HDL Anti-inflammatory Effects Show Prognostic Potential

April 14, 2021

The high-density-lipoprotein (HDL) particle's complexity as a mediator of cardiovascular (CV) risk was on display in a case–control study that, the researchers say, points to its anti-inflammatory capacity as potentially a worthy addition to standard CV risk assessments.

A measure of HDL anti-inflammatory capacity in a prospective community cohort was inversely related to future CV risk independent of HDL's role in cholesterol transport, total cholesterol, and other established biomarkers, as well as any lipid-modifying therapy.

The current analysis "identified an impaired HDL anti-inflammatory capacity as a functional metric prospectively associated with increased cardiovascular risk in the general population," observe the authors of the study, published April 12 in Circulation, led by Congzhuo Jia, MD, University of Groningen, the Netherlands.

"In contrast with the cholesterol efflux function of HDL that tracks moderately with HDL cholesterol levels," they write, HDL anti-inflammatory capacity was not significantly correlated with actual levels of the lipoprotein or a major constituent, apolipoprotein A1 (apoA1). Nor was it correlated with levels of a more generalized inflammatory biomarker, C-reactive protein by high-sensitivity assay (hsCRP).

In a test of its independence as a prognosticator, HDL anti-inflammatory capacity significantly and meaningfully improved prediction of CV events in the study after it was added to the familiar Framingham risk equations.

Measurement of HDL anti-inflammatory properties, therefore, has the potential to improve current CV risk assessments in people without clinical heart disease, the authors propose.

The study "adds to our understanding of the potential cardioprotective role of HDL," Michael Miller, MD, University of Maryland School of Medicine, Baltimore, told theheart.org | Medscape Cardiology.

"We've known for some time that HDL has anti-inflammatory properties in vitro, and my understanding is this is the first study to assess these anti-inflammatory properties in a clinical trial," said Miller, who studies lipid metabolism and directs the Center for Preventive Cardiology at his center but isn't an author of the report.

The study is part of a long line of research aiming to "untangle the complexities of HDL and try to get a better handle as to the properties that make it cardioprotective," he said. For example, "high levels are not always associated with cardioprotection, and low levels don't always imply increased risk."

The current findings highlight a quality of HDL that might be prognostic but also independent of its concentrations, apoA1 content, or cholesterol efflux capacity, Miller noted. That makes HDL anti-inflammatory capacity a "promising feature" of HDL that, if confirmed in further studies, could potentially be brought into the mainstream for CV risk prediction. "But it's too premature at this time."

The study of participants in the population-based PREVEND cohort study compared 340 patients with a first CV event — CV death, ischemic heart disease, nonfatal myocardial infarction, or coronary revascularization — over a median of about 10 years with the same number of participants without such events. The two cohorts of people from the same city in the Netherlands had been matched according to sex, smoking status, age, and HDL cholesterol levels at baseline.

No measured clinical or laboratory value, the group writes, was significantly correlated with HDL anti-inflammatory capacity, defined here as ability to suppress vascular cell adhesion molecule-1 (VCAM-1) mRNA expression as induced by tumor necrosis factor alpha (TNFα) in endothelial cells in vitro.

HDL anti-inflammatory capacity was significantly lower in the case cohort compared with the control cohort (< .001) and was inversely related to new CV events, at an odds ratio (OR) per 1 standard deviation of 0.74 (95% CI, 0.61 - 0.90; P = .002). Covariate adjustments included body mass index; alcohol intake; diabetes and hypertension status; use of lipid-lowering meds; levels of total cholesterol, apoA1, triglyceride, and hsCRP; and measures of renal function.

No significant association was seen between HDL anti-inflammatory capacity and cholesterol efflux capacity (coefficient of correlation, −0.02; > .05). But both metrics were independently associated with CV disease events. The OR per 1 standard deviation was 0.74 (95% CI, 0.61 - 0.90; = .002) for cholesterol efflux capacity and 0.66 (95% CI, 0.54 - 0.81; < .001) for HDL anti-inflammatory capacity.

Adding HDL anti-inflammatory capacity to the Framingham risk score significantly improved its predictive power; its likelihood-ratio statistic rose from 10.50 to 20.40 (= .002), the group writes. The addition of cholesterol efflux capacity further elevated the risk score's likelihood-ratio statistic to 32.84 (= .0005).

The analysis has all the limitations of a case–control study, Miller said, but it does "show a potential reasonable association" between anti-inflammatory capacity and CV risk "that needs to be taken to the next level."

For example, it could be explored in a controlled trial that tracks anti-inflammatory capacity in individuals who receive an intervention that is likely to improve the biomarker — such as weight loss, he proposed — and follows them for clinical outcomes.

"If you want to elevate the stature of the anti-inflammatory index," Miller said, "you will need to show that it's clinically meaningful."

Jia reports no conflicts; disclosures for the other authors are in the report. Miller has no relevant disclosures.

Circulation. Published online April 12, 2012. Full text

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