BACKGROUND:Individuals diagnosed with depression during pregnancy are more likely to develop cardiovascular disease (CVD) later in life. However, it remains unclear whether subclinical depressive symptoms or symptom trajectories across time are associated with indicators of cardiovascular health (CVH). Therefore, the present study evaluated the relationship between longitudinal depressive symptom trajectories beginning in pregnancy and future CVH. METHODS:This secondary analysis of the multisite prospective nuMoM2b-Heart Health Study and included participants with complete longitudinal data from early pregnancy to 2-7 years post-delivery. Participants self-reported depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) at 6-13 weeks gestation (early pregnancy), 22-29 weeks gestation (mid- to late-pregnancy), and 2-7 years post-delivery. Latent class mixture modeling was conducted to identify longitudinal patterns of depressive symptoms across early pregnancy, mid-late pregnancy, and extended postpartum follow-up. Structural equation modeling was used to test whether EPDS trajectories were associated with latent CVH, adjusted for length of follow-up interval, pre-pregnancy BMI, gravidity, adverse pregnancy outcomes, smoking history, age, education, income, and use of psychiatric medications. RESULTS:A total of 3,934 participants (mean (M) ± standard deviation (SD) age=27.6±5.6 years) met inclusion criteria with a mean follow-up interval of 3.2±0.9 years. A 4-class model, which provided the best fit to the EPDS data (mean posterior probability across classes=0.81), produced the following trajectories: (1) stable low (n=2412; 61.1%), (2) increasing severity (n=848; 21.5%), (3) decreasing severity (n=476; 12.1%), and (4) stable high (n=212; 5.4%). Compared to the stable low group, all groups exhibited significantly lower CVH (stable high: β=0.06, p<0.01; decreasing severity: β=0.05, p=0.02; increasing severity: β=0.08 p<0.01). Pairwise comparisons among the three elevated-symptom groups revealed no significant differences in latent CVH (all ps >0.24). DISCUSSION:The longitudinal course of depressive symptoms from pregnancy to 2-7 years post-delivery varied across individuals. Compared to those with consistently low depressive symptoms, individuals with higher severity symptoms at any point all exhibited lower CVH, regardless of the specific trajectory of symptoms. These findings support a life-course perspective in which depressive symptom patterns may represent an early indicator of cardiometabolic vulnerability.

BACKGROUND:More favorable maternal cardiovascular health (CVH) is linked to a lower risk of adverse pregnancy outcomes (APOs). OBJECTIVES:The aim of the study was to estimate the proportion of APOs that could be prevented if maternal CVH was improved. METHODS:Pregnant participants ≥18 years and without prepregnancy hypertension or gestational diabetes from the Nulliparous Pregnancy Outcomes Study were included. First trimester CVH was assessed by current physical activity, diet, sleep, nicotine use, body mass index, and blood pressure. CVH scores ranged from 0 to 100, with higher scores representing better CVH. APOs included new-onset hypertensive disorders of pregnancy, gestational diabetes, and preterm birth. Multivariable logistic regression models assessed the association of early pregnancy CVH and APOs, and impact fractions estimated the proportion of APOs that could be prevented if maternal CVH was improved. RESULTS:Participants (N = 8,927) were 27.2 years (SD: 5.4), and 25.3% experienced an APO. A lower CVH score was associated with a higher APO risk (adjusted OR: 1.46; 95% CI: 1.39-1.54). An estimated 12% of APOs would be prevented if a hypothetical intervention shifted all participants with a CVH score <50 to 50 points (5.8% of participants). Moreover, a dose-response relationship was observed with 15% and 40% of APOs estimated to be prevented if a hypothetical intervention shifted participants with a CVH score <80 to 80 points (51.4% of participants) or shifted everyone to 100 points (96.6% of participants), respectively. Similar findings were observed for each APO subtype. CONCLUSIONS:In this cohort of nulliparous pregnant individuals, potential benefits of improving maternal CVH to reduce APOs are considerable.

