Journal of the American Heart Association

Background: Placental function is associated with congenital heart defects (CHD), frequently presenting with malperfusion lesions and small-for-gestational-age size. However, placental villous vasculature in the setting of CHD is understudied. This study evaluated differences in placental, neonatal, and maternal outcomes among maternal/infant dyads with versus without CHD. Methods: We conducted a gestational age- and fetal sex-matched retrospective case control study using specimens prospectively collected by a local biobank. Neonatal outcomes included birthweight, placental weight, and their ratio (placental efficiency). We estimated the proportion of placental villous tissue comprised of fetal vascular endothelial cells (%FVE) using anti-CD34 immunohistochemistry and a pixel count algorithm. Placental weight multiplied by %FVE estimated the grams of placental tissue comprised of villous vasculature (placental vascular index). Maternal outcomes included hypertensive disorders of pregnancy and gestational diabetes. We compared cases and controls using linear and logistic regression adjusted for maternal smoking and cold ischemia time. Stratified analyses examined associations by preterm birth status. Results: Dyads (n=34 with CHD, n=34 without CHD) had maternal age of 29.4 +/- 4.9 years and were 35.6 +/- 4.0 gestational weeks at delivery. Groups had similar placental, neonatal, and maternal parameters. Among preterm neonates, we observed small-to-moderate effect sizes indicating lower placental weight, %FVE, and placental vascular index, and higher placental efficiency, in CHD cases. Among term neonates, moderate effect sizes suggested lower birthweight, placental weight, and placental vascular index in CHD cases. Conclusions: Though differences between groups were not significant, moderate effect sizes suggested that placental vascularization was lower among preterm neonates with CHD.

IntroductionPregnancy is a critical test of womens cardiovascular risk. Structural factors may influence long-term cardiovascular health beyond individual, social experiences. We examined associations of neighborhood-level deprivation and individual-level social vulnerability (SV) during pregnancy with postpartum blood pressure (BP). MethodsThis secondary analysis of a prospective cohort study used data from 3,728 nulliparous women in the nuMoM2b-HHS cohort followed from early pregnancy to 2-7 years post-delivery (Mage: 30.8 years, 65% non-Hispanic White, 14% with adverse pregnancy outcomes [APOs]). Multivariable linear and logistic regression models tested relations of the Area Deprivation Index (ADI) and SV (a composite of perceived stress, discrimination, pregnancy experiences, social support, health literacy, depression, and anxiety) with systolic BP (SBP), diastolic BP (DBP), and incident hypertension, adjusting for demographic and behavioral covariates. Effect modification by APO history was assessed. ResultsIn unadjusted models, both ADI and greater SV were positively associated with SBP and DBP (all ps<0.001). After adjustment, ADI remained positively associated with BP: each 10-unit increase in ADI was associated with 1.0 mmHg higher SBP (p=0.008) and 0.6 mmHg higher DBP (p=0.013). However, SV was no longer associated with BP after adjustment. ADI and SV were not associated with incident hypertension. No evidence of effect modification by APO history was observed (interactions p>0.20). ConclusionsNeighborhood deprivation during pregnancy was associated with higher BP up to seven years later, independent of individual social vulnerability. Structural context during pregnancy may contribute to early maternal cardiovascular risk.

Background: Resting electrocardiogram (ECG) is not currently recommended as part of cardiovascular disease (CVD) risk assessment, although accumulating evidence suggests a potential role. Objective: To examine the association between ECG abnormalities and incident CVD events as assessed by the 2023 Predicting Risk of Cardiovascular Disease Events (PREVENT) equations. Design: Secondary data analysis from the REasons for Geographic And Racial Differences in Stroke (REGARDS) prospective cohort, including study participants without a baseline CVD. Exposure: ECG abnormalities were classified by Minnesota Code (MC) as normal, any minor, or major abnormality at baseline (2003-2007). Outcome: Participants were followed for expert adjudicated incident CVD events through December 31, 2021. Results: Among 19,173 participants (mean age at baseline of 63.7 years; 57.8% were female). According to the PREVENT risk equations, 39.4% were classified as <7.5% 10-year risk CVD risk, 44.6% as 7.5-20% risk, and 16.0% as >20% risk. Overall, 47.0% had normal ECG, 44.0% had any minor abnormality, and 9.0% had any major abnormality. During follow-up, CVD events occurred in 12.4% of participants with normal ECG, 17.0% of those with any minor abnormality, and 25.4% of those with any major abnormality. Compared to those without ECG abnormality, the adjusted HR for incident CVD were 1.19 (95% CI 1.10-1.29) for any minor abnormality, and 1.53 (1.36-1.72) for any major ECG abnormality. In the <7.5% risk group, 43.6% had at least one ECG abnormality; in this risk group compared to those without ECG abnormality, the HR for incident CVD associated with any major ECG abnormality, present in 5.0% of the <7.5% risk group, was 1.87 (95% CI 1.34-2.62), The HR for any minor ECG abnormalities, present in 38.6% was 1.13 ( 95% CI 0.93 - 1.37). Conclusion: ECG abnormalities were associated with risk of CVD events across PREVENT risk groups. A substantial proportion of low-risk participants (according to the PREVENT equation) had ECG abnormalities and associated elevated risk. This supports the potential for using ECG to identify a subgroup of low-risk patients who may benefit from more aggressive primary prevention especially with major ECG abnormalities. Addition of electrocardiographic evaluation to the PREVENT risk equations may improves cardiovascular risk discrimination.

