American Journal of Physiology-Heart and Circulatory Physiology

Background | Angina with nonobstructive coronary arteries (ANOCA) is a heterogeneous condition encompassing distinct endotypes representing different underlying pathophysiological mechanisms. Endothelial dysfunction is considered a central hallmark of ANOCA. However, studying patient-derived endothelial cells (ECs) remains challenging due to the limited availability of disease-specific endothelial samples. We therefore aimed to assess the feasibility of isolating and culturing ECs from catheterization material obtained during routine coronary function testing in ANOCA patients. Methods | Catheterization material was collected from 79 ANOCA patients (84% female, age 58{+/-}10 years) undergoing coronary function testing. ECs were isolated, expanded and characterized using immunostaining, flow cytometry, gene expression profiling and functional assays. Results | EC isolation was successful in 43% of cases and resulted in 34 primary EC cultures that were expanded up to passage 10. Isolation success was independent of clinical or procedural characteristics. Isolated cells exhibited typical EC morphology and expressed EC markers confirmed by immunostaining, flow cytometry and gene expression analyses. EC marker gene expression remained largely stable over passages. However, stress- and defense-related gene expression programs increased over time, while proliferation-related processes decreased. Functional assays demonstrated that the coronary catheterization-derived ECs showed typical properties of wound healing, angiogenesis, activation responses upon stimuli and monocyte adhesion. Conclusions | This study demonstrates the feasibility of isolating and expanding ECs directly from catheterization material collected during routine coronary function testing in ANOCA patients. These patient-derived ECs retain characteristic endothelial features and functionality. This approach offers primary EC cultures to study the mechanisms underlying endothelial dysfunction in ANOCA.

BackgroundSympathetic modulation via the stellate ganglia is increasingly recognized as a contributor to ventricular arrhythmogenesis after myocardial infarction. However, the mechanisms by which autonomic remodeling interacts with chronic infarct substrates to shape arrhythmic vulnerability remain incompletely understood. ObjectivesTo test the hypothesis that left- and right-sided stellate ganglion-mediated SNS modulation differentially reshapes ventricular arrhythmic vulnerability in chronic post-infarcted substrates, and that the RVI detects changes in vulnerability beyond conventional stimulation-based inducibility. MethodsFourteen patient-specific ventricular models with chronic post-infarcted remodeling were reconstructed from imaging data. A total of 336 simulations were performed under different combinations of stellate ganglion modulation, border zone remodeling, and fibroblast density. Arrhythmic vulnerability was quantified using 3D RVI mapping during paced rhythms and compared with conventional stimulation-based inducibility outcomes. ResultsStellate ganglion modulation induced marked, regionally heterogeneous changes in repolarization timing, resulting in lower and more negative RVI values in vulnerable regions. More negative RVI values reflect increased propensity for wavefront-waveback interaction and reentry initiation. Across the cohort, stellate modulation consistently decreased RVImin, even when inducibility outcomes remained unchanged. These findings indicate that SNS modulation can create a substrate more permissive to reentry independently of whether ventricular arrhythmia is triggered during programmed stimulation. ConclusionsStellate ganglion-mediated sympathetic modulation dynamically reshapes ventricular arrhythmic vulnerability in chronic post-infarcted substrates. RVI provides a spatially resolved, vulnerability-based metric that complements inducibility testing by revealing autonomic-substrate interactions underlying arrhythmogenesis Condensed AbstractSympathetic modulation via the stellate ganglia can alter ventricular repolarization and promote arrhythmogenesis after myocardial infarction, yet clinical responses remain heterogeneous. Using 14 patient-specific post-infarction ventricular models, we simulated left- and right-sided stellate modulation across combinations of border zone remodeling and fibrosis (336 simulations). Stellate modulation induced regionally heterogeneous repolarization shortening and reduced RVI values, even when programmed stimulation inducibility remained unchanged. These findings suggest that RVI captures substrate-level vulnerability beyond binary induction testing and may improve mechanistic assessment of autonomic-substrate interactions in chronic infarct substrates.