CONTEXT:Endothelial dysfunction and altered psychological measures have been identified in women with functional hypothalamic amenorrhea (FHA). Estradiol (E2) replacement, a known vasodilator, may potentially reverse vascular dysfunction and improve psychological health. OBJECTIVE:To evaluate 12 weeks of physiologic E2 replacement on vascular, hormonal, and psychological outcomes in women with FHA. METHODS:A randomized, double-blind, placebo-controlled trial was conducted in 29 women with FHA with 0.1 mg/day transdermal E2 (n = 14) or placebo patch (n = 15) twice weekly for 12 weeks. FHA was defined as amenorrhea ≥3 consecutive months, E2 < 50 pg/mL, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) <10 mIU/L, LH:FSH <1, excluding other etiologies. Endothelial dysfunction (reactive hyperemic index ≤ 1.67) was assessed, as were hormonal and psychological measures. RESULTS:Women with FHA had a mean age of 26.2 ± 6.3 years, body mass index of 21.5 ± 3.3 kg/m2, with 63% being non-Hispanic White. Baseline characteristics did not differ between groups. After 12 weeks, E2 levels were significantly higher in the E2 group (112.0 vs 36.5 pg/mL, P = .0002). However, there were no significant differences in vascular, hormonal, or psychological outcomes between E2 and placebo groups at week 12. Cortisol levels showed a near-significant decrease in the E2 group compared to an increase with placebo (-.4 vs 3.1 µg/dL, P = .05). CONCLUSION:In women with FHA, 12 weeks of transdermal E2 increased serum E2 levels but did not improve vascular or psychological health measures. Further studies with larger sample sizes and longer follow-up are needed to explore the long-term effects of E2 therapy on cardiovascular and mental health outcomes in this population.

Cardiovascular disease (CVD) accounts for more deaths in women than breast cancer, lung cancer and chronic lung disease combined, with a comparable mortality to that of men. Many women and physicians do not identify CVD as a major morbidity and mortality in women, resulting in significant delays in diagnosis and treatment. While advances have been made in the diagnosis, treatment and outcomes of CVD in women, there often remains insufficient evidence to guide effective, lifesaving care of women. This review of sex-specific and traditional CVD risk and risk-enhancing factors in women identifies areas of knowledge gaps to consider for investigation. A focus on the coronary vasculature reveals physiological differences of clinical relevance which can be interrogated. Inspection of and addressing disadvantage and gender bias in both the medical and lay communities should continue to be addressed. As CVD results from traditional risk factors and emerging risk-enhancing factors, a focus on the detection of preclinical cardiovascular disease may be of particular importance for women. Unique risk markers originate early in pre-menopausal women, as this is considered a healthy period of life. Awareness and implementation of the existing knowledge of sex-specific risk factors and sex-specific thresholds to educate women and physicians are needed. The anticipated life course of women supports a broadening focus on CVD toward that of lifelong care and emphasize key transitional stages for women—early risk factor onset, pregnancy, menopausal transition, and so on. This review is a call to action to re-envision a health system approach for lifespan prevention, detection, and treatment pathways to reduce CVD risk in women.

Relentless mechanical work of the heart is powered by continuous oxygen consumption. How the heart uses oxygen is a defining feature of its health. Invasive studies have established that impaired oxygen consumption by the myocardium predicts contractile dysfunction and adverse outcomes. Despite its importance, noninvasive quantification of myocardial oxygen use remains limited. Magnetic resonance imaging (MRI) signal is known to be sensitive to blood oxygenation and has the potential to quantify myocardial oxygen consumption noninvasively, without exogenous contrast agents and free of ionizing radiation. However, its clinical translation has been impeded by the need for complex biophysical calibration, vulnerability to imaging artifacts and consistent vital motions, and the requirement of lengthy acquisition times. Here, we introduce a rapid, self-calibrated cardiac MRI framework that overcomes these barriers through high-resolution, motion-resolved coronary sinus oximetry, which can quantify myocardial oxygen extraction of the whole heart within 3 minutes. We optimized the imaging parameters via numerical simulations and validated them against invasive coronary sinus catheterization in a porcine model. We combined the method with clinical MRI sequences and demonstrated the feasibility of quantifying myocardial oxygen consumption and myocardial oxygen efficiency in patients with and without heart failure secondary to myocardial infarction in a single institution. This needle-free approach establishes a practical framework for noninvasive characterization of myocardial oxygen metabolism. It holds the potential to facilitate early disease detection, inform personalized therapeutic strategies, and guide the development of cardiometabolic therapies aimed at addressing the ongoing heart failure epidemic.

