Hypertension

Background. The imprecision of current metrics to capture the complex genetic admixture and racial identity among Hispanic/Latino individuals in the United States [US] is a concern. We examined the relationship of self-reported race and genetic ancestry with hypertension [HTN] among Hispanics/Latinos. Methods. Cross-sectional study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), including 10,586 Hispanic/Latino unrelated adults. Genetic ancestry: West African [AA], Amerindian [AI], and European [EA]. Self-reported race: White, Black, Native American, or Multiple/Missing (More than one race or Unknown/Not reported/Refused). HTN: systolic (SBP) [≥]130 mmHg, diastolic blood pressure (DBP) [≥]80 mmHg, and/or use of HTN medications. Age- and sex adjusted models were used. Results. Self-reported race was White (38{middle dot}6%), Black (3{middle dot}6%), Native American (4{middle dot}1%), and Multiple/Missing (53{middle dot}7%), with Unknown/Not reported/Refused representing 32{middle dot}7%. Black and White Hispanics/Latinos had the greatest AA (55{middle dot}7%) and EA (69{middle dot}3%) ancestries, respectively. Each 10% AA increase was associated with OR 1{middle dot}15, SBP beta +0{middle dot}9 mmHg, and DBP beta +0{middle dot}7 mmHg. Conversely, each 10% AI increase was associated with OR 0{middle dot}83, SBP beta -0{middle dot}4 mmHg, and DBP beta -0{middle dot}6 mmHg. HTN prevalence was highest among those with Black race or in the highest AA quantile (45{middle dot}6% and 48{middle dot}0%, respectively), and lowest among those with Native American race or in the highest AI quantile (37{middle dot}6% and 26{middle dot}7%, respectively). Conclusion. One-third of Hispanics/Latinos did not self-report race. Black or White self-reporting race did somewhat relate to AA or EA ancestry, respectively. HTN profiles were related to self-reported race and genetic ancestry in this admixed population.

Objectives To validate two computational fluid dynamics (CFD) models derived from computed tomography angiography (CTA) for estimating trans-stenotic pressure gradients, using invasive intra-arterial pressure measurements as the reference standard in patients with renal artery stenosis (RAS). Background We assessed whether non-invasive assessment of the pressure gradient using CFD could be a reliable alternative to intra-arterial measurements for identifying hemodynamically significant RAS. Methods We performed intra-arterial measurements at rest and during dopamine-induced hyperemia to assess the trans-stenotic pressure gradient in 28 patients with RAS. A pre-intervention CTA scan was used to simulate the pressure gradient with a CFD model using a strategy based on Murray's law (CFD-Mu) and cortical volume (CFD-C). The agreement between the simulated and measured pressure gradients was assessed using intraclass correlation coefficients (ICC), Bland-Altman analysis and diagnostic agreement on the presence of a hemodynamically significant stenosis. Results In 20 patients, successful measurements and simulations were obtained. The ICC between measured pressure gradient and the CFD pressure gradient was 0.78 and 0.94 during baseline and 0.86 and 0.72 during hyperemia, for CFD-Mu and CFD-C, respectively. The sensitivity of CFD-Mu and CFD-C was 70% for both models at rest and 100% compared to the hyperemic measurements, whereas the specificity was 90% and 70% at rest and 79% and 72% during hyperemia, respectively. Conclusions The results support the use of individualized CFD simulations for hemodynamic assessment of RAS using CTA as input. The CFD models demonstrated high accuracy for the identification of a hemodynamically significant stenosis.