Background: Among cardiac measures, diastolic parameters demonstrate the earliest and most consistent age-related changes. This can be leveraged to develop a continuous left ventricular (LV) Diastolic Age from routine echocardiographic parameters. Analogous to how epigenetic clocks weight molecular markers against mortality risk, we calibrated Diastolic Age by weighting echocardiographic features against the validated PREVENT-Heart Failure (HF) risk score. Methods: We analyzed 1,952 participants from the Project Baseline Health Study (median age 50 [36-64] years, 54% female). The measure was derived using partial least-squares regression anchored on PREVENT-HF and calibrated within a healthy reference subgroup. External validation was performed in the WASE (n=1,708) and Stanford Cardiovascular Aging (n=313) cohorts. Associations with ASE-defined LV diastolic dysfunction (LVDD), epigenetic clocks, and major adverse cardiovascular events (MACE) were examined. Results: Diastolic Age correlated strongly with chronological age (r=0.78) with robust external validation (WASE r=0.76; Stanford r=0.82; calibration slopes {approx}1.0). It increased progressively across grades of diastolic dysfunction and discriminated LVDD with an AUC of 0.89 (95% CI 0.87-0.92), and was independently associated with hypertension, diabetes, and elevated C-reactive protein. While correlated with the Levine (r=0.76) and Horvath (r=0.41) epigenetic clocks, residual analyses indicated that Diastolic Age captures a distinct cardiac-specific dimension of biological aging. Over median follow-up of 4.2 years, it independently predicted MACE (HR 2.30, 95% CI 1.70-3.18), with accelerated diastolic aging across all age groups among those with events. Discrimination was comparable to ASE-defined LVDD (C-index 0.83 vs. 0.82). Conclusion: Diastolic Age provides a continuous, echocardiography-derived measure of cardiac biological aging that complements categorical diastolic grading and epigenetic aging clocks, and independently predicts cardiovascular outcomes.

Aims: Responses to remote pulmonary artery pressure data vary across programs. We evaluated SMART-HF, a structured pulmonary artery diastolic pressure (PAD)-guided workflow, in a community heart failure cohort. Methods: We retrospectively analysed adults with heart failure and an implanted pulmonary artery pressure sensor managed with SMART-HF. Pulmonary artery diastolic pressure (PAD) was calculated from prespecified 14-day windows at baseline, 90 days, and 6 months. Two hemodynamic management performance indices (HMPI) were prespecified: the 6-Month Delta HMPI (PAD reduction >2 mmHg from baseline) and the 90-Day Target HMPI (PAD [&le;]20 mmHg at 90 days). Exploratory analyses evaluated patients with baseline PAD >20 mmHg. Results: Of 37 patients, 36 had paired 90-day and 29 had paired 6-month windows. Mean PAD decreased from 18.3 +/- 7.0 to 16.1 +/- 6.3 mmHg at 90 days and from 18.8 +/- 6.8 to 15.5 +/- 5.8 mmHg at 6 months (both P < 0.001). The 90-Day Target HMPI was achieved in 26/36 (72.2%) and the 6-Month Delta HMPI in 19/29 (65.5%) [95% CI 45.7-82.1]. In the exploratory subgroup (baseline PAD >20 mmHg), mean PAD changes were -2.9 +/- 3.6 mmHg at 90 days (n = 19; P = 0.002) and -4.9 +/- 4.9 mmHg at 6 months (n = 15; P = 0.002). Conclusions: SMART-HF was associated with improved ambulatory pulmonary artery diastolic pressure control at 90 days and 6 months. Exploratory subgroup findings support further evaluation in patients with elevated baseline pulmonary artery diastolic pressure.

Abstract Background: ST-elevation myocardial infarction (STEMI) is reported to be a leading cause of mortality worldwide. While cardiac troponins are the gold standard for myocardial injury detection but creatine kinase-MB (CK-MB) and total creatine phosphokinase (CPK) retain prognostic use in resource-limited settings. Objective: To evaluate the prognostic significance of admission CK-MB and CPK levels in STEMI patients and to assess their association with hematological parameters for integrated risk stratification. Methods: This cross-sectional study enrolled 15 consecutive STEMI patients from the Punjab Institute of Cardiology, Lahore, during January 2024. Comprehensive laboratory analysis including cardiac biomarkers (CK-MB, CPK, troponin-I, LDH), complete blood count, renal function, serum electrolytes, and metabolic parameters, was performed on admission. Pearson correlation and comparative statistical analyses were also conducted to assess the relationships between cardiac biomarkers and hematological indices. Results: The cohort includes 15 patients (mean age 50.1 +/- 12.2 years; 73.3% male). Cardiac biomarker elevation was prevalent: CK-MB was elevated in 12/15 (80%), CPK was elevated in 12/15 (80%), with concordant elevation in 11/15 (73.3%), which indicates extensive myocardial necrosis. Troponin-I showed the highest elevation rate at 13/15 (86.7%). Hematological abnormalities included anemia (60%), WBC elevation (53.3%), and RBC reduction (40%). Random glucose averaged 150.80 +/- 63.55 mg/dL, with 66.7% highlighted the hyperglycemia. Remarkably, electrolyte balance was preserved in all of the patients (0% sodium, potassium, and bicarbonate abnormalities), indicating maintained homeostasis. Pearson correlation analysis revealed a significant correlation between CK-MB and CPK (r = 0.615, p = 0.0126), while correlations between cardiac biomarkers and hematological parameters were weak (p > 0.05). Risk stratification identified 53.3% of patients as high-risk who required intensive management. Conclusions: CK-MB and CPK demonstrate significant concordance and retain prognostic value in STEMI patients, particularly in resource-limited settings where troponin access may be constrained. While troponin-I remains the most sensitive biomarker, combined assessment of conventional cardiac enzymes supports reliable evaluation of myocardial injury. Hematological parameters reflect systemic response but show limited correlation with cardiac biomarkers.