BackgroundFetal alcohol spectrum disorders (FASDs) impact up to 5% of U.S. school age children; however, the burden of congenital and acquired cardiovascular disease (CVD) in adults with FASDs remains poorly defined. We investigated associations between FASDs, cardiometabolic abnormalities, and CVD using electronic health record (EHR) data. MethodsWe performed a retrospective cohort study of adults ([&ge;]18 years) receiving ambulatory care with a FASD diagnosis (n = 208, mean age 38.4{+/-}14.5, 50% female) and age- and sex-matched control patients without FASD (n = 824, mean age 41.6{+/-}14.5, 50% female). Cardiometabolic outcomes were overweight/obesity, dyslipidemia, and diabetes mellitus. Cardiovascular outcomes were congenital heart defects (CHDs), heart murmur, hypertension, conduction defects, arrhythmias, structural heart remodeling, systolic and diastolic dysfunction, heart failure, myocardial infarction (MI), stroke, and thromboembolic events. Associations were assessed using age-adjusted logistic and Poisson regression, with sex-by-diagnosis interaction testing. Multivariable logistic regression was then used to estimate the odds of cardiovascular outcomes with additional adjustment for cardiometabolic conditions. Associations between CHD and CVD outcomes were evaluated using Fishers exact tests. ResultsAdults with FASDs had a higher prevalence (p<0.05) of cardiometabolic abnormalities, including dyslipidemia, type 2 diabetes, and the co-occurrence of multiple cardiometabolic abnormalities (overweight/obese, HDL cholesterol < 40 mg/dL, and type 2 diabetes mellitus). Overweight/obesity was more prevalent in females with FASDs but not males. CHDs were significantly more common in individuals with FASDs than controls (6% vs 1%, p < 0.001). Compared with controls, the FASD cohort had a higher incidence of systolic and diastolic dysfunction (6% vs. 2%), structural heart remodeling (11% vs 5%), MI (6% vs. 2%), stroke (4% vs 1%), and thromboembolic events (4% vs 1%; all p < 0.05). Significant sex-by-diagnosis interactions were observed for hypertension, arrhythmia, and heart failure, with elevated rates specific to FASD females. In individuals with FASDs, CHD diagnosis was associated with an increased incidence of conduction defects, arrhythmias, heart remodeling, heart failure, and systolic and diastolic dysfunction. Increased CVD burden in FASD adults remained significant after adjustment for BMI, composite cardiometabolic abnormalities, and hyperlipidemia. ConclusionsAdults with FASDs exhibit an increased burden of CVD not fully explained by conventional cardiometabolic risk factors. These findings support enhanced cardiovascular screening in individuals with FASDs.

Sex specific differences in stroke are recognized. Whether differences in incident stroke risk persists in recent periods needs further elucidation to aid public health preventive efforts. Aim: To determine long-term sex specific trends in stroke and stroke risk factors at different epochs among Framingham Heart Study participants. Methods: We examined age-adjusted 10-year stroke incidence using Cox regression in women and men in five epochs: 1962-1969 (epoch 1, reference), 1971-1976 (epoch 2), 1987-1991 (epoch 3), 1998-2005 (epoch 4), 2015-2021 (epoch 5). We compared stroke incidence by sex across epochs, estimated decade-wise linear trends overall and by sex. We compared risk factors in successive epochs to the first, and estimated sex-specific trends in risk factors. Interactions between baseline risk factors with epoch and trends were assessed by sex. Secondary analyses were repeated in participants <60 years old. Results: Incident stroke occurred in 4.5% (178/3996) in epoch 1, 3.9% (227/5786) in epoch 2, 3.9% (199/5137) in epoch 3, 2.7% (207/7642) in epoch 4, 2.2% (119/5534) in epoch 5. Men had higher risk of incident stroke in each epoch with significant difference in epochs 2 (HR 1.41, 95% CI [1.08, 1.84]) and 4 (HR 1.46, 95% CI [1.11, 1.91]) overall, and in epoch 4 (HR 2.13, 95% CI [1.17, 3.87]) among those <60 years. Stroke incidence declined by 16% per decade in men (HR 0.84, 95% CI [0.79, 0.89]) and 19% per decade in women (HR 0.81, 95% CI [0.76, 0.86]). Among those <60 years, stroke incidence declined by 22% per decade in women (HR 0.78, 95% CI [0.67, 0.95]). Hypertension declined by 8% per decade in women only ([OR] 0.92, 95% CI [0.90, 0.94]), while Atrial fibrillation and diabetes increased in both. Conclusion: Stroke incidence continues to decline in recent periods for women and men. Among participants <60 years, decline was observed only in women, possibly related to decline in hypertension in women.

