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.

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.

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.

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

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.

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.

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.

Pregnancy complications such as preeclampsia are associated with circulating cell-free mitochondrial DNA (mtDNA), a damage-associated molecular pattern capable of activating Toll-like receptor 9 (TLR9). We hypothesized that acute mtDNA exposure induces maternal inflammation and endothelial dysfunction during pregnancy via TLR9 activation. Non-pregnant and pregnant rats (gestational days 14-15) were treated intravenously with saline or purified mtDNA and euthanized 4 h after treatment. mtDNA increased cytokine mRNA expression in lung and liver of non-pregnant and pregnant rats, with magnitude varying by pregnancy status and organ. Aortas from pregnant, but not non-pregnant, rats exhibited reduced acetylcholine (ACh)-induced relaxation following mtDNA treatment (Emax, saline: 90.1 {+/-} 3.9 % vs. mtDNA: 62.1 {+/-} 20.7 % KClmax, p<0.05), while uterine artery function was preserved, indicating vascular bed-specific effects. Ex vivo incubation of aortic rings with mtDNA {+/-} white blood cells did not replicate in vivo findings, implicating systemic rather than direct vascular mechanisms. Nuclear DNA did not affect ACh-induced relaxation (p>0.05), confirming that the vascular effects were mtDNA-specific. Pharmacological antagonism of TLR9 with ODN2088 partially attenuated mtDNA-induced maternal endothelial dysfunction. Although overt vascular ROS increases were not detected, aortas from pregnant rats had reduced sod-1 expression (p<0.05) and increased eNOS protein abundance (p<0.05). Acute mtDNA exposure during pregnancy induces maternal organ inflammation and impairs endothelium-dependent vasodilation, with partial TLR9 involvement. In conclusion, aortic transcriptional changes in antioxidant pathways and increased eNOS abundance were also observed, though their functional significance remains to be determined. New & NoteworthyTo our knowledge, this is the first study to demonstrate that acute exposure to circulating mtDNA induces pregnancy-specific maternal endothelial dysfunction and organ-selective inflammatory responses. Our findings reveal pregnancy- and vascular-bed specific responses of the maternal vasculature to mitochondrial danger signals, with partial TLR9 involvement. Aortic transcriptional changes in antioxidant pathways and increased nitric oxide synthase abundance were identified as molecular correlates of this dysfunction.

Pregnant women are particularly susceptible to adverse outcomes from environmental heat, yet the physiological effects of acute heat exposure during pregnancy remain poorly understood. Some physiological changes are monitored in humans; however, investigation of underlying molecular mechanisms requires invasive methods that can only be ethically applied in mammalian models. Moreover, research with animal models has largely focused on early and lethal teratogenic effects of heat exposure and lacks longitudinal physiological monitoring, detailed parameterisation of heating regimes and in-depth investigation of underlying mechanisms. Here we used a mouse model to investigate the impact of a controlled acute heat exposure at mid-gestation (E12{middle dot}5), slowly elevating core body temperature (CBT) over 210mins to raise CBT by [~]1{degrees}C. Using high-frequency ultrasound and morphological analyses, we observed delayed alterations in placental and foetal cerebral blood flow indicative of a brain-sparing response, alongside reduced placental labyrinth zone size. Additionally, maternal cardiac function was impaired, accompanied by cardiac and renal fibrosis and elevated circulating soluble Flt-1 levels, an anti-angiogenic biomarker of gestational hypertension. These findings demonstrate that brief heat stress at mid-gestation can induce lasting effects on placental function and maternal cardiovascular health in a mammalian model, highlighting potential risks for pregnancy outcomes under increasing global temperatures. Together this data suggests that an acute exposure to heat elevating core body temperature by 1{middle dot}2{degrees}C can induce a long-term impact on both placenta and maternal health in a mouse model. It will be important to understand the molecular changes which underpin the pathophysiology and whether this is translated to humans.