Background. In Europe, first-trimester combined screening with the Fetal Medicine Foundation (FMF) algorithm identifies women at increased risk of preeclampsia who may benefit from personalized aspirin prophylaxis. However, a substantial proportion of early-onset preeclampsia (EOPE) remains undetected at clinically acceptable specificity. Objective. To evaluate the first-trimester performance of MaiRa for early-onset preeclampsia (EOPE) risk stratification by benchmarking it against FMF screening in the same women, characterizing discordant patient-level classification profiles and exploring potential implementation strategies. Study Design. This secondary case-control analysis was nested within the prospective, multicentre PREMOM cohort [NCT04990141], which enrolled women with singleton pregnancies across 14 tertiary hospitals in Spain. First-trimester MaiRa and FMF risk estimates were evaluated in the same 126 pregnant women, comprising 99 uncomplicated controls and 27 EOPE cases, defined by disease onset before 34 weeks. Discrimination was compared using a stratified paired bootstrap analysis of the areas under the receiver-operating-characteristic curves. Performance was assessed at prespecified clinical thresholds, and detection rates were evaluated at fixed false-positive rates. Universal and contingent MaiRa implementation strategies were also evaluated. Results. MaiRa showed greater first-trimester discrimination for EOPE than FMF combined screening (AUC, 0.974 vs 0.900; P=.040) and consistently achieved higher detection rates across fixed false-positive rates. At false-positive rates of 5% and 10%, MaiRa detected 85.2% and 92.6% of EOPE cases, compared with 44.4% and 70.4% for FMF, respectively. Patient-level analysis demonstrated that MaiRa identified 12 of 27 EOPE cases (44.4%) classified as low risk by FMF; these pregnancies generally exhibited less abnormal conventional first-trimester profiles, including fewer maternal risk factors, lower mean arterial pressure and lower uterine artery pulsatility index, yet 8 of 12 (66.7%) subsequently developed severe EOPE. Exploratory implementation analyses showed that universal MaiRa screening achieved the highest EOPE detection, whereas a contingent strategy using FMF for triage and reflex MaiRa testing reduced molecular testing to 35.7% of pregnancies while maintaining 77.8% sensitivity and 97.0% specificity. Conclusion. MaiRa provided greater first-trimester discrimination for EOPE than conventional combined screening and detected additional pregnancies that later developed severe disease despite less abnormal conventional screening profiles. The findings suggest that maternal plasma cfRNA profiling captures biological alterations not fully reflected by combined first-trimester screening and support further prospective evaluation in an independent, unselected obstetric population. Key words: early-onset preeclampsia; first-trimester screening; cell-free RNA; liquid biopsy; Fetal Medicine Foundation algorithm; combined screening; risk stratification; aspirin prophylaxis.

Background: Severe aortic stenosis is associated with systemic and splanchnic hemodynamic disturbances that may alter gut microbial metabolism and host inflammatory responses. Objectives: We aimed to determine whether TAVI remodels the gut microbiome-derived metabolome and whether post-procedural SCFA dynamics are associated with the inflammatory cytokine response. Methods: We conducted a prospective paired single-center study of patients undergoing elective TAVI at Bern University Hospital. Stool and blood samples were collected before and three months after the procedure. Gut microbial composition was profiled by full-length 16S rRNA sequencing, circulating short-chain fatty acids (SCFAs) by targeted metabolomics, and inflammatory mediators by multiplex cytokine analysis, and integrated with hemodynamic and clinical data. Results: Forty patients were enrolled. Following TAVI, microbial richness declined without significant restructuring of overall community composition. In contrast, circulating SCFA profiles were significantly remodeled, driven by selective reductions in butyrate and isovalerate. A greater decline in circulating butyrate was inversely associated with IL-18 elevation (rho=0.668, p<0.001, n=36), independent of aortic valve calcification burden, hemodynamic improvement, and cardiovascular medications. Baseline isovalerate was nominally associated with 1-month adjudicated adverse events (AUC 0.77; exploratory). Conclusions: TAVI is associated with selective changes in gut microbiome-derived metabolic output rather than broad alterations in microbial community structure. Declining circulating butyrate identifies a gut-metabolite-immune axis linked to IL-18 dynamics and represents a potential biomarker of inflammatory recovery following valve intervention.

Contemporary national-scale electronic health record (EHR) trends in documented acute myocardial infarction (AMI) rates during the high-sensitivity cardiac troponin (hs-cTn) and Type 2 myocardial infarction (T2MI) era are not well characterized. We conducted a serial cross-sectional analysis of U.S. adults aged 18 years in Epic Cosmos from 2016-2024, encompassing 821,859,867 patient-years. Age- and sex-standardized AMI diagnosis rates increased 75.7%, from 343.1 to 602.7 per 100,000 patients. This increase was predominantly driven by T2MI, which increased 133.8% from 99.9 per 100,000 in 2018 to 233.4 per 100,000 in 2024; NSTEMI increased 13.8% while STEMI decreased 4.1%. Annual hs-cTn-tested encounters increased 34.5-fold from 2017 through 2024. The proportion of tested encounters associated with any AMI remained relatively stable after 2021, whereas T2MI continued to increase and surpassed NSTEMI in 2024 as the most frequently diagnosed AMI subtype per hs-cTn-tested encounters. Males had higher absolute AMI rates across all age groups, although relative increases were greater among females. Documented AMI epidemiology shifted substantially toward T2MI during expanding hs-cTn utilization, underscoring the need for evidence-based approaches to the evaluation and management of T2MI.

