Nature Cardiovascular Research

Advances in single-cell and spatial assays have revolutionized the scale and resolution of molecular tissue profiling. Here we present MetaPlaq, a multimodal atlas of human atherosclerotic arterial beds comprising over a million cells across single-cell transcriptomics, epigenomics and high-resolution spatial expression assays. We map granular cell states and disease-relevant transcriptional programs within the native tissue context of coronary arteries. Furthermore, we map cardiovascular GWAS signals to smooth muscle cells (SMCs) and endothelial cells (ECs) and uncover the cis-regulatory architecture governing their phenotypic transitions. Our comprehensive epigenomic reference allowed us to build cell-specific enhancer-gene link maps and multimodal gene regulatory networks (GRNs) underlying disease-relevant states such as osteogenic SMCs and ECs undergoing mesenchymal transition. We also integrate SMC and EC disease-associated gene sets with GRNs to nominate key transcription factors such as PRRX1, BNC2 and ELK3 regulating atherosclerosis-relevant transcriptional programs. Finally, we layer single-cell and spatial modalities to fine-map GWAS variants with improved cell and anatomical context. We highlight candidate cell-specific regulatory mechanisms at less characterized CAD loci, including FGD5 and MCF2L in ECs. Together, this atlas represents an important step towards fully interpreting genetic risk loci and informing new therapeutic strategies for cardiovascular disease.

Diastolic heart failure (HF) in primary cardiomyopathy is under-recognized and often diagnosed late, particularly in children. While recent studies have advanced understanding of HF with preserved ejection fraction in older adults, the prevalence, outcomes and molecular drivers of diastolic HF in pediatric and young adult cardiomyopathy remain poorly defined, where disease is typically driven by primary myocardial disease rather than acquired co-morbidities. The Canadian Cardiomyopathy Collaborative (C3) was assembled to leverage three of Canadas leading pediatric and adult cardiomyopathy biobank registries. Its flagship initiative, Artificial Intelligence to Model Diastolic Heart Failure (AID-HF), aims to integrate deep phenotyping - including comprehensive diastolic function assessment - with genomics, lipidomics and proteomics and apply machine learning to identify biological and clinical signatures that drive cardiac function and outcomes in cardiomyopathy. Harmonized phenotyping and multiomics protocols across registries will create a uniquely integrated national data resource and enable the goals of AID-HF i.e., earlier diagnosis and new therapeutic targets for diastolic HF in cardiomyopathy.

Background Atrial fibrillation (AF) is a leading cause of stroke, cardiovascular morbidity, and mortality. Atrial myopathy, characterized by progressive metabolic, electrical, and structural changes, creates the arrhythmogenic substrate that drives AF. Defining the key drivers of atrial myopathic processes is essential for targeted therapies that can mitigate AF progression. Here we explore how reduced ERBB4 expression contributes to the development of left atrial myopathy. Methods We analyzed the Cleveland Clinic Biobank to compare left atrial ERBB4 levels in patients grouped by AF diagnosis. To investigate the impact of reduced ERBB4 levels on atrial tissue substrate, we created mouse models of cardiac-specific Erbb4 deficiency using Mlc2a (myosin light chain 2a)-Cre. Comprehensive physiological assessments were performed. Transcriptomic analyses of the left atrium were performed in an Erbb4 haploinsufficient mouse model and compared with human atrial datasets. Molecular validation of key dysregulated pathways was performed. Results We found that left atrial ERBB4 levels are reduced in patients with AF. Adult cardiomyocyte-specific Erbb4 heterozygous (Erbb4fl/+;Mlc2a-Cre) mice exhibited prolonged P-wave duration in the absence of ventricular dysfunction. Left atrial transcriptomic analysis in Erbb4 haploinsufficient mice showed upregulation of pathways related to fibrosis, apoptosis, and coagulation, and downregulation of pathways related to fatty acid metabolism and mitochondrial function, mirroring changes observed in pressure overload mouse models. A cross-species transcriptomic comparison revealed significant overlap between ERBB4-correlated gene expression and functional pathways in adult human atria and mice with Erbb4 haploinsufficiency. Validating the transcriptomic data, protein and functional assays demonstrated increased fibrosis, apoptosis, and oxidative stress in the mutant left atrial tissue. Conclusion Left atrial ERBB4 levels are reduced in AF patients. A mouse model of Erbb4 deficiency and human atrial transcriptomic analyses highlight a role for ERBB4 in supporting normal atrial metabolism while protecting against inflammation, apoptosis, and fibrosis.