Background and Aims Despite treatment, patients with established atherosclerotic cardiovascular disease (ASCVD) are at high risk of recurrent events. Existing clinical risk scores for recurrence provide only moderate predictive performance and rely largely on the same conventional risk factors used to predict disease onset. Proteomics is a promising source of new biomarkers but the technologies need focused use cases in order to achieve utility and implementation. We aimed to determine whether plasma proteomics improves prediction of recurrent cardiovascular events beyond established clinical risk models in secondary prevention in a population-scale cohort. Methods Plasma proteomic profiles from ~9,300 participants in the UK Biobank with established ASCVD at baseline were analysed using machine learning methods to derive and evaluate proteomic predictors of recurrent cardiovascular events. The top performing model comprised proteins with non-zero weights (full protein score). Predictive performance of the proteomic predictors, an established clinical risk score (SMART2), and their combination was evaluated across six pre-defined testing datasets representing multiple ethnic and geographic groups. A parsimonious set of proteins with existing clinical-grade enzyme-linked immunosorbent assays (ELISAs) available was then derived. Results The full protein score achieved higher performance for recurrent ASCVD than the SMART2 risk score across all ethnic and geographic subgroups (mean C-index 0.743 vs 0.653). Adding the full protein score to SMART2 improved discrimination, with the largest increase in White Irish participants ({Delta}C-index, 0.140; 95% CI, 0.074-0.205; P<0.001). However, adding SMART2 to the protein score provided minimal additional value. The parsimonious score preserved most of the discrimination of the full protein model with C-indices of the recurrent ASCVD risk model comprising age, sex and the parsimonious protein score being nearly identical to the full protein model in the largest testing set (0.723 vs 0.728 for White British in England and Wales). The parsimonious protein score showed a marked gradient of risk with the top, middle and bottom quintiles showing 10-year recurrent ASCVD rates of ~27.4%, ~9.6% and ~2.4%, respectively. Conclusions In patients with established ASCVD, plasma protein measurements substantially improved prediction of recurrent events beyond conventional clinical risk factors, supporting their potential as a complementary tool to guide secondary prevention of cardiovascular disease.

Background: Late gadolinium enhancement (LGE) quantification by cardiovascular magnetic resonance is central to risk stratification in hypertrophic cardiomyopathy (HCM), yet conventional techniques require contour tracing and region-of-interest (ROI) placement, which may reduce reproducibility and increase analysis time. We developed a novel visual standardized approach, the Visual Standardized Quantification of LGE (VISTAQ), that does not require myocardial contouring, arbitrary ROI positioning, or dedicated post-processing software. Methods: In this multicenter, multivendor retrospective study, LGE images from 400 patients (100 prior myocardial infarction, 250 HCM, 50 other non-ischemic heart diseases) were analyzed. VISTAQ subdivides each myocardial segment into transmural mini-segments and classifies LGE visually using predefined criteria, expressing global LGE burden as the percentage of positive mini-segments. Reproducibility was assessed in 250 patients across different observer expertise levels using intraclass correlation coefficients (ICC) and Bland?Altman analysis. In 100 HCM patients, VISTAQ was compared with conventional methods (mean+2SD, +5SD, +6SD, FWHM, visual thresholding). Prognostic performance was evaluated in 250 HCM patients over a median 5-year follow-up. Results: VISTAQ demonstrated excellent intra- and inter-observer reproducibility (ICC up to 0.98 and 0.97, respectively), consistent across disease subtypes. Compared with conventional techniques, VISTAQ showed similar ICC to FWHM but significantly lower net and absolute inter-observer differences (median absolute difference 1.3%). Mean+2SD markedly overestimated LGE, whereas mean+6SD slightly underestimated LGE compared with VISTAQ, mean+5SD, FWHM, and visual thresholding. Analysis time was substantially shorter with VISTAQ (median 105 vs. 375 seconds, p<0.0001). During follow-up, 21 hard cardiac events occurred in HCM population. An LGE threshold >10% predicted events with higher accuracy using VISTAQ (AUC 0.90; sensitivity 85%; specificity 94%) compared with mean+6SD (AUC 0.75; sensitivity 57%; specificity 93%). Conclusions: VISTAQ provides highly reproducible, time-efficient LGE quantification without dedicated software and demonstrates non-inferior prognostic discrimination in HCM compared with conventional threshold-based techniques.

