Journal of the American Heart Association

Background: The manifestations of cardiovascular disease (CVD) among people with HIV (PWH) differ by region globally. While HIV disease is associated with increased atherosclerotic CVD risk in the global North, non-ischemic heart failure (HF) is more common in sub-Saharan Africa, the global HIV epicenter. We estimated the effect of treated HIV on the frequency and phenotype of HF and its cardiac precursors in South Africa (SA). Methods: In an observational study, we recruited PWH on antiretroviral therapy (ART), age [≥]40 years and people without HIV (PWoH) with similar distributions of age, sex, ethnicity, and hypertension, from a community clinic in Khayelitsha (Cape Town, SA). Procedures included a clinical assessment, echocardiography (Echo), and b-type natriuretic peptide (BNP) measure. Echo parameters defined structural abnormalities, left ventricle (LV) filling pressure, and LV systolic and diastolic dysfunction (DD). HF was defined by symptoms and/or BNP [≥]35pg/mL and LV dysfunction, subcategorized as reduced, mildly reduced, or preserved ejection fraction (HFrEF, HFmrEF, and HFpEF). Comparisons by HIV status were adjusted for age, sex, hypertension, smoking, obesity, diabetes, elevated LDL-cholesterol, and hazardous alcohol use. Results: Between September 2022 and August 2025, we enrolled 1008 PWH and 500 controls [median (Q1-Q3) age 48 years (43-53), 77% female]. Among PWH and controls respectively, 37% and 39% had hypertension, 21% and 25% were current smokers, 40% and 45% were obese, and 9% and 17% had diabetes. LV systolic dysfunction (1%) and HFrEF (1%) were rare, and undiagnosed HFpEF (8%) was the predominant HF phenotype. Compared to controls, PWH had higher odds of elevated LV mass index (LVMI) (OR 2.1; 95%CI 1.5-3.0) and DD (OR 1.4; 95%CI 1.0-2.0). Risk for elevated LVMI and DD was greatest among women with HIV, who also had an increased risk for undiagnosed HFpEF (OR 1.9; 95%CI 1.2-3.2), compared to women without HIV; effects which were not seen among men (p=0.051 for HIV*Sex interaction). Conclusions: In a peri-urban SA community with a high burden of cardiometabolic risk factors, the frequency of abnormal structural and functional cardiac precursors of HFpEF was greater amongst ART-treated PWH. This was most pronounced amongst women with HIV, who also had increased risk of undiagnosed HFpEF.

Abstract Background Cardiogenic shock (CS) is a heterogeneous syndrome with diverse etiologies, treatment pathways, and outcomes. Prior studies of sex differences in CS have largely focused on acute myocardial infarction-related CS or evaluated CS as a single entity. Whether sex-based differences in outcomes and treatment utilization vary across distinct CS phenotypes remains incompletely defined. Methods We performed a retrospective cohort study using the National Inpatient Sample, a nationally representative all-payer database of United States hospitalizations. Adult hospitalizations with CS were identified using ICD-10-CM code R57.0 and categorized into clinically relevant phenotypes, including acute myocardial infarction (AMI), heart failure (HF), arrhythmia-related shock, myocarditis/Takotsubo, valvular disease, and other etiologies. Survey-weighted analyses accounting for the complex sampling design were used for primary analyses. The primary outcome was in-hospital mortality. Secondary outcomes included use of mechanical circulatory support (MCS) and mechanical ventilation. Propensity score-matched analyses were performed as sensitivity analyses. Results Among 254,691 weighted CS hospitalizations, 158,747 (62.3%) occurred in men and 95,896 (37.7%) in women. In survey-weighted analyses, women had higher in-hospital mortality in AMI-related CS (36.1% versus 31.3%; OR, 1.24; 95% CI, 1.19-1.28), HF-related CS (30.5% versus 25.8%; OR, 1.27; 95% CI, 1.23-1.30), and arrhythmia-related CS (37.3% versus 31.6%; OR, 1.28; 95% CI, 1.20-1.38). Women were less likely to receive ECMO (2.4% versus 2.9%), IABP/Impella (13.1% versus 18.9%), or any MCS (14.6% versus 20.4%), but were more likely to receive mechanical ventilation (44.9% versus 42.9%). In propensity-matched analyses, mortality differences were attenuated but persisted in AMI-related, HF-related, and valvular CS. Conclusions Sex differences in CS outcomes and treatment utilization are strongly phenotype dependent. Women experienced higher mortality in major CS phenotypes while receiving less advanced mechanical circulatory support. These findings support early recognition, rapid phenotype classification, and sex-conscious but non-delayed escalation strategies for women with CS.