Background: Fibrosis, characterised by excessive accumulation of collagen type I (COL1), is a common feature of chronic diseases, including liver diseases (LDs), chronic kidney disease (CKD) and heart failure (HF). COL1 degradation products can be detected in urine by proteomics/ peptidomics analyses and may serve as non-invasive biomarkers of fibrosis. We aimed to identify a common molecular signature of fibrosis across these diseases that may ultimately guide interventions to slow disease progression and prevent organ damage. Methods: Using capillary electrophoresis coupled to mass spectrometry (CE-MS), naturally occurring COL1 degradation products (peptides) in the urine of patients with fibrotic disease, LDs (n=127), CKD (n=263) or HF (n=187), were investigated and compared with the same number of matched controls. Disease-associated COL1 peptides were identified separately for each condition, and peptides showing consistent associations across the three diseases were selected to define a common fibrosis signature. A support vector machine model based on the selected peptides was developed and validated in independent cohorts of patients with LDs (n=110), CKD (n=93), HF (n=32) and controls (n=643). Results: We identified a common fibrotic signature consisting of 50 COL1 degradation products, mainly downregulated in fibrosis. A model based on these peptides achieved a strong performance, with an area under the receiver operating characteristic curve (AUC) of 0.935 (95% confidence interval (CI) 0.917-0.953, p<0.0001) in an external validation cohort comprising pooled disease groups (LDs, CKD, and HF) and controls. Performance was maintained in LDs, CKD and HF, with AUCs of 0.917 (95% CI 0.890-0.944, p<0.0001), 0.951 (95% CI 0.931-0.971, p<0.0001) and 0.950 (95% CI 0.903-0.997, p<0.0001), respectively. The model scores were significantly associated with fibrosis stage in LDs (p=0.0097) and with interstitial fibrosis and tubular atrophy in CKD (p=0.045). Conclusion: A model of urinary COL1 peptides captures a shared collagen degradation signature across organs and diseases, enabling the non-invasive assessment of fibrosis irrespective of its origin. As these peptides exclusively reflect collagen degradation, the findings suggest impaired collagen degradation as a driver in fibrosis. Future clinical studies are warranted to evaluate the utility of this model for early fibrosis detection and earlier implementation of anti-fibrotic interventions.

BACKGROUND: Cerebral ischemia following subarachnoid hemorrhage (SAH) has traditionally been considered transient because functional alterations of the cerebral microcirculation are thought to be self-limiting. However, we identified a previously unrecognized vasculopathy, perivascular fibrosis of the cerebral microcirculation (PFCM), characterized by excessive type I collagen deposition after SAH. This study investigated the mechanisms underlying PFCM and its subsequent effects on cerebral hemodynamics. METHODS: In vivo SAH was modeled in mice by autologous blood injection, whereas oxygenated hemoglobin (OxyHb) exposure was used to mimic SAH in vitro. Pericyte-deficient mice (Pdgfr{beta}+/-) and pericyte-specific vestigial-like family member 3 (VGLL3) conditional knockout mice (Vgll3{Delta}PC) were generated. Pericyte contractility was measured by nanoindentation and traction force microscopy. Molecular mechanisms were examined using Western blotting, immunofluorescence, CUT&Tag, RNA-seq, transmission electron microscopy, and molecular docking. PFCM, impaired dilation of the cerebral microcirculation, and cerebral autoregulation were assessed by two-photon imaging, transcranial Doppler with continuous blood pressure monitoring, super-resolution ultrasound imaging, and photoacoustic imaging. RESULTS: After SAH, mice developed long-term cerebral autoregulation dysfunction marked by impaired dilation of the cerebral microcirculation, with the abnormality being most evident within the relatively lower blood pressure range. The marked reduction in PFCM in Pdgfr{beta}+/- mice indicated that pericytes were the principal cellular contributors. Mechanistically, OxyHb-induced cytoskeletal remodeling in vitro increased pericyte contractility and promoted nuclear translocation of SAH-upregulated VGLL3. This was followed by increased genomic occupancy, Col1a1 transcriptional activation, and type I collagen deposition. Pericyte-specific VGLL3 knockout abolished PFCM and, consequently, significantly alleviated long-term cerebral autoregulation dysfunction. CONCLUSIONS: Our findings identify PFCM mediated by pericytic VGLL3 as a novel vasculopathy leading to long-term cerebral autoregulation dysfunction after SAH.

