Journal of Molecular and Cellular Cardiology

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: Pediatric dilated cardiomyopathy (DCM) is a leading cause of heart failure and transplantation, with variable prognosis and high early mortality. This study developed and validated a nomogram predicting short-term mortality risk to guide clinical decisions. Methods: The data were sourced from the Pediatric Cardiomyopathy Database at Shandong Provincial Hospital. Cox regression analysis was conducted to determine outcome-associated factors, and a nomogram was developed to estimate 1, 3, and 5year mortality risks for children with DCM. Model effectiveness was assessed through the concordance index (C-index) and area under the receiver operating characteristic curve (AUC). Additionally, calibration curves and decision curve analysis (DCA) were employed to evaluate the model's predictive accuracy and clinical relevance. Results: A cohort of 106 children diagnosed with primary DCM and who underwent genetic analysis was studied, with a median diagnostic age of 10 months (ranging from 5 to 84 months), comprising 50 girls (47.2%). The rate of detecting genetic mutations was 28.3%, uncovering 14 gene variants linked to DCM, with TTN mutations being the most common. Both univariate and multivariate Cox regression analyses indicated that both sex and NT-proBNP levels had a significant impact on survival rates among pediatric DCM patients.The model exhibited strong discriminative performance, calibration, and clinical net benefit, as assessed by the C-index, calibration plots, and decision curve analysis (DCA). Conclusions: The prediction model created in this research shows strong accuracy in forecasting survival rates at 1, 3, and 5 years for children with DCM, highlighting its significant relevance in clinical settings.

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.

Background: Post-operative hypotension and vasoplegia are well recognised following cardiac surgery but remain poorly characterised after major non-cardiac surgery, despite associations with acute kidney injury (AKI), cardiovascular complications, and increased mortality. Dysregulation of the renin angiotensin aldosterone system (RAAS) may underpin haemodynamic instability in this setting, yet data in abdominal surgery are limited. Objectives: The POLECAT (Perioperative delta Renin) study aims to determine whether changes in circulating renin concentration (delta renin) from pre-operative baseline to the early post-operative period are associated with post-operative vasoplegia in patients undergoing major abdominal surgery requiring intensive care admission. Methods: POLECAT is a single-centre, prospective observational study conducted at a UK tertiary referral hospital. Adult patients undergoing planned or emergency abdominopelvic surgery with anticipated intensive care admission are enrolled. Blood samples are obtained pre-operatively, within four hours post-operatively, and on post-operative day one to measure renin and a panel of endothelial, renal, and immune biomarkers. The primary outcome is post-operative vasoplegia, defined as the requirement for a vasopressor infusion at 08:00 on post-operative day one. Secondary outcomes include alternative vasoplegia definitions, AKI (KDIGO criteria), vasopressor burden, organ dysfunction, cardiovascular complications, length of stay, and mortality. Multivariable regression, receiver operating characteristic analyses, and predefined subgroup analyses will be performed, with sensitivity analyses addressing missing data. Conclusions: This study will clarify the relationship between peri-operative RAAS dysfunction and vasoplegia following major abdominal surgery. Findings may support biomarker-guided risk stratification and inform future interventional trials targeting haemodynamic instability in this high-risk population.

Background: Heterotopic caval valve implantation using the TricValve(R) (OrbusNeich P&F) is a unique interventional approach for treatment of severe Tricuspid Regurgitation in patients who are deemed ineligible for surgery. Given the complexity and novelty of TricValve(R) implantation, there is a pressing need for robust clinical data to evaluate its safety, efficacy, and long-term outcomes. Our study assesses the clinical results of patients followed up for 1 year from our center. Methods: Retrospective, single center registry involving patients who have undergone TricValve(R) Transcatheter Bicaval Valves System (OrbusNeich P&F) implantation for the treatment of severe tricuspid regurgitation. Results: Fourteen patients were included. The mean age was 67.5 {+/-} 8.7 years, with high surgical risk (mean EuroSCORE II 6.1 {+/-} 3.7). Procedural success was achieved in thirteen patients, with no reported in-hospital mortality or stroke among all fourteen patients. At 1-year, significant improvements were observed in New York Heart Association (NYHA) functional class (86% Class III at baseline to 0% Class III at 1 year, P=0.002) and Kansas City Cardiomyopathy Questionnaire (KCCQ-12) scores (mean 32.0 {+/-} 7.4 to 42.4 {+/-} 12.0, P=0.015). TR Regurgitant Volume significantly decreased (65.5 {+/-} 16.9 ml to 38.2 {+/-} 13.6 ml, P=0.005). No deaths or strokes occurred during follow-up. Rehospitalization due to heart failure occurred in 14% (2 out of 14) of patients. Conclusion: In this single-center registry of high-risk patients, TricValve(R) implantation was associated with a favorable safety profile, significant reduction in tricuspid regurgitant volume, and meaningful improvements in functional status and quality of life at 1 year follow-up.