Importance Dilated cardiomyopathy (DCM) is a major cause of heart failure that disproportionately affects individuals of African genetic ancestry (AFR), among whom familial clustering of disease is also more pronounced relative to those of European ancestry (EUR). However, established monogenic DCM genes, identified primarily in EUR populations, explain a smaller proportion of DCM cases in AFR populations. A recent study identified a common AFR-specific nonsense variant in CD36 that accounts for a substantial burden of DCM in AFR. How the risk and population impact of this variant compare with those of established genetic causes of DCM is unknown. Objective To compare the contribution of a CD36 nonsense variant to DCM risk with that of truncating variants in TTN and pathogenic or likely pathogenic (P/LP) variants in other established DCM genes. Design, Setting, and Participants Multicohort genetic association study including AFR and EUR participants with exome or genome sequence and DCM case status from four datasets: All of Us, Million Veteran Program, Penn Medicine Biobank, and the DCM Precision Medicine Study. Exposure Carrier status for TTN truncating variants, P/LP variants in 11 high confidence DCM genes, and the CD36 nonsense variant (Y325*; 0, 1, or 2 copies). Main Outcomes and Measures Odds of DCM; prevalence of risk-variant carriers among DCM cases; and population attributable fraction (PAF) for DCM. Results Among 82,623 AFR individuals across four studies, the mean age was 53.4 years and 1,625 had DCM. CD36 Y325* risk-allele homozygotes had 4.8-fold (95% CI, 3.1-7.3) increased odds of DCM, and CD36 Y325* heterozygotes had 1.4-fold (95% CI, 1.2-1.7) increased odds. TTN truncating variants also conferred elevated risk of DCM in AFR participants (OR, 8.46; 95% CI, 5.3-12.3). Among AFR DCM cases, 2.5% were CD36 homozygotes, second only to TTN truncating variants (4.3%) and exceeding all other high-confidence DCM genes combined (1.5%). In population-level analyses incorporating both heterozygous and homozygous CD36 Y325* carriers, the population-attributable fraction for CD36 (9.0%) surpassed that of TTN truncating variants (3.6%). Conclusions and Relevance An ancestry-specific CD36 variant contributes more to DCM burden in AFR ancestry than established DCM genes, including TTN truncating variants, typically considered the most common genetic cause of DCM. These findings reshape the known genetic architecture of DCM in individuals of African ancestry and highlight the importance of representation in genomic research.

Background and Aims: Clinical interpretation of the precordial leads V1-V6 assumes that Wilson's central terminal (WCT) has a fixed anatomical location. Consequently, a positive signal corresponds to electrical activation spreading from WCT towards the respective electrode, and vice versa. However, the location of WCT has never been systematically investigated. Yet, a better understanding of WCT location could improve the interpretation of the precordial leads. This work aims to characterize the spatial expansion and location of the physical WCT i.e., the electrical potential defined by the WCT, during the P-wave on the body surface. Methods: An intensive analysis of body surface potential maps (BSPMs) during atrial depolarization in an in silico patient cohort and clinical data was conducted. Results: During the P-wave, the location of WCT was not stationary but the spatial extent and location varied across time as well as across individuals. Four distinct spatial patterns of WCT distribution on the body surface were identified in silico, and three of these were found in the clinical cohort. WCT signals agreed with BSPM signals at commonly assumed positions of WCT only for a small fraction of the P-wave. Conclusion: The spatial extension and location of WCT changes during the P-wave and thus should be considered when interpreting the precordial leads.

Background Artificial intelligence-enhanced electrocardiography (AI-ECG) enables scalable, low-cost cardiac dysfunction screening, but existing models are annotation-intensive and predominantly adult-derived, leaving paediatric generalizability uncertain. Paediatric cohorts exhibit highly variable cardiac morphology and function compared to adults, which may be useful for learning generalizable AI-ECG models. Methods We pretrained ECG-Fyler on a predominantly paediatric, all-age cohort at Boston Children's Hospital (1992-2023), annotated with a cardiology-specific coding system (Fyler codes), and evaluated it on assessments from echocardiography (echo) and cardiac magnetic resonance (CMR) studies. We validated on an external adult cohort from Columbia University Irving Medical Center. Performance was benchmarked against several AI-ECG foundation models by AUROC across age groups, lesion types, and limited-data scenarios. Findings The pretraining cohort comprised 782,138 ECGs from 255,271 patients (median age: 10.9 years, IQR: [2.8-16.8]). Internal evaluation included 178,495 ECG-echo pairs (median age: 10.9 [3.7-17.0]) and 8,584 ECG-CMR pairs (median age: 20.7 [15.6-29.6]). External validation included 82,543 ECG-echo pairs from adults (median age: 64.0 [52.0-74.0]). ECG-Fyler improved AUROC across biventricular dysfunction and dilation tasks, with the largest gains in low-data settings. In internal validation, ECG-Fyler detected low left ventricular ejection fraction (LVEF [&le;] 40%) from only 100 fine-tuning samples (AUROC: 0.80, 95% CI: [0.78-0.80]), outperforming other models (AUROC < 0.65) and improving with additional fine-tuning (AUROC: 0.94 [0.93-0.94]). Similar improvements were observed for CMR-derived LVEF, RVEF, and ventricular dilation. In external validation on adults, ECG-Fyler exhibited an AUROC of 0.83 (CI: [0.82-0.85]) for LVEF [&le;] 40%. After fine-tuning on less than 10% of external data, LVEF [&le;] 45% performance (AUROC: 0.87 [0.86-0.88]) outperformed a fully trained, site-specific prior model (AUROC: 0.85 [0.84-0.87]). Interpretation Pretraining on richly annotated, paediatric-dominant ECGs yields models that transfer efficiently across institutions and ages, supporting AI-ECG screening and triage when labels or imaging access are limited. Funding National Institutes of Health (R01LM012973); Kostin Innovation Fund, Boston Children's Hospital