BACKGROUND:Half of women with ischemic symptoms have non-obstructive coronary artery disease (CAD), while the pathophysiology of their condition has not been characterized. Noncalcified (NCP) and low-attenuation plaque (CT density<30 Hounsfield units, LAP) burden quantified from coronary computed tomography angiography (CCTA) is associated with ischemia in patients with obstructive CAD. We hypothesize that NCP burden is related to angina in women with ischemic symptoms and Non-Obstructive Coronary Arteries (INOCA). METHODS:Women with INOCA enrolled in the WARRIOR trial were evaluated for angina severity with Seattle Angina Questionnaire (SAQ) at study entry. Baseline CCTA of 117 women were quantitatively analyzed with AI-based software for NCP, LAP and calcified plaque (CP) volumes and burdens (%, normalized to vessel volume) across the coronary tree. Machine-learning ischemia risk score (ML-IRS) integrating quantitative lumen and plaque features from CCTA was automatically measured. RESULTS:Among 109 women with visible plaque on CCTA (age 61.9, SD 10.3 years) median total plaque burden is 26.6% (IQR 18.6,32.0) and median SAQ score is 61.4 (IQR 54.6,69.1). Patients with more severe angina (SAQ ≤ 60) are younger (58.1 vs 62.0 years, p = 0.015), have higher total cholesterol (195 vs 165 mg/dL, p = 0.006), but less frequently receive statins (31.8 vs 64.4%, p = 0.006) compared with patients with SAQ > 60. Patients with SAQ ≤ 60 have higher total plaque (33.3 vs 24.3%, p = 0.001), and NCP burden (33.3 vs. 23.2%, p = 0.00065), and lower CP burden (0.0 vs. 0.3%, p = 0.005) compared with patients with SAQ > 60. On multivariable linear regression adjusted for risk factors, higher NCP burden (β = -0.50, p = 0.001), LAP burden (β = -4.50, p = 0.008) and ML-IRS (β = -3.09, p = 0.04) are associated with lower SAQ score, i.e. more severe angina. CONCLUSIONS:In women with INOCA, high-risk atherosclerotic plaque phenotypes are related to more severe angina.

In December 2025, the Division of Aging Biology, National Institute on Aging (NIA) at the National Institutes of Health (NIH), in collaboration with staff from other NIA divisions, NIH institutes and the Veterans Health Administration, convened a workshop to explore the mechanistic bases and health effects of sex differences across tissues and ages. Novel research discoveries, technologies and visions to advance sex-differences research were discussed.

Acute myocardial ischaemic syndromes frequently arise from rupture or erosion of non-flow-limiting vulnerable plaques. Despite major advances in lipid-lowering and anti-inflammatory therapies, a substantial residual cardiovascular risk persists under optimal medical therapy, driving interest in preventive percutaneous coronary intervention (PCI) to stabilize these high-risk lesions. Contemporary intracoronary imaging techniques, including intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy, can identify plaques at greatest risk of rupture, and preventive PCI, as demonstrated in the PREVENT trial, may reduce composite outcomes of cardiac death, myocardial infarction, revascularization, and unstable angina compared with medical therapy alone. Sealing such plaques may prevent future acute coronary events, particularly in high-risk patients with multivessel disease. However, these benefits were driven mainly by softer endpoints observed in an open-label design, and were not accompanied by significant reductions in mortality or hard outcomes. Concerns remain regarding the procedural risks and cost-effectiveness of preventive PCI, and the impact of novel and more intensive lipid-lowering therapies in this clinical setting has not been adequately explored. Although preventive PCI represents an intriguing paradigm shift that challenges physiology-guided treatment strategies, further studies are needed to confirm its safety, durability, and incremental value over contemporary medical therapy. This Great Debate examines whether preventive PCI should be considered the default management strategy for non-flow-limiting vulnerable plaques.