Objective To evaluate the associations between maternal history of psychiatric disorders and the risk cardiovascular disease (CVD) in offspring. Design Population based cohort study. Setting Nationwide health registers in Sweden. Participants All 4 171 005 liveborn singletons in Sweden from 1973 to 2014. Follow-up started at birth and ended until the first diagnosis of CVD, death, emigration, or December 31st, 2023, whichever occurred first. Exposures for observational studies Maternal psychiatric disorders diagnosed before delivery (n=208,680, 5.0%). Main outcome measures The primary outcome was the first diagnosis of CVD in offspring, identified through hospital registers. Additional outcomes included specific CVD subtypes. To address potential familial confounding, a cousin comparison was performed, comparing the risk of CVD in offspring born to mothers who were biological sisters. Mediation analyses examined the roles of congenital heart disease, small for gestational age, and preterm birth. Results During up to 51 years of follow-up, 307 596 (7.4%) offspring had a diagnosis of CVD. Maternal history of psychiatric disorders was associated with a higher risk of overall CVD both in the full cohort (hazard ratio 1.19, 95% confidence interval 1.17 to 1.21) and the cousin-comparison cohort (n=1 577 113; 1.08, 1.03 to 1.13). In disease-specific analyses, a prominent association with heart failure was robustly observed in both the full cohort (1.59, 1.37 to 1.85) and the cousin comparison cohort (1.51, 1.06 to 2.17). Mediation analyses indicated that congenital heart disease mediated 9.5% of the association between maternal psychiatric disorders and offspring CVD risk. Preterm birth and small for gestational age contributed minimally (<3%) to the observed associations. Conclusions Maternal history of psychiatric disorders was associated with an increased risk of CVD up to early middle-age in offspring. Congenital heart disease partly mediated this association.

BackgroundHypertension is the most potent modifiable risk factor for recurrent intracerebral hemorrhage (ICH), yet blood pressure (BP) control after ICH remains suboptimal, particularly among disadvantaged racial and socioeconomic groups. To what extent post-ICH BP disparities reflect pre-existing hypertension inequities versus differences in post-ICH management is unknown. We examined disparities in BP control before and after ICH, assessed whether post-ICH care differentially improves BP across groups and whether post-ICH disparities persist after accounting for pre-existing BP differences. MethodsWe performed a case-only study in the All of Us Research Program, identifying ICH survivors using electronic health record diagnosis codes. Mean systolic BP was calculated for pre-ICH (1-365 days before) and post-ICH (30-365 days after) windows. Neighborhood deprivation tertiles were calculated using 3-digit ZIP codes. The primary outcome was uncontrolled BP ([&ge;]140 mmHg). Logistic regression estimated odds of uncontrolled BP, and mediation analysis estimated the proportion of post-ICH disparities explained by pre-ICH BP. ResultsAmong 2,226 ICH survivors (mean age 60; 50.6% female), 1,760 had pre-ICH and 1,852 had post-ICH BP data. Uncontrolled BP was more common in Black than White survivors both pre-ICH (38.9% vs 21.4%; p<0.001) and post-ICH (34.3% vs 16.3%; p<0.001), and in Deprived versus Privileged neighborhoods post-ICH (23.7% vs 15.8%; p<0.001). In adjusted models, Black race (OR 3.51; 95% CI 2.55-4.83; p<0.001) and Deprived neighborhoods (OR 1.38; 95% CI 1.00-1.91; p=0.048) were associated with uncontrolled post-ICH BP. Among survivors uncontrolled before ICH, 67% of White but only 45% of Black survivors achieved control afterward (p=0.001). Adjusting for pre-ICH BP control status only modestly attenuated the Black-White disparity (OR 4.05 to 2.95; P<0.001). In mediation analyses, pre-ICH BP explained only 27% of the racial (P<0.001) and 26% of the deprivation (P=0.014) disparity. ConclusionsRacial and socioeconomic disparities in BP control persist after ICH, but most post-ICH disparities are not explained by pre-existing inequalities. More advantaged populations achieve greater BP improvement, suggesting effective post-ICH management exists but does not reach all patients equitably. Targeted interventions addressing barriers to post-ICH BP control in disadvantaged populations may substantially reduce persistent disparities.

Background: Resting electrocardiogram (ECG) are associated with heart failure (HF) events, even though it is not currently recommended in risk assessment. Objective: To examine the association between ECG abnormalities and incident HF events according to the 2023 PREVENT HF equation. And identify a subgroup of individuals who are misclassified as being at low risk. Design: Secondary data analysis from the REasons for Geographic And Racial Differences in Stroke (REGARDS) prospective cohort, including study participants without baseline HF. Exposure: ECG abnormalities were classified by Minnesota Code (MC) as normal, only minor, or any major abnormality at baseline (2003-2007). Outcome: Participants were followed for expert adjudicated incident HF hospitalizations/ deaths through December 2021. Results: Among 20,923 participants (mean age at baseline 63.6 years, 53.7% female), 26.0% of the sample was classified as low risk (<3%), 17.5% as borderline risk (3-<5%), 27.5% as intermediate risk (5%-<10%), and 29.0% as high risk (10%). Compared to those without ECG abnormality, the adjusted HR for incident HF was 1.56 (95% CI 1.35-1.80) for any minor abnormality and 2.56 (2.18-3.00) for any major abnormality. 43.5% of the population were in the less than 5% risk by PREVENT among whom 45.8% had any ECG abnormalities. The fully adjusted HR for only minor ECG abnormalities in the <3% was 1.47 (95% CI 0.72-3.01), and the fully adjusted HR for any major ECG abnormality was 5.22 (95% CI 2.42-11.30). In the borderline risk group, the fully adjusted HR for only minor ECG abnormalities was 1.37 (95% CI 0.89 - 2.11), and the fully adjusted HR for any major ECG abnormality was stronger than the HR in the intermediate and high-risk groups; 3.05 (95% CI 1.85 - 5.03). Conclusion: ECG abnormalities were common and associated with HF events across all PREVENT risk groups, especially in the low/borderline risk groups with major ECG abnormalities.