BackgroundCardiovascular disease (CVD) is the leading cause of pregnancy-related morbidity and mortality in the United States. Several studies have evaluated readmission rates in the general HF population, but in patients with pregnancy-related HF, readmissions have been understudied. This study aims to characterize the 30-day HF readmission patterns in pregnancy-related admissions to identify vulnerable patient populations. MethodsThe National Readmission Database from 2016 to 2021 was used to identify women aged 13-49 with an index hospitalization in which HF was coded as either the primary or secondary diagnosis during a pregnancy-related antepartum, delivery, or postpartum admission, identified by diagnosis-related group (DRG) codes and ICD-10 codes. The primary outcome was 30-day all-cause readmission. We performed descriptive and comparative analyses to describe the differences in patient characteristics and readmission patterns between groups. ResultsThe overall 30-day all-cause readmission rate was 13% when readmissions for delivery were excluded. The readmission rate increased with age, peaking at 15.1% in the 38-49yr age group. Higher readmission rates were also associated with combined (systolic and diastolic) HF (16.1%), systolic HF (14.8%), lower socioeconomic status (15.3%), substance use disorder (17.2%), and alcohol use (18.6%). Patients whose index hospitalization was for delivery had the highest absolute risk of 30-day readmission at 19.3%. Readmissions peaked between days 6 and 8 post discharge, with more than 50% of all readmissions occurring within the first two weeks post-discharge ConclusionsIn our study, the highest risk of readmission occurred after an index hospitalization for delivery, and most readmissions occurred in the first 2 weeks post-discharge. Our findings suggest that a post-discharge follow up within 7 days of admission complicated by HF should be extended to patients with pregnancy-related HF and effective readmission reduction strategies must include a better understanding of heart failure phenotypes, and a proactive approach to addressing social risk factors.

Although cholesterol (Chol) is widely recognized as a risk factor for cardiovascular disease, dietary Chol intake has been reported to extend the lifespan of stroke-prone spontaneously hypertensive rats (SHRSP). The mechanisms responsible for this paradoxical effect remain unclear. The present study examined changes in organ lipid profiles and associated molecular factors in SHRSP rats fed a Chol-enriched diet. Four-week-old male SHRSP/Izm rats were assigned to three groups and fed ad libitum for 12 weeks with either a control diet (Ctr), a diet supplemented with 1% w/w Chol (Chol), or a diet containing 1% w/w Chol plus 0.025% w/w lovastatin (Stt) to suppress endogenous Chol synthesis. Systolic blood pressure was measured before and after the feeding period, and tissues were collected for analyses of sterol content, fatty acid composition, prostaglandin E2 (PGE2) levels, and renal histopathology. Relative to the Ctr group, the Chol group exhibited a significant 9-10% reduction in systolic blood pressure. This reduction was accompanied by pronounced alterations in lipid profiles, including changes in phytosterol content and decreased arachidonic acid ratios in serum and kidney. There was a downward trend in hepatic PGE2 levels, and a similar tendency was observed in the kidney. Comparable changes in lipid profiles were observed in the Stt group. Histological analysis revealed modest attenuation of renal pathological features in Chol-fed rats. This study demonstrates for the first time that dietary Chol reduces renal phytosterol accumulation and suppresses the AA-PGE2 axis, changes that coincide with a 9-10% reduction in systolic blood pressure and attenuated glomerular inflammation. These integrated findings provide a mechanistic framework linking dietary Chol to the previously reported lifespan extension in this stroke-prone model. Although these changes may contribute to improved renal pathology, further studies are required to clarify causal relationships.

Background: Children with congenital heart disease (CHD) require specialized care and may face worse outcomes if they experience food insecurity (FI). FI is associated with poor nutrition, hospitalizations, and developmental delays, compounding cardiac risks. Limited research evaluated impact of FI on health status among children with CHD. This study examines socioeconomic factors and the relationship between FI and health status in children with CHD. Methods: 2023 National Survey of Children?s Health (NSCH) data were used to compare rates of FI between children ages < 17 years with and without CHD and to assess overall health status of those with CHD. Descriptive, univariate, and multivariable logistic regression were utilized. Results: Among 53,477 children, 1,233(2%) had CHD. FI was reported in 35% of children with CHD vs. 27% without CHD(p=0.005). After adjustment, children with CHD had higher odds of FI (OR 1.49; 95% CI: 1.05?2.12). Hispanic ethnicity, residence in Midwest or South, lower household education, and lower poverty index were significantly associated with FI. Households receiving food assistance had higher FI. Living in grandparent household was associated with lower odds of FI. Within the CHD subgroup, 5% reported fair or poor health. Children with CHD experiencing FI had greater odds of fair or poor health than those without FI (OR 3.91, 95% CI 1.70?9.02; p=0.001). Conclusions: Children with CHD face higher odds of FI, which is strongly associated with worse reported health. Addressing socioeconomic vulnerability and FI may improve outcomes and reduce disparities in this high-risk population through targeted screening and intervention strategies nationwide. Keywords: Congenital Heart Disease, Food Insecurity Screening, National Survey of Children?s Health (NSCH), Health Disparities

