iconstar paper   HIV Articles  
Back grey arrow rt.gif
 
 
Reduced ovarian reserve relates to monocyte activation and subclinical coronary atherosclerotic plaque in women with HIV
 
 
  Download the PDF here
 
AIDS Jan 28 2016
 
Looby, Sara E.a,b; Fitch, Kathleen V.a,b; Srinivasa, Sumana,b; Lo, Janeta,b; Rafferty, Daniellea,b; Martin, Amandaa,b; Currier, Judith C.c; Grinspoon, Stevena,b; Zanni, Markella V.a,b
 
"In the United States, HIV-infected women face a three-fold increased rate of myocardial infarction and two-fold increased rate of stroke compared with non-HIV-infected women. Reproductive aging leading to menopause (cessation of menses ≥12 months) is characterized by loss of ovarian reserve. Ovarian reserve may be quantified through measurement of anti-Mullerian hormone (AMH), a protein encoded by the AMH gene and secreted by ovarian granulosa cells
 
Among women with reduced ovarian reserve (versus the group with measurable AMH), there was an increased prevalence of any subclinical coronary atherosclerotic plaque (52 versus 6%, P = 0.0007) and an increased number of coronary atherosclerotic plaque segments per participant (2.1 ± 2.8 versus 0.1 ± 0.2, P = 0.002) (Table 3). There was also an increased prevalence of noncalcified coronary atherosclerotic plaque (48 versus 6%, P = 0.002) (Supplemental Figure 1, http://links.lww.com/QAD/A787) and an increased number of noncalcified coronary atherosclerotic plaque segments (1.3 ± 1.7 versus 0.1 ± 0.2, P = 0.003). Immune parameters also differed between groups: Among women with reduced ovarian reserve (versus women with measurable AMH), there were higher levels of log sCD163 (P = 0.0004) and log MCP-1 (P = 0.006), and there was a trend toward higher levels of log CXCL10 which did not reach statistical significance. In contrast, log sCD14 was higher among women with measurable AMH as compared with women with reduced ovarian reserve (P = 0.04)."
 
"In this study, we show for the first time that HIV-infected women with reduced ovarian reserve defined by undetectable levels of AMH have a higher prevalence and burden of subclinical coronary atherosclerotic plaque and noncalcified plaque versus premenopausal HIV-infected with measurable AMH. We further show that among HIV-infected women, reduced ovarian reserve relates to noncalcified coronary atherosclerotic plaque even after controlling for traditional CVD risk factors - including chronological age - encompassed in the Framingham point score. We also demonstrate that among HIV-infected women, levels of select markers of immune activation including sCD163 and MCP-1 increase across the reproductive aging spectrum. Ongoing work is needed to characterize mechanisms through which reproductive aging influences immune activation and coronary atherosclerotic plaque among HIV-infected women."
 
Abstract
 
Objective: To investigate differences in subclinical coronary atherosclerotic plaque and markers of immune activation among HIV-infected and non-HIV-infected women categorized by degree of ovarian reserve and menopause status.
 
Design: Cross-sectional evaluation.
 
Methods: Seventy-four women (49 HIV-infected, 25 non-HIV-infected) without known cardiovascular disease (CVD) were classified as premenopausal, premenopausal with reduced ovarian reserve, or postmenopausal based on menstrual history and anti-Mullerian hormone (AMH) levels. Participants underwent contrast-enhanced coronary computed tomography angiography and immune phenotyping. Comparisons in coronary atherosclerotic plaque burden and immune markers were made between the HIV-infected and non-HIV-infected women overall and within the HIV-infected and non-HIV-infected women by reproductive classification group.
 
Results: Among the overall group of HIV-infected women, the women with reduced ovarian reserve (undetectable AMH) had a higher prevalence of coronary atherosclerotic plaque (52 versus 6%, P = 0.0007) and noncalcified plaque (48 versus 6%, P = 0.002), as well as higher levels of log sCD163 (P = 0.0004) and log MCP-1 (P = 0.006), compared with the premenopausal women with measurable AMH. Furthermore, reduced ovarian reserve in the HIV-infected group related to noncalcified plaque, controlling for traditional CVD risk factors (P = 0.04) and sCD163 (P = 0.03).
 
Conclusion: HIV-infected women with reduced ovarian reserve have increased subclinical coronary atherosclerotic plaque compared with premenopausal women in whom AMH is measurable. This relationship holds when controlling for CVD risk factors (including age) and immune activation. Our findings demonstrate that reduced ovarian reserve may contribute to CVD burden in HIV-infected women and support a comprehensive assessment of CVD risk prior to completion of menopause in this population.
 