BackgroundIndividuals with spinal cord injury (SCI) experience accelerated atherosclerotic cardiovascular disease that is not fully explained by traditional risk factors. Endothelial dysfunction is a key mechanism in atherosclerosis. We tested the hypothesis that endothelium-dependent vasodilation is impaired in adults with SCI and is due, at least in part, to oxidative stress. MethodsTwenty-four adults (age:19-58 yr) free of overt cardiometabolic disease were studied: 12 non-injured adults (9 M/3 F) and 12 adults with chronic SCI (8 M/4 F; time since injury 1.5 - 25 years). Forearm blood flow was determined (FBF; via strain-gauge plethysmography) in response to intra-arterial infusion of acetylcholine and isoproterenol in the absence and presence of the antioxidant vitamin C as well as the FBF response to sodium nitroprusside. ResultsAdults with SCI demonstrated significantly lower vasodilator response to acetylcholine (from 4.1{+/-}0.6 to 10.7{+/-}2.6 mL/100 mL tissue/min vs 4.1{+/-}1.1 to 15.7{+/-}3.4 mL/100 mL tissue/min) and isoproterenol (4.0{+/-}0.6 to 11.2{+/-}2.2 mL/100 mL tissue/min vs 4.3{+/-}1.0 to 15.0{+/-}2.6 mL/100 mL tissue/min) compared with non-injured adults. FBF response to sodium nitroprusside was not significantly different between the groups. Co-infusion of vitamin C significantly increased the vasodilator response to acetylcholine (~45%) and isoproterenol (~25%) in the adults with SCI to levels comparable with non-injured adults. ConclusionsChronic SCI is associated with endothelial-dependent vasodilator dysfunction. Impaired vasodilation across two distinct endothelial agonists suggests that chronic SCI is associated with endothelial dysfunction not confined to a specific receptor or intracellular signaling pathway. Moreover, oxidative stress is a contributing factor underlying SCI-related endothelial vasodilator dysfunction. NCT06443151 CLINICAL PERSPECTIVEO_LIThe novel finding of this study is that individuals with SCI demonstrate impaired endothelial vasodilator function in absence of traditional cardiovascular risk factors. C_LIO_LIOxidative stress is a contributing factor to SCI-related endothelial vasodilator dysfunction. C_LIO_LIFuture studies are needed to determine the efficacy of therapeutic interventions, either lifestyle or pharmacologic, in improving endothelial function in order to mitigate the elevated ASCVD risk after SCI. C_LI

BackgroundNeighborhood social vulnerability may shape cardiovascular health (CVH), but its association with Lifes Essential 8 (LE8), and whether changes in vulnerability track with changes in CVH during midlife, are unclear. We examined cross-sectional and longitudinal associations of the Social Vulnerability Index (SVI) with LE8 and assessed differences by SVI domain, LE8 component, race, and sex. MethodsWe analyzed CARDIA participants at Year 15 (Y15; 2000-2001; n = 3,168; mean age 40 years) and Year 30 (Y30; 2015-2016; n = 2,267; mean age 55 years). Residential addresses were geocoded and linked to 2000 and 2016 SVI. Participants were stratified by SVI quartiles. CVH scores were calculated from LE8 metrics (range 0-100; higher is better CVH), excluding sleep. Using multivariable linear regression adjusted for age, sex, race, and educational attainment, we estimated LE8 differences across SVI quartiles and associations of 15-year SVI change/residential mobility with change in LE8. Cox models estimated incident CVD associations. ResultsHigher SVI was associated with lower LE8 at both exams. Adjusted Q4 vs Q1 differences in overall LE8 were -5.34 points (95% CI, -6.90 to -3.78) at Y15 and -4.60 points (95% CI, -6.51 to -2.69) at Y30. Among the four SVI domains, SES and household characteristics drove most of the disparity in LE8 scores (Y30 Q4 vs. Q1: SES {Delta} = -6.98; household {Delta} = -6.56 points). Component-level differences across quartiles of SVI were largest for nicotine exposure at Y15 (-13.09 points) and physical activity at Y30 (-13.09 points). Changes in SVI and residential mobility were not significantly associated with change in LE8. ConclusionHigher social vulnerability was associated with significantly lower CVH. Socioeconomic and household factors, along with behavioral gaps in nicotine exposure and physical activity, may be key targets for community-level interventions to improve cardiovascular health equity.

