Syndemic burden and menopause each pushed cardiovascular risk higher in midlife women
Women aging with HIV carry more than one layer of cardiovascular vulnerability, and this preprint places two of those layers side by side: accumulated social and behavioral stressors, and reproductive aging. In a multicenter U.S. cohort, syndemic burden and postmenopausal status were each associated with higher estimated 10-year atherosclerotic cardiovascular disease risk among women aged 45 years and older. The signal was modest, but it ran in the same direction across the main analyses and in the virally suppressed subgroup.
The study drew on the MACS/WIHS Combined Cohort Study, with visits from October 2020 through March 2025. The full analytic sample included 1,993 women, 1,446 of whom were living with HIV. A secondary analysis focused on 1,063 women who were virally suppressed at baseline and contributed 4,009 visits. Median age was 56 years, 63% were non-Hispanic Black, and 57% had two or more syndemic conditions. In practical terms, the cohort was not a narrow or homogeneous group; it reflected the layered clinical and social complexity that often shapes cardiovascular prevention in real-world HIV care.
Each additional syndemic condition corresponded to a 0.40-point higher estimated risk score on the Pooled Cohort Equations, with a 95% confidence interval of 0.01 to 0.78 and a p value of 0.043. Postmenopausal status carried a 1.3-point higher score than premenopause, with a 95% confidence interval of 0.39 to 2.3 and a p value of 0.006. The interaction between syndemic burden and menopause stage did not reach significance overall. In a clinically plain reading, the burdens moved independently rather than amplifying each other in a statistically detectable way across the full cohort.
Menopause and social stressors act through different biological channels
The combined effect makes biological sense even without a formal interaction. Menopause shifts lipid profiles, vascular tone, and body-fat distribution through estrogen withdrawal and related endocrine changes, while syndemic burden captures exposures that can sustain inflammation, sympathetic activation, disrupted sleep, tobacco-related endothelial injury, and lower adherence to preventive care. When those forces accumulate in the same patient, the arterial wall is exposed to more than one pathway toward atherosclerosis.
The study operationalized syndemic burden as the sum of six conditions: elevated depressive symptoms, current tobacco use, hazardous alcohol use, recent stimulant use, physical inactivity, and material insecurity. The design treats these not as isolated behaviors but as interlocking pressures on cardiometabolic health. A woman with depression, tobacco exposure, and material insecurity does not simply have three separate issues; each can reduce access to exercise, medications, follow-up, and stable nutrition, while also worsening inflammatory and autonomic stress pathways.
One sentence captures the bedside consequence plainly: cardiovascular risk rose as these burdens accumulated.
Among virally suppressed women, the menopause interaction showed an exploratory signal with an estimate of 0.50 and a p value of 0.079. The preprint stops short of claiming a definitive subgroup effect, but the direction is worth attention. Viral suppression may reduce one major source of HIV-related inflammatory stress, making the residual effects of social adversity and reproductive aging easier to detect. It also may reveal a population in which routine HIV biomarkers are not enough to explain cardiovascular risk, leaving menopause and social determinants to account for more of the variance.
Machine learning ranked creatinine, BMI, syndemic burden, and menopause among top predictors
Investigators also trained random forest classifiers to predict high estimated cardiovascular risk, defined as 7.5% or greater. Discrimination was moderate, with areas under the curve of 0.727 and 0.704. For a clinical prediction task built from cohort data, those values suggest the model captured meaningful structure without achieving near-perfect separation. The strongest predictors included serum creatinine, body mass index, syndemic burden, and postmenopausal status.
The appearance of serum creatinine and body mass index near the top of the predictor list is clinically familiar. Creatinine tracks renal function, which often clusters with vascular disease and can influence risk estimation through chronic kidney burden, while body mass index reflects the metabolic load that travels with hypertension, dyslipidemia, insulin resistance, and inflammation. Syndemic burden ranking among the top predictors is the more novel point: social and behavioral stressors were not just background noise in the model. They carried predictive weight comparable to variables traditionally used in cardiovascular risk assessment.
The Pooled Cohort Equations were the outcome framework here, so the study does not prove that syndemic burden directly causes atherosclerotic events. It does show that women with more social and behavioral adversity accumulated higher estimated risk scores, and that the same pattern held when reproductive stage was considered separately. For clinicians, this means routine risk conversations in midlife women with HIV may miss a meaningful part of the picture if they focus only on blood pressure, lipids, and smoking status in isolation.
Why this matters for HIV care and cardiovascular prevention
Women with HIV have long been underrepresented in cardiovascular studies, and menopausal transition adds another layer that standard calculators do not fully capture. This preprint argues for a more integrated risk review in midlife: reproductive stage, mental health, tobacco exposure, substance use, exercise habits, and material insecurity should be reviewed alongside traditional vascular risk factors. A patient may not fit a high-risk profile on one axis and still carry meaningful cumulative burden across several others.
The data also reinforce a familiar tension in prevention medicine. Risk tools are useful, but they can flatten lived complexity. A woman with well-controlled HIV, normal clinic vitals, and no obvious acute symptoms may still have a higher estimated cardiovascular burden if she is postmenopausal and navigating depression, tobacco use, or material insecurity. Those domains do not behave as side issues; they shape medication adherence, inflammatory burden, and the feasibility of sustained lifestyle change.
Because this is a preprint, the findings remain provisional until peer review clarifies modeling choices, robustness, and transportability. The outcomes are estimated risk scores rather than observed cardiovascular events, and the interaction between syndemic burden and menopause was not statistically significant in the primary analysis. Even so, the study leaves a concrete message for practice-oriented readers: cardiovascular stratification in midlife women with and without HIV should account for both social adversity and reproductive aging, not one or the other.
The next question is whether these modest elevations in estimated risk translate into measurable event differences over time, especially in women with sustained viral suppression and multiple social stressors.