BackgroundPathogenic desmin (DES) variants have been implicated in early-onset atrial disease, yet the mechanisms by which desmin dysfunction alters atrial structure and function remain unclear. Desmin anchors the cytoskeleton to the nuclear envelope (NE) through the linker of nucleoskeleton and cytoskeleton (LINC) complex, suggesting that defects in this network may drive atrial cardiomyopathy. MethodsHuman desmin wild-type (WT) and the pathogenic variants p.S13F, p.N342D, and p.R454W were stably expressed in HL-1 atrial cardiomyocytes. Desmin organization, nuclear morphology, LINC-complex integrity (nesprin-3, lamin A/C), and DNA leakage, assessed by cyclic GMP-AMP synthase (cGAS), were analyzed by confocal microscopy. Action potential duration (APD) and calcium transients (CaT) were measured optically. Human myocardium samples from DES variant carriers were analyzed for validation. Data-independent acquisition (DIA) mass spectrometry profiled atrial proteomes from desmin-network (DN) and titin variant carriers and controls. The heat-shock proteins (HSPs) inducer geranylgeranylacetone (GGA) was evaluated for rescue effects. Resultsp.N342D caused severe filament-assembly defects with prominent perinuclear aggregates, whereas p.S13F showed mixed phenotypes with frequent perinuclear aggregates, and p.R454W largely preserved filamentous networks. p.N342D and p.S13F induced nuclear deformation with disrupted nesprin-3 and lamin A/C distribution. In p.N342D and p.S13F, desmin aggregates drove focal lamin A/C accumulation, nuclear envelope (NE) rupture, DNA leakage, and increased cGAS activation. DES variants significantly shortened APD20/90 and reduced CaT amplitude, indicating pro-arrhythmic electrical remodeling. Atrial proteomics revealed a DN-specific signature enriched for cytoskeletal, NE, intermediate filament, and chaperone pathways, consistent with the structural injury observed in vitro. GGA prevented desmin aggregation and nuclear morphology changes, and mitigated APD shortening in p.N342D-expressing cardiomyocytes. Human myocardium from DES variant carriers showed concordant desmin aggregation and polarized lamin A/C distribution. ConclusionsDES variants induce a desmin-dependent atrial cardiomyopathy characterized by cytoskeletal disorganization, disruption of LINC-complex, NE rupture with DNA leakage, and pro-arrhythmic electrophysiological remodeling. These findings provide mechanistic insight into how DN variants promote atrial disease. HSPs induction by GGA partially restores structural and functional integrity, identifying a potential therapeutic approach for desmin-related atrial cardiomyopathy. Clinical perspectiveWhat is new? O_LIPathogenic DES variants induce a previously unrecognized atrial cardiomyopathy characterized by desmin aggregation, and desmin-network (DN) collapse, disruption of the linker of nucleoskeleton and cytoskeleton (LINC) complex, and nuclear envelope rupture with DNA leakage. C_LIO_LIVariants that lead to desmin aggregation (e.g., p.N342D) cause focal lamin A/C polarization, cyclic GMP-AMP synthase (cGAS) activation, and structural injury at the nuclear envelope. C_LIO_LIDES variants produce pro-arrhythmic electrical remodeling, including action potential duration shortening and impaired Ca{superscript 2} handling in HL-1 atrial cardiomyocytes. C_LIO_LIAtrial proteomics from DN variant carriers reveals enrichment of pathways related to cytoskeletal, nuclear envelope, intermediate filament, and chaperone, supporting a desmin-dependent remodeling program. C_LIO_LIThe heat-shock protein inducer geranylgeranylacetone (GGA) prevents desmin aggregation, restores nuclear morphology, and mitigates electrical and Ca{superscript 2} handling remodeling. C_LI What are the clinical implications? O_LIThese findings establish DN dysfunction as a distinct cause of atrial cardiomyopathy, providing a mechanistic basis for the association between pathogenic DES variants and atrial arrhythmias, including atrial fibrillation. C_LIO_LINuclear envelope rupture and cytosolic DNA leakage represent new mechanistic evidence which links cytoskeletal injury and atrial arrhythmogenesis. C_LIO_LIIdentifying structural vulnerability in DES variant carriers fosters awareness of genetic counseling for atrial disease, enabling early detection and risk stratification. C_LIO_LIThe protective effects of GGA suggest that restoring proteostasis may be a therapeutic strategy for desmin-related atrial cardiomyopathy and potentially other genetic atrial diseases. C_LI Novelty and significance statementO_ST_ABSNoveltyC_ST_ABSThis study identifies a desmin-dependent atrial cardiomyopathy driven by cytoskeletal aggregation, LINC-complex disruption, and nuclear envelope rupture with DNA leakage. We show that pathogenic DES variants are associated with pro-arrhythmic molecular remodeling and that human atrial proteomics confirm nuclear envelope and cytoskeletal injury as core features. Importantly, the heat-shock protein-inducer GGA rescues structural, molecular, and electrophysiological defects, revealing a modifiable pathway in desmin-mediated atrial disease. SignificanceThese findings provide the first integrated mechanistic explanation linking DN variants to atrial cardiomyopathy. By uncovering nuclear envelope rupture and cGAS activation as key drivers of atrial cardiomyopathy, this work expands the molecular framework for inherited atrial disease and highlights proteostasis enhancement as a potential therapeutic strategy for patients carrying DES and related cytoskeletal variants. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/26348559v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1fb0bfborg.highwire.dtl.DTLVardef@cfc00borg.highwire.dtl.DTLVardef@1493578org.highwire.dtl.DTLVardef@1556b61_HPS_FORMAT_FIGEXP M_FIG C_FIG