INTRODUCTION
 
With respect to mechanisms underlying this heightened risk, HIV-infected women have higher rates of select traditional cardiovascular disease (CVD) risk factors than are seen in the general population [4]. Compared with non-HIV-infected women, HIV-infected women on antiretroviral therapy (ART) also have higher-level immune activation [5], a potential nontraditional risk factor for HIV-associated CVD. Further, among HIV-infected women without known CVD, immune activation is increased in relation to presence of subclinical noncalcified coronary atherosclerotic plaque [5]. In regions where ART is readily accessible, the percentage of HIV-infected adults greater than 50 years old is steadily increasing [6]. Thus, it will be critical to understand the ways in which reproductive aging contributes to CVD risk in this population. Reproductive aging leading to menopause (cessation of menses ≥12 months) is characterized by loss of ovarian reserve. Ovarian reserve may be quantified through measurement of anti-Mullerian hormone (AMH), a protein encoded by the AMH gene and secreted by ovarian granulosa cells [7]. AMH levels decline as women transition into menopause and levels may drop nearly 5 years before the final menstrual period [8]. Indeed, AMH levels may be useful in predicting age at menopause [8,9]. Among HIV-infected women (versus non-HIV-infected women), the menopausal transition appears to occur earlier [10,11], and age-adjusted AMH levels are lower in HIV-infected women versus uninfected women [12]. Prior studies suggest a potential relationship between reduced ovarian reserve and increased CVD risk [13,14]. However, the relationship between reduced ovarian reserve, postmenopausal status, and CVD risk among HIV-infected women remains unknown. Moreover, there is incomplete understanding as to how the hormonal milieu in aging HIV-infected women influences immune activation/immunosenescence and whether changes in immune function brought about by reproductive aging contribute to HIV-associated CVD.
 
In this study, we investigate differences in CVD risk parameters, including immune markers and subclinical atherosclerotic plaque, among HIV-infected and non-HIV-infected women carefully characterized by menopause status and degree of ovarian reserve. CVD risk parameters among HIV-infected women in sequential stages of reproductive aging are assessed.
 
Discussion
 
In this study, we show for the first time that HIV-infected women with reduced ovarian reserve defined by undetectable levels of AMH have a higher prevalence and burden of subclinical coronary atherosclerotic plaque and noncalcified plaque versus premenopausal HIV-infected with measurable AMH. We further show that among HIV-infected women, reduced ovarian reserve relates to noncalcified coronary atherosclerotic plaque even after controlling for traditional CVD risk factors - including chronological age - encompassed in the Framingham point score. We also demonstrate that among HIV-infected women, levels of select markers of immune activation including sCD163 and MCP-1 increase across the reproductive aging spectrum. Ongoing work is needed to characterize mechanisms through which reproductive aging influences immune activation and coronary atherosclerotic plaque among HIV-infected women.
 
In the general population, postmenopausal women are at increased risk of CVD (versus premenopausal women) but the mechanisms underlying this heightened risk remain unclear [17]. Compared with premenopausal women, postmenopausal women have alterations in lipid metabolism; a higher prevalence of hypertension and diabetes; increased BMI and visceral adiposity; increased endothelial dysfunction and decreased arterial dispensability; and alterations in immune function and oxidative stress potentially relevant to atherogenesis [18-21]. Among aging women, the relative contributions of chronological/somatic aging versus reproductive aging (altered hormonal milieu [22]) to increased atherogenicity remain unclear. Importantly, numerous atherogenic changes contributing to heightened CVD risk occur along a continuum among aging women and begin well before the menopause transition is complete [23]. Thus, imperatives exist to refine strategies for identifying women at heightened risk for CVD and to elucidate mechanisms underlying this risk.
 
Through our work, we compare CVD risk across reproductive aging categories employing a carefully designed classification scheme based on menstrual history and levels of AMH, which are not dependent on menstrual cycle phase [7]. The most widely accepted traditional reproductive aging classification scheme is based on the stages of reproductive aging workshop (STRAW) criteria [24]. These criteria are reliant on menstrual history as well as levels of FSH and E2 timed to menstrual cycle day 3. There are challenges, however, to applying the STRAW criteria to HIV-infected women. Among HIV-infected women, menstrual irregularity/anovulation is frequently observed [25]. Thus, timing hormonal assessments to day 3 of the menstrual cycle represents a serious logistic challenge for clinic patients and clinical trial participants alike. Indeed, the original STRAW system was initially developed and validated in a cohort of healthy women, and the North American Menopause Society has advised against application among women with chronic illness and/or menstrual irregularity [24]. The above caveats also apply to the updated STRAW-10 criteria [26]. Synthesizing data on AMH with data on menstrual cycles, as we do, permits us to distinguish between women with reduced ovarian reserve who have not yet completed the menopausal transition (cycles within the year and undetectable AMH) and women who have indeed completed menopause (no cycles ≥ 1 year and undetectable AMH). Our paradigm may be usefully applied to future studies characterizing effects of reproductive aging on CVD risk in HIV. Such studies are much needed, as our work suggests that CVD risk significantly increases prior to completion of the menopause transition among HIV-infected women. Whether reduced ovarian reserve relates causally to increased subclinical atherosclerosis and CVD risk among HIV-infected individuals remains to be determined. Intriguingly, a study among female cynomolgus macaques fed an atherogenic diet revealed that those monkeys with the lowest tertile of baseline AMH went on to develop the largest atherosclerotic plaques [14]. In humans, no such studies relating baseline AMH levels to development of atherosclerotic plaque over time have been conducted. However, a recent study suggested that reduced duration of ovarian hormone exposure (menarche to menopause) increased a woman's risk of developing acute myocardial infarction, ischemic heart disease, or stroke [27]. Among women with HIV, the menopausal transition may occur earlier than in women without HIV [10,11]. Whether AMH falls to undetectable levels earlier among premenopausal HIV-infected women (versus premenopausal non-HIV-infected women) and whether AMH levels predict time-to-menopause among HIV-infected women remains unknown.
 