BackgroundVaping among adolescents and young adults (AYA) could affect cardiovascular health. While pulmonary outcomes of vaping are well-documented, the link between vaping and abnormalities of heart rhythm remains unclear. We conducted a retrospective cohort study to test the hypothesis that the risk of heart rhythm abnormalities is increased in AYA who vape. MethodsWe used data from the TriNetX network to identify two cohorts of AYA (11 to 24 years old). The first cohort included individuals who vaped, and the second cohort was a comparison of individuals who did not report vaping. Individuals in the vaping cohort were matched 1:1 with those in the comparison cohort using propensity scores. The primary outcome was the association between vaping and diagnoses of heart rhythm abnormalities. The study analyzed data from 114,404 patients (57,202 in each cohort) with no significant differences in baseline characteristics. ResultsPatients who vaped had 82% higher odds of being diagnosed with heart rhythm abnormalities compared to those who did not vape (OR: 1.82, 95% CI: 1.74-1.91, p < 0.001). Furthermore, the hazard of developing heart rhythm abnormalities was approximately twice as high among vapers compared to those who did not (HR: 1.97, 95% CI: 1.88-2.06, p < 0.001). ConclusionThis study shows a significant association between e-cigarette use and an increased risk of heart rhythm abnormalities in AYA. These findings highlight the potentially harmful cardiac electrophysiological outcomes of vaping in this population and underscore the importance of health interventions and surveillance.

IntroductionPreterm pre-eclampsia is associated with increased risk of later cardiovascular disease. This study examines cardiometabolic health 3-6 years post-preterm pre-eclampsia and explores whether early postnatal cardiovascular phenotypes relate to later cardiovascular morbidity. MethodsPICk-UP trial participants who experienced preterm pre-eclampsia underwent assessments including anthropometry, blood pressure (BP), arteriography, echocardiography, biomarkers and cardiac magnetic resonance (CMR) imaging 3-6 years postpartum. The primary outcome was hypertension prevalence, with secondary outcomes including cardiac fibrosis, remodelling, and function, obesity, and lipid abnormalities. Associations between baseline, pregnancy and postnatal characteristics with the primary and secondary outcomes were explored. ResultsForty-five women were included; 37 underwent echocardiography and 20 had CMR. At 3-6 years, 53% had hypertension, 32% developed de novo hypertension, 30% had adverse left ventricular (LV) remodelling, 49% had diastolic dysfunction, and 27% were obese. Myocardial fibrosis was detected in 35% of CMR participants. No cardiovascular measures changed from 6 months postpartum to 3-6 years. Women who developed hypertension demonstrated higher BP and LV mass index, from 6 weeks postpartum, with distinct postnatal BP trajectories. Women with myocardial fibrosis exhibited higher sFlt and CRP concentrations from 6 weeks postpartum, with sFlt correlating with native T1 at 3-6 years. DiscussionWomen with prior preterm pre-eclampsia show significant cardiometabolic morbidity 3-6 years postpartum. Early postnatal phenotypes indicate long-term cardiovascular risk. Persistent anti-angiogenic imbalance and inflammation may contribute to myocardial fibrosis. Early BP, weight, and biomarker measurement may help identify at-risk women, warranting further studies on optimising postnatal care to mitigate cardiovascular risk after preterm pre-eclampsia.

Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) is a lifesaving intervention used to manage non-compressible torso hemorrhage by temporarily occluding the aorta to minimize blood loss and preserve perfusion to vital organs. Partial REBOA (p-REBOA) has been proposed to mitigate ischemic injury associated with full-REBOA (f-REBOA). However, implementation of p-REBOA clinically has been challenging due to our limited understanding of the acute hemodynamics with p-REBOA particularly in relation to cardiac, carotid, and renal perfusion. In this study we developed and utilized a novel porcine model to continuously measure cardiac, carotid, renal and systemic hemodynamic responses to varying degrees of hemorrhagic shock and aortic occlusion. Yorkshire pigs (N=54) underwent instrumentation for continuous hemodynamic monitoring and hemorrhage was induced for 30 minutes to achieve 10%, 20%, or 30% blood volume loss (n=18/group), followed by randomized treatments of either no occlusion, p-REBOA, or f-REBOA occlusion strategies (n=6/group) for 30 minutes. After occlusion, shed blood was re-transfused over 15 minutes, and REBOA balloons were deflated and removed. This was followed by a 3-hour automated resuscitation and critical care period. Renal and carotid perfusion decreased progressively with hemorrhage severity. Interestingly, 30 minutes of f-REBOA resulted in significant ischemia-reperfusion injury where renal perfusion was profoundly suppressed to 40% of baseline renal flow. On the other hand, p-REBOA yielded superior renal perfusion, while maintaining cardiac function and carotid perfusion. p-REBOA also required less fluid and vasopressors. This translational pig model offers new opportunities to assess acute cardiovascular hemodynamics during interventions for the management of hemorrhagic shock.