Importance Women with angina due to suspected ischaemia referred for coronary angiography often have no obstructive coronary artery disease (ANOCA/INOCA).Objective To determine if intensive medical treatment (IMT) reduces major ischaemic events (major adverse cardiovascular event, MACE) among women with suspected ANOCA/INOCA.Design Randomised, prospective, blinded-outcomes evaluation.Setting 71 sites in the USA.Participants 2476 women with suspected ANOCA/INOCA.Interventions IMT-high intensity statin, ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) and aspirin versus usual care (UC).Main outcomes and measures Primary: all cause death, myocardial infarction, stroke/transient ischaemic attack, hospitalisation for angina or heart failure (MACE). Secondary: components of the primary, quality of life and win ratio.Results Recruitment was lower than planned (n=2476), yielding an aged population (mean, 64 years) with well-controlled blood pressure and low-density lipoprotein cholesterol at baseline, and relatively high rates of statin and ACEI/ARB use. At 2.5 years, 421 events occurred (221 in IMT, 200 in UC) with no difference in the primary outcome (HR=1.13 (95% CI 0.94 to 1.37) for IMT vs UC, p=0.20) or secondary outcomes. Hospitalisations for angina were the dominant contributor to MACE. Sensitivity analysis of contamination provided an estimated HR for IMT versus UC of 0.74 95% CI (0.352 to 1.558), p=0.43.Conclusions and relevance Among women with suspected ANOCA/INOCA, outcomes were dominated by chest pain and IMT did not improve outcomes, although limited power precludes concluding that it may not be helpful. The findings support the need for more investigation in this population with high burden of angina hospitalisation, health resource consumption and poor quality of life.Trial registration number NCT03417388.

INTRODUCTION:Coronary microvascular dysfunction (CMD) has been proposed as a pathophysiological contributor to heart failure with preserved ejection fraction (HFpEF). Elevated left ventricular end-diastolic pressure (LVEDP) is often present in patients with CMD. HYPOTHESIS:We hypothesized that CMD-mediated impairment in LV relaxation may contribute to elevated LVEDP. METHODS:Women (n = 253) with signs and symptoms of ischemia and no obstructive coronary artery disease (INOCA) underwent invasive coronary functional testing (CFT) for measurement of resting LVEDP and coronary microvascular function. A pre-defined sequential subset of these women underwent cardiac MRI (CMRI). Two sample t-test, Fisher's exact test and Spearman correlation were performed. RESULTS:Group mean LVEDP was 14.4 ± 5.0 mmHg, with 150 women (59%) having LVEDP >12 mmHg. LVEDP directly related with body mass index (BMI) (r = 0.324, p < 0.001), and systolic blood pressure (r = 0.176, p = 0.01) at time of CFT, as well as time to peak filling rate (r = 0.13, p = 0.050). There were no relationships between LVEDP and invasive or non-invasive measures of CMD. CONCLUSIONS:Among women with suspected CMD, elevated resting LVEDP is associated with higher BMI and systolic blood pressure. There were no significant associations between LVEDP and measurements of CMD. Further analyses are needed to further evaluate LVEDP, CMD and development of HFpEF.