Background The postmenopausal period is associated with a more adverse cardiometabolic risk factor profile as well as unfavourable cardiac remodelling patterns. However, it remains unclear whether and how the associations between risk factors and cardiac remodelling differ before and after menopause and in the corresponding age groups in men. Methods We used cross-sectional data from the baseline examination of the population-based German National Cohort (NAKO, age range 19-74 years). Cardiovascular resonance imaging (CMR) was performed on 3T MRI, and morphofunctional data of both ventricles were derived from standard short-axis cine balanced steady-state free precession. Associations between cardiometabolic risk factors and cardiac parameters were evaluated using adjusted multivariable linear regression, stratified by menopausal status in women and age group (<50 / [&ge;]50 years) in men. Results The final sample comprised 20,152 participants (40% women; mean age 47{+/-}12 years) from the NAKO MRI subsample. Cardiometabolic risk factor profiles differed across the stratified groups, with higher systolic blood pressure and less favourable lipid profiles in older participants. Ventricular volumes declined and concentric remodelling increased with age in both sexes, with a steeper age-related pattern observed in women than in men. Higher BMI in women was associated with higher left ventricular concentricity index (LVCI) in postmenopausal than in premenopausal women (0.097 vs. 0.047; p for difference = 0.016). Associations between triglycerides and ventricular volumes were strongest in premenopausal women and significantly stronger than in men younger than 50 years (e.g., right ventricular end-diastolic volume (RVEDV): -0.173 vs. -0.064, p for difference < 0.001). Sleep problems were more strongly associated with cardiac parameters in men, with significant sex differences in older men compared with postmenopausal women (e.g. left ventricular end-diastolic volume (LVEDV): -0.105 vs. 0.043, p for difference = 0.023). Conclusions Less favourable cardiac remodelling observed in postmenopausal women appeared to be associated with a higher burden of cardiometabolic risk factors rather than stronger associations between these risk factors and cardiac structure. Several associations showed sex- and age-specific patterns, including Body Mass Index (BMI), triglyceride levels, and sleep problems. These findings highlight the importance of controlling cardiometabolic risk factors across adulthood, and raising awareness for sex-specific differences.

We aimed to evaluate disparities in perinatal ICU admissions at an urban medical center and to contextualize these findings relative to national U.S. data provided by the Centers for Disease Control and Prevention (CDC). To do so, we performed a retrospective review of all pregnant and < 6-week postpartum patients admitted to the ICU between October 2023 and June 2025. The cohort included 58 patients: 81% were non-Hispanic Black, and 91% were publicly insured. These local data can be compared to national data, which demonstrate higher rates of severe maternal morbidity (SMM) and ICU admission among Black patients and those insured by Medicaid. In 2023, the U.S. maternal mortality rate was 18.6 per 100,000 live births, down from 22.3 in 2022. However, significant disparities persist, with mortality rates of 50.3 per 100,000 among Black women compared with 14.5 per 100,000 among White women. The most frequently reported indications for obstetric ICU admission include hypertensive disorders of pregnancy, obstetric hemorrhage, and severe underlying medical comorbidities.

BackgroundVentricular assist devices (VADs) are used as treatment for end-stage heart failure in children and adults. We previously demonstrated decreased mitochondrial function and changes in cardiolipin, a mitochondrial phospholipid, in explanted pediatric and adult failing hearts. In this study, we tested the hypothesis that VAD unloading of failing hearts leads to positive changes in myocardial cardiolipin in both pediatric and adult hearts. MethodsVentricular tissue was collected from the same patient at time of VAD implantation and at transplant. Ejection fraction (EF), left ventricular internal diameter at end-diastole (LVIDd) and brain natriuretic peptide (BNP) were assessed pre- and post-VAD. Cardiolipin species from paired VAD core and explants were quantified using liquid chromatography mass spectrometry. Mitochondrial respiration was measured in ventricular tissue pre- and post-VAD in paired pediatric samples using the Oroboros Oxygraph-2k. ResultsVAD support led to increased EF and decreased LVIDd and BNP. The predominant cardiolipin species in cardiac mitochondria, tetralinoleoylcardiolipin, was positively remodeled in pediatric post-VAD myocardium, while adult post-VAD myocardium demonstrated significantly increased total cardiolipin and decreased oxidized cardiolipin but did not demonstrate the tetralinoleoylcardiolipin remodeling seen in pediatric hearts. In pediatric patients, VAD support resulted in significant increases in Complex I+II activity, and a trend toward increases in Complex I activity. ConclusionOur data demonstrate age-related differences in VAD-associated cardiolipin remodeling and suggest that improved mitochondrial function in pediatric VAD-supported hearts could be related to increased tetralinoleoylcardiolipin.