Patients with Fontan circulation face evolving risk for cardiovascular morbidity and mortality, yet the interplay between cardiac function, vascular properties, and circulating proteins is incompletely defined. We hypothesized that biochemical biomarkers and multimodal cardiovascular profile differ significantly between Fontan patients and controls, and that selected markers may serve as predictors of reduced single ventricle function. We conducted a prospective observational study at a tertiary pediatric heart center including 31 individuals with Fontan circulation and 52 matched controls. Cardiac function was assessed by echocardiography; vascular phenotyping included carotid intima-media thickness, central and peripheral blood pressure, augmentation index corrected for heart rate, carotid-femoral pulse wave velocity, aging index, and reactive hyperemia index. Compared to controls, the Fontan group had increased pulse wave reflection and central systolic pressure as well as decreased echocardiographic markers of systolic and diastolic function, while pulse wave velocity and other vascular parameters were not significantly different between the groups. Levels of 92 circulating cardiovascular biomarkers were quantified in a subset of 25 of the Fontan cohort and 81 controls using a proximity extension assay. Twenty-two biomarkers differed significantly in the Fontan group compared to controls, including FGF23, REN, HAOX1, and IL17D. Levels of several of these biomarkers correlated with patient age. Most importantly, HAOX1 (a peroxisomal oxidase linked to redox metabolism) and FGF23 (a bone-derived hormone regulating phosphate and vitamin D homeostasis) correlated negatively with ejection fraction within the Fontan group. By contrast, BNP was not associated with cardiac function in the Fontan group. None of the biomarkers correlated with central arterial parameters. In summary, central arterial hemodynamics and biomarkers such as FGF23 and HOAX1 may improve monitoring of cardiovascular function in single ventricle patients with Fontan circulation.

The epidermal growth factor receptor (EGFR) family network comprises 4 receptors (EGFR, ERBB2, ERBB3, ERBB4) and numerous ligands, and is dysregulated in many cancers. Since anti-cancer drugs that target these receptors are cardiotoxic for some patients, it is important to understand the network in cardiac cells. Data from the Human Protein Atlas established that EGFR family members and their ligands are differentially expressed in cardiac cell types. Ligand expression was altered in human failing hearts and may contribute to disease. These ligands stimulated extracellular signal-regulated kinases 1/2 (ERK1/2) and Akt in rat cardiomyocytes but to different degrees. Afatinib (at a concentration to inhibit all EGF family receptors) was used to assess the role of the network in a mouse model of cardiac hypertrophy induced by angiotensin II (AngII). Echocardiography and segmental strain analysis demonstrated that afatinib reduced AngII-induced cardiac hypertrophy and caused cardiac dysfunction. This was associated with loss of cardiomyocyte hypertrophy, enhanced cardiac fibrosis, and reduced expression of Nrg1. NRG1 binds to ERBB4 in cardiomyocytes which homodimerizes or heterodimerises with ERBB2. The role of ERBB2 in the cardiomyocyte response to NRG1 compared with EGF was dissected using tucatinib (a selective ERBB2 inhibitor) and mRNA expression profiling. Most, but not necessarily all, of the response to NRG1 required ERBB2 signalling; most, but not all, of the response to EGF did not. Thus, the EGFR family network plays an important role in the heart. Understanding this network may identify therapeutic approaches to avoid cardiotoxicity associated with EGFR family anti-cancer drugs. Clinical perspectivesO_LIAnti-cancer drugs that target the epidermal growth factor receptor (EGFR) family are cardiotoxic for some patients; it is therefore important to understand the network in cardiac cells. C_LIO_LIThe EGFR family and their ligands are differentially expressed in cardiac cells with changes in ligand expression in heart failure; inhibition of all receptors in a mouse model of hypertrophy reduces cardiac hypertrophy and causes cardiac dysfunction with attenuation of cardiomyocyte hypertrophy and enhanced cardiac fibrosis and loss of neuregulin 1 (NRG1); in rat cardiomyocytes, NRG1 signalling to gene expression is largely mediated via ERBB2. C_LIO_LIThe EGFR family network plays an important role in the heart; understanding this network may identify therapeutic approaches to avoid cardiotoxicity associated with anti-cancer drugs targeted against it. C_LI

Objectives To examine the acute effects of a single bout of high-intensity interval training (HIIT) on fetal blood flow distribution during the third trimester of pregnancy. Methods Thirty-four healthy pregnant participants (mean age 31.6 years, standard deviation (SD) 4.1; gestational week 33.8 (SD 0.4) completed eight 30-second high-intensity cycling work-bouts interspersed with 2-minute rest periods. Fetal heart rate (FHR), maternal blood pressure, and Doppler-derived blood flow indices in the middle cerebral artery, umbilical artery and vein, and ductus venosus were assessed before and after exercise. We estimated fetal liver blood flow and the ratio of umbilical vein flow to ductus venosus. Maternal heart rate (HR) and FHR were recorded throughout exercise. Paired t-tests compared pre- and post-exercise values. Results No significant changes were observed in fetal blood flow indices or distribution following exercise. Average maternal HR and FHR during the work-bouts were 158 bpm (SD 16) and 152 bpm (SD 12), respectively. Following HIIT, maternal systolic blood pressure increased by 5 mmHg (95% CI 1 to 8, p=.014), maternal HR by 22 bpm (95% CI 15 to 28, p<.001), and FHR by 13 bpm (95% CI 10 to 17, p<.001). We recorded 16 instances of FHR above normal range during HIIT. Conclusion A single HIIT session in late pregnancy increased maternal blood pressure and HR and transiently elevated FHR but did not affect fetal blood flow indices or distribution. Brief episodes of fetal tachycardia were observed but appeared to be clinically insignificant. Future research should investigate the effects of repeated HIIT exposure during pregnancy.