Importance:Hypertensive disorders of pregnancy (HDP; ie, preeclampsia/eclampsia and gestational hypertension) are associated with earlier development of chronic hypertension. Whether genetic risk for high systolic blood pressure (SBP) can stratify risk of new-onset hypertension after pregnancy is unclear. Objective:To test the association of genetic risk for high SBP with new-onset hypertension at 2 to 7 years after delivery, independent of clinical characteristics and HDP history. Design, Setting, and Participants:This was a cohort study of women enrolled during pregnancy between 2010 and 2013 and followed up at 2 to 7 years post partum. Included in the study were genotyped participants without pregestational chronic hypertension in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) Heart Health Study. The setting included 8 US clinical sites. Study data were analyzed from October 2024 to January 2026. Exposures:SBP genetic risk was calculated using a genome-wide SBP polygenic score and categorized as low (bottom quintile), intermediate (quintiles 2-4) or high (top quintile). Main Outcomes and Measures:The primary outcome was stage 1+ hypertension (≥130/80 mm Hg or use of antihypertensive medication) at 2 to 7 years post partum. Logistic regression tested the association of SBP genetic risk with development of hypertension, adjusted for sociodemographic factors, prepregnancy diabetes, first-trimester BP, HDP history, and postpartum body mass index (BMI). Key secondary analyses were stratified by HDP history and compared population attributable risk for high SBP genetic risk, HDP history, and postpartum BMI. Results:Among 2852 participants (mean [SD] age, 30.8 [5.5] years; 353 [12.4%] with prior HDP), 509 (17.8%) developed hypertension by 2 to 7 years (mean [SD], 3.2 [0.9] years) after delivery. SBP genetic risk was independently associated with incident hypertension (high vs low SBP genetic risk: adjusted odds ratio [aOR], 1.50; 95% CI, 1.09-2.07; P = .01). In stratified analyses, SBP genetic risk was associated with incident hypertension in those without prior HDP (aOR, 1.25; 95% CI, 1.12-1.40 per SD; P < .001) but not in those with prior HDP (aOR, 1.01; 95% CI, 0.79-1.28 per SD; P = .92; P for interaction = .10). High SBP genetic risk, HDP history, and BMI greater than or equal to 25 (calculated as weight in kilograms divided by height in meters squared) accounted for 4.7%, 10.8%, and 41.5%, respectively, of population attributable risk for hypertension. Conclusions and Relevance:Results of this cohort study reveal that higher SBP genetic risk was independently associated with higher risk of developing new-onset hypertension 2 to 7 years after delivery. However, HDP history and elevated BMI were more important contributors to hypertension risk.

Background Adverse pregnancy outcomes (APOs) are associated with increased hypertension risk. Black women experience higher rates of APOs and hypertension compared with White women, but whether APOs contribute to Black‐White hypertension disparities remains unknown. Methods The nuMoM2b‐HHS (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers‐To‐Be–Heart Health Study) prospectively recruited nulliparous pregnant people at 8 US centers (2010–2013) with follow‐up 2 to 7 years postpartum (2014–2017). Race, which represents a social construct, was self‐identified. The primary outcome was incident hypertension at follow‐up. APOs included hypertensive disorders of pregnancy, preterm birth, and small‐for‐gestational age birth. Potential confounders (psychological health, social factors, and health behaviors) were assessed via validated questionnaires. We used targeted maximum likelihood‐based estimation to estimate Black‐White hypertension differences that would remain if racial disparities in APOs were eliminated. Results Among 3335 participants (17% Black; 83% White; mean [SD] age, 27.6 [5.1] years), APO incidence was higher in Black versus White individuals (rate differences [RDs] per 1000 births: hypertensive disorders of pregnancy: 52.5 [95% CI, 20.0–85.1]; preterm birth: 45.4 [95% CI, 20.8–70.1]; small‐for‐gestational age: 102.4 [95% CI, 75.8–129.1]). Incident hypertension at median 3 years postpartum was higher in Black versus White individuals (RD, 107.1 [95% CI, 69.6–144.4]). APOs mediated the racial disparity in hypertension; eliminating Black‐White disparities in APOs would decrease the Black‐White disparity in hypertension by 18.2% for hypertensive disorders of pregnancy (RD, 87.6 [95% CI, 36.1–139.2]), 16.3% for preterm birth (RD, 89.6 [95% CI, 41.7–137.6]), and 13.9% for small‐for‐gestational age (RD, 92.2 [95% CI, 41.6–142.9]). Conclusions Black‐White differences in hypertension were partially mediated by APOs. APOs may represent a pregnancy‐specific pathway contributing to racial disparities in hypertension.

