graham S.; Chalmers, John; Woodward, Mark; Meikle, Peter J.

doi:10.1161/circulationaha.116.023233

Cited by 215 publications

(228 citation statements)

References 43 publications

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“…65 Mass spectrometry has also shown that sphingolipids, phospholipids, cholesterol esters, and gylcerolipids are associated with an increased risk of adverse cardiovascular events in patients with diabetes mellitus. 66 High-throughput metabolite profiling by nuclear magnetic resonance spectroscopy has also identified a further 33 lipids and metabolites that are predictive of cardiovascular events, although only 4 metabolites showed independent risk of adverse cardiovascular events when routine lipids were adjusted for, phenylalanine and monounsaturated fatty acid levels were associated with increased risk whereas omega-6 fatty acids and docosahexaenoic acid were associated with decreased risk. 67 Novel lipid-related markers, including serum levels of proprotein convertase subtilisin/kexin type 9, 5 oxidized phospholipids, 68 and secretory phospholipase A 2 69 (Table 1), have also recently been shown to be associated with a risk of developing coronary artery disease in the general population.…”

Section: Lipidsmentioning

confidence: 99%

Novel Risk Markers and Risk Assessments for Cardiovascular Disease

Thomas

Lip

2017

Circulation Research

111

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Abstract:The use of risk markers has transformed cardiovascular medicine, exemplified by the routine assessment of troponin, for both diagnosis and assessment of prognosis in patients with chest pain. Clinical risk factors form the basis for risk assessment of cardiovascular disease and the addition of biochemical, cellular, and imaging parameters offers further refinement. Identifying novel risk factors may allow greater risk stratification and a steady, but gradual progression toward precision medicine. Indeed, the generation of data in this area of research is explosive and when combined with new technologies and techniques provides the potential for more refined, targeted approaches to cardiovascular medicine. Although discussing the most recent developments in this field, this review article aims to strike a balance between novelty and validity by focusing on recent large samplesize studies that have been validated in a separate cohort in most cases. Risk markers related to atherosclerosis, thrombosis, inflammation, cardiac injury, and fibrosis are introduced in the context of their pathophysiology. Rapidly developing new areas, such as assessment of micro-RNA, are also explored. Subsequently the prognostic ability of these risk markers in coronary artery disease, heart failure, and atrial fibrillation is discussed in detail. ( addition to these roles in the pathogenesis of coronary artery disease, lipid-related molecules have been identified to be markers of inflammation and oxidative stress (Table 1). Thrombosis-Related Risk MarkersAfter atherosclerotic plaque rupture, platelets adhere to exposed subendothelial components, such as collagen and von Willebrand factor, which promotes platelet activation and aggregation. 10 In addition, platelet activation is potentiated by exposure to released soluble agonists, such as thrombin and ADP.10 Activated platelets then further release ADP, which acts on platelet P2Y 12 ADP receptors and has a central role in amplifying the response of platelets to the initial stimulus. 10 Platelet reactivity to various agonists, including ADP, has been studied extensively in the context of acute coronary syndrome (ACS; Table 2). 11 The VerifyNow and Multiplate pointof-care tests allow for the measurement of platelet aggregation in response to stimulation, and it has been shown that high platelet reactivity is associated with adverse cardiovascular events. 26 Platelet microparticles are released on platelet activation, and their role in cardiovascular disease is an area of active investigation (Table 2). 15 Circulating microparticles are released from cells undergoing activation or apoptosis and are a type of small plasma membrane vesicle that retain defined properties from their original cell lineage. 15 Platelet activation and aggregation lead to the activation of the coagulation cascade and the formation of a stable crosslinked fibrin clot. The balance between prothrombotic factors and endogenous fibrinolysis determines whether the thrombus propagates or instead proceeds to dis...

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Section: Lipidsmentioning

confidence: 99%

Novel Risk Markers and Risk Assessments for Cardiovascular Disease

Thomas

Lip

2017

Circulation Research

111

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“…General characteristics of the 12 selected articles are shown in Table . Half of the articles (6/12) were published in 2014, and all except 2 were conducted using European and/or US populations. These 12 articles include 19 separate primary discovery (or “learning”) and replication (or “validation”) analyses of metabolites in relation to CVD risk.…”

Section: Resultsmentioning

confidence: 99%

“…In 3 articles participants had a previous history of suspected coronary disease at baseline. Another article included older participants, of whom 68% had a prior history of CVD, and 2 articles included exclusively individuals with type 2 diabetes mellitus coupled with history of CVD or other CVD risk factors …”