Heightened immune activation represents a theoretical intermediary between reduced ovarian reserve and heightened subclinical atherosclerosis among women with HIV. We found that among women with HIV, select immune activation markers (sCD163, MCP-1) increase along the reproductive aging spectrum [5]. Situating this finding, Fitch et al. demonstrated synergistic effects of age, sex, and HIV serostatus on levels of sCD163 [5]. Martin et al. further showed that age-associated changes in immune activation are accelerated among HIV-infected women (versus uninfected women) [28]. Non-HIV studies have suggested that menopause is associated with immune activation/immunosenescence [29], and work from our group and others has suggested that these processes may promote atherogenesis in HIV [30-32]. Indeed, the recently launched REPRIEVE trial, a randomized clinical trial of pitavastatin versus placebo among 6500 HIV-infected individuals with low-to-moderate traditional CVD risk, tests the hypothesis that statin therapy will reduce ASCVD events in HIV in part through effects to dampen immune activation. It is worth noting, however, that although reduced ovarian reserve may plausibly exacerbate immune activation and subclinical atherosclerosis in HIV, the reverse causality may also be entertained [33].
 
That is, among HIV-infected individuals, vasculopathy and/or associated immune activation may contribute to accelerated loss of ovarian reserve. Future, prospective studies among HIV-infected women are needed to tease out the complex interplay between reduced ovarian reserve, immune activation, and accelerated atherosclerosis.
 
Loss of endogenous estrogen may be another theoretical intermediary between reduced ovarian reserve and heightened subclinical atherosclerosis among women with HIV. Numerous studies suggest endogenous estrogen may protect against atherogenesis, favorably influencing lipid homeostasis as well as endothelial function [34]. In our study, estradiol levels were assessed but blood sampling was not timed to the menstrual cycle, precluding inferences about the relationship between estradiol levels and subclinical coronary atherosclerosis. Future research analyzing the relationship between reduced ovarian reserve, decreased endogenous estrogen production, and atherogenesis among HIV-infected women is needed. Future research is also needed to ascertain how different nontraditional CVD risk factors (such as cocaine use [35,36]) influence atherogenesis among HIV-infected women across the reproductive aging spectrum. Results from our multivariate modeling suggest that among women with HIV, reduced ovarian reserve contributes to the burden of noncalcified coronary atherosclerotic plaque even when controlling for Framingham point score (which encompasses chronologic age). Moreover, in the HIV-infected group, the relationship between reduced ovarian reserve and noncalcified coronary atherosclerotic plaque does not appear to be mediated entirely through heightened immune activation. Additionally, in the HIV-infected group, reduced ovarian reserve relates to noncalcified coronary atherosclerotic plaque controlling for HCV co-infection. These findings are important, as noncalcified atherosclerotic plaque has been shown in the general population to be more vulnerable to rupture and result in myocardial infarction, as compared with calcified coronary atherosclerotic plaque [37]. Of note, in our cohort, parallel modeling among non-HIV-infected women suggests that Framingham point score relates strongly to the burden of noncalcified coronary atherosclerotic plaque in this group, overshadowing the potential contribution of reduced ovarian reserve. The overall predictive value of the model is stronger in the non-HIV-infected group. These findings reinforce that increased subclinical plaque may be seen among HIV-infected men and women with low traditional CVD risk indices [15,32,5].
 
Strengths of our study include the application of a reproductive aging categorization paradigm (incorporating both menstrual history data and cycle-independent AMH data) to relate loss of ovarian reserve and/or menopause to CVD risk in HIV. This paradigm may be employed in future studies of cardiometabolic health among HIV-infected women. Limitations of our study include the relatively small sample size, the recruitment of study participants from a single demographic region, and the cross-sectional design, which precludes determinations of causality.
 
Our finding that reduced ovarian reserve among women with HIV relates to subclinical atherosclerotic plaque even after controlling for traditional CVD risk (including age) is novel and clinically relevant. This finding suggests that careful CVD risk assessment may be usefully directed to HIV-infected women well before they complete the menopause transition, along with strategies to manage modifiable CVD risk factors and counseling to report cardiovascular symptoms. Moreover, our observations that markers of immune activation increase along the reproductive aging spectrum among HIV-infected women provides direction for future work analyzing the mechanistic relationship between reduced ovarian reserve and atherosclerosis in HIV.

 
 
 
 
  iconpaperstack View Older Articles   Back to Top   www.natap.org