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Large-scale plasma lipidomic profiling identifies lipids that predict cardiovascular events in secondary prevention
Piyushkumar A. Mundra, … , Peter J. Meikle, LIPID Study Investigators
Piyushkumar A. Mundra, … , Peter J. Meikle, LIPID Study Investigators
Published September 6, 2018
Citation Information: JCI Insight. 2018;3(17):e121326. https://doi.org/10.1172/jci.insight.121326.
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Clinical Medicine Cardiology Metabolism

Large-scale plasma lipidomic profiling identifies lipids that predict cardiovascular events in secondary prevention

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Abstract

BACKGROUND. Plasma lipidomic measures may enable improved prediction of cardiovascular outcomes in secondary prevention. The aim of this study is to determine the association of plasma lipidomic measurements with cardiovascular events and assess their potential to predict such events. METHODS. Plasma lipids (n = 342) were measured in a retrospective subcohort (n = 5,991) of the LIPID study. Proportional hazards regression was used to identify lipids associated with future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and cardiovascular death. Multivariable models adding lipid species to traditional risk factors were created using lipid ranking established from the Akaike information criterion within a 5-fold cross-validation framework. The results were tested on a diabetic case cohort from the ADVANCE study (n = 3,779). RESULTS. Specific ceramide species, sphingolipids, phospholipids, and neutral lipids containing omega-6 fatty acids or odd-chain fatty acids were associated with future cardiovascular events (106 species) and cardiovascular death (139 species). The addition of 7 lipid species to a base model (11 conventional risk factors) resulted in an increase in the C-statistics from 0.629 (95% CI, 0.628–0.630) to 0.654 (95% CI, 0.653–0.656) for prediction of cardiovascular events and from 0.673 (95% CI, 0.671–0.675) to 0.727 (95% CI, 0.725–0.728) for prediction of cardiovascular death. Categorical net reclassification improvements for cardiovascular events and cardiovascular death were 0.083 (95% CI, 0.081–0.086) and 0.166 (95% CI, 0.162–0.170), respectively. Evaluation on the ADVANCE case cohort demonstrated significant improvement on the base models. CONCLUSIONS. The improvement in the prediction of cardiovascular outcomes, above conventional risk factors, demonstrates the potential of plasma lipidomic profiles as biomarkers for cardiovascular risk stratification in secondary prevention. FUNDING. Bristol-Myers Squibb, the National Health and Medical Research Council of Australia (grants 211086, 358395, and 1029754), and the Operational Infrastructure Support Program of the Victorian government of Australia.

Authors

Piyushkumar A. Mundra, Christopher K. Barlow, Paul J. Nestel, Elizabeth H. Barnes, Adrienne Kirby, Peter Thompson, David R. Sullivan, Zahir H. Alshehry, Natalie A. Mellett, Kevin Huynh, Kaushala S. Jayawardana, Corey Giles, Malcolm J. McConville, Sophia Zoungas, Graham S. Hillis, John Chalmers, Mark Woodward, Gerard Wong, Bronwyn A. Kingwell, John Simes, Andrew M. Tonkin, Peter J. Meikle, LIPID Study Investigators

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Figure 1

Consort diagram for lipidomic profiling of the LIPID study and ADVANCE study.

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Consort diagram for lipidomic profiling of the LIPID study and ADVANCE s...
In the LIPID trial, 9,014 participants were randomized to receive pravastatin treatment or placebo. Lipidomic profiling was performed on all participants with baseline samples available (n = 5,991). Of these, 1,359 experienced a cardiovascular event and 708 experienced cardiovascular death. In the ADVANCE study, from 7,376 available baseline samples, a case cohort (n = 3,779) was selected for lipidomic profiling. This consisted of n = 3,154 randomly selected participants and all additional cases of cardiovascular events, renal events, and all-cause mortality (n = 625). Of these, n = 698 experienced a cardiovascular event and 355 experienced cardiovascular death.

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