Background. Whether predictors of intraoperative hypotension (IOH) add information beyond the mean arterial pressure (MAP) already displayed on the monitor is contested: selection bias in common evaluation designs inflates apparent performance, and the field has called for comparisons against simple MAP-based references under bias-resistant protocols. Existing predictors also depend on proprietary waveform analysis or pulse-contour monitors, restricting both deployment and external validation. Methods. Using 807 non-cardiac surgery patients from the open VitalDB database, we derived an additive gradient boosting model (one split per tree: a learned shape function per variable, no interactions) from three variables computable from an arterial line alone: current MAP, its drift from the patient's own 20-minute baseline, and the growth of its rolling variance (critical slowing down). Evaluation used patient-level 5-fold cross-validation under a strict protocol - exclusion of the 65-75 mmHg grey zone and of all samples already hypotensive at prediction time - with MAP alone (same learner class) as comparator. The frozen model was then validated, without any refitting, on an independent cohort from another continent (MOVER, University of California Irvine) following a pre-registered plan sealed before external data access. Results. In development the pressure-only model reached AUROC 0.907 vs. 0.884 for MAP alone (Delta AUROC +0.023, 95% CI +0.017 to +0.029) at 5 min, with +0.031 and +0.032 at 10 and 15 min, and good calibration (Brier skill +0.418 vs. prevalence). In external validation on 3,069 patients (442,194 samples, 1-minute charting, event prevalence 5.8%), the advantage not only transferred but was larger than in development: AUROC 0.696 vs. 0.638, Delta AUROC +0.058 (95% CI +0.051 to +0.064), meeting both pre-registered gates. Discrimination transferred; calibration did not (external Brier skill -0.014), requiring local recalibration. In the unrestricted scenario, where samples already at threshold are retained, the advantage collapsed (+0.007), reproducing the selection effect this paper documents. A secondary model adding pulse-contour cardiac output and stroke volume variation improved development discrimination further (Delta AUROC +0.035) but could be externally validated in only 39 patients, because those signals are rarely recorded. Conclusions. The dynamics of arterial pressure itself - drift from a patient-specific baseline and variance growth - carry predictive information beyond its current value, in a fully interpretable additive model that requires only an arterial line, no waveform access and no proprietary hardware. The advantage is confirmed in a pre-registered frozen-model external validation of over three thousand patients, and is largest at coarse recording cadence, where instantaneous pressure is least informative.

Background: Pulmonary arterial hypertension (PAH) is a serious disease with poor prognosis, especially in infants or preterm babies and there is still no optimal treatment for this disease. Noradrenalin (NE) is a vasoactive mediator which is released by sympathetic ganglion. According to previous studies, NE/1-adrenoreceptors is not only in regulating normal physiologic responses, but also in the pathogenesis of PAH. However, the mechanisms of NE in PAH are not fully understood. Methods: Human PASMC (PASMC) was used in this study. Cell viability assay and Wound healing assay were used to evaluate the proliferation and migration of PASMC. Immunoprecipitation and western blots analysis were used to investigate the mechanisms which involved in NE-induced PASMC proliferation. Results: We investigated that NE could induce human PASMC proliferation and migration. Furthermore, we first find that endothelin 1 (ET-1) signaling pathway plays an important role in NE-induced PASMC proliferation. ET1 is a critical molecular which is known for regulating cell growth and migration. We investigated that NE could increase NE-1 secretion, further enhancing ET-1 bind to its receptors. For further clarifying the downstream signals in NE/ET-1 induced PASMC proliferation, we detected the phosphorylation and expression levels of ERK and JNK. Conclusions: By combining the results from ours and previous studies, we believed that JNK/c-jun pathway may play an important role in NE-induced PASMC proliferation. Key Words: Noradrenaline; Pulmonary Arterial Hypertension; Pulmonary Artery Smooth Muscle Cells; Endothelin-1; JNK/c-Jun Signaling.

Rationale: Pulmonary hypertension is defined by pulmonary hemodynamics, but diagnostic and prognostic biomarkers remain limited. Nuclear magnetic resonance (NMR) spectroscopy provides detailed insights, particularly in the lipid metabolism. Objectives: To explore circulating NMR-derived metabolites and lipoprotein-related parameters for their association with pulmonary hemodynamics and to analyse their prognostic properties in pulmonary arterial hypertension (PAH). Methods: Retrospective analysis of a PAH cohort with complete diagnostic workup including right heart catheterization and baseline serum samples, from the prospective GRaz Pulmonary Hypertension-Metabolism (GRAPH-M) registry. Measurements: NMR-derived metabolites and lipoprotein-related parameters were analyzed for their association with clinically relevant parameters of PAH. We defined PHIHDL, a score derived from high-density lipoprotein (HDL) related measures based on their strong association with pulmonary hemodynamics, and evaluated its prognostic value. Results: We included 100 patients with PAH treated at the PH clinic of LKH University Hospital, Medical University of Graz, between 2011 and 2021. Age was 61{+/-}15 years, female/male ratio 2.5, BMI 26 {+/-}7 kg/m2, mPAP 41{+/-}16 mmHg, PAWP 8.8{+/-}3.2 mmHg, PVR 8.0{+/-}4.9 WU, and median survival was 8.0 years. During follow-up, 46 patients died. We identified a cluster of 12 HDL-related measures that showed significant inverse association to pulmonary hemodynamics and derived PHIHDL from the reversed scaled average of these particles. PHIHDL was associated with all-cause mortality after adjustment for age and sex (HR 2.96, 95% CI 1.52-5.70), independent of the clinical risk scores COMPERA 2.0 and REVEAL Lite2. Conclusion: PHIHDL, a pulmonary hemodynamics-based metabolomic score, provides independent prognostic information beyond established risk scores in PAH.

