Why Do Women With HIV Have a Higher Heart Attack Risk Than Men?

When researchers published data from the Multicenter AIDS Cohort Study in 2014 showing that people living with HIV were more likely to have increased fat around their hearts, and that that volume was associated with increased coronary plaque, it seemed possible that such fat could be implicated in subclinical atherosclerosis in people living with HIV.

But that study,^[1] like so many investigating the effects of statins and other heart disease risks, only followed men. And Suman Srinivasa, MD, of Harvard Medical School wondered whether women's hearts might be different.

"No one has teased out epicardial fat volume among women," she told Medscape. That's in women with or without HIV. And, Dr Srinivasa added, "If we don't fully understand heart disease risk among the non–HIV-infected population, there's still much more to understand among the HIV population, as well."

So she and a team of researchers at Harvard looked at women with and without HIV to investigate epicardial fat volume, systemic inflammation, and cardiovascular disease risks. What they found, in a poster presented at the 2017 Conference on Retroviruses and Opportunistic Infections,^[2] is that, unlike in men, epicardial fat was no more voluminous in women with HIV than in those without this infection.

But even without increased epicardial fat volume, women with HIV had far higher levels of systemic inflammation. And those few women with HIV with higher-than-median epicardial fat volume had the highest systemic inflammation. The finding challenges the notion that cytokine-producing epicardial fat itself may be associated with atherosclerosis in people with HIV, and points to how far we still have to go to understand—and intervene in—the cardiovascular risk in women living with HIV.

"I do think it points to the fact that information derived from an all-male cohort can't necessarily be extrapolated to women," said Dr Markella Zanni, MD, Harvard Medical School.

HIV and the Heart

From the beginning of the epidemic, the hearts of people living with HIV behaved in surprising ways. First, there were the heart attacks, described in case studies, in young men with HIV. Then came data, published in the Journal of Acquired Immune Deficiency Syndromes, showing that women were far more likely to experience adipose tissue alterations as the result of antiretroviral treatment than were men.^[3]

Then, in 2007, a team led by Steven Grinspoon, MD, at Harvard Medical School revealed that women living with HIV were 2.98 times as likely to have an acute myocardial infarction than other women, whereas men living with HIV were 1.4 times as likely to have a heart attack than their HIV-negative peers.^[4]

That paper was what changed Dr Zanni's clinical and research career. When Dr Grinspoon's paper came out, she was completing her clinical fellowship in endocrinology. The data, she said, posed an exciting clinical question: Why do people living with HIV have higher risk for heart disease than others, and why do women in particular have the highest increase in risk?

Those questions led her to Dr Grinspoon's lab and to a career of studying immune activation, inflammation, fat deposits, and heart disease risk factors in men and women living with HIV. Along with Dr Sara Looby, MD, she is one of the principal investigators on the Randomized Trial to Prevent Cardiovascular Events in HIV (REPRIEVE) Women's Objectives Project, a National Institutes of Health-funded study specifically on women and heart disease risk.

The increased risk, especially among women, is puzzling, Dr Zanni said. On the one hand, people living with HIV do tend to have high levels of traditional risk factors for HIV—high rates of cigarette smoking and metabolic disorders.

On the other hand, that risk doesn't fully explain the higher rates of heart attack and stroke among women with HIV. In studies she's been part of, researchers have shown that people living with HIV with low heart disease risk according to the Framingham Risk Score nevertheless have rates of aortic inflammation that rival those in people without HIV who already have atherosclerosis. This is despite effective antiretroviral therapy (ART), which improves immune function without dampening immune activation.

Data has shown that some ART regimens^[5] may contribute to heart disease, especially protease inhibitors.^[6] And ART regimens have been associated with the location of visceral fat in people living with HIV. But that, too, doesn't fully explain the risk, she said.

"That's one of the questions that drove this poster about epicardial tissue," said Dr Zanni, who is a coauthor of the poster.

Epicardial Fat and Women's Hearts

Systemic inflammation is even higher among women living with HIV. A study from Dr Grinspoon's lab in 2013 found that whereas both men with and men without HIV had low Framingham Risk Scores for cardiovascular disease, women with living with HIV had demonstrably higher activation of CD163 and CD14 than any man, whether he had HIV or not.^[7]

"Women with HIV have the highest levels of immune activation, compared with both women and men," Dr Zanni said. "This is a critical piece of the puzzle."