Section: Resultsmentioning

confidence: 99%

“…In the reporting of results of these untargeted analyses, independent associations of each metabolite feature were not presented in either the main text or supplemental material (likely due to limitations of space); thus, all unreported associations are presumed to be null. However, 11 out of 12 articles, whether targeted or untargeted in their approach, included univariate‐ or multivariate‐adjusted estimates of statistically significant single metabolite associations with CVD incidence in either the main text or supplemental material. Among the studies including only targeted/known metabolites, there was a minimum of 31 metabolites in the study by Kume and colleagues and a maximum of 310 lipid species in the study by Alshehry and colleagues .…”

Section: Resultsmentioning

confidence: 99%

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Comprehensive Metabolomic Profiling and Incident Cardiovascular Disease: A Systematic Review

Ruíz-Canela

Hruby

Clish

et al. 2017

JAHA

113

111

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BackgroundMetabolomics is a promising tool of cardiovascular biomarker discovery. We systematically reviewed the literature on comprehensive metabolomic profiling in association with incident cardiovascular disease (CVD).Methods and ResultsWe searched MEDLINE and EMBASE from inception to January 2016. Studies were eligible if they pertained to adult humans; followed an agnostic and/or comprehensive approach; used serum or plasma (not urine or other biospecimens); conducted metabolite profiling at baseline in the context of examining prospective disease; and included myocardial infarction, stroke, and/or CVD death in the CVD outcome definition. We identified 12 original articles (9 cohort and 3 nested case‐control studies); participant numbers ranged from 67 to 7256. Mass spectrometry was the predominant analytical method. The number and chemical diversity of metabolites were very heterogeneous, ranging from 31 to >10 000 features. Four studies used untargeted profiling. Different types of metabolites were associated with CVD risk: acylcarnitines, dicarboxylacylcarnitines, and several amino acids and lipid classes. Only tiny improvements in CVD prediction beyond traditional risk factors were observed using these metabolites (C index improvement ranged from 0.006 to 0.05).ConclusionsThere are a limited number of longitudinal studies assessing associations between comprehensive metabolomic profiles and CVD risk. Quantitatively synthesizing the literature is challenging because of the widely varying analytical tools and the diversity of methodological and statistical approaches. Although some results are promising, more research is needed, notably standardization of metabolomic techniques and statistical approaches. Replication and combinations of novel and holistic methodological approaches would move the field toward the realization of its promise.

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“…Studies that are relevant to the topic have already been published, such as Alshehry et al[6], who found that sphingolipids, phospholipids, cholesterol esters and glycerolipids were associated with future cardiovascular events and cardiovascular death in people with type 2 diabetes mellitus; Zhang et al[7], identified various metabolomic biomarkers in patients with ovarian epithelial cancer; and De Oliveira et al[8], identified some lipids in greater abundance in the plasma of pregnant women in pre-eclampsia.…”

Section: Introductionmentioning

confidence: 99%

Alterations in postmenopausal plasmatic lipidome

et al. 2018

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BackgroundMenopause consists of a physiological process in women between 40 and 50 years of age, and it has substantial consequences for health, ranging from disturbances in lipid and glycidic metabolism to psychological stress and sleep alterations, thereby increasing women’s risk of cardiovascular diseases. Here, we attempted to identify potential lipid alterations not identified by the classic methods.Methods and resultsWe analyzed the serum lipid profile in 40 women in pre- and post-menopause using a lipidomic approach and mass spectrometry. Lipid species presented increased concentrations, with a difference of more than 25% post-menopause and with the ceramides (N.C23:0.Cer, N.C23:0(OH).Cer and N.C24:0(OH).Cer) standing out with a fold change of 1.68, 1.59, and 1.58, respectively. It was also observed that 14 metabolites presented a significant difference in the average concentrations between pre- and post-menopause, especially the ceramide species. Strong and positive correlations were identified between various metabolites and fasting glucose, glycated hemoglobin, total cholesterol, LDL, and triglycerides. Of note were the association ceramide (N.C10:0.Cer) and lysophosphatidylethanolamine (LPE.a.C18:0) between fasting glucose and glycated hemoglobin.ConclusionThis study detected lipid alterations, especially in ceramides, post-menopause, as well as correlations with glycidic and lipid markers, which may in the future be useful to investigate diseases associated with menopause.

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Plasma Lipidomic Profiles Improve on Traditional Risk Factors for the Prediction of Cardiovascular Events in Type 2 Diabetes Mellitus

Abstract: URL: https://clinicaltrials.gov. Unique identifier: NCT00145925.

Cited by 215 publications

References 43 publications

Novel Risk Markers and Risk Assessments for Cardiovascular Disease

Novel Risk Markers and Risk Assessments for Cardiovascular Disease

Comprehensive Metabolomic Profiling and Incident Cardiovascular Disease: A Systematic Review

Alterations in postmenopausal plasmatic lipidome

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