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: 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 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.

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

Background: Citrin deficiency, caused by biallelic pathogenic variants in SLC25A13, must be identified early to prevent serious complications such as hyperammonemia and liver failure. However, clinical diagnosis is often delayed due to its nonspecific presentation and limited sensitivity of amino acid-based newborn screening methods. Although genome-based evaluations are being investigated to address these issues, concerns about their cost, turnaround time, variant interpretation ability, and data handling highlight the need for a more practical yet reliable alternative. We investigated the feasibility of applying proteomic approach on dried blood spots (DBS), which are routinely used in newborn screening. Methods: We performed untargeted liquid chromatography-tandem mass spectrometry to analyze the proteome of DBS using a previously developed "non-targeted analysis of non-specifically DBS-absorbed proteins" (NANDA) workflow. SLC25A13 protein abundance was quantified in individuals with biallelic loss-of-function mutations, compound loss-of-function/missense mutations, and heterozygous carriers; this was also evaluated in healthy and diseased controls representing relevant differential diagnoses. To leverage proteomic information, we derived a multivariate proteomic signature using feature selection and evaluated its performance with leave-one-out cross-validation. Biological relevance was assessed by enrichment analysis, and complementary transcriptomics was performed using RNA sequencing. Results: A total of 7,474 proteins, including SLC25A13, were consistently detected in DBS. SLC25A13 was undetectable in individuals with biallelic loss-of-function mutations. However, individuals with compound loss-of-function/missense genotypes showed reduced but measurable SLC25A13 levels, comparable to those observed in heterozygous carriers. In contrast, a compact 15-protein signature accurately identified individuals with compound loss-of-function/missense genotypes (AUC, 0.99; sensitivity, 1.00; specificity, 0.95). The signature was enriched for Ca2+-response, and transcriptomics showed downregulation of genes related to multimodal ion channels in affected individuals compared to controls. Conclusions: DBS-based proteomic profiling may assist in the diagnosis of citrin deficiency through SLC25A13-quantification and a biologically plausible multivariate signature. More broadly, this strategy offers a promising new diagnostic layer for protein disorders, providing a proteomic readout in a clinically practical DBS format with potential utility for future diagnostic and screening applications.

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: Regular exercise is a highly effective yet underutilized strategy to reduce cardiometabolic disease burden. Whether brief structured exercise programs confer lasting cardiometabolic benefits remains unclear. The STRRIDE-Prediabetes Reunion study examined legacy effects of exercise training on cardiorespiratory fitness, body composition, and cardiometabolic health. Methods: Seventy-three participants (71.3 {+/-} 7.2 years; 64% women; 77% White) completed Reunion assessments ~11 years after completing one of four 6-month interventions differing in exercise amount, intensity, and inclusion of diet-induced weight loss. Linear mixed effects models evaluated longitudinal trajectories; secondary analyses examined baseline-adjusted associations among short-term intervention response and Reunion outcomes. Results: Abdominal adiposity improved across all groups from baseline to Reunion, with waist circumference decreasing ~3 cm over the follow-up period. In contrast, cardiorespiratory fitness and fat-free mass declined significantly. A significant group by time interaction was observed for total fat mass (p=0.01), with continued fat mass reductions observed in women randomized to high amount exercise. After baseline adjustment, greater short-term intervention response was associated with more favorable Reunion outcomes across fitness, body composition, and cardiometabolic domains; fat-free mass showed the strongest association ({beta}=0.84, p<0.0001). Conclusions: In older adults with prediabetes, the STRRIDE-Prediabetes interventions produced several legacy health effects persisting more than a decade later. Legacy effects differed by sex and exercise dose, and short-term intervention response relative to baseline was associated with long-term outcomes, supporting targeted exercise strategies to preserve cardiometabolic health and functional independence with aging.