Background: Echocardiographic assessment of tricuspid regurgitation (TR) remains valve-centric, and right-heart remodeling is not captured. Strain parameters carry prognostic value but are evaluated in isolation. Objectives: To develop integrated right atrial (RA) and right ventricular (RV) remodeling indices using automated echocardiography and assess their utility for TR severity grading, phenotyping, and prognostic stratification. Methods: We analyzed 8,231 patients with functional TR (mild-or-greater) from two tertiary centers (2023-2024) using an automated AI-based echocardiographic solution. The RA remodeling index (RA reservoir strain/RA volume index) and RV remodeling index (RV free wall strain/RV end-diastolic area) were derived automatically; patients were classified into four RA-RV remodeling phenotypes. The primary outcome was all-cause death or heart failure (HF) hospitalization. Results: During median follow-up of 19.3 months, the primary outcome occurred in 574 patients (7.0%). Both indices outperformed individual components for severe TR discrimination (RA: AUC 0.857 vs. 0.757; RV: 0.710 vs. 0.601; both P<0.05). After multivariate adjustment, the RA (HR per unit decrease, 1.27; 95% CI, 1.09-1.49; P=0.002) and RV remodeling indices (2.32; 1.76-3.06; P<0.001) were independently associated with the primary outcome; on mutual adjustment, only the RV index retained significance and provided incremental prognostic value ({Delta}C-index +0.010; NRI +0.237; both P<0.05). The four phenotypes showed progressively divergent risk (log-rank P<0.001), with combined remodeling (Low RA/Low RV) carrying the highest risk. Conclusions: Automated integrated RA and RV remodeling indices improved TR severity discrimination and enabled clinically meaningful right-heart phenotyping. The RV index conferred incremental prognostic value, whereas the RA index better reflected atrial-stage remodeling and disease burden.