Background. Durable mitral isthmus (MI) block remains challenging in persistent atrial fibrillation (PeAF) ablation. Recent epicardial vein of Marshall (VoM) recordings have shown incomplete MI transmurality and time-dependent conduction recovery after pulsed field ablation (PFA). Whether systematic VoM ethanol infusion (VoM-EI) followed by focal PFA provides stable acute MI block remains unknown. **Objectives.** To assess the incidence, timing, and procedural implications of early MI conduction recovery after systematic VoM-EI followed by focal Sphere-9 PFA. Methods.In this prospective single-center study, 55 consecutive patients undergoing first ablation for symptomatic PeAF with planned MI ablation were screened. VoM-EI was systematically attempted before left atrial access and successfully performed in 51 (92.7%), who constituted the study cohort. Pulmonary vein isolation, roof-line, and MI ablation were performed with the Sphere-9? lattice-tip catheter. After bidirectional MI block, conduction was systematically reassessed during a standardized 30-minute waiting period. Results.Mean age was 70.3 {+/-} 8.2 years, and 36 patients (70.6%) were men. Initial bidirectional MI block was achieved in 50/51 patients (98.0%). During the waiting period, conduction recovered in 9/50 (18.0%; 95% CI, 9.8%-30.8%), at a median of 16 minutes (IQR, 10-20; range, 8?23). Six of 9 patients with recovery (66.7%) required targeted coronary sinus (CS) ablation. Block was restored in all 9, yielding a final block rate of 50/51 (98.0%). Median procedure duration was 82 minutes (IQR, 73-95), with no major complications. Conclusions. Immediate bidirectional MI block was not synonymous with stable block. Despite systematic VoM-EI followed by focal Sphere-9 PFA, conduction recovered in approximately one in five patients, including beyond 20 minutes, and two thirds required targeted CS ablation. These findings support standardized 30-minute reassessment and targeted CS interrogation rather than reliance on immediate block. Chronic invasive remapping is required to determine whether this strategy improves long-term MI block durability.

BACKGROUND The optimal antiplatelet regimen in patients with acute coronary syndrome (ACS) and multivessel disease undergoing drug-coated balloon (DCB) angioplasty remains unclear. METHODS This was a prespecified subgroup analysis of the REC-CAGEFREE II trial, which was conducted at 41 sites in China and randomized 1948 exclusively DCB-treated participants with ACS to stepwise dual antiplatelet therapy (DAPT) de-escalation or standard DAPT. The primary endpoint was net adverse clinical events (NACE; including all-cause death, stroke, myocardial infarction, revascularization, and BARC type 3 or 5 bleeding) at 12 months. Participants were stratified into multivessel and single-vessel subgroups according to angiographic characteristics. RESULTS Overall, 720/1948 (37.0%) patients had multivessel disease. The multivessel subgroup was associated with a significantly higher risk of NACE compared with the single-vessel subgroup (12.5% versus 6.7%, HR IPTW:1.84, 95%CI:1.35-2.51, P<0.001). No significant interaction was observed between vessel status (multivessel or single-vessel) and treatment allocation with respect to NACE (Pinteraction=0.542). In the multivessel subgroup, NACE occurred in 44/368 (12.1%) and 45/352 (12.9%) in the stepwise de-escalation and standard DAPT groups (HR IPTW:0.95, 95%CI:0.62-1.75, P=0.818), respectively. In the single-vessel subgroup, NACE occurred in 43/607 (7.1%) and 39/621 (6.3%) in the stepwise de-escalation and standard groups (HR IPTW:1.12, 95%CI:0.72-1.70, P=0.611), respectively. For the prespecified hierarchical secondary endpoint, win ratio analyses yielded more wins for stepwise de-escalation in both subgroups. CONCLUSIONS Among patients with ACS undergoing DCB-only angioplasty, those with multivessel disease were associated with a higher risk of NACE than those with single-vessel disease. Stepwise DAPT de-escalation and standard DAPT exhibited similar risk-benefit profiles in both subgroups.

We present our Stage-1 Registered Report as a full clinical trial article with all methods in past tense and including mock results, table and figures for the primary analysis. To remind the reader that this Stage-1 article is written before data collection, we highlight in color that these mock results are only for illustrative purposes and will be replaced by the actual results in the Stage-2 Registered Report. Background In patients experiencing out-of-hospital cardiac arrest, optimization of oxygen delivery during cardiopulmonary resuscitation is a critical. Although both positive end-expiratory pressure (PEEP) and zero end-expiratory pressure (ZEEP) are employed during CPR, their respective impacts on clinically relevant outcomes is yet to be clearly established. Methods This investigator-initiated, pragmatic, registry-based, multicenter, triple-blind randomized controlled superiority trial evaluates whether applying 8 cm H2O PEEP during cardiopulmonary resuscitation improves outcomes compared with ZEEP in adults with non-traumatic, non-drowning out-of-hospital cardiac arrest. Pre-randomized CPR kits (1:1 PEEP vs. sham) were used by ambulance sites during manual ventilation throughout the resuscitation process. The primary analysis was conducted in the principal stratum of patients who received either a supraglottic airway or endotracheal tube. The primary outcome was neurological status at hospital discharge measured by a utility-weighted score on the modified Rankin Scale. Secondary outcomes included prehospital return of spontaneous circulation, 30-day survival, and 6-month quality of life. The primary safety outcome was clinically significant pneumothorax.

