HDL Functionality Inversely Linked With CVD Outcomes: Dallas Heart Study

November 18, 2014

CHICAGO, IL — Cholesterol-efflux capacity, which is a marker of HDL function that measures reverse cholesterol transport, is inversely associated with incident atherosclerotic cardiovascular disease in a large population of patients healthy at baseline[1].

The findings, say researchers, support "retiring" the HDL cholesterol hypothesis—the idea of simply raising HDL cholesterol to reduce the risk of cardiovascular disease—and instead should shift the focus to measures of HDL functionality.

"HDL cholesterol is a risk factor for heart disease, where low levels of HDL cholesterol connote increased risk," lead investigator Dr Anand Rohatgi (University of Texas Southwestern Medical Center, Dallas, TX) told heartwire . "However, it's confounded mostly by an association with insulin-resistance phenotypes, and therapies that modulate HDL-cholesterol levels have failed to reduce outcomes. That's why everyone, including ourselves, are looking 'under the hood,' so to speak, to figure out what's going with HDL metabolism."

In studies, including their own, Rohatgi said that HDL-cholesterol levels are not reflective of HDL functionality. One of the key functions of HDL cholesterol is the cholesterol-efflux pathway, which is the pathway where cholesterol is removed from macrophages within the arterial walls back into the bloodstream and out to the liver. As one of the key functions of HDL, their hypothesis was that if they could measure HDL-cholesterol–efflux capacity, they'd have a better handle on the role of HDL in atherosclerosis.

The HDL-cholesterol field, as Rohatgi noted, has seen a number of once-promising therapies not work out when tested in clinical-outcomes studies. For example, two major HDL-raising studies with high-dose extended-release niacinAIM-HIGH and HPS2-THRIVE—were both negative, while the CETP inhibitors dalcetrapib and torcetrapib both failed to have an impact on clinical outcomes. Torcetrapib, in fact, was stopped because of an increased risk of death and cardiovascular events. Other CETP inhibitors, including anacetrapib (Merck, Whitehouse Station, NJ) and evacetrapib (Eli Lilly, Indianapolis, IN), are still being tested in large-scale studies.

HDL Function and Incident CVD

The cholesterol-efflux study was presented today at the American Heart Association (AHA) 2014 Scientific Sessions and published online November 18, 2014 in the New England Journal of Medicine. In it, investigators measured HDL-cholesterol levels, HDL-particle concentration, and cholesterol-efflux capacity in 2924 adults without cardiovascular disease at baseline in the Dallas Heart Study.

In their study, Rohatgi and colleagues first performed a cross-sectional analysis with multiple variables, including patient demographics and risk factors. He said factors such as age, sex, and adiposity affect HDL-cholesterol levels, so they wanted to determine whether these variables affected cholesterol-efflux capacity as well.

"Instead, we found a discordance, where cholesterol-efflux capacity didn't track with sex and race, like HDL cholesterol, and efflux didn't associate with adiposity, insulin resistance, lipids, or body composition," he said. "So we theorized that whatever pathways are reflected by efflux capacity, they're not governed by the same risk factors that are associated with HDL cholesterol."

To measure HDL cholesterol-efflux capacity, Rohatgi told heartwire , macrophages are labeled in vitro with cholesterol. The macrophages are then incubated with plasma that has been depleted of apolipoprotein B (apoB). Next, they quantify the amount of labeled cholesterol that moves from the macrophages in the apoB-depleted plasma—this is the cholesterol-efflux measurement, said Rohatgi.

For the primary results, individuals with higher levels of cholesterol-efflux capacity—those in the highest quartile—had a significantly lower risk of developing cardiovascular disease than individuals in the lowest quartile. Overall, when comparing the highest vs lowest quartiles, those with greater functionality had a 67% lower risk of MI, stroke, coronary revascularization, or death from cardiovascular causes after adjustment for traditional risk factors, HDL-cholesterol level, and HDL-particle concentration.

In contrast, HDL-cholesterol levels were not inversely associated with cardiovascular risk in the Dallas Heart Study population.

"I think this is really exciting for a number of reasons," said Rohatgi. "It really helps put the nail in the coffin when focusing on HDL cholesterol. It also opens the door to a new biological pathway with immediate relevance. One of the things that has plagued our field, as well as others, is that whatever has been found in the preclinical realm doesn't always translate into humans. Here we're seeing direct signals in humans. Now we have to go back to understand the whats, whys, and hows."

The development of bioassays that work in humans, including this one that measures macrophage-specific cholesterol-efflux capacity, also open up possibilities in terms of investigating therapeutic responses to novel therapies, he said.

Speaking during the AHA special report session, Dr Daniel Rader (University of Pennsylvania Perelman School of Medicine, Philadelphia) noted that his group had previously demonstrated cholesterol-efflux capacity was associated with prevalent coronary heart disease. While nice to show, the question in the HDL field has been whether or not cholesterol-efflux capacity is associated with first-incident cardiovascular events. By answering this question, the researchers help move the field forward by getting closer to proving causality, said Rader.

Rohatgi and Rader both said the results will need to be confirmed in another study. As Rader pointed out, there were just 132 cardiovascular events over 9 years of follow-up, so replication in other cohorts is important.

Researchers and companies are currently testing formulations of apolipoprotein A1 (apoA1) in early-stage clinical trials. In AEGIS, a phase 2b dose-ranging study sponsored by CSL, investigators are testing the safety and tolerability of an apoA1 formulation in 1200 patients with MI. In another, the Medicines Company is testing a complex of recombinant apoA1 Milano and phospholipid in a much smaller phase 1 study. Both compounds are designed to promote reverse cholesterol transport.

The study was supported by grants from the Donald W Reynolds Foundation; the National Center for Advancing Translational Sciences of the National Institutes of Health; the National Heart, Lung, and Blood Institute; and the American Heart Association and by a research grant from the investigator studies program of Merck Sharp & Dohme. Rohatgi is on the speaker's bureau for AstraZeneca, serves as a consultant to Aegerion, and receives fees for his role as associate editor, cardiac biomarkers clinical community, CardioSource editorial board. Disclosures for the coauthors are available at nejm.org.

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