Background: Socioeconomic factors impact cardiovascular health. We investigated the association between patient education level and incident heart failure (HF), acute myocardial infarction (AMI), and stroke following a first hospitalization with atrial fibrillation (AF). Methods: In this nationwide retrospective cohort study using linked Swedish national registers, we included all patients receiving a diagnosis of AF while hospitalized in Sweden from 1995 through 2008; categorized education level as primary, secondary, or academic; and followed patients for up to five years. Outcomes were first hospitalization for HF, AMI, or stroke. Associations were assessed using sex-stratified Cox proportional hazards models adjusted for age, calendar year of AF diagnosis, and measures of comorbidity burden (Charlson Comorbidity Index) and thromboembolic risk (CHA2DS2VA score). Results: The cohort comprised 263,172 patients (mean age 72.5 {+/-} 10.4 years; 56.2% male). Compared with primary education, secondary and academic education attainment were associated with lower adjusted risk of HF and AMI in both females and males. For HF, adjusted hazard ratios (HR) were 0.96 (95% CI 0.93 - 1.00) for secondary and 0.82 (95% CI 0.77 - 0.87) for academic education for females and 0.93 (95% CI 0.90 - 0.96) and 0.76 (95% CI 0.72 - 0.80), respectively, for males. For AMI, adjusted HRs were 0.89 (95% CI 0.85 - 0.93) and 0.71 (95% CI 0.65 - 0.78) for females and 0.91 (95% CI 0.87 - 0.94) and 0.75 (95% CI 0.71 - 0.80) for males. For stroke, lower adjusted risk was observed only in the academic education group. Baseline comorbidity burden and thromboembolic risk were higher in lower education groups. Conclusions: Education level was inversely associated with risk of incident HF and AMI over five years, while the association with stroke risk was weaker. Documenting education level may help identify patients at increased risk who could benefit from careful monitoring and optimized preventive care.

Background: APOL1 risk alleles are prevalent in individuals of West African ancestry and associated with increased risk of kidney disease. Although preeclampsia disproportionately affects women of Black ethnic backgrounds, evidence linking APOL1 alleles to preeclampsia remains conflicting. Objectives: The purpose of this study was to explore whether maternal APOL1 alleles contribute to preeclampsia risk and associated adverse pregnancy outcomes. Study design: We conducted a nested case-control study of 5210 pregnant women, including 745 preeclampsia cases and 949 controls of Black self-reported ethnicity, 1385 preeclampsia cases and 2131 controls of White self-reported ethnicity. APOL1 G1 and G2 risk alleles were directly genotyped on the Illumina Infinium Global Screening Array. Associations with preeclampsia, early preeclampsia, recurrent preeclampsia, birthweight centiles and gestational age at delivery were examined using regression models assuming a recessive mode of inheritance with adjustment for established risk factors and stratification by self-reported ethnicity and genetically-determined ancestry. Results: Presence of APOL1 risk alleles was almost exclusively observed in women of Black self-reported ethnicity. 168/949 controls (17.7%) and 133/745 cases (17.9%) carried two APOL1 risk alleles, and these women did not have a significantly increased risk of preeclampsia compared to those with zero or one APOL1 risk alleles in adjusted analyses (OR 1.00, 95% CI 0.76-1.29, p=0.972). When restricting analysis to women of Black self-reported ethnicity only, no association was observed between APOL1 genotype and preeclampsia risk (adjusted OR 0.94, 95% CI 0.61-1.25, p=0.673). When restricting analysis to women of pan-African genetically-determined ancestry only, also no association was observed between APOL1 genotype and preeclampsia risk (adjusted OR 1.00, 95% CI 0.76-1.32). No associations were found between number of APOL1 risk alleles and early preeclampsia, recurrent preeclampsia, birthweight centile or gestational age at delivery after adjustment for established risk factors and stratification by self-reported ethnicity or genetically-determined ancestry. Conclusions: Maternal APOL1 risk alleles do not independently influence preeclampsia risk or related adverse outcomes in a multi-ethnic pregnancy study. Future studies should examine whether fetal APOL1 genotypes, alone or in interaction with maternal genotypes, contribute to preeclampsia risk.