Background:Stroke continues to be one of the major causes of death and long-term disability worldwide, with a greater impact in low-and middle-income countries. In India, there is limited evidence examining stroke burden and its changes over time and across regions. Therefore, we aimed to assess the burden of stroke in India from 1990 to 2023 using the latest data from the Global Burden of Disease (GBD) Study, along with projections up to 2035. Methods:We used estimates from the GBD 2023 study to examine stroke incidence, prevalence, mortality, and disability-adjusted life years (DALYs) in India from 1990 to 2023. Age-standardized rates were analyzed to understand how these measures have changed over time. We also conducted state-level analyses to explore regional differences in stroke burden. The contributions of all major modifiable risk factors were assessed using population-attributable fractions. In addition, we projected future trends in stroke burden up to 2035. Results:From 1990-2023, the percentage change in overall stroke burden in India showed minimal variation across key indicators. Incidence remained largely stable (0.00%[-0.04 to 0.05]), while prevalence showed a slight increase(0.06%[0.03 to 0.10]). Mortality (-0.11%[-0.36 to 0.20]) and DALYs (-0.17%[-0.38 to 0.12]) demonstrated modest declines over the study period. Notable regional disparities were evident, with states such as Chhattisgarh, Assam, and Jharkhand bearing the highest burden. High systolic blood pressure remained the leading risk factor in 2023, contributing the largest share of stroke-related deaths, followed by dietary risks, air pollution, tobacco use, and high body mass index. Future projections indicate that by 2035, stroke prevalence is likely to increase, while incidence, mortality, and DALYs are expected to show only modest changes. Conclusions: Stroke remains a major and growing public health challenge in India with a continuing increase in burden despite slight improvements in age-standardized rates over time. Addressing this challenge will require stronger prevention efforts, better control of key risk factors, and focused strategies to reduce regional disparities in stroke burden nationwide.

Background Elevated resting heart rate (RHR) predicts mortality in older adults, primarily through cardiovascular disease (CVD). Prior cohort evidence suggests that RHR also predicts mortality in younger adults, but whether this association operates through cardiovascular or non-cardiovascular pathways has not been directly tested. Methods and Results We analyzed 3291 adults aged 20 to 49 years from NHANES 1999-2004 linked to mortality data through 2019 (median follow-up, 17.8 years; 120 deaths). RHR and heart rate reserve (HRR) were modeled per 10-bpm increment using Cox regression adjusted for demographic, lifestyle, and comorbidity covariates. Each 10-bpm RHR increase was associated with higher all-cause mortality (hazard ratio [HR], 1.26; 95% CI, 1.07-1.50; P=.007), driven by non-CVD mortality (HR, 1.28; 95% CI, 1.07-1.55; P=.009) rather than CVD mortality (HR, 1.15; 95% CI, 0.77-1.71; P=.51). A behavioral/external composite (accidents and NCHS residual causes, including suicide and liver disease) reached significance (HR, 1.35; P=.02), whereas a disease-oriented composite did not (P=.20). The association was absent before age 35 (HR, 0.98; P=.88) but pronounced at ages 35-39 (HR, 2.60; P=.001). HRR was not associated with any outcome. Conclusions In young US adults, elevated RHR predicted mortality through non-cardiovascular rather than cardiovascular pathways, concentrated among behavioral and external causes. The association emerged at age 35, below current screening thresholds. HRR under submaximal conditions carried no prognostic value. RHR in young adults may reflect global health vulnerability rather than cardiovascular risk alone.

AimMaternal iron deficiency (ID) during pregnancy induces cardiovascular adaptations, including reduced blood pressure and improved cardiac efficiency in hypertensive pregnancy. Iron is essential for mitochondrial function, particularly oxidative phosphorylation, where it serves as a cofactor within electron transfer complexes. Given the high metabolic demands of the maternal heart and irons central role in mitochondrial metabolism, we examined how maternal ID affects cardiac mitochondrial ultrastructure, respiration, dynamics, and redox status in pregnant spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Methods and ResultsFemale SHR and WKY rats were fed iron-replete or iron-restricted diets before and throughout gestation. On gestational day 21, cardiac mitochondrial ultrastructure was assessed by transmission electron microscopy (TEM), respiration by high-resolution respirometry, and the expression of proteins involved in fusion, fission, autophagy, and apoptosis markers by immunoblotting. Antioxidant gene expression was quantified by RT-qPCR. Data were analyzed by two-way ANOVA with Holm-Sidaks post hoc test. Maternal iron restriction reduced hemoglobin levels in both strains. TEM revealed enlarged, morphologically heterogeneous mitochondria with reduced and disrupted cristae architecture in ID dams of both strains. Iron restriction reduced succinate-supported respiration and tended to reduce NADH-supported respiration, in both strains. SHR dams exhibited reduced fusion signalling, reflected by a lower L-OPA1:S-OPA1 ratio. MFN1 expression was reduced by ID in both strains, whereas MFN2 expression was lower in SHR and further reduced by ID. In contrast, DRP1 phosphorylation increased selectively in ID-WKY dams. Iron restriction increased LC3-II:I ratio and BNIP3 in SHR, and increased PINK1 in both strains, while Parkin and p62 were unchanged. Antioxidant gene expression increased in ID-SHR but decreased in ID-WKY dams. Despite these alterations, markers of oxidative damage and apoptosis were unchanged by iron restriction. ConclusionMaternal ID induces marked remodeling of myocardial mitochondrial ultrastructure and selectively constrains iron-dependent respiration in hypertensive pregnancy without overt oxidative damage or apoptosis. These mitochondrial alterations occur alongside previously observed reductions in blood pressure and improved cardiac efficiency, suggesting favorable hemodynamic adaptations may coexist with underlying bioenergetic constraints in the maternal heart. Translational PerspectiveMaternal iron deficiency anemia (IDA) may alter the course of hypertensive pregnancy in ways not evident from hemodynamic indices alone. Here, IDA was associated with abnormal myocardial mitochondrial ultrastructure, selective reductions in respiratory capacity and stress response pathways, despite previously observed improvements in blood pressure and cardiac efficiency. These findings suggest that favourable hemodynamic changes may reflect reduced metabolic demand rather than enhanced bioenergetic capacity. If confirmed in human pregnancy, management of ID in women with underlying hypertension may need closer attention to cardiac metabolic health, as cardiovascular adaptions could coexist with myocardial stress and may vary with anemia severity and duration.