Background: Women with severe aortic stenosis (AS) are diagnosed later and experience poorer outcomes than men, partly because clinical approaches rely on 2D, valve-centric thresholds derived from male-predominant cohorts that underutilize information from 3D left ventricular (LV) geometry. We hypothesize that a sex-specific computational framework integrating statistical shape analysis (SSA) of pre-TAVR CT with machine learning would improve prediction of 1-year LV mass regression (LVMR). Objective: To develop a computational framework leveraging 3D LV geometry and evaluate whether it improves sex-specific prediction of 1-year LVMR after TAVR. Methods: We studied 339 patients with severe AS who underwent TAVR from 2013 to 2020 and had pre-TAVR CT and 1-year post-TAVR echocardiography. LV geometries were segmented into digital twins, and shape modes predictive of LVMR were extracted using SSA and partial least squares. These modes were incorporated into support vector regression models and compared with conventional echocardiographic predictors, including pre-TAVR LVEF, LVMI, and E/A ratio. Performance was assessed using RMSE and R^2. Results: After one year, 65% of patients showed positive LVMR, with median regression of approximately 10%; regression was significant overall and within each sex (p<0.001) and similar between sexes (p=0.99). Predictive shape modes differed by sex (p<0.01), with women showing more localized variation and men broader geometric gradients. Sex-specific shape modes outperformed general modes and clinical metrics, particularly in women (R^2=0.80, RMSE=0.09 vs. R^2=0.59, RMSE=0.13; clinical-only baseline R^2=0.16, RMSE=0.22). In men, sex-specific modes also performed strongly (R^2=0.89, RMSE=0.08). Conclusion: In severe AS, 3D LV geometry predicts post-TAVR reverse remodeling more accurately than conventional metrics and may improve risk stratification, particularly in women.

BackgroundSocial determinants of health (SDOH) affect access to transcatheter aortic valve replacement (TAVR), yet their impact on post-procedural mortality remains incompletely defined. We investigated the association between neighborhood-level social deprivation and post-TAVR mortality, readmission, cardiovascular events, and procedural outcomes. MethodsWe performed a retrospective cohort study of 727 consecutive TAVR patients (2023-2024) with 1-year follow-up data at a central New Jersey tertiary care academic medical center, stratified into quartiles based on the composite Social Deprivation Index (SDI) and its seven constituent domains (Q1 = least deprived; Q4 = most deprived). Kaplan-Meier survival analysis with log-rank testing and Cox proportional hazards regression adjusted for STS-PROM score were used to evaluate mortality across quartiles. ResultsThe cohort (mean age 80.4 years; 46% female; 87% White; mean STS-PROM 5.5%) was skewed toward lower-deprivation neighborhoods (85% in Q1-Q2). Survival differed significantly across SDI quartiles at 30 days (log-rank p=0.037) and 90 days (p=0.049), but not at 1 year (p=0.164). In Cox regression, composite SDI was not a significant predictor of one-year mortality. Domain-specific analysis identified single-parent household density as the only significant mortality predictor, with patients in Q4 having higher 1-year mortality than those in Q1 (aHR 2.65, 95% CI 1.15-6.14, p=0.023). Procedural events, overall 30-day readmissions, and 30-day composite cardiovascular events did not differ significantly across SDI quartiles (all p>0.05). ConclusionNeighborhood-level social deprivation was not independently associated with post-TAVR all-cause mortality, though underrepresentation of patients from highly deprived neighborhoods highlights ongoing access disparities. Single-parent household density, a marker of social fragmentation, demonstrated a hypothesis-generating association with increased mortality risk, suggesting a potential role for neighborhood social fragmentation in post-TAVR outcomes that warrants prospective validation. These findings support equitable TAVR access while highlighting social support as an area for future investigation.

Background: Poor physical performance, measured by gait speed and chair stands, is associated with mortality; associations may differ by history of cardiovascular disease (CVD). Methods: Among 14,137 REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants, gait speed and chair stand times (2013-2016) were categorized into quartiles and a fifth category with those who were unable to complete the test. Associations with adjudicated CVD and all-cause mortality through 2020 were examined among participants with and without history of CVD. Results: Average age was 72.5 {+/-} 8.5 years. Among participants without history of CVD, those in slowest vs. highest gait speed quartile had HRs of 2.01 (95% CI 1.18-3.43) for CVD and 1.66 (1.33-2.07) for all-cause mortality; among those unable to complete the test, HRs were 2.37 (1.12-5.03) for CVD and 2.33 (1.72-3.17) for all-cause mortality. Among participants with history of CVD, slowest gait speed quartile had HRs of 1.28 (0.96-1.72) for CVD and 1.72 (1.45-2.04) for all-cause mortality; HR among those unable to complete the test were 1.87 (1.29-2.70) for CVD and 2.74 (2.22-3.38) for all-cause mortality (p-interaction between with and without history of CVD <0.05). Inability to complete chair stand test was associated with higher mortality in both groups. Conclusions: Poor physical performance was associated with greater CVD-related and all-cause mortality among both individuals with and without a history of CVD, with the highest risks observed among those who were unable to the assessments.