Background: Unruptured intracranial aneurysms (UIAs) pose a significant risk of subarachnoid hemorrhage. Both hypertension and hyperhomocysteinemia are recognized as independent risk factors for vascular disease; however, their combined impact (H-type hypertension) on aneurysm instability and rupture remains unclear. Methods: We analyzed a prospective cohort of 358 adults with UIAs (475 aneurysms) using high-resolution vessel-wall MRI (HRVWI) for cross-sectional and longitudinal assessment. H-type hypertension was defined as hypertension with plasma homocysteine ?10 ?mol/L. Multivariable logistic regression assessed associations with AWE and aneurysm growth (longitudinal sub-cohort: n = 82, 89 aneurysms). Mendelian randomization (MR) analyses evaluated the causal role of homocysteine in hypertension and aSAH. Proteomic profiling identified potential molecular mechanisms. Results: AWE occurred in 33.7% of aneurysms, which were larger, irregular, and had higher PHASES scores. Elevated homocysteine (10.3 vs 9.5 ?mol/L, p = 0.004) and H-type hypertension (43.8% vs 28.3%, p < 0.001) were associated with AWE. After adjustment, H-type hypertension independently predicted AWE (OR = 3.18) and aneurysm growth (OR = 3.63). MR analyses showed homocysteine increased aSAH (OR = 1.39) and hypertension risk (OR = 1.10), while hypertension increased aSAH risk (OR = 1.58). Mediation analysis did not support hypertension as a mediator (p = 0.20). Proteomic analyses identified key pathways related to inflammation?immune dysregulation, extracellular matrix remodeling, and signaling activation as potential mediators. Conclusions: H-type hypertension amplifies aneurysmal-wall instability and growth. Combined control of blood pressure and homocysteine merits prospective evaluation for UIA prevention.

Sickle cell disease (SCD) is associated with substantial cardiovascular morbidity, but echocardiographic data from Latin American populations remain scarce. We aimed to characterise the structural, functional, and haemodynamic echocardiographic profile of adults with SCD attending a tertiary referral centre in Cali, Colombia. We conducted an observational, cross-sectional study based on systematic review of medical records and transthoracic echocardiography reports of consecutive adult patients ([&ge;]18 years) with confirmed SCD evaluated between January 2022 and December 2024. Patients with complex congenital heart disease, severe valvular disease of unrelated aetiology, pregnancy, or echocardiograms of insufficient quality were excluded. Of 669 patients screened, 57 met inclusion criteria. Reporting followed STROBE recommendations. The median age was 24 years (interquartile range [IQR] 21-32) and 59.6% were female; the SS genotype was the most frequent (76.4%) and 71.4% were on hydroxyurea. Median haemoglobin was 10.2 g/dL (IQR 9.3-11.4) and median NT-proBNP 491 pg/mL (IQR 98-1290). Most patients had preserved left ventricular dimensions and systolic function (median ejection fraction 63%, IQR 57-66.5; mean global longitudinal strain -18.9% {+/-} 2.9). Right ventricular function was preserved (mean tricuspid annular plane systolic excursion 25.4 {+/-} 4.6 mm). Left ventricular geometry was normal in 42.1%, with concentric remodelling in 24.6%, concentric hypertrophy in 21.1%, and eccentric hypertrophy in 12.3%. Diastolic function was normal in 71.4%. Valvular disease, when present, was predominantly mild. Tricuspid regurgitation velocity exceeded 2.5 m/s in 29.8% of patients and exceeded 3.0 m/s in 10.5%, identifying a substantial subgroup at intermediate-to-high probability of pulmonary hypertension. In this Colombian cohort of relatively young adults with SCD, cardiac structure and biventricular function were largely preserved, but nearly one-third of patients had echocardiographic findings suggestive of pulmonary hypertension. These findings support the routine use of transthoracic echocardiography as an accessible tool for early cardiovascular risk stratification in adults with SCD in low- and middle-income settings.