Background and Aims: Acute myocarditis (AM) is a T cell-mediated myocardial disease with clinical manifestations ranging from mild chest pain to cardiogenic shock. Reliable biomarkers to stratify patients and guide therapy are currently lacking. In particular, the extent of the dysregulation of inflammatory pathways, and the impact on myocardial dysfunction, remain elusive. Methods: Serum analyses were performed in prospectively recruited AM patients (n = 103) from two independent cohorts. Multimodal data integration combining profiling of cytokine and chemokine dysregulation with clinical biomarkers was used to define clinical phenotypes with distinct inflammatory signatures. Machine-learning and regression models were applied to determine biomarkers that indicate clinical severity. Results: Immuno-proteomic profiling revealed conserved inflammatory patterns across AM cohorts, dominated by T cell-related cytokines and chemokines. In addition, AM patients showed dysregulation of fibroblast-derived cytokines, including hepatocyte growth factor (HGF), bone morphogenic protein 4 (BMP4) and the BMP4 inhibitors Gremlin-1 (GREM1) and Gremlin-2 (GREM2). Data integration and unsupervised clustering revealed two immuno-clinical phenotypes, linking T cell activation and fibroblast dysregulation to disease severity. Machine learning-based analysis identified CXCL10, GREM2 and LVEF as critical parameters for stratifying disease severity. Conclusions: These findings highlight a systemic T cell activation signature as diagnostic hallmark of AM. In addition, dysregulation of fibroblast-derived tissue cytokines serves as an indicator for distinct immuno-clinical phenotypes in myocardial inflammatory disease. Thus, the clinically relevant link between T cell-driven immune activation, myocardial inflammation and fibroblast-driven remodelling provides a versatile set of parameters to identify severe manifestations of AM.

BACKGROUND: Guidelines recommend aortic valve replacement (AVR) in patients with severe aortic regurgitation (AR) based on progressive changes in left ventricular (LV) function or size. We aimed to reassess the clinical relevance of current guideline recommendations pertaining to traditional echocardiographic measurements in routine practice. METHODS: Retrospective analysis of patients with severe AR who underwent serial echocardiographic follow-up over at least 18 months. The composite outcome was symptom-driven AVR, acute heart failure hospitalization, or death. We used a joint modelling approach to handle within-subject correlation and censoring. RESULTS: The cohort consisted of 140 patients, with a median follow?up of 93 months (interquartile range 58?130). LV end-systolic (LVESD) and fractional shortening (FS) showed a small but statistically significant longitudinal trend, while LVEDD did not. Changes in all three parameters in parallel joint models adjusted for age and gender were consistently associated with increased risk of the composite event. Each 1?mm increase in LVESD and LVEDD was associated with a 6% and 5% increase in risk, respectively; each 1% decrease in FS corresponded to a 12% increase in risk. Only 8 (5.7%) of patients were predicted to exceed the guideline-recommended LVEDD threshold of 65 mm over 10 years. Age at onset was also a significant risk factor, with each decade increasing risk by 65% for each of the three parallel joint models. CONCLUSIONS: LV parameters show modest changes over time, despite holding strong prognostic value in patients with severe AR. LVEDD, while associated with overall risk, does not predictably or significantly dilate over time in most patients. AVR decisions should be based on comprehensive clinical and volumetric assessment rather than waiting for simple linear progression to guideline cutoffs.