Background Exercise capacity varies among individuals with a Fontan circulation. Percent predicted peak oxygen consumption (%pVO2) may be influenced by ventricular morphology, Fontan subtype, and conduit characteristics, but data explaining variability in exercise capacity are limited. This study examined whether anatomical and surgical factors are associated with %pVO2 later in life. Methods Participants enrolled in the multicenter Single Ventricle Outcomes Network (SV-ONE) database who had cardiopulmonary exercise testing (CPET) data were included. Published reference equations were used to estimate %pVO2. Multivariable regression models evaluated associations between anthropometric, anatomical (diagnosis and dominant ventricle), and surgical (Fontan subtype, conduit size, and surgical era) factors and %pVO2. Restricted spline analyses assessed nonlinearity. Results 561 individuals with a Fontan circulation were included in the analysis; age 20 {+/-} 8 years, 54% male, mean %pVO2 was 63 {+/-} 16%. Sex and exercise modality were the strongest predictors of %pVO2, with females being 12% higher than males and treadmill 4.6% higher than a cycle. Age at CPET was a predictor of exercise capacity with %pVO2 decreasing by 0.8% per year. Ventricular morphology, diagnosis, and Fontan subtype did not have a statistical association with the primary outcome. In models restricted to patients with an extracardiac conduit (n = 330), conduit diameter and area were not associated with %pVO2, even after indexing to body surface area. Univariable nonlinear spline analyses suggested an optimal conduit size of 18 mm for %pVO2, but this was not significant after body size adjustments. Conclusion In this large multicenter cohort, surgical and anatomical features were not as important as sex, age, and body size as determinants of exercise performance in patients with a Fontan circulation. Reduced exercise capacity in this population appears to reflect progressive pathophysiological changes of the Fontan circulation rather than specific characteristics such as conduit size, ventricular morphology, or anatomy.

BackgroundEarlier age at menopause and shorter reproductive span (time from menarche to menopause) have been linked to an increased risk of cardiovascular diseases (CVD), presumably because of limited lifetime exposure to endogenous estrogen. Our intention is to determine whether genetic liability to earlier vs later menarche and menopause are associated with risk of common cardiovascular diseases in women. We also aim to investigate effects of exogenous estrogen exposure in the form of systemic hormonal contraceptive and menopausal hormone therapy use. Methods and resultsWe determined GWAS summary statistics for age at menopause, age at menarche, and length of the reproductive period with data derived from UK Biobank (UKBB) European-ancestry participants. We calculated polygenic scores for women from FinnGen study (N=184 132) that indirectly capture genetic variation in endogenous estrogen exposure: age at menopause, age at menarche, and length of reproductive span. We also investigated exogenous hormone exposure associated with use of menopausal hormone therapy or systemic hormonal contraceptives. We used Cox proportional hazards model to investigate associations between PGSes and exogenous estrogen exposure and risk of hypertension, stroke, and coronary heart disease (CHD) events. Median follow-up time was 25.8 years. During the follow-up 56 143 women experienced hypertension, 18 200 women experienced strokes, and 13 879 women experienced major CHD events. Genetic liability to later menopause and longer reproductive span were weakly associated with a higher risk of stroke: in models adjusted with smoking and BMI, the hazard ratio (HR) per one standard deviation increase in PGS was 1.03 [1.01-1.05] for both. Menopausal hormone therapy use was associated with lower risk of stroke (HR 0.85 [0.82 - 0.89]) and CHD (HR 0.80 [0.76 - 0.84]). Systemic hormonal contraceptive use was associated with lower risk of hypertension (HR 0.96 [0.93 - 0.99]), stroke (HR 0.84 [0.80 - 0.99]) and CHD events (HR 0.83 [0.78-0.89]). ConclusionsAlthough observational evidence consistently associates a longer reproductive span with lower cardiometabolic risk, the polygenic component of metabolic timing (PGSes for reproductive span and age at menopause) showed the opposite direction of association. This discrepancy likely reflects the fact that these scores capture genetic pathways only partially overlapping with phenotypic lifetime estrogen exposure. Importantly, the observed cardioprotective associations of menopausal hormone therapy and systemic hormonal contraception underscore that genetic predisposition and exogenous hormonal exposure represent distinct biological dimensions relevant to cardiovascular risk in women. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIWe combined genetic data and information of register-based hormone purchases from over 180 000 women to investigate associations between endogenous and exogenous estrogen exposure and cardiovascular diseases. C_LI What Are the Clinical Implications?O_LIOur results suggest that genetic predisposition to a later natural menopause and longer reproductive span are not protective towards cardiovascular diseases. C_LIO_LIExogenous hormones were associated with lower long-term risk of stroke and coronary heart disease events. This implies that even if the current use of exogenous estrogen may increase stroke risk, the long-term stroke risk may decrease compared to women who never used hormones. C_LI