Congenital heart disease contributes substantially to chronic morbidity, growth impairment, and repeated healthcare utilization among children. Evidence regarding nutritional burden and outpatient healthcare patterns among pediatric patients with congenital heart disease in Indonesia remains limited. This study aimed to evaluate clinical characteristics, nutritional status, healthcare utilization, and factors associated with malnutrition among pediatric outpatients with congenital heart disease at Adam Malik General Hospital, Indonesia. A retrospective observational study was conducted using medical records of pediatric outpatients treated between January and December 2024. Demographic characteristics, cardiac diagnoses, nutritional status, complications, and outpatient visit history were analyzed. Logistic regression analysis was performed to identify factors associated with malnutrition. A total of 606 pediatric outpatients were included. Non cyanotic congenital heart disease predominated the cohort, with ventricular septal defect representing the most common diagnosis followed by patent ductus arteriosus and atrial septal defect. Nearly half of all patients demonstrated underweight or severe underweight nutritional status, while pulmonary hypertension emerged as the most frequent complication. Younger pediatric age groups and higher cumulative clinical burden independently increased the odds of malnutrition. Children with congenital heart disease at this tertiary referral center carried a substantial nutritional and clinical burden. Early nutritional surveillance and integrated long term outpatient management may improve growth outcomes and reduce chronic disease burden in resource limited settings.

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.

Acute coronary syndrome (ACS) remains a major contributor to cardiovascular mortality despite advances in emergency cardiovascular intervention and coronary revascularization strategies. This retrospective cohort study evaluated the association between early hemodynamic instability and major adverse cardiovascular events (MACE) among 1,248 ACS patients admitted between January 2023 and December 2025. Patients were categorized into stable and unstable groups based on early emergency department hemodynamic assessment including blood pressure, lactate level, Killip classification, vasopressor requirement, and cardiac output estimation. The primary outcome consisted of 30-day MACE including cardiovascular mortality, recurrent myocardial infarction, cardiogenic shock, ventricular arrhythmia, and urgent revascularization. A total of 372 patients (29.8%) demonstrated early hemodynamic instability and experienced significantly higher rates of cardiogenic shock, ventricular arrhythmia, mechanical ventilation, ICU admission, and 30-day mortality compared with stable patients. Multivariable regression analysis identified serum lactate >4 mmol/L (adjusted OR 3.42; 95% CI 2.10-5.11), systolic blood pressure <90 mmHg (adjusted OR 2.96; 95% CI 1.88-4.47), and left ventricular ejection fraction <35% (adjusted OR 2.71; 95% CI 1.77-4.09) as independent predictors of MACE. Early hemodynamic instability was strongly associated with poor short-term cardiovascular outcomes, suggesting that integrated emergency hemodynamic profiling may improve early risk stratification and facilitate timely cardiovascular intervention.

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.

Clonal hematopoiesis of indeterminate potential (CHIP) represents the age-related expansion of hematopoietic stem cells with preleukemic mutations. However, its association with all-cause and cause-specific mortality has not been well characterized in older adults. We aimed to evaluate whether CHIP is associated with all-cause and cause-specific mortality in a population of older women in the United States. Our study included 6,704 participants in the Women?s Health Initiative Long Life Study (WHI-LLS) without hematologic malignancy. The co-primary exposures were any CHIP (variant allele frequency [VAF] [&ge;] 2%) and large CHIP (VAF [&ge;] 10%), and the primary outcome was all-cause mortality. Multivariable-adjusted Cox proportional hazards models tested the associations of CHIP and CHIP subtypes with all-cause and cause-specific mortality. Any CHIP and large CHIP were independently associated with all-cause mortality, with multivariable-adjusted hazard ratios (aHRs) of 1.12 (95% confidence interval [CI] 1.04-1.21; P = 0.003) and 1.28 (95% CI 1.15-1.43; P < 0.001), respectively. In gene-specific analyses, non-DNMT3A CHIP was associated with all-cause mortality (aHR: 1.22 [95% CI: 1.12-1.34], P < 0.001), while DNMT3A CHIP was not (aHR: 1.07 [95% CI: 0.98-1.18], P = 0.13). Furthermore, large CHIP was associated with cardiovascular (aHR: 1.29 [95% CI: 1.08-1.55], P = 0.006), cancer (aHR: 1.49 [95% CI: 1.11-2.02], P = 0.009), and neurologic (aHR: 1.40 [95% CI: 1.07-1.84], P = 0.02) death. In this cohort of older women, CHIP, particularly large clones and non-DNMT3A CHIP, was associated with all-cause and cause-specific mortality. These findings suggest that clonal size and subtype may differentially influence mortality risk.

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.