Introduction:Functional hypothalamic amenorrhea (FHA) accounts for 30% of secondary amenorrhea and is characterized by hypothalamic hypercortisolemia, hypothalamic hypothyroidism, and anovulation with hypoestrogenemia due to disrupted GnRH drive. While FHA is associated with decreased bone mineralization; it remains unclear how bone health compares to menopausal women, who also experience bone loss. This study compared dual-energy x-ray absorptiometry (DXA) bone health parameters among women with FHA, eumenorrheic controls, and recently menopausal women. It also examined the impact of prior combined oral contraceptive (COC) use on bone mineral density (BMD) in women with FHA. Methods:This cross-sectional study included 20 women with FHA, 9 eumenorrheic controls, and 12 recently menopausal women who underwent hip and spine DXA. None of the participants were taking hormone therapy. FHA was defined as ≥3 months of amenorrhea, estradiol <50 pg/ml, FSH and LH <10 mIU/L, excluding other etiologies. DXA bone parameters were measured using Lunar iDXA (GE) including BMD from lumbar spine (L1-L4) and hip. Results:By design, age differed significantly across groups (p < 0.0001), with median ages of 27.8 years [23.4, 34.1] in women with FHA, 29.6 years [28.3, 32.4] in eumenorrheic controls, and 55.3 years [53.5, 56.6] in recently menopausal women. There were no significant differences in weight or BMI across groups. Significant differences were observed at all measured skeletal sites, including all lumbar spine levels, femur neck, total femur, and total BMD (all p < 0.05). Pairwise comparisons revealed that lumbar spine BMD was significantly lower in FHA compared to eumenorrheic controls (p = 0.04), while FHA and menopausal women did not significantly differ from each other (p = 0.07). Among FHA women with prior COC use, L1-4 BMD was not significantly different from controls (p = 0.19). Conclusions:Lumbar spine BMD in young women with FHA was comparable to that of recently menopausal women, highlighting the profound skeletal impact of chronic estrogen deficiency. Prior COC use may partially attenuate FHA-associated bone loss, though larger studies are needed to confirm this observation. Future studies should explore whether skeletal outcomes vary by FHA etiology and the potential role of COC duration in preserving BMD.

PurposeIdentify demographic, behavioral lifestyle, psychological, and clinical factors associated with suboptimal activity patterns several years after a first pregnancy and delivery.DesignCross-sectional, secondary analysis.Setting and SampleWomen (n = 2843) from eight U.S. centers assessed 2-7 years after delivery in the nuMom2b Heart Health Study.MeasuresSelf-reported leisure time moderate-to-vigorous intensity physical activity (MVPA) and sedentary behavior (SB) were used to define patterns based on meeting recommendations for MVPA (active at ≥150 minutes/week) and leisure time SB (low SB at ≤3 hours/day). Factors (demographic, behavioral lifestyle, psychological, and clinical) assessed at study visits and hypothesized to be related to MVPA-SB patterns were included.AnalysisMultinomial logistic regression with forward selection identified factors associated with MVPA-SB patterns.ResultsParticipants most frequently reported the optimal active + low SB pattern (37.8%). Modifiable factors significantly associated with suboptimal patterns included lower diet quality (odds ratios [OR] 0.18-0.62; P < 0.001), higher body mass index (BMI) (ORs 1.15-2.49; P = 0.001), less sleep (ORs 1.27-1.46; P = 0.0013), and higher perceived stress (ORs 1.20-1.52, P = 0.0015). Lower income (ORs 0.39-0.60, P = 0.0002), lower education (ORs 0.38-0.40; P = 0.0323) and working/studying full-time (ORs 1.42-1.97, P-0.0021) were also associated with suboptimal patterns.ConclusionsFuture research designing "sit less, move more" interventions following pregnancy and delivery could consider simultaneous intervention for modifiable factors and tailored strategies for low income/education and full-time working/student women who may face additional barriers.