ImportanceIndividuals exposed to perinatal risk factors are at increased risk for cardiovascular and neurodevelopmental disorders. Heart rate variability, an index of autonomic nervous system function, is widely used to assess long-term health risk in these populations, yet findings remain inconsistent. ObjectiveTo quantify heart rate variability differences between individuals with perinatal risk factors (including preterm birth, intrauterine growth restriction, and low birth weight) and healthy full-term controls, and to examine sources of heterogeneity. Data sourcesPubMed, EMBASE, Web of Science, Scopus, and APA PsycArticles were searched through April 2025, supplemented by ClinicalTrials.gov and reference screening. Study selection: Peer-reviewed studies reporting heart rate variability in perinatal risk populations versus healthy controls after hospital discharge. Of 7,781 screened articles, 27 met inclusion criteria. Data extraction and synthesisThis review followed PRISMA 2020 guidelines and was registered on PROSPERO (CRD42024527673). One reviewer extracted data using a standardized form, with verification by a second reviewer. A total of 176 effect sizes were extracted. Multilevel random-effects models accounted for dependency within studies. Main outcome(s) and measure(s)The primary outcome was heart rate variability difference between groups, expressed as Cohens d. ResultsAcross 27 studies (1,890 participants) and 176 effect sizes, the overall effect was modest and marginally significant (d = -0.24; 95% CI: -0.50 to 0.02; p = 0.07), with substantial heterogeneity (I{superscript 2} = 87.7%). Effect sizes differed significantly by perinatal condition (p < 0.001). Congenital heart disease (d = -1.07) and genetic syndromes (d = - 1.02) showed large heart rate variability reductions, while growth-related conditions showed moderate effects (d = -0.44). Heart rate variability differences attenuated with age ({beta} = +0.027 per year; p = 0.04), with strongest effects in early development (d = -0.85) and apparent normalization during adolescence. Conclusions and relevanceAutonomic consequences of perinatal adversity are condition-specific and developmentally dynamic. Structural and genetic conditions show pronounced deficits, while other conditions show substantial developmental heterogeneity. These findings underscore the importance of age- and condition-specific assessment and longitudinal follow-up. Key PointsO_ST_ABSQuestionC_ST_ABSDo individuals with perinatal risk factors show altered heart rate variability (HRV) compared to healthy controls, and what factors explain between-study heterogeneity? FindingsIn this meta-analysis of 27 studies, perinatal risk groups showed modestly reduced HRV compared to controls, with effects varying significantly by condition. Congenital heart disease and genetic syndromes showed large HRV reductions. Growth-related conditions showed moderate reductions. HRV differences were largest in early development and attenuated significantly with age. MeaningAutonomic consequences of perinatal adversity are condition-specific and developmentally dynamic, warranting age- and condition-specific clinical assessment.

ObjectivesTo assess if maternal stress is higher in pregnancies with congenital heart disease (CHD) compared to low-risk pregnancies and if maternal stress is associated with placental microstructure and function. To explore if CHD alters the relationship between maternal stress and placental measures. MethodsIn this prospective observational study, 27 participants carrying a fetus with CHD and 42 participants with typical low-risk pregnancies underwent 1-2 combined diffusion{square}T2* relaxation placental MRIs from 20 weeks gestation (GA) and completed the Edinburgh Postnatal Depression Scale and State Trait Anxiety Inventory [43 male fetuses, median (IQR) GA at assessment 30.86 weeks (27.43-34.00), interval between assessments 6.00 weeks (4.86-7.14)]. 98 complete placental MRI and maternal stress datasets were available. Generalized Estimating Equations were used for analyses. ResultsHigher trait anxiety was associated with higher placental apparent diffusion coefficient (p=0.023) adjusting for CHD, sex, GA at assessment, GA at assessment2, state anxiety, depressive symptoms and previous mental health treatment. Maternal state anxiety (p=0.005) and depressive symptoms (p=0.046) were higher in pregnancies with CHD adjusting for GA at assessment and previous mental health treatment. CHD did not alter these relationships (p>0.119). ConclusionsMaternal proneness to anxiety, measured with the trait anxiety inventory, is associated with increased diffusivity in the placenta, which may reflect altered microstructural maturation. Mothers with fetal CHD show more depressive symptoms and feelings of anxiety and may benefit from screening for elevated maternal stress. The findings contribute to a growing body of research regarding the influence of prenatal stress on placental development. HighlightsO_LIMaternal stress and placental MRI data acquired in pregnancies with and without CHD C_LIO_LIMaternal trait anxiety is associated with increased placental diffusivity C_LIO_LIMaternal state anxiety and depressive symptoms are higher in fetal CHD C_LIO_LIState anxiety and depressive symptoms not associated with placental MRI measures C_LIO_LICHD did not moderate relationships between placental MRI measures and stress C_LI