Background: Comprehensive assessment of hypertension-mediated organ damage (HMOD) across multiple organ systems in sub-Saharan Africa is limited. We assessed the prevalence and correlates of multidomain HMOD in a geographically diverse population in Ghanaian adult. Methods: This cross-sectional secondary analysis of the Ghana Heart Study, which included 1,106 adults aged [&ge;]18 years from four Ghanaian regions between September 2016 and March 2017. Multidomain HMOD was determined using a pre-specified 9-domain composite score [&ge;]2, using an ESH/ESC 2018 guideline-informed selection of HMOD domain with baPWV instead of carotid-femoral PWV (cfPWV), due to device unavailability, and a threshold of [&ge;]14 m/s which was derived from analysis within the cohort. LODO sensitivity analyses were used to address issues of predictor-outcome circularity. We used logistic regression models to examine association between each predictor and multidomain HMOD, adjusted for age, systolic blood pressure, body mass index, presence of dyslipidaemia and smoking status. We also performed receiver operating characteristic (ROC) analysis to determine correlates of multidomain HMOD and compare the discriminative ability of each predictor against the others. Results: The mean age of participants was 46.9{+/-}17.2 years of which 58% were females. Multidomain HMOD was observed in 21.3% (235/1,106; zero-imputation lower bound 21.2%) of participants studied. There was a marked increase in the prevalence of multidomain HMOD with advancing age. Thus, while 8.6% (44/ 511) of adults<45years had multidomain HMOD, 20.6% (63/306) of 45- to 59-yr-olds and 44.4% (128/ 288) of individuals [&ge;]60 years had multidomain HMOD. HMOD-positive adults were older (59.1{+/-}8.4 vs 43.6{+/-}13.4y, p<0.001), had higher systolic BP (147{+/-}22 vs 123{+/-}21 mmHg, p<0.001), and had higher prevalence of hypertension (73% vs 28%, p<0.001) than their HMOD-negative counterparts. Using the primary (circular) specification, the strongest co-occurrence among all domains of HMOD was observed between peripheral artery disease and other HMOD (OR 41.2, 95% CI 20.7-81.6; p<0.001) followed by valvular burden and other HMOD (OR 14.4, 95% CI 4.8-43.8; p<0.001) and between ECG-LVH and other HMOD (OR 9.0, 95% CI 5.9-13.8; p<0.001) (S2 Table). After LODO correction to remove the self-inclusive co-occurrence between each predictor domain and the outcome (all p-values calculated in S2 Table), there was no significant association between the remaining 8 HMOD domains and the prevalence of multidomain HMOD (all p-values>0.05; S2 Table). This was not the case for baPWV, however. Thus, whereas the AUC of the best performing non-self-inclusive HMOD domain (ECG-CMD) only reached 0.688{+/-}0.016 (vs 0.827{+/-}0.008 for self-inclusive AUC calculated for the sake of interest only and provided as supplementary material), baPWV demonstrated good discriminative capacity (LODO-adjusted AUC = 0.702, 95% CI 0.654-0.751; S3 Fig). However, this AUC did not significantly exceed that for age alone (AUC = 0.752; {Delta}AUC = -0.050, 95% CI ?0.103 to 0.03; p=0.106; S3 Fig). Most importantly, after adjustment for SBP (a direct mediator in this pathway), the LODO AUC for baPWV did not exceed that for the single variable age (S3 Fig), indicating that baPWV does not possess independent discriminative power for multidomain HMOD above and beyond the information provided by SBP and age. Importantly, however, the adjusted OR for baPWV did not reach statistical significance (OR 1.094, 95% CI 0.986-1.213; p=0.091), suggesting that while circularity prevented validation of biological association, it did not prove the absence of association altogether. Sensitivity analysis (estimating total as opposed to direct effect) in which SBP was excluded from the regression model to estimate the total effect of baPWV on the prevalence of HMOD showed that, indeed, the OR for baPWV was significantly elevated (OR 1.261; 95% CI 1.150-1.382; p<0.001) in this specification. The effect of SBP, a direct mediator in this pathway, therefore apparently accounted for the non-significance in the original model entirely. Formal mediation analysis using the aforementioned specification yielded that SBP indeed mediated 69.9% (95% CI 41.3-128.8%) of the effect of baPWV on the prevalence of HMOD. Conclusions: One in five Ghanaian adults has hypertension-mediated organ damage in multiple HMOD domains. baPWV has good discriminative power for HMOD risk prediction in a Ghanaian adult population under the non-circular LODO estimand (LODO- adjusted AUC = 0.702; 95% CI: 0.654, 0.751) than the PCE (AUC = 0.496; 95% CI: 0.438, 0.555; {Delta}AUC = +0.206; p < 0.001). However, baPWV LODO AUC (0.702) was not statistically significantly greater than age alone (AUC = 0.752; 95% CI: 0.730, 0.774; {Delta}AUC = -0.050, p = 0.106). AUC for self- inclusive model was provided in supplementary materials for the reader's perusal, and that AUC (0.827; 95% CI: 0.794, 0.860) is circular. The prevalence of ECG-LVH was substantially higher (42%) than that of echocardiographic- LVH (5.9%) in this Black African population. These findings support further research on the role of baPWV for HMOD risk prediction in a Ghanaian adult population. Prospective validation of baPWV would be needed before clinical use.

Catheter ablation is an established rhythm-control strategy for atrial fibrillation, but outcomes in persistent atrial fibrillation (PsAF) remain heterogeneous across evolving strategies and energy modalities. An updated synthesis is needed to define current effectiveness and adverse-event profiles in the modern ablation era. We conducted a systematic review and meta-analysis of prospective clinical trials of catheter ablation for PsAF published from 2010 through December 2025. We included randomized and nonrandomized prospective interventional studies reporting effectiveness and adverse events, and pooled outcomes using random-effects models. Prespecified subgroup analyses evaluated ablation strategy (pulmonary vein isolation [PVI] vs PVI with adjunctive lesion sets [PVI+]), ablation modality (radiofrequency [RF], cryoballoon [CRYO], and pulsed field [PF]), and endpoint definition (recurrence-only vs composite measures). Thirty-two studies (9,194 patients) met inclusion criteria; 28 (7,948 patients) contributed to effectiveness analyses. The pooled 12-month arrhythmia-free proportion was 0.65 (95% CI, 0.61-0.68), with substantial heterogeneity. Effectiveness was numerically higher with PVI+ than PVI-only (0.66 [0.60-0.72] vs 0.63 [0.59-0.67]), similar for PF (0.65 [0.57-0.72]) and RF (0.65 [0.61-0.69]), and slightly lower for CRYO (0.64 [0.54-0.74]). Recurrence-only endpoints yielded higher effectiveness than composite endpoints (0.67 [0.63-0.71] vs 0.60 [0.55-0.64]). Safety analyses included 32 studies (9,002 patients). Adverse events were low but heterogeneous (0%-14.56%); pooled vascular access and pericardial complication incidences were each 1%, while thromboembolic events, accessory organ injury, and mortality were rare (pooled 0%). PF ablation showed numerically lower overall complication incidences than RF and CRYO. In contemporary trials, catheter ablation for PsAF shows moderate effectiveness and low overall adverse-event risk. Adjunctive strategies and PF ablation are promising, but no approach is consistently superior. These findings support tailored, patient-specific ablation selection in PsAF.