Background: Few studies have examined racioethnic disparities in cardiovascular disease (CVD) in women after breast cancer treatment, who are at higher risk due to cardiotoxic cancer treatment. Methods: Based on the Pathways Heart Study of women with a history of breast cancer, this analysis examines the association between cardiometabolic risk factors (hypertension, diabetes, and dyslipidemia) and CVD events with self-reported race and ethnicity, as well as genetic similarity. Multivariable logistic and Cox proportional hazards regression models were used to test race and ethnicity and genetic similarity with prevalent and incident cardiometabolic risk factors and CVD events. Results: Of the 4,071 patients in this analysis, non-Hispanic Black (NHB), Asian, and Hispanic women were more likely to have prevalent and incident diabetes than non-Hispanic White (NHW) women. Analysis of genetic similarity revealed results consistent with self-reported race and ethnicity. For CVD risk, NHB women were more likely to develop heart failure and cardiomyopathy than NHW women. In contrast, Hispanic women were at lower risk of any incident CVD, serious CVD, arrhythmia, heart failure or cardiomyopathy, and ischemic heart disease, which was consistent with the associations found with Native American ancestry. Conclusions: This is the largest multi-ethnic study of disparities in CVD health in breast cancer survivors, demonstrating corroborating findings between self-reported race and ethnicity and genetic similarity. The results highlight disparities in cardiometabolic risk factors and CVD among breast cancer survivors that warrant more research and clinical attention in these distinct, high-risk populations.

Background: Cardiovascular diseases (CVD) are more common in lower occupational classes, but the mediating role of health behaviours remains unclear. This study aimed to quantify the extent to which health behaviours mediate the association between occupational class and CVD, evaluate their relative contributions to CVD risk, and assess occupational class differences in the effects of health behaviours. Methods: Municipal employees from Helsinki, aged 40-60 at baseline, were followed from 2000-2002 (response rate 67%) to 2022. CVD events were identified from national registers, including hospitalizations, long-term sickness absence, disability pensions, and mortality. Counterfactual mediation analysis using additive survival regression was used to assess the contribution of health behaviours - excessive alcohol consumption, smoking, unhealthy diet, and insufficient physical activity - to the association of occupational class and CVD. Occupational class differences in the effects of health behaviours were assessed with Cox regression. Results: During follow-up, 50% of participants in the low occupational class and 46% in the high occupational class had a CVD event. All unhealthy behaviours except heavy alcohol use were more common in the low occupational class. Health behaviours explained approximately 40% of the excess risk of CVD when moving from high occupational class to low occupational class. Insufficient physical activity (HR 1.44, 95% CI 1.35-1.54) was the strongest predictor of CVD. Unhealthy diet was more strongly associated with CVD in the high occupational class. Conclusion: Health behaviours explained a part of occupational class inequalities in CVD, but most of the inequality remained unexplained, highlighting broader social determinants.

Background Poor physical function has been associated with higher cardiovascular disease (CVD) risk. However, the association between physical function and atrial fibrillation (AF) remains understudied. The comprehensive investigation of the association between physical function and incident AF risk could highlight a novel target for AF prevention. Methods A total of 4,803 participants without diagnosed AF from the Atherosclerosis Risk in Communities (ARIC) Study cohort with physical function assessed in 2011-2013 were studied. Physical function was measured using Short Physical Performance Battery (SPPB), 4-meter walk time, and grip strength. Hospital discharge codes and death certificates were used to ascertain incident AF through 2022, and through 2020 for participants from Jackson. Cox regression was used to assess the association between physical function and incident AF risk, adjusting for multiple covariates. Z-score transformations were performed to identify the physical function measure most strongly associated with incident AF risk, and SPPB component analysis was performed to identify the most influential SPPB component. Results Mean age of the study participants was 75.1 {+/-} 5.0 years, with 41.2% being male participants and 22.2% being black participants. During a median follow-up of 9.2 years, there were 809 incident AF events. SPPB (HR: 0.93, 95% CI: 0.90-0.96, per 1-point increase) and grip strength (HR: 0.87, 95% CI: 0.78-0.96, per 10kg increase) were inversely associated with incident AF risk, while 4-meter walk time (HR: 1.08, 95% CI: 1.03-1.13, per 1-second increase) was positively associated with incident AF risk. SPPB had the strongest association with incident AF risk. Within SPPB, only the chair stand component was significantly associated with incident AF risk. Conclusions The findings suggest that better physical function is associated with reduced incident AF risk, with higher SPPB having the strongest association. Given the modifiable nature of physical function, these findings highlight a potential novel target for AF prevention in aging populations.