BackgroundOmega-3 polyunsaturated fatty acids are known to confer benefits in the prevention of cardiovascular diseases. Among these, eicosapentaenoic acid (EPA) appears to be more effective than docosahexaenoic acid (DHA) in ischemic vascular conditions. However, the specific roles of EPA and DHA in limb angiogenesis and post-ischemic reperfusion remain unclear. Moreover, omega-3 fatty acids remain understudied for peripheral artery disease (PAD) intervention. The aim was to compare the effect of high dose omega-3 fatty acids, EPA and DHA on ischemic tissue reperfusion, angiogenesis and vascular remodelling in mice. MethodsHind limb ischemia (HLI) was performed in mice and reperfusion was measured using laser speckle contrast imaging over two weeks post-HLI. Mice were treated daily with oral high-dose EPA or DHA (600 mg/kg/day) or vehicle (olive oil). Gastrocnemius muscle tissue was collected for analysis of mRNA and protein markers of angiogenesis. ResultsFollowing HLI, blood flow was restored more rapidly in mice treated with EPA compared with vehicle. DHA treatment did not enhance reperfusion. Histological assessment revealed significant muscle fibre regeneration after HLI, which was further improved by EPA. CD31+ neo vessel density was also increased in the EPA group. Collectively, these findings indicate that EPA promotes angiogenesis after peripheral vascular ischemia, whereas DHA does not. The beneficial effects of EPA are associated with upregulation of hypoxia inducible factor . ConclusionsHigh-dose EPA accelerated post-ischemic reperfusion, while DHA was ineffective. These results highlight EPA as a potential therapeutic strategy for improving limb perfusion and vascular repair in patients with PAD. Research PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIOmega-3 fatty acid, eicosapentaenoic acid (EPA) accelerates post-ischaemic reperfusion following hind limb ischemia injury in mice. C_LIO_LIOmega 3 fatty acid, docosahexaenoic acid (DHA), does not show the same improvement in reperfusion after hind limb ischemia C_LIO_LIEPA can promote vasculogenesis and stimulate muscle fibre regeneration. C_LI What question should be addressed next?O_LIHigh dose purified EPA, in the form of icosapent ethyl reduces mortality from coronary artery disease. Peripheral artery disease (PAD) is a common co-morbidity yet high quality interventional trials for icosapent ethyl for PAD are lacking. Therapeutic angiogenesis has the potential to improve PAD symptoms and disease progression but there are no efficacious candidates. Icosapent ethyl should be trialled to determine whether functional outcomes are improved in PAD. C_LI

BackgroundAcute type A aortic dissection (AAAD) complicated by cardiopulmonary arrest is characterized by high mortality rates, rendering the selection of surgical candidates a subject of intense debate. Despite the necessity for cardiopulmonary resuscitation (CPR) prior to the completion of a definitive intervention, the prognostic impact of CPR duration on postoperative survival and neurological outcomes remains insufficiently elucidated. This study sought to evaluate the association between pre- and intra-operative CPR duration and the incidence of early mortality and central nervous system (CNS) complications in patients undergoing emergent surgical repair for AAAD. MethodsThis retrospective, cohort study was conducted at two tertiary community hospitals in Japan. All the patients who underwent emergency surgery for AAAD between January 2014 and December 2024 were enrolled. A multilevel Cox proportional hazards model, with each patient as level 1 and institutions as level 2, was used to evaluate the association between pre-or intra-operative CPR events and early postoperative mortality and CNS complications. ResultsOf the 880 patients enrolled, 785 (89.2%), 13 (1.5%), and 82 (9.3%) were without CPR, with CPR <15 min, and with CPR [&ge;]15 min, respectively. Among them, death within 30 days post-surgery occurred in 76/785 (9.7%), 3/13 (23.1%), and 47/82 (57.3%), respectively. CNS complications within 30 days post-surgery occurred in 141/785 (18.0%), 5/13 (38.5%), and 38/82 (46.3%) without CPR, CPR <15 min, and [&ge;]15 min, respectively. In multivariable analysis, CPR lasting [&ge;]15 min was associated with mortality within 30 days post-surgery (adjusted hazard ratio, 7.66; 95% confidence interval [CI], 3.56-16.5; P<0.001). Both CPR <15 min and [&ge;]15 min were associated with an increase in the sub-hazard ratio of CNS complications within 30 days post-surgery (adjusted sub-hazard ratios, 4.49; 95% CI, 3.92-5.11; P<0.001, and 3.62; 95% CI, 2.73-4.81; P<0.001, respectively). ConclusionA preoperative CPR duration of [&ge;]15 min prior to the initiation of cardiopulmonary bypass or extracorporeal membrane oxygenation was associated with a substantial escalation in 30-day mortality compared with patients without CPR. These findings suggest that CPR duration might serve as a pivotal prognostic indicator, necessitating careful consideration for surgical indication in patients with AAAD complicated by CPR. CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABSO_LIPre- or intra-operative cardiopulmonary resuscitation lasting [&ge;]15 min in patients with acute type A dissection is associated with a nearly seven-fold increase in 30-day postoperative mortality. C_LIO_LIBoth short (<15 min) and prolonged ([&ge;]15 min) cardiopulmonary resuscitation are associated with a higher risk of early postoperative complications in the central nervous system. C_LI What are the clinical implications?O_LIPatients with acute type A dissection who require pre- or intra-operative cardiopulmonary resuscitation [&ge;]15 min should undergo careful multidisciplinary evaluation, as the risk of early mortality is substantially elevated. C_LIO_LIEven brief cardiopulmonary resuscitation is associated with increased neurological complications, highlighting the need for early neurological monitoring and supportive care postoperatively. C_LI