And because the Multicenter AIDS Cohort Study found a larger volume of epicardial fat in men living with HIV that was associated with increased markers of atherosclerosis, Dr Zanni joined up with Dr Srinivasa and others in the lab to see whether epicardial fat, which is woven through with coronary arteries and might carry immune-activating monocytes and hormones throughout the body, could be at least partly to blame.

"Knowing in general that women are at risk for fat redistribution with HIV, we would have hypothesized that we'd be seeing a larger volume of epicardial fat," said Dr Srinivasa, "and that having a larger volume, you'd have a larger quantity associated with increase inflammation."

EAT, ART, and Inflammation in Women

But that's not what they found.

In fact, what they found was that of the 55 women living with HIV and the 27 age-matched non–HIV-infected controls, epicardial adipose tissue (EAT) volume was essentially unchanged. But inflammation wasn't. None of the women in the study had a history of heart disease.

"This one did have a surprise," Dr Zanni said.

When they parsed the data even further, dividing the women into four groups depending on their HIV status and whether they had below-average or above-average median EAT, another picture emerged.

It turned out that although the overall EAT volume didn't vary by HIV status, the small number of women who had both higher-than-median volumes of EAT and were living with HIV also had higher markers for inflammation and noncalcified coronary atherosclerotic plaque.

What's more, said Dr Zanni, EAT was not associated with total Framingham Risk Score. But it was associated with ART—specifically, the use of nucleoside reverse transcriptase inhibitors and duration of ART.

"What that last piece suggests to me is that the overall volume of EAT may not be different in women with and women without HIV," Dr Zanni said, "but that there might be a possible underlying mechanism to effect the deposits in each group."

Those hypotheses and others will have to be borne out in larger cohorts and in prospective or randomized trials, said Dr Zanni.

"Right now, we have more questions than answers," she said.

Applying the Lessons Clinically

For Phyllis Tien, MD, at the University of California, San Francisco, the findings raise the question of how EAT volume in these women compares with that in men—she would have liked to have seen a direct comparison between the two. Plus, she said, while the study tests for antimüllerian hormone (AMH), it doesn't discuss the significance of the hormone.

AMH is a marker of ovarian reserve. Women reach undetectable levels years before their last period. That's also the time, she said, when visceral adipose tissue and subclinical atherosclerosis increases.^[8]

"Perhaps that could be a driver [of cardiovascular disease risk] too," Dr Tien said. "It would have been nice to see whether there was a difference among premenopausal, early perimenopausal, late perimenopausal, and postmenopausal women."

Dr Tien, who is chair of the Women's Interagency HIV Study executive committee, is working on a study now on AMH levels and liver and cardiovascular disease.

"The question is, do we need to intervene when AMH is undetectable, 5 years before the end of the menstrual period, in terms of liver disease and cardiovascular disease?" she said.

For Anthony Fauci, MD, of the National Institutes of Health, the findings are "just another confirmation that immune activation is bad when dealing with the risk of cardiovascular disease that we see in women."

And although both Drs Zanni and Srinivasa said they'd like to see a study that takes these data and attempt an intervention that reduces EAT and inflammation, Dr Fauci said the most promising intervention right now is in the REPRIEVE trial. The trial, which is still enrolling participants, will follow 6500 women and men with HIV to see whether a statin can reduce cardiovascular events.

"Giving a statin is about as good a tool as we have to not only decrease risk for cardiovascular disease, but also decrease immune activation," said Dr Fauci. "If that's one of the mechanisms of heart disease risk among women with HIV, you get a twofer with statins."

Until those results are out, however, Dr Zanni suggested that there's enough information now to start intervening earlier in women aging with HIV who have traditional cardiac risk factors.

"What I would take to the clinic is that women with HIV may be at quite high risk for heart disease. Don't presume them to be at lower risk just by virtue of being women."

She added, "Women with HIV are at increased risk for cardiovascular disease even before men. So that clinical attention to modify traditional risk factors may need to be applied even earlier."

Dr Zanni has participated in an SAB meeting for Roche Diagnostics. Dr Srinivasa, Dr Tien, and Dr Fauci have disclosed no relevant financial relationships.

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