Background. Peripheral artery disease (PAD) may amplify procedural risk during atrial fibrillation (AF) catheter ablation, but dedicated evidence is lacking. We aimed to evaluate the association between PAD and in-hospital outcomes among adults undergoing AF ablation in the National Inpatient Sample (NIS). Methods. We identified inpatient AF ablation hospitalizations in the 2016 through 2020 National Inpatient Sample using ICD-10-PCS procedure codes and a concurrent AF diagnosis. PAD was identified from ICD-10-CM diagnosis codes used in prior claims-based PAD studies. Stabilized inverse probability of treatment weighting based on the propensity score was used to balance baseline differences. The primary outcome was in-hospital mortality. Fourteen secondary outcomes and 2 composite end points were prespecified. Results. Among 22,166 AF ablation hospitalizations, 899 (4.06%) involved patients with PAD. Compared with patients without PAD, those with PAD were older and had a substantially greater cardiovascular, renal, and smoking/tobacco comorbidity burden. In-hospital mortality did not differ significantly (1.39% vs 1.06%; aOR, 1.32; 95% CI, 0.66 - 2.64; P= 0.44). PAD was associated with higher odds of major bleeding (aOR, 1.62; 95% CI, 1.17 - 2.24; P = 0.004), vascular or access-site complications (aOR, 1.80; 95% CI, 1.04 - 3.12; P = 0.04), acute kidney injury (aOR, 1.31; 95% CI, 1.05 - 1.64; P = 0.02), and composite major adverse hospital events (aOR, 1.29; 95% CI, 1.05 - 1.59; P = 0.02). Total hospital charges were 13% higher (charge ratio, 1.13; 95% CI, 1.04 - 1.22; P = 0.003). Major bleeding, vascular/access-site complications, cardiac arrest, and composite major adverse in-hospital events remained elevated in sensitivity analysis. Conclusion. PAD was independently associated with higher bleeding risk, vascular or access-site complications, acute kidney injury, and composite major adverse hospital event during AF ablation, identifying a clinically relevant subgroup with elevated periprocedural risk.

Background: Hypertensive disorders of pregnancy contribute substantially to maternal morbidity and mortality, and occur with increased frequency among women with uterine fibroids. Biomarkers involved in oxidative stress and endothelial function, including folate, vitamin B12, vitamin D, and homocysteine, have been studied in relation to hypertensive disorders of pregnancy, but their relationship to fibroid-associated risk has not been well characterized, particularly in racially and ethnically diverse populations. Study Design: This study was a retrospective analysis of the Boston Birth Cohort, a prospective cohort recruited at a large urban medical center. The analytic sample included 722 women with complete data on hypertensive disorder status, uterine fibroid status, and plasma biomarker measurements. Uterine fibroids and hypertensive disorders of pregnancy were ascertained through physician-assigned diagnostic codes and ultrasound report review. Plasma folate, vitamin B12, vitamin D, and homocysteine were measured in maternal or cord blood and analyzed as continuous variables and quartiles. Multivariable logistic regression models were used to estimate independent associations, evaluate interaction terms, and assess joint exposure categories. Results: Of the 722 participants, 12% (86/722) had uterine fibroids and 10% (72/722) had a hypertensive disorder of pregnancy. Plasma micronutrient concentrations did not differ significantly by fibroid status. Women with hypertensive disorders of pregnancy had higher plasma homocysteine concentrations compared with those without (p=0.028). Hypertensive disorders of pregnancy were more common in the lowest folate quartile compared with the highest quartile (p=0.018) and in the highest homocysteine quartile compared with lower quartiles (p=0.031). In joint-effects analyses, higher odds of having a hypertensive disorder of pregnancy were observed among women with both uterine fibroids and low folate compared with women without fibroids and with adequate folate (p=0.027). No significant joint associations were observed for vitamin D, vitamin B12, or homocysteine. Conclusion: In this cohort, the co-occurrence of uterine fibroids and lower folate concentrations was associated with hypertensive disorders of pregnancy. This joint exposure delineates a subgroup that may be clinically relevant for future studies aimed at refining maternal risk characterization and exploring targeted nutritional supplementation strategies.