Background: Quantitative lipid assessment is central to identifying rupture-prone coronary plaques and represents a therapeutic target for lipid-lowering therapy. Near-infrared spectroscopy (NIRS)-derived lipid core burden index (LCBI) is well validated and widely used for detecting lipid-rich lesions. Optical frequency domain imaging (OFDI) is increasingly adopted for guiding percutaneous coronary intervention (PCI) due to its high-resolution structural imaging capabilities. Depolarization-sensitive OFDI (depOFDI) provides intrinsic lipid contrast and may enable combined structural and compositional plaque characterization within a single OFDI-based platform. Objective: To define an OFDI-derived lipid metric and evaluate its agreement with NIRS-derived LCBI. Methods: Thirty-three patients underwent both polarization-sensitive OFDI and NIRS-intravascular ultrasound imaging during PCI. After exclusion of 4 datasets, 29 co-registered pullbacks were analyzed. A signal-to-noise-corrected depolarization metric was used to identify lipid-rich regions and generate depOFDI chemograms. maxLCBI4mm value and location, as well as total LCBI, were computed and compared with NIRS. Results: depOFDI demonstrated strong agreement with NIRS, showing high correlation for maxLCBI4mm (r^2 = 0.862) and total LCBI (r^2 = 0.867), along with strong spatial concordance for the location of the maxLCBI4mm (r^2 = 0.900). Bland-Altman analysis of LCBI4mm showed minimal bias (10.7) with 95% limits of agreement of [81.4 to 102.8]. Conclusions: depOFDI enables accurate quantification of lipid burden alongside the high-resolution structural information inherently provided by OFDI. Because depolarization metrics can be derived from polarization-diverse detection available in many commercial OFDI systems, this approach provides a practical pathway toward comprehensive plaque characterization within existing PCI workflows, without the need for additional imaging modalities.

Background Non-vitamin K antagonist oral anticoagulants (NOACs) are the guideline-recommended standard for stroke prevention in atrial fibrillation (AF), yet bleeding risks limit real-world adherence. Percutaneous left atrial appendage closure (LAAC) offers a mechanical alternative without definitive comparative synthesis. Objectives To evaluate percutaneous LAAC versus NOAC therapy by synthesizing all contemporary NOAC-era randomized controlled trials (RCTs). Methods Five databases and registries (PubMed, MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov) were searched from inception to 8 May 2026 for RCTs comparing percutaneous LAAC against NOACs in adults with non-valvular AF. Risk of bias was assessed using Cochrane RoB 2. Ischemic stroke was pooled using a random-effects DerSimonian-Laird model; primary efficacy composite and non-procedural bleeding were evaluated via pre-specified narrative synthesis. Results Four RCTs (CHAMPION-AF, OPTION, PRAGUE-17, CLOSURE-AF) comprising 5,890 patients were included. LAAC achieved noninferiority for the primary efficacy composite in three trials and demonstrated a statistically significant 45-56% reduction in non-procedural bleeding across the three moderate-risk trials. CLOSURE-AF did not meet noninferiority but retained a directionally consistent bleeding reduction. Pooled ischemic stroke analysis (HR 1.31; 95% CI 0.96-1.80; I^2=0%) showed no statistically significant increase in stroke risk, though a consistent directional trend toward more ischemic events was observed. Conclusions LAAC significantly reduces non-procedural bleeding in moderate-risk AF patients, though this benefit attenuates in very high-risk populations. A consistent, statistically nonsignificant ischemic stroke trend and population-dependent efficacy establish LAAC as a shared decision-making alternative to NOACs rather than a universal replacement, pending 5-year CHAMPION-AF data.

Cardiovascular disease is the leading cause of death worldwide. Sudden cardiac death (SCD) accounts for roughly 50% of all cardiac deaths. The electrocardiogram (ECG) is widely used for early diagnosis of cardiac disease. However, the complexity of accurate interpretation limits the ECG's efficacy. Modern deep learning methods have been applied to assist clinicians in diagnosis. We applied Neural Architecture Search (NAS), an automated machine learning technique, to identify optimal deep learning architectures for classifying cardiac arrhythmias from ECGs. We applied the Differentiable Architecture Search strategy to an AutoFormer search space to identify optimal self-attention architectures for arrhythmia classification. We trained, validated, and tested the resulting model on the PhysioNet Challenge 2021 dataset (n = 88,253), comprising ECGs across three continents. We performed a hyperparameter optimisation on the NAS output, exploring input patch size, class weighting, and loss function. We evaluated performance using the PhysioNet Challenge metric and the area under the receiver operating characteristic curve (AUROC). The NAS converged towards minimal architectural configurations (embedding dimension: 384, depth: 4, self-attention heads: 4, MLP ratio: 1) with a validation challenge metric of 0.66 (PhysioNet Challenge 21 Winner: 0.63). The NAS-created network achieved an AUROC of 0.97 and a challenge metric of 0.71 during testing. Normal Sinus Rhythm and Sinus Tachycardia achieved AUROCs of 0.99. Low-QRS Voltage and T-wave abnormality were the worst-performing arrhythmias, with AUROCs of 0.89 and 0.90, respectively. We interpret that architectural simplicity drives performance in arrhythmia classification. Because SCD is unexpected, prevention strategies in free-living environments require lightweight computational resources suitable for wearable devices. Class imbalance fundamentally limits classification performance for rare arrhythmias such as Low-QRS Voltage and T-wave inversion, irrespective of hyperparameter choices. However, the self-attention mechanism can autonomously abstract clinical representations, simplifying clinical deployment by eliminating the need for an explicit feature-extraction pipeline.