Background: Current understanding of acute kidney injury (AKI) risk factors remains largely descriptive, offering limited precision into how specific biomarker values or physiologic thresholds influence susceptibility. We aimed to synthesize knowledge from machine learning models trained across multiple health systems to identify generalizable, value-specific risk drivers and biomarker interactions contributing to AKI risk. Methods: We analyzed electronic health records (EHRs) from 785,497 adult inpatients between 2010 and 2019 across nine U.S. academic medical centers within PCORnet. Interpretable gradient boosting machine models were independently developed at each health system to quantify predictor-outcome associations. Meta-regression was applied to integrate these site-level results, characterize nonlinear value-risk relationships, and identify bivariate interactions between predictors. Results: Meta-analysis revealed consistent, value-specific risk drivers across health systems. An increase in glucose from 100 mg/dL to 140 mg/dL was associated with a 1.46-fold higher risk of AKI. Chloride and anion gap also demonstrated elevated AKI risk with risk increases overlapping portions of their reference ranges, with anion gap showing a 1.14-fold increase across 4-12 mmol/L and chloride a 1.28-fold increase across 96-100 mEq/L. Electrolytes including potassium, calcium, and sodium showed quadratic associations with AKI risk. Bivariate meta-regression identified interactions between key predictors, highlighting pathways that jointly modulate AKI risk. Conclusion: This cross-system meta-analysis synthesizes machine learning-derived evidence into clinically interpretable knowledge, revealing how specific biomarker ranges and interactions modulate AKI risk. By moving beyond surface-level associations to quantitative, generalizable physiologic thresholds, these findings provide actionable insights to enhance risk stratification and personalized prevention in hospital care.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of cardioembolic stroke. Although polygenic risk scores (PRS) are well characterized to quantify inherited susceptibility for AF, they provide limited insight into the pathways and tissues underlying genetic risk, which are critical to uncover for individual risk prediction. In this study, we develop a pathway-level multi-omics representation learning framework that converts individual genetic profiles into interpretable biological features by integrating GWAS-derived pathway burden scores with tissue-specific transcriptomic pathway signals. We constructed machine learning models to assess population-level AF risk prediction performance across genomic and transcriptomic tissue contexts; the pathway-based global attention models substantially improved risk prediction performance over PRS and other baselines (AUROC improved from 0.601 to 0.738). Transformer and graph neural network frameworks then assessed individual-level pathway interpretability, revealing heterogeneous contributions from electrical signaling, cardiac development, and DNA repair pathways to AF risk. This added interpretability highlights the potential of this pathway approach to enable more mechanistically informed risk stratification than static PRS by capturing underlying heterogeneity. To independently assess whether prioritized pathways reflected cardiac regulatory biology, we compared pathway rankings with transcriptional effects predicted by the AlphaGenome foundation model. Variants in highly ranked pathways showed significantly greater predicted effects on expression in atrial and ventricular tissues (FDR = 0.032) relative to controls, providing orthogonal evidence that the model identifies biologically relevant mechanisms. Overall, this work reframes polygenic risk from a single measure of susceptibility to tissue-informed pathway mechanisms, providing a framework for interpretable genomic stratification in complex diseases.

