Dataset Information

Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease.

ABSTRACT: As biologic, epidemiologic, and clinical trial data have demonstrated, inflammation is a key driver of atherosclerosis. Circulating biomarkers of inflammation, including high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), are associated with increased risk of cardiovascular events independent of cholesterol and other traditional risk factors. Randomized trials have shown that statins reduce hsCRP, and the magnitude of hsCRP reduction is proportional to the reduction in cardiovascular risk. Additionally, these trials have demonstrated that many individuals remain at increased risk due to persistent elevations in hsCRP despite significant reductions in low-density lipoprotein cholesterol (LDL-C) levels. This "residual inflammatory risk" has increasingly become a viable pharmacologic target. In this review, we summarize the data linking inflammation to atherosclerosis with a particular focus on residual inflammatory risk. Additionally, we detail the results of Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), which showed that directly reducing inflammation with an IL-1? antagonist reduces cardiovascular event rates independent of LDL-C. These positive data are contrasted with neutral evidence from CIRT in which low-dose methotrexate neither reduced the critical IL-1? to IL-6 to CRP pathway of innate immunity, nor reduced cardiovascular event rates.

SUBMITTER: Aday AW

PROVIDER: S-EPMC6403155 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease.

Aday Aaron W AW Ridker Paul M PM

Frontiers in cardiovascular medicine 20190228

As biologic, epidemiologic, and clinical trial data have demonstrated, inflammation is a key driver of atherosclerosis. Circulating biomarkers of inflammation, including high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), are associated with increased risk of cardiovascular events independent of cholesterol and other traditional risk factors. Randomized trials have shown that statins reduce hsCRP, and the magnitude of hsCRP reduction is proportional to the reduction in cardiova ...[more]

PMID: 30873416

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Project description:BackgroundEven when low-density lipoprotein-cholesterol (LDL-C) levels are lower than guideline thresholds, a residual risk of atherosclerosis remains. It is unknown whether triglyceride (TG) levels are associated with subclinical atherosclerosis and vascular inflammation regardless of LDL-C.ObjectivesThis study sought to assess the association between serum TG levels and early atherosclerosis and vascular inflammation in apparently healthy individuals.MethodsAn observational, longitudinal, and prospective cohort study, including 3,754 middle-aged individuals with low to moderate cardiovascular risk from the PESA (Progression of Early Subclinical Atherosclerosis) study who were consecutively recruited between June 2010 and February 2014, was conducted. Peripheral atherosclerotic plaques were assessed by 2-dimensional vascular ultrasound, and coronary artery calcification (CAC) was assessed by noncontrast computed tomography, whereas vascular inflammation was assessed by fluorine-18 fluorodeoxyglucose uptake on positron emission tomography.ResultsAtherosclerotic plaques and CAC were observed in 58.0% and 16.8% of participants, respectively, whereas vascular inflammation was evident in 46.7% of evaluated participants. After multivariate adjustment, TG levels ≥150 mg/dl showed an association with subclinical noncoronary atherosclerosis (odds ratio [OR]: 1.35; 95% confidence interval [CI]: 1.08 to 1.68; p = 0.008). This association was significant for groups with high LDL-C (OR: 1.42; 95% CI: 1.11 to 1.80; p = 0.005) and normal LDL-C (OR: 1.85; 95% CI: 1.08 to 3.18; p = 0.008). No association was found between TG level and CAC score. TG levels ≥150 mg/dl were significantly associated with the presence of arterial inflammation (OR: 2.09; 95% CI: 1.29 to 3.40; p = 0.003).ConclusionsIn individuals with low to moderate cardiovascular risk, hypertriglyceridemia was associated with subclinical atherosclerosis and vascular inflammation, even in participants with normal LDL-C levels. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Project description:It is uncertain whether pharmacological reductions in very-low-density lipoproteins (VLDLs), and their component triglyceride and cholesterol could reduce residual risk of atherosclerotic cardiovascular disease (ASCVD) events among individuals in whom low-density lipoprotein cholesterol (LDL-C) has been adequately lowered. We examined whether individuals with greater on-statin reductions in VLDL-related measures-beyond reductions in LDL-C-were at further reduced risk of ASCVD.In 9423 participants in the JUPITER (Justification for the Use of Statins in Prevention) trial (NCT00239681), at baseline and on statin we measured standard lipids, 400-MHz proton nuclear magnetic resonance spectroscopy-measured VLDL particle subclasses (small, medium, and large VLDL lipoprotein particle concentration), and total VLDL cholesterol mass. Compared with individuals allocated to placebo, we examined risk of incident ASCVD (N=211) among statin-allocated participants who achieved minimal (<median) or greater (?median) marker reductions using adjusted Cox models. On-statin changes in VLDL-related markers were only modestly correlated (Spearman r?0.29) with change in LDL-C. On-statin median LDL-C was 54 mg/dL and triglyceride was 101 mg/dL. Dose-response reductions in ASCVD risk were observed for greater reductions in LDL-C, VLDL cholesterol mass, and small VLDL lipoprotein particle concentration; the latter 2 remained significant after incremental adjustment for change in LDL-C (P?0.006). Conversely, there was no further risk reduction with greater reductions in triglycerides or large/medium VLDL lipoprotein particle concentration.Pharmacological reduction in small, cholesterol-enriched, triglyceride-depleted VLDL was associated with reduction in ASCVD risk. Chemically measured triglycerides may not sufficiently capture risk related to VLDL pathways. These findings also support broader profiling of lipid and lipoprotein changes in response to statins as prognostic markers of individual benefit, supporting more precision-medicine, individualized approaches to cardiovascular risk reduction.URL: https://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Dataset Information

Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease.

Publications

Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease.

Similar Datasets

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