Background Cardioplegic arrest during complex aortic arch repair imposes prolonged global myocardial ischaemia, which may contribute to postoperative low cardiac output syndrome (LCOS) and mortality. Whether cardioplegic arrest can be entirely avoided -- performing the complete procedure on a continuously perfused, beating heart -- has not previously been evaluated in a clinical series. Methods and Results Between November 2017 and January 2026, 29 consecutive patients underwent total beating-heart aortic arch repair without any cardioplegic arrest at a single centre. Continuous antegrade myocardial perfusion (warm blood, 34{degrees}C, 300-400 mL/min, perfusion pressure 60-80 mmHg) was delivered via an aortic root needle vent throughout each procedure. Two variants were employed: axillary cannulation with selective antegrade cerebral perfusion (n = 24, 82.8%), and direct aortic cannulation with extra-anatomical left carotid bypass for distal Zone 2 pathology (n = 5, 17.2%). Mean age was 55.4 {+/-} 13.6 years; 41.4% presented with aortic dissection (B/non-A-non-B). No patient required conversion to cardioplegic arrest. Perioperative myocardial infarction and LCOS occurred in none of the patients. Median peak CK-MB was 44.0 U/L. Thirty-day mortality was 10.3% (n = 3); all deaths were due to respiratory failure or visceral ischaemia complicating acute type B dissection. Conclusions Total beating-heart aortic arch repair without cardioplegic arrest is technically feasible and clinically safe in appropriately selected patients and is associated with the complete absence of perioperative myocardial infarction and LCOS across a heterogeneous, high-risk cohort. These findings support prospective, multicentre evaluation of no-arrest myocardial protection as a strategy to reduce the cardiac morbidity of complex arch surgery.

COVID-19 risk scores developed during the pandemic relied on measurements contemporaneous with infection, leaving unresolved whether the metabolic and inflammatory vulnerability they capture pre-existed as a stable trait or was triggered by acute illness. Here, using 501,946 UK Biobank participants whose blood was drawn between 2006 and 2010---at least ten years before SARS-CoV-2 emerged---we show that baseline proteomic and metabolic profiles predict both COVID-19 hospitalization (2,783 events; C-statistic =0.676 [0.666--0.686]) and COVID-19 mortality (1,564 deaths; C-statistic =0.730 [0.701--0.760]) from parsimonious, regularized feature sets. The IL-1 pathway index (xIL1, +0.093) was independently selected for hospitalization but not mortality, while the IL-6 trans-signaling index (xIL6, + 0.040) was selected for mortality but not hospitalization---a differential pathway weighting corroborated by independent LightGBM/SHAP analysis and mirroring the subsequent success of tocilizumab (anti-IL-6R) and the limited efficacy of anakinra (anti-IL-1R) in reducing COVID-19 mortality in randomized trials conducted years later. The mortality model was additionally characterized by central adiposity (waist-hip ratio, +0.386), a respiratory compromise index (xRSP, +0.149), and prodromal cardiovascular disease (pCVD, +0.246). These findings establish that vulnerability to a novel pathogen is, in substantial part, a pre-existing and measurable prodromal state, with implications for pandemic preparedness and population-level risk stratification.

Background: People with ischemic heart disease (IHD) remain at high risk of recurrent major cardiovascular events despite contemporary therapy. Over two decades, a translational research program has evaluated pressure pain sensitivity (PPS) as a non-invasive marker of central autonomic dysfunction and a mutual risk phenotype in IHD and type 2 diabetes. A PPS-guided non-pharmacological intervention has been shown to substantially reduce five-year all-cause mortality in IHD. Methods: In a randomized controlled trial, 213 adults with stable IHD and elevated PPS, suggesting ANSD, were allocated to PPS-guided intervention (n=106) or control (n=107). The active group received three months of structured education (daily PPS self-measurement, cutaneous sensory nerve stimulation, supportive mental and physical exercises, telemedical feedback) followed by self-directed continuation. Controls received a booklet on general stress-management. The primary endpoint for this prespecified secondary analysis was a composite of eight major cardiovascular events. Results: Over 5 years, at least one major adverse cardiovascular event occurred in 19.8% of the PPS-guided group versus 43.8% of controls (odds ratio 0.32, 95% CI 0.17-0.62, P=0.0003). Incidence rates were directionally in favor of active intervention across all event categories (P=0.004). Conclusions: A brief PPS-guided non-pharmacological intervention, followed by self-directed continuation, was associated with a marked long-term reduction in major adverse cardiovascular events, complementing previously reported large reductions in all-cause mortality in the same cohort. Within the context of a multi-decade PPS research program, these findings support PPS-guided care as a low-resource autonomic intervention ready for pragmatic scale-up testing as an adjunct to cardiometabolic care.