Background: High-sensitivity cardiac troponin (hs-cTn) assays enable safe early discharge of patients at very low risk for myocardial infarction. We previously developed a single-sample rule-out pathway using the ARCHITECT hs-cTnI assay to risk stratify patients with suspected acute coronary syndrome. In a secondary analysis of the POC-ET (Point of Care Evaluation of High-sensitivity Cardiac Troponin) study, we evaluated performance of risk stratification with the Alinity hs-cTnI assay. Methods: Patients presenting with possible myocardial infarction in the POC-ET (NCT05665127) study were included. The primary outcome was type 1, 4b or 4c myocardial infarction or cardiac death at 30 days. Cardiac troponin I (cTnI) was measured in stored materials using the ARCHITECT and Alinity hs-cTnI assays. The sex-specific 99th percentile upper reference limit (URL) are 34 ng/L in men and 16 ng/L in women for both assays. Agreement was assessed with Bland-and-Altman limit of agreement method, Passing Bablok regression, and Pearson's correlation coefficient. Distributions of presentation measurements were compared with Kolmogorov-Smirnov test. Performance was evaluated in the overall population and prespecified subgroups. The negative predictive value (NPV) and sensitivity were determined and proportion of patients identified as low, intermediate, and high risk were calculated and modelled using ordinal logistic regression. Results: In 986 patients (60 [51-70] years, 38% female), 78 (7.9%) had a primary outcome. Strong agreement was found in the raw cTnI measurements (99% samples within the Bland-Altman limit of agreement; correlation coefficient r: 0.967 (95% CI 0.964-0.969, P<0.001); Passing Bablok regression: slope 1.12 [1.11-1.13], intercept -0.16 [-0.18 to -0.13]). At presentation, distributions of cTnI measurements by the two assays were similar (P=0.810). Both assays showed comparable diagnostic performance using a risk stratification threshold of <5 ng/L and the sex-specific diagnostic threshold, with the same NPV (Alinity 100 [99.7-100]% versus ARCHITECT 100 [99.7-100]%) and sensitivity (Alinity 100 [97.3-100]% versus ARCHITECT 100 [97.3-100]%). Similar proportions of patients stratified as low- (Alinity 67% versus ARCHITECT 67%), intermediate-risk (23% versus 24%) and high-risk (10% versus 9%) at presentation with minor reclassification. Similar efficacy was observed across subgroups stratified by sex, age, history of myocardial infarction, renal function, and symptom duration. Conclusions: The Alinity hs-cTnI and the ARCHITECT hs-cTnI assays can be used interchangeably in the assessment of suspected myocardial infarction with comparable safety and efficacy.

Background: Unstructured biomedical data, such as echocardiography reports, are rich in information but time consuming to analyze at scale. Rule-based, regular expression-driven terminology mapping can only extract individual variables while large language models (LLMs) offer scalable and clinically meaningful interpretations of heterogeneous disease processes. Right ventricular dysfunction (RVD) is an example of a multifactorial disease state in which key structural and physiologic features are captured both narratively and in structured fields, making it an ideal test case for evaluating whether LLMs can recover complex phenotypes that rules based methods routinely miss. Purpose: To compare an LLM-based extraction method to a conventional rules-based schema for identifying and phenotyping echocardiographic features associated with RVD in a large TTE dataset. Methods: MIMIC-III NOTE2NUM echocardiography reports (n = 45,794) were analyzed using GPT-4o-based LLM extraction deployed within a secure health system enclave and were benchmarked against echocardiographic measurements defined in the MIMIC-III dictionary schema. In MIMIC-III, PH was recorded qualitatively (mild/moderate/severe) based on tricuspid regurgitant (TR) jet velocity and then re-coded as present vs. absent. LLM based extraction defined RVD as (1) RV structural abnormality (>= 1 of hypertrophy, dilation, or wall hypo-/akinesis) or (2) RV pressure/volume overload (>= 2 of the following: estimated right atrial pressure > 8 mmHg, TR jet velocity > 2.8 m/s, fractional area change < 35%, tricuspid annular planar systolic excursion < 17 mm, S' < 9.5 cm/s, or E/e' > 14), with PH defined as estimated pulmonary artery systolic pressure > 35 mmHg or qualitative documentation of PH. Results: LLM extraction identified PH in 15,394 (33.6%), RV pressure/volume overload in 14,449 (31.6%), and RV structural abnormalities in 11,955 (26.1%). Co-occurrence was common: overload + structural changes in 9,380 (20.5%), overload + PH in 9,756 (21.3%), structural changes + PH in 6,183 (13.5%), and all three in 5,620 (12.3%). Using the MIMIC-III dictionary schema, PH prevalence was similar (15,371; 33.6%), but RV overload fields were captured less often (pressure overload 1,357 [3.0%], volume overload 1,128 [2.5%], pressure + volume overload 1,093 [2.4%]; any overload field 3,578 [7.8%]), and RV pressure/volume overload with PH was identified in only 731 (1.6%). Conclusions: LLM-based extraction outperforms rules-based schemas for identifying complex disease states not defined by any single variable. By synthesizing multifactorial signals, LLMs can phenotype RVD with higher fidelity and support population-level assessment. Further validation using multimodality imaging, invasive hemodynamics, and clinical outcome data is needed.

Background and Aims: Epicardial adipose tissue (EAT) has emerged as an important cardiovascular biomarker that reflects both inflammatory and cardiometabolic risk. EAT volume and density vary significantly across populations, yet there is a lack of multicenter studies investigating the predictive value of population-specific EAT percentiles. Methods: In this multicenter study, we retrospectively analyzed low-dose computed tomography correction scans from 42,842 patients undergoing myocardial perfusion imaging. A derivation cohort of 15,082 patients was used to establish sex- and age-specific nomograms for EAT density and EAT volume indexed to body surface area. Percentile-based thresholds were tested for outcome prediction in a validation cohort of 27,760 patients. For clinical implementation, we developed an online EAT percentile calculator. Results: Percentile curves demonstrated increased BSA-indexed EAT volume and decreasing EAT density with age. Over a median follow-up of 3.6 years (IQR: 1.83 - 5.14), 4,956 patients experienced a nonfatal myocardial infarction or death. In multivariable Cox models, patients above the 95th sex- and age-specific percentile had significantly worse outcomes for BSA- indexed EAT volume [adjusted hazard ratio 1.30, 95% CI: 1.14 - 1.49, p < 0.001] and EAT density [adjusted hazard ratio 1.7, 95% CI: 1.51 - 1.92, p<0.001] when compared to patients below the 50th percentile (p<0.001). Conclusion: Age- and sex-specific EAT percentiles provide a clinically interpretable framework for contextualizing automated EAT measurements and identifying patients at increased cardiovascular risk. EAT density was a stronger prognostic marker and identified elevated risk even among patients with normal BMI, supporting its potential to provide information beyond conventional anthropometric assessment.