Introduction Cardiovascular disease (CVD) remains Vietnam's leading cause of mortality, yet no comprehensive national analysis of burden trends and future projections exists. This study characterizes Vietnam's CVD burden from 1990 to 2023 and projects burden through 2050. Methods Using Global Burden of Disease 2023 data, we analyzed CVD prevalence, incidence, mortality, and disability-adjusted life years (DALYs) in Vietnam from 1990 to 2023, stratified by sex and age. Joinpoint regression quantified temporal trends. Decomposition analysis separated contributions of population growth, aging, and epidemiological change. ARIMA modeling, validated against pre-pandemic and COVID 19 periods, projected burden through 2050. Results Despite age-standardized CVD prevalence below global estimates, stroke mortality and DALYs rates exceeded global benchmarks. Age-standardized CVD mortality (ASMR) declined significantly (average annual percentage change [APC]:-1.34%), yet absolute deaths nearly doubled from 121,611 to 223,068. Population aging contributed 140.9% to observed mortality increases while epidemiological improvements averted over 102,000 deaths. Male age-standardized CVD mortality was approximately twice that of females. High systolic blood pressure remained the leading attributable risk factor, while high BMI and alcohol use showed the largest rank escalations. CVD incidence reversed its declining trend during 2019 - 2023 (APC:+0.69%). By 2050, ASMR are projected to decline by 51.0% (218.8 to 107.1 per 100,000 [95%CI: 64.1 - 150.2]), while absolute deaths are projected to increase by 43.4% (206,677 to 296,335 [95%CI: 272,323 - 320,348]). Conclusions Vietnam faces a demographic paradox of improving age-specific outcomes alongside a rising absolute burden driven by population aging, demanding urgent reorientation toward aging-specific prevention, hypertension control, and chronic cardiovascular care.

BACKGROUNDChronic thromboembolic pulmonary hypertension (CTEPH) is a severe and progressive condition characterized by dyspnea and fatigue. Our previous study reported cognitive impairment in pulmonary hypertension (PH) patients. However, balloon pulmonary angioplasty (BPA) capable of alleviating cognitive impairment in patients with CTEPH is largely unknown. METHODSThis was a prospective study involving a total of 131 patients with CTEPH who underwent BPA at the Shanghai Pulmonary Hospital. We collected Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) questionnaires and examined plasma A{beta} and phosphorylated-tau217 (p-tau217) levels to assess the cognitive function of patients with CTEPH between the pre-BPA and post-BPA stages. RESULTSFollowing BPA, patients exhibited improved cognitive performance, accompanied by reduced plasma levels of A{beta}1-42 and p-tau217. After the third BPA session, patients with a mean pulmonary arterial pressure (mPAP) of[&ge;]25 mmHg had significantly lower MMSE and MoCA scores compared to those with an mPAP of <25 mmHg. Linear regression analyses revealed that baseline and post-intervention MMSE or MoCA total scores were significant predictors of cardiac output (CO) levels measured after the last BPA procedure. Logistic regression analyses incorporating pre- and post-BPA clinical parameters identified three independent predictors of baseline cognitive dysfunction: lower educational attainment, higher baseline A{beta}1-42 levels, and elevated baseline p-tau217 concentrations. CONCLUSIONSOur findings suggest promising therapeutic effects of BPA, associated with improvements in cognitive dysfunction and reductions in plasma A{beta}1-42 and p-tau217 levels in patients with CTEPH. NOVELTY AND RELEVANCEO_ST_ABSWhat Is New?C_ST_ABSThis is the first study to demonstrate that balloon pulmonary angioplasty (BPA) improves cognitive function (MMSE/MoCA scores) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). And the first report that BPA reduces plasma levels of A{beta}1-42 and p-tau217-- key Alzheimers disease-related proteins--in CTEPH patients, establishing a peripheral biomarker for CTEPH-associated cognitive impairment. What Is Relevance?Cognitive impairment is common but underrecognized in CTEPH, BPA now addresses both cardiopulmonary and cognitive dysfunction, improving quality of life beyond hemodynamic recovery. Findings support the cardiopulmonary-brain axis in CTEPH: improved pulmonary hemodynamics and oxygenation reduce systemic pathological protein release, benefiting brain function. Clinical/Pathophysiological Implications?Our findings suggest promising therapeutic effects of BPA, associated with improvements in cognitive dysfunction and reductions in plasma A{beta}1-42 and p-tau217 levels in patients with CTEPH.