Background: The specific 3D morphological substrates distinguishing the newly defined massive and torrential functional tricuspid regurgitation (FTR) phenotypes from standard severe disease remain under-characterized. Objectives: This study investigates the 3D geometric changes of the tricuspid valve (TV) apparatus across the spectrum of FTR, specifically focusing on the structural definition of massive and torrential grades. Methods: Three-dimensional (3D) transesophageal echocardiography (TEE) was performed in 322 patients with FTR secondary to left-sided heart disease. Patients were stratified into mild-moderate (n=166), severe (n=82), and massive-torrential (n=74) groups. TV geometry, including annular dimensions, leaflet tethering, and subvalvular apparatus, was quantified using 3D modeling software. Results: Patients with massive-torrential TR were characterized by advanced age, female predominance, and atrial fibrillation (75%). 3D analysis demonstrated that massive-torrential TR represents a distinct phenotype defined by extreme annular circularization (ellipticity index 1.0) and planar flattening (P < 0.001). Furthermore, these patients exhibited a critical leaflet-annulus uncoupling, where compensatory leaflet growth (relative length < 80%) failed to match the massive annular dilation. Consequently, the regurgitant orifice in massive-torrential grades appeared highly complex, frequently manifesting as multiple irregular orifices. Conclusions: Massive and torrential FTR are characterized by a unique geometric profile involving extreme annular circularization, severe leaflet tethering, and leaflet-annulus uncoupling. These morphological insights suggest that conventional repair strategies may be insufficient for these advanced phenotypes, highlighting the necessity for pre-procedural 3D TEE to guide device selection.

Background: Polygenic risk scores (PRS) for coronary artery disease (CAD) are associated with cardiovascular events, but the relationship between inherited risk and routinely reported coronary computed tomography angiography (CTA) findings has not been studied. Objectives: To evaluate associations between a genome-wide PRS for angiographic coronary disease burden and coronary CTA-derived measures of atherosclerotic severity in a real-world clinical cohort. Methods: We studied Penn Medicine BioBank participants with available genotypes and clinically obtained coronary CTA reports. A previously published PRS for angiographic CAD burden was calculated using pgsc_calc. CAD-RADS scores and coronary artery calcium (CAC) values were extracted from radiology reports using the large language model Llama 3.1 8B. Associations between PRS and CAD-RADS severity were evaluated using Bayesian cumulative ordinal logit regression, while associations with log-transformed CAC burden were assessed using Bayesian linear regression. Results: Among 630 participants, median age was 59 years (IQR 49 - 68), 53% were female, 62% were genetically similar to a European reference population, and 34% to an African reference population. LLM-extracted CAD-RADS and CAC values demonstrated near-perfect agreement with manual abstraction. Higher PRS was associated with greater coronary atherosclerotic burden on CTA. Each 1-standard deviation (SD) increase in PRS was associated with a 20% higher odds of belonging to a more severe CAD-RADS category (cumulative OR 1.20, 95% credible interval 1.06-1.44). Higher PRS was also associated with greater CAC burden ({beta} 0.38, 95% credible interval 0.15 - 0.61). Conclusions: Polygenic risk for angiographic coronary disease burden is reflected in clinically reported coronary CTA severity measures, including CAD-RADS and CAC. These findings demonstrate that inherited susceptibility to CAD manifests as greater anatomic atherosclerotic burden at the time of clinical presentation and support further investigation of genetic risk integration into imaging-based cardiovascular risk assessment.