STRUCTERED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSCoronary artery bypass graft (CABG) is a widely performed procedure for coronary artery disease (CAD), yet its association with Impaired Cognition (IC), i.e., mild-cognitive impairment or all-cause dementia, while accounting for APO ({varepsilon}) genotype, remains unclear. METHODSWe analyzed AllofUS participants with CAD (Age[&ge;]60 yrs) from 2017-2023. We defined CAD as a history of angina/myocardial infarction/chronic ischemic heart disease or having percutaneous coronary intervention/CABG, and IC as mild cognitive impairment or all-cause dementia using ICD/SNOMED codes. We performed logistic regression analyses to assess the association between CABG and IC, adjusting for clinical factors (age, sex, hypertension, diabetes, hyperlipidemia, depression, stroke, smoking, alcohol use, statin/antihypertensive/antidiabetic use), social determinants (self-reported race/ethnicity, income, employment), and APO ({varepsilon}) genotypes. We further performed stratified analyses across APO ({varepsilon}) genotypes ({varepsilon}2/{varepsilon}2, {varepsilon}2/{varepsilon}3 {varepsilon}3/{varepsilon}3, {varepsilon}2/{varepsilon}4, {varepsilon}3/{varepsilon}4, {varepsilon}4/{varepsilon}4). We defined significance at p [&le;] 0.05. RESULTSWe included 22,349 with CAD and identified 908 with IC after CAD till 2023. 40% were females, 70% were White, 12% were Black, and 9% were Hispanic. The proportion of IC was higher (5.1% vs 3.5%, p=1e-08) in CABG (n=8,135) vs non-CABG (n=14,214). After adjusting for clinical factors, social determinants, and APO ({varepsilon}) genotypes, CABG (1.23;1.06-1.41, p = 0.005) was associated with IC. In APO ({varepsilon}) stratified analysis, the association of CABG with IC was strongest in the APO {varepsilon}2/{varepsilon}3 group (1.91;1.21-3.02, p = 0.005). CONCLUSIONIn the AllofUS cohort, we observed an association between CABG and IC in CAD participants, with the strongest association in the APO {varepsilon}2/{varepsilon}3 group. Key MessageO_ST_ABSWhat is already known on this topicC_ST_ABSCoronary artery disease (CAD) and Impaired Cognitive (IC) disease, i.e., mild cognitive impairment and all-cause dementia, share genetic, sociodemographic, and clinical factors, including cardiovascular conditions like coronary artery bypass grafting (CABG) procedure. What this study addsWe observed an association between CABG and IC in CAD participants after adjusting for sociodemographic, clinical factors, and APO ({varepsilon}) effects. Further, when CAD participants were stratified across APO ({varepsilon}) groups, CABG was significantly associated with IC in the APO {varepsilon}2/{varepsilon}3 group. How this study might affect research, practice or policyOur observations highlight the role of APO ({varepsilon}) genotype evaluation in CAD patients for IC risk assessment.

ObjectiveTo explore the interpretation of unexpected results from a randomized controlled trial (RCT). Study Design and SettingAdjunctive frequentist (power and type{square}M error) and Bayesian analyses were performed on a recently published RCT reporting a statistically significant relative risk reduction (p <0.01) for caffeinated coffee drinkers compared with abstinence on atrial fibrillation (AF) recurrence. Individual patient data for the Bayesian survival models were reconstructed from the RCT published material and priors informed by the RCT power calculations. ResultsThe original RCT design had limited power for realistic effect sizes, increasing susceptibility to type{square}M (magnitude) error. Bayesian analyses also tempered the benefit for caffeinated coffee implied by standard statistical analysis resulting in only modest probabilities of clinically meaningful risk reductions (e.g., hazard ratio < 0.9 of 88% or a risk difference > 2% of 82%). ConclusionsSupplemental frequentist and Bayesian approaches can provide robustness checks for unexpected RCT findings, providing contextualization, clarifying distinctions between statistical and clinical significance, and guiding replication needs. HighlightsO_LIRandomized controlled trial (RCT) results may be unexpected and challenge prior beliefs C_LIO_LISupplemental frequentist and Bayesian analyses can clarify interpretation of surprising findings C_LIO_LIPower and type{square}M error assessments help evaluate design adequacy for realistic effects C_LIO_LIBayesian posterior probabilities provide additional nuanced insights into contextulaization and clinical significance C_LI

While the need for continuous blood pressure (BP) monitoring in Japan is high, there are no commercially available cuffless devices for personal daily monitoring use. Fingertip-based sensors are a promising alternative as they eliminate the discomfort of repeated cuff inflation. However, their reliability during winter has been a major technical limitation due to cold-induced peripheral vasoconstriction. This study aimed to address this issue by validating a novel fingertip-based continuous BP monitor used by exercising adults during summer and winter. Eleven community-dwelling older adults (mean age, 73.1 {+/-} 8.8 years) were included in this seasonal comparative study. During exercise, we compared a personal fingertip-based continuous monitor (ArteVu) with a standard oscillometric cuff device (Omron) in summer (mean, 26.5{degrees}C) and winter (mean, 7.4{degrees}C). The study also evaluated the device's accuracy during exercise-induced BP fluctuations and seasonal environmental changes. Awareness of the participants regarding BP management was also assessed using questionnaires. There were strong correlations for systolic BP (SBP) between summer and winter (r = 0.93 in summer; r = 0.88 in winter). Although the mean difference for the SBP was higher in winter than in summer (3.1 {+/-} 11.2 mmHg vs. 0.2 {+/-} 9.4 mmHg), the values remained within a clinically acceptable range for personal monitoring. Notably, 72.7% of participants reported that the ease of using the fingertip-based device significantly increased their awareness and motivation for daily BP management. This study confirms the feasibility of cuffless fingertip-based continuous BP monitoring across different seasons, including in winter. By overcoming the seasonal limitations, this device fills a critical gap in the Japanese health-monitoring market. Our findings support the development of smaller and more portable models, representing a shift from traditional "snapshot" cuff measurements to continuous and integrated lifestyle monitoring for older adults.

