HDL Cholesterol May Not Be Cardioprotective in Postmenopausal Women

Patrice Wendling

August 08, 2018

Higher high-density lipoprotein cholesterol (HDL-C) could be a marker of HDL dysfunction rather than cardioprotection in postmenopausal women, a new Multi-Ethnic Study of Atherosclerosis (MESA) analysis suggests.

"When it comes to high HDL cholesterol, it does not necessarily mean protective," lead investigator Samar R. El Khoudary, PhD, MPH, University of Pittsburgh, Pennsylvania, told theheart.org | Medscape Cardiology. "If it's very high, then you need to look further at other risk factors because we showed in our study that if a woman has more large particles at this period, she is at risk."

The team hypothesizes that the decrease in estrogen, a cardioprotective sex hormone, during menopause along with changes in body fat composition and acceleration of the metabolic syndrome, may alter HDL from a cardioprotective particle to one that promotes inflammation and oxidation.

El Khoudary previously reported that increases in HDL-C levels are independently associated with greater carotid intima-media thickness (cIMT) as women transitioned to menopause in the Study of Women's Health Across the Nation (SWAN).

A substudy of 46 women in SWAN also showed a showed a switch in the relationship between HDL-C and atherosclerosis risk, such that HDL-C was protective before but not after menopause.

"The most exciting and important thing is that we were able to replicate the finding in MESA," said El Khoudary.

She noted that it was fascinating to see the switch in the relationship between HDL and atherosclerosis risk across the menopausal transition, but the problem with SWAN is that it lacks detailed measures of HDL other than the conventional test of HDL.

"When we are doing our studies and just using HDL cholesterol, we don't really know what's going on. It's like we are touching the surface."

Deeper Dive

For a more detailed look at HDL-C and its relationship to the menopausal transition, the investigators turned to 1380 women aged 45 through 84 in the ongoing MESA, who had conventional HDL metrics and ion-mobility analysis, which separates ions by size and can count lipoprotein particles ranging from the smallest, most dense 5-nm HDL particles (HDL-P) to very large 53-nm low-density lipoprotein particles (LDL-P).

In all, 21% of participants had gone through surgical menopause, 61.4% had gone through natural menopause, and 18% were perimenopausal. Mean lipids and ion-mobility particle concentrations in the three groups were:

  • 58.1 vs 56.5 vs. 53.7 mg/dL, HDL-C;

  • 120.2 vs 118.4 vs 113.8 mg/dL, LDL cholesterol;

  • 204.7 vs 200.2 vs 189.3 mg/dl, total cholesterol;

  • 7.08 vs 6.80 vs 6.51 µmol/L, large HDL-P (range, 14.5 - 10.5 nm);

  • 20.39 vs 19.81 vs 19.30 µmol/L, small HDL-P (range, 10.5 - 7.65 nm); and

  • 1.31 vs 1.29 vs 1.26 µmol/L, total LDL-P.

The women's mean age was 61.8 years, and 16% of women were receiving lipid-lowering medications.

After adjustment for each other, higher total HDL-P but not HDL-C was associated with significantly less cIMT (P = .001). In contrast, higher HDL-C but not HDL-P was associated with greater risk for carotid plaque (P = .04).

The association between HDL-C and carotid plaque should be interpreted with caution because the interaction was no longer significant after exclusion of age as a factor and stratified analyses showed a positive interaction only in women with more than 10 years since menopause, the authors report in Arteriosclerosis, Thrombosis and Vascular Biology, published online July 19.

Small but not large HDL-P was significantly associated with lower cIMT in models adjusted for study covariates, HDL-C, and LDL-P. This association was consistent regardless of age or time since menopause.

On the other hand, higher concentrations of large HDL-P were associated with lower cIMT as time since menopause increased, "suggesting a potential adverse change in the quality of these particles close to menopause, which seems to be restored later in life," the authors say.

"This is going hand-in-hand with our hypothesis that the menopausal transition seems to affect the quality of HDL — but how it impacts, what exactly it changes — that is what we are trying to find out in the new study," said El Khoudary, who recently received funding from the National Institute on Aging to continue to research her research.

"The bottom line is that the menopausal transition is a critical period in women," she said. "We need to make sure we are monitoring them because these changes when combined can impact their risk later in life and the number one killer of women is cardiovascular disease."

Menopause vs Aging

Vera Bittner, MD, University of Alabama at Birmingham, who was not involved in the research, said strengths of the study are its large sample size and consistency in lipoprotein and IMT measurements but because it is cross-sectional, it provides only a correlation between risk factors, lipids, and IMT measurements at a single snapshot in time.

"I don't think it invalidates what they found, but I think it is difficult to put a mechanism on something that at this point in time is basically a correlation," she said in an interview.

"What is very clear from this study, from the SWAN study, and other data is that HDL cholesterol level, even though it is a risk marker, should not be considered necessarily a protective factor in this age group of women," Bittner added.

That's important, she noted, "Because there are still a lot of people out there who say, 'Well, we know that you have hypertension, we know your cholesterol is high, and your sugar is a little bit abnormal, but you'll be okay because your HDL cholesterol is high.'

"That's really an outdated notion that we need to get away from but it's not necessarily based on this paper but the overall gestalt that HDL cholesterol is a less than perfect marker for HDL function."

While both women would like to see more research focusing on HDL particles, El Khoudary said the researchers are hoping the concept of the menopausal transition can be introduced into the guidelines soon because "there is a combination of research showing changes in cardiovascular health around this time."

Bittner countered, "I don't think that the guidelines have to change for the simple reason that we already know that in all of us, whether we're women or men, our risk factor profiles tend to become more adverse as we age."

"Let's say I have a 52-year-old woman in front of me who's still menstruating regularly but her blood pressure is going up a bit and her glucose looks kind of funny," she said. "Then I have exactly the same woman that tells me she has been skipping some periods. I don't think my approach to these risk factors should be any different just because one of these women is skipping periods and the other is still menstruating regularly. I think the emphasis needs to be on risk factor reduction in both of them."

To bolster her argument, Bittner pointed to "absolutely striking differences" in the risk profiles of participants who were perimenopausal vs those who underwent natural or surgical menopause described in this paper.

"Your hypertension will not increase from 17.8% to 51.5% to 59% just from the menopausal transition; the majority of that is going to be aging," she said. "And you can see the same wide width in diabetes, the need for blood pressure medication, and the need for lipid-lowering medications."

"So I think this overemphasis on menopause kind of takes our eyes off the real goal, which is primary prevention starting preferably in childhood and, if not, in early adulthood, and being really vigorous in not developing risk factors or if they do, in making sure they stay well controlled."

The research was supported by grants from the National Institute of Health and a grant from Quest Diagnostics. El Khoudary reports no relevant financial relationships. Coauthor James H. Stein receives royalties from the Wisconsin Alumni Research Foundation for a patent related to carotid wall thickness and arterial aging. The arterial age algorithms were not used in this research. Bittner reports serving on the executive steering committee for ODYSSEY Outcomes, as a national coordinator for STENGTH, CLEAR, and DalGene; and as a site principal investigator for COMPASS and ARTEMIS. She is also a coinvestigator on a contract between her university and Amgen; and has received honoraria for attending two advisory boards for Sanofi in recent years.

Arterioscler Thromb Vasc Biol. Published July 19, 2018. Abstract

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