Background: Cardiovascular magnetic resonance (CMR) quantification of the left ventricular (LV) volumes and ejection fraction (EF) typically involves manual segmentation of many short axis (SAx) and long axis (LAx) slices of the left ventricle. The scan time and the number of breath holds is proportional to the number of slices. We aimed to evaluate a geometric model of the left ventricle that could enable planimetry from a reduced number of slices. We sought to determine whether acceptable accuracy was retained for evaluating the End Diastolic Volume (EDV), End Systolic Volume (ESV), Stroke Volume (SV), and EF to provide a rapid and reliable clinical alternative. Methods: A cohort of 342 patients, median age: 54 (40 - 65) years, with full-stack CMR examinations was used. Nine geometrical combinations were evaluated: 3, 4 or 5 short axis slices and one of three LAx orientations (2-chamber, 3-chamber or 4-chamber) by retrospectively decimating the full-stack acquisition. LV volumes were calculated as a sum of trapezoidal approximations for apical and mid-cavity slices and a generalized prismoidal model at the base. The accuracy of the volume calculations was quantified against the full-stack reference for the EDV, ESV, SV, and EF using concordance correlation coefficient (CCC), two-way repeated measures ANOVA, pairwise tests, and Bayes factor log10(BF10) analysis. Results: The choice of the long axis (LAx) view was the most influential driver of accuracy (g2 = 0.104, for EDV), approximately 50 times more impactful than the number of SAx slices (g2 = 0.002, for EDV). Volumes calculated using the combination of 2-chamber LAx view and 5 SAx slices had the highest concordance with the full stack (CCC>0.90). While the estimated absolute volumes displayed a systematic negative bias, EF and SV remained highly robust due to bias cancellation. For a 2ch + 5 SAx protocol, EF bias was just 0.83% (LoA: -6.18 to 7.84%), with a minimum detectable change (MDC) of 7.01%, compared to 8.7% reported for expert human readers, suggesting strong concordance. Bayesian paired-samples t-tests yielded log10(BF10) = 6.42 in favor of 5 SAx over 3 SAx, constituting decisive evidence on the Jeffreys scale. The bias and limits of agreement (LoA) for stroke volume and ejection fraction were found to be lower than scan-rescan reproducibility in literature. Conclusion: This reduced-slice geometric model allows for reduced number of breath holds compared to a conventional full-stack CMR acquisition and provides an acceptable accuracy with bias less than scan-rescan variability.

We present the TopBrain 2025 Challenge, the first benchmark for fine-grained multiclass segmentation of the whole brain vasculature in both computed tomography angiography (CTA) and magnetic resonance angiography (MRA). Building on the TopCoW challenge, TopBrain scales vessel annotation from the Circle of Willis to the entire brain, introducing a dataset of 90 annotated volumes across 48 landmark vessel classes spanning arterial and venous systems, of which 50 training volumes are publicly released. Vessel definitions were consolidated from established neuroanatomical references into a unified annotation scheme, and vessel caliber measurements along the centerline are reported for the first time across the whole brain vascular anatomy. To address the unique challenges of multiclass brain vessel segmentation, we propose an evaluation framework that accounts for detection in segmentation performance, assesses anatomical plausibility, and introduces novel contamination metrics that characterize inter-class prediction errors. Fifteen teams from over 220 registered participants submitted algorithms to the benchmark. The top-performing teams built on nnUNet with principled system design choices, achieving around 80% Dice scores, near-zero invalid neighbor counts, over 60% F1 scores for side-road vessels, and below 18% foreground contamination ratio. Larger vessels are easier to segment, while smaller and more complex vessels remain the true bottleneck. The annotated datasets and podium-finish algorithms are made publicly available on Zenodo.

Background: Coronary artery bypass grafting (CABG) remains the standard of care for complex multivessel and left main coronary artery disease. However, current preoperative planning remains largely subjective, relying on qualitative interpretation of coronary CT angiography (CCTA), operator-dependent stenosis grading, and fragmented multi-software workflows. Invasive fractional flow reserve (FFR), the reference standard for physiologic lesion assessment, is infrequently acquired preoperatively, leaving distal anastomosis planning without an objective hemodynamic basis. Methods: We developed a fully automated, AI-powered platform that converts routine CCTA into a patient-specific CABG planning workflow through five integrated modules: nnU-Net based segmentation of coronary lumen and calcification; quantitative morphological and topological characterization generating more than thirty descriptors; automated stenosis detection using a local reference-radius formulation; a nine-point composite scoring framework for distal anastomosis site selection incorporating luminal caliber, landing-zone length, calcification burden, distal perfusion reserve, and bifurcation proximity; and interactive virtual graft construction coupled to a distributed reduced-order solver for pre- and post-bypass FFR estimation. Results: Lumen segmentation achieved a mean Dice similarity coefficient of 0.96 {+/-} 0.01, whereas calcium segmentation achieved 0.73 {+/-} 0.15 on the held-out cohort. Platform-derived FFR demonstrated strong agreement with invasively measured FFR (r=0.96, mean absolute relative difference 1.73 {+/-}1.42%) across the evaluated lesions, supporting the physiologic validity of the reduced-order hemodynamic solver. End-to-end analysis from raw CCTA to hemodynamic assessment and virtual graft planning was completed in approximately seven minutes per case on a standard workstation, representing a substantial reduction in processing time compared with conventional multi-tool and CFD-based workflows. Conclusions: The proposed platform demonstrates the feasibility of rapid, reproducible, and physiology-informed CABG planning using routine CCTA. By integrating anatomical characterization, automated target-site analysis, virtual graft construction, and reduced-order hemodynamic assessment into a single workflow, the framework provides objective, quantitative surgical decision support compatible with routine clinical workflows. Keywords: Coronary artery bypass grafting (CABG); Fractional flow reserve (FFR); Coronary CT angiography (CCTA); Surgical planning