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.

Modelling of hemodynamics in the circle of Willis (CoW) depends on vascular segmentation, which may vary based on imaging modality. Computed tomography angiography (CTA) is commonly used in clinic but involves radiation and injection of contrast agents, whereas magnetic resonance angiography (MRA) offers a non-invasive alternative. This study aims to compare CoW morphology and modelled cerebral perfusion pressure of CTA and MRA segmentations, validating if MRA can replace CTA in modelling workflows. CTA and time-of-flight MRA (TOF-MRA) of the CoW was performed in 19 patients undergoing elective aortic arch surgery (67{+/-}7 years, 8 women). The CoW was semi-automatically segmented based on signal intensity thresholding. A TOF-MRA threshold was optimized against the CTA segmentation, using the CTA as reference standard. Computational fluid dynamics (CFD) modelling with boundary conditions based on subject-specific flow rates from 4D flow MRI simulated cerebral perfusion pressure in the segmented geometries. A baseline simulation and a unilateral brain inflow simulation, i.e., occlusion of a carotid, were carried out. Linear mixed models indicated there was no effect of choice of modality on either average arterial lumen area (CTA - TOF-MRA: -0.2{+/-}1.3 mm2; p=0.762) or baseline pressure drops (0.2{+/-}1.9 mmHg; p=0.257). In the unilateral inflow simulation, we found no difference in pressure laterality (-6.6{+/-}18.4 mmHg; p=0.185) or collateral flow rate (10{+/-}46 ml/min; p=0.421). TOF-MRA geometries can with signal intensity thresholding be matched to produce similar morphology and modelled cerebral perfusion pressure to CTA geometries. The modelled pressure drops over the collateral arteries were sensitive to the segmentation regardless of modality.

Objective: Skin sympathetic nerve activity (SKNA) has emerged as a promising non-invasive surrogate measure of sympathetic drive, but its relevant physiological characteristics remain ill-defined. This observational study aims to investigate its regulatory patterns during rest and Valsalva maneuver (VM) in healthy participants. Method: Using a two-layer strategy integrating signal analysis and physiological modelling, we analyzed data recorded from 41 subjects performing repeated VMs. The observational layer includes time-domain feature comparisons using linear mixed-effect models, and time-varying spectral coherence analysis. The mechanistic layer proposes a mathematical model to investigate whether baroreflex and respiratory modulation are sufficient to reproduce the observed HR and average SKNA (aSKNA) dynamics. Main Results: Mean integrated SKNA (iSKNA) showed more significant change than HRV for VM induced effects. We also found mean iSKNA increase during VM varies with BMI and sex. The coherence analysis indicated that iSKNA strongly synchronized with EDR under resting conditions. The proposed model successfully reproduced main characteristics of aSKNA dynamics, yielding a high median Pearson correlation coefficient of 0.80 ([Q1, Q3] = [0.60, 0.91]). In contrast, HR dynamics were only partially captured, with a median PCC of 0.37 ([Q1, Q3] = [0.16, 0.55]). These results likely suggest SKNA provides a more direct representation of sympathetic burst dynamics during VM in healthy subjects. Significance: This study provides convergent evidence that SKNA reflects known autonomic regulatory influences in healthy subjects. These findings strengthen the physiological interpretability of SKNA while clarifying its appropriate use as a practical biomarker of sympathetic function.

Class imbalance in clinical electrocardiogram (ECG) datasets limits the diagnostic sensitivity of automated arrhythmia classifiers, particularly for rare but clinically significant beat types. We propose a three-stage hybrid generative pipeline that combines a spectral-guided conditional Variational Autoencoder (cVAE), a class-conditional latent Denoising Diffusion Probabilistic Model (DDPM), and a Quantum Latent Refinement (QLR) module built on parameterized quantum circuits to augment minority arrhythmia classes in the MIT-BIH Arrhythmia Database. The QLR module applies a bounded residual correction guided by Maximum Mean Discrepancy minimization to align synthetic latent distributions with real class-specific latent banks. A lightweight 1D MobileNetV2 classifier evaluated over five independent random seeds and four augmentation ratios serves as the downstream benchmark. Our findings establish latent diffusion augmentation as an effective strategy for imbalanced ECG classification and motivate further investigation of quantum-classical hybrid methods in cardiac diagnostics.