Background: Patients in socioeconomically disadvantaged neighborhoods face barriers to care. Missing BP documentation may signal gaps in risk-factor management, a crucial component of primary and secondary prevention of intracerebral hemorrhage (ICH). We tested whether neighborhood deprivation was associated with absent electronic health record (EHR) blood pressure (BP) documentation surrounding ICH and whether absent documentation predicted subsequent uncontrolled BP. Methods: We conducted a case-only study within the NIH All of Us Research Program. We included ICH survivors (ICD-10 I61.x, surviving >=1 year) with available ZIP3-based Deprivation Index. Deprivation was categorized as Privileged, Intermediate, or Deprived using cohort-based tertiles. We excluded BP measurements collected by All of Us. Outcomes were (1) absent EHR-derived BP documentation and (2) uncontrolled BP (mean systolic BP >=140 mmHg) during three windows: 1-365 days before ICH; 30-365 days and 1-5 years after ICH. Multivariable logistic regression tested associations adjusting for age, sex, and race/ethnicity. Results: 1,474 ICH survivors were included (mean age 60.1, 50.4% female). Compared to privileged neighborhoods, those living in deprived neighborhoods had higher odds of absent EHR BP documentation in the year prior to ICH (OR 2.10, 95% CI 1.60-2.76; p<0.001), 30-365 days post-ICH (OR 2.82, 95% CI 2.14-3.73; p<0.001) and 1-5 years post-ICH (OR 2.81, 95% CI 2.13-3.71; p<0.001). Absence of EHR BP documentation in the year before ICH predicted uncontrolled BP 30-365 days (OR 1.97, 95% CI 1.36-2.85; p<0.001; N=888) and 1-5 years (OR 1.83, 95% CI 1.24-2.69; p=0.002; N=814) after ICH. Absence of BP documentation 30-365 days post-ICH also predicted uncontrolled BP 1-5 years post-ICH (OR 1.66, 95% CI 1.10-2.50; p=0.017; N=814). Conclusions: Neighborhood deprivation is associated with persistent gaps in EHR BP documentation surrounding ICH, and absent documentation before or soon after ICH predicts subsequent uncontrolled BP. These findings highlight the need for community-level strategies that ensure equitable BP monitoring for socioeconomically disadvantaged populations.

BackgroundDoxorubicin (DOX) causes sex-specific cardiotoxicity. Metabolic impairment is a well-established cardiotoxic effect of DOX treatment that can contribute to other detrimental effects such as increased reactive oxygen species, reduced ATP, inflammation etc. We hypothesized that preserving cardiac metabolism by exercise can attenuate DOX cardiotoxicity. MethodsMale and female C57BL/6J mice at 15 weeks of age were randomly assigned to one of four groups, 1) Control (sedentary), 2) EX (exercised, treadmill running), 3) DOX (doxorubicin at 5 mg/kg/week for 6 weeks), and 4) EXDOX (exercise + doxorubicin). Echocardiography was performed every other week during the 6-week protocol to measure cardiac mechanical function. At the end of the protocol, optical mapping and seahorse analysis were performed to measure electrophysiology and metabolism, respectively. RNA sequencing, cytokine array assay and transmission electron microscopy were also performed to determine sex-specific mechanisms of DOX cardiotoxicity. ResultsDOX reduced stroke volume and left ventricular diameter in males only and exercise did not prevent these effects of DOX. In female mice, DOX prolonged action potential duration (APD) and slowed conduction velocity (CV), and importantly, exercise prevented DOX-induced CV slowing. Exercise-induced cardioprotection against DOX in female mice was associated with preservation of aerobic metabolism and attenuation of inflammation which modulated ion channel gene expression. Specifically, Cacna1c was increased in both DOX and EXDOX females, but not in males and correlated with APD prolongation. Interestingly, despite CV slowing, Gja1 and Scn5a were increased. However, increased Kcnj8 along with metabolic impairment could cause membrane hyperpolarization and underlie CV slowing. ConclusionsDOX cardiotoxicity is sex specific. Mechanical dysfunction is more prevalent in DOX-treated males while arrhythmogenic electrical remodeling is more prevalent in DOX-treated females. Exercise therapy during DOX did not prevent DOX induced mechanical dysfunction in male hearts but attenuated electrical remodeling in females by preserving metabolism and attenuating inflammation.

Background: Most approaches to suicide risk assessment consider clinical conditions as independent risk factors, potentially overlooking prognostic information in the order in which conditions accumulate. We applied temporal sequence mining to linked claims and mortality data to identify ordered clinical diagnostic trajectories associated with suicide death. Results: The cohort included 3 647 059 insured Maryland residents aged 10 years or older with available claims records in the Maryland Suicide Data Warehouse from January 1, 2016, to December 31, 2020, among whom 768 suicide deaths were ascertained through medical examiner linkage. Sequential pattern mining of ICD-10-CM diagnoses grouped into Clinical Classifications Software Refined categories identified 89 221 candidate sequences, of which 1 816 remained significantly associated with suicide death in time-varying Cox models. Adjusted hazard ratios (AHRs) ranged from 2.4 to 134.1. Two-thirds of significant trajectories ended in physical conditions, and approximately half crossed from psychiatric to physical endpoints. Among suicide decedents, 62% were exposed to at least 1 significant sequence (median, 16 per case); median sequence duration was 18.7 months, and median time from completion to death was 13.1 months. In landmark analyses, among patients with depression who later developed suicidal ideation (n = 26 356), the path through anxiety, then anemia, was associated with higher risk (AHR, 4.6; 95% CI, 2.2-9.5), whereas the anxiety-only path was not (AHR, 1.3; 95% CI, 0.8-2.1). Among patients with anxiety who later developed hypertension (n = 149 215), the path through history of self-harm was associated with higher risk (AHR, 32.0; 95% CI, 16.6-61.6). Associations were generally consistent across sex and age. Conclusions: Temporal ordering of clinical conditions may carry prognostic information for suicide death. Clinical trajectories incorporating physical illness within psychiatric sequences identified higher-risk groups. These findings suggest that opportunities for risk detection may extend beyond psychiatric settings and that suicide risk signals may be fragmented across care settings and not apparent within isolated encounters.