Background: Percutaneous mechanical circulatory support (pMCS) is increasingly used in critically ill patients, yet its value in relation to cost and outcomes remains unclear. We evaluated national variation in utilization, outcomes, and cost, and introduced a value of care framework integrating risk-adjusted outcomes and expenditures. Methods: We performed a retrospective cohort study using the National Inpatient Sample to identify non-elective hospitalizations of critically ill patients undergoing intra-aortic balloon pump (IABP) or percutaneous left ventricular assist device (pLVAD) placement using ICD-10 codes. Multivariable logistic regression and generalized linear models were used to estimate expected outcomes and costs. Observed-to-expected (O/E) ratios were calculated, and a value index was derived to compare procedural strategies. Results: A total of 57,910 weighted hospitalizations were included (IABP 78%, pLVAD 22%). In-hospital mortality exceeded 30% across regions. Significant regional variation was observed, with the West demonstrating the highest costs and the Midwest the lowest (p<0.001). Mean hospital charges were higher for pLVAD compared with IABP ($403,731 vs $320,769). Both strategies achieved outcomes better than expected after risk adjustment (O/E 0.92); however, costs were higher than expected for both, with greater relative cost inflation observed for IABP (O/E 1.41) and higher absolute costs for pLVAD. In value-of-care analysis, IABP was associated with lower cost and comparable outcomes, while pLVAD demonstrated higher cost without proportional outcome improvement. Conclusion: Substantial variation exists in the cost, outcomes, and value of pMCS strategies. While both IABP and pLVAD achieve favorable risk-adjusted outcomes, pLVAD is associated with higher costs without commensurate clinical benefit.

BACKGROUND People with type 2 diabetes mellitus (T2DM) are at higher risk of cerebral small vessel disease and left ventricular hypertrophy (LVH), potentially contributing to cognitive decline and dementia. We aimed to describe brain volume and cognitive trajectories over 2 years in a cohort of people with T2DM and to determine whether LVH causes increased brain atrophy and cognitive decline. METHODS Diabetes and Dementia (D2) study is a multicentre observational cohort study in Melbourne, Australia. Participants aged >50 years were recruited via 2 hospital outpatient clinics, 3 private clinics, and study advertisements. Participants with pre-existing cognitive impairment, life-limiting medical illness, and severe chronic renal impairment were excluded. Participants attended study visits for brain MRI, transthoracic echocardiography (TTE), and cognitive testing at baseline and 2 years. The exposure was LVH determined on baseline TTE. Pre-specified outcomes were total brain volume (TBV) change and cognitive decline (z-score change?-1 in any cognitive domain) over 2 years. Regression analyses examined associations between baseline variables and outcomes. A causal inference approach was utilized using inverse probability of treatment weighting to standardize for confounding covariates, excluding participants for non-positivity on age and baseline TBV. RESULTS Participants were recruited 20May2016 to 20March2020: 2378 screened, 702 eligible, 196 consented, 150 baseline and 123 2-year assessments with complete MRI, TTE, and cognitive data (17.4% attrition). At baseline, LVH was associated with female sex, older age, lower educational attainment, lower mood, hypertension, obesity, beta-blocker use, and smaller TBV. Participants with baseline cognitive impairment exhibited greater brain atrophy. Lower educational attainment, hypertension, and lower baseline cognitive scores were associated with cognitive decline. Causal inference analysis included 62 participants with no LVH (20(32%) women; mean [SD]=66.9[5.9] years), and 31 with LVH (17(55%) women, 67.4[5.4] years). LVH caused lower TBV change: standardized mean difference (95% CI) 6.3 (0.1, 12.5) cm3, P=.048. LVH had no effect on cognitive decline. CONCLUSIONS Brain atrophy and cognitive decline were associated with baseline cognitive impairment. LVH caused less brain atrophy and cognitive decline in people with T2DM. We conclude that guideline-directed LVH therapies such as beta-blockers have both cardioprotective (remodelling) and neuroprotective effects. TRIAL REGISTRATION ACTRN12616000546459 UTN: U1111-1181-6659