Background: Deep brain stimulation (DBS) is a treatment option for Parkinson disease (PD). However, the effect of DBS on the arterial pressure (AP) remains unexplored. We aimed to develop an artificial baroreflex system for treating orthostatic hypotension (OH) due to central baroreflex failure in patients with PD. To achieve this, we developed an appropriate algorithm after estimating the dynamic responses of the AP to DBS using a white noise system identification method. Methods: We randomly performed DBS while measuring the AP tonometrically in 3 trials involving 3 patients with PD treated with DBS. We calculated the frequency response of the AP to the DBS using a fast Fourier transform algorithm. Finally, the feedback correction factors were determined via numerical simulation. Results: The frequency responses of the systolic AP to random DBS were identifiable in all 3 trials, and the steady state gain was 8.24 mmHg/STM. Based on these results, the proportional correction factor was set to 0.12, and the integral correction factor was set to 0.018. The computer simulation revealed that the system could quickly and effectively attenuate a sudden AP drop induced by external disturbances such as head-up tilting. Conclusion: An artificial baroreflex system with DBS may be a novel therapeutic approach for OH caused by central baroreflex failure.

Importance: Assessment of cardiovascular health (CVH) during may unmask latent metabolic vulnerability and indicate long-term disease risk. However, the prognostic value of the AHA's Life's Essential 8 (LE8) framework during pregnancy remains uncertain. Objective: To evaluate CVH during using a modified Life's Essential 8 (mLE8) score in association with time to incident cardiometabolic disease. Design: Prospective cohort study with electronic medical record (EMR) surveillance for 7 years postpartum (August 2018-March 2026). Adjusted accelerated time-to-failure models estimated mLE8 associations with incident conditions. Setting: A population-based prenatal cohort recruited from a large academic medical system in South Carolina. Participants: Singleton pregnancies in individuals aged 18 to 44 years without pre-existing diabetes or cardiovascular disease (CVD) Exposures: A 7-component mLE8 score assessed during pregnancy, incorporating hypertensive disorders of pregnancy (HDP), 50-g glucose tolerance test results, pre-pregnancy body mass index, smoking status, sleep adequacy, diet quality, and physical activity. Scores ranged from 0 to 100, with higher scores indicating more favorable CVH. Main Outcomes and Measures: Post-delivery incident cardiometabolic conditions captured through EMRs and classified as chronic hypertensive conditions, chronic metabolic conditions (e.g., dyslipidemia, impaired glucose regulation), and CVD (e.g. cardiac arrest, cardiomyopathy). Time to incident diagnosis was measured in days from delivery. Results: Among 1,225 pregnancies (mean age, 25.0 [5.3] years), 499 incident cardiometabolic events occurred over a median follow-up of 6.2 (2.8) years. Each 10-point higher mLE8 score was associated with a longer time to incident diagnosis of chronic hypertensive conditions (time ratio [TR], 1.26; 95% CI, 1.11, 1.42) and chronic metabolic conditions (TR, 1.20; 95% CI, 1.11, 1.29). Healthier HDP, glucose, BMI, and sleep scores were most strongly associated with longer time to diagnosis of chronic metabolic disease. Results were robust to sensitivity analyses excluding individuals who developed gestational diabetes or HDP. Conclusions and Relevance: In this racially diverse, low-income cohort study of 1,225 pregnancies, better CVH during pregnancy was associated with a longer time to incident post-delivery diagnosis of cardiometabolic conditions. Pregnancy-based CVH assessment may help identify individuals with elevated and emerging cardiometabolic risk who could benefit from early, targeted intervention and enhanced longitudinal surveillance.

Background: Continuous adhesive patch electrocardiographic (ECG) wearables are increasingly prescribed. Patient experience with these devices can influence adherence, but research in this area is limited. This study aimed to explore the perceptions and experiences of patients receiving wearable cardiac monitoring technology as part of their routine care through the lens of treatment burden. Methods: This was a qualitative study with semi-structured phone interviews conducted between February and May 2024. We recruited participants from primary care and outpatient clinics using maximum variation sampling to ensure diversity in sex, ethnicity, and education levels. Interviews were audio-recorded, transcribed, and analysed using reflexive thematic analysis. Results: Sixteen participants (mean age 51 years, 63% female) were interviewed (average duration: 33 minutes). Three themes were developed: 1) ?Experience using the device: Burden vs Ease of Use?, which captured participants? perceptions of how easily they could integrate the device in their daily lives; 2) ?Individual variability in responses to ECG self-monitoring? covered participants? emotional and cognitive response to knowing their heart rhythm was monitored; and 3) ?The care process shapes patient experiences? reflected support preferences during the set-up and monitoring period and the uncertainty regarding timely clinical and device feedback. Conclusions: Patients valued cardiac wearables for facilitating diagnosis and felt reassured knowing they were clinically monitored. However, gaps in information provided to patients seemed to cause anxiety for some participants. These concerns could be mitigated through clearer clinician communication and patient education at the time of prescription.