European Heart Journal

Background Patients with normal perfusion, normal myocardial flow reserve (MFR) and no coronary artery calcium (CAC) on myocardial perfusion imaging are considered low risk. Yet, adverse events still occur and no routinely reported imaging marker stratifies residual risk. This study aims to determine whether fully automated ascending aortic calcification (AAC) from the attenuation correction CT stratifies risk in these patients. Methods In the multicenter REFINE-PET registry, AAC was quantified from non-contrast CT using deep learning aortic segmentation and Agatston scoring. Triple-normal was defined as stress total perfusion deficit (TPD) <5%, MFR >2 and CAC 0. The primary endpoint was cardiovascular death, myocardial infarction or heart failure admission, with heart failure admission as key secondary endpoint. Cox models were adjusted for clinical confounders. Results Of 21,923 patients, 3,580 (16.3%) were triple-normal, of whom 1,322 (36.9%) had AAC (median Agatston 65, IQR 22-212). Agreement with three blinded readers was good to excellent (Intraclass correlation coefficient 0.87-0.90). Over a median follow-up of 52 months (IQR 26-69), 194 primary events occurred. Per standard deviation, AAC was independently associated with the primary endpoint (adjusted HR 1.24, 95% CI 1.09-1.40; p<0.001), heart failure admission (adjusted HR 1.30, 95% CI 1.10-1.55; p=0.003) and all-cause mortality (adjusted HR 1.17, 95% CI 1.04-1.32; p=0.009). AAC improved model fit beyond clinical factors, MFR and TPD (p< or =0.009), with modest gains in discrimination ({Delta}C 0.007-0.009). Conclusions In patients with normal PET readouts, automated AAC was independently associated with adverse outcomes, most strongly heart failure admission, beyond clinical risk factors, perfusion and flow.

Observational studies suggest an association between COVID-19 and acute myocardial infarction (AMI), however, whether this relationship is causal remains unclear. We conducted a multi-ancestry Mendelian randomization (MR) study across European, East Asian, South Asian, and African populations, evaluating three COVID-19 phenotypes: very severe COVID-19, hospitalized COVID-19, and general infection association with AMI. GWAS summary statistics were obtained from the COVID-19 Host Genetics Initiative Round 7 and UK Biobank/Biobank Japan for AMI. Inverse-variance weighted (IVW) MR was the primary method, with fixed- or random-effects models selected according to heterogeneity test. MR-Egger, weighted median and weighted mode were conducted as sensitivity analyses. In European ancestry, genetic liability to very severe COVID-19 and hospitalized COVID-19 was slightly inversely associated with AMI risk, but without statistical significances across sensitivity analyses. Hospitalized COVID-19 showed a suggestive but non-significant inverse association in South Asian ancestry. No significant associations were identified in East Asian or African ancestries. Our findings did not support a robust causal association between COVID-19 susceptibility or severity and AMI risk across ancestries, suggesting that the observed cardiovascular burden may be driven more by acute pathophysiological mechanisms than shared genetic architecture.

Background: Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of the more than 64 million heart failure cases globally, yet its pathophysiology is incompletely understood, its molecular determinants are poorly defined, and disease-specific therapies remain limited. Comprehensive characterization of the cardiac motion abnormalities central to HFpEF has not been feasible at the population level. Methods: We developed a deep learning framework integrating image segmentation with optical flow motion analysis and applied it to standard cine cardiac magnetic resonance images from 83,569 UK Biobank participants, deriving 32 myocardial and inner cavity velocity phenotypes spanning the cardiac cycle, including mid-diastolic velocities not previously quantified at population scale. We examined the prognostic relevance, genetic architecture, and candidate causal mediators of the optical flow velocity phenotypes. Results: In a pragmatically defined HFpEF subcohort, mid-diastolic and late-diastolic optical flow velocities were reduced relative to healthy reference participants, while higher systolic left ventricular myocardial velocity was associated with lower all-cause mortality (HR 0.61 per SD; 95% CI 0.45-0.82). Genome-wide association analyses identified 12 risk loci associated with optical flow velocity phenotypes. Phospholamban (PLN), the canonical regulator of sarcoplasmic reticulum calcium reuptake, demonstrated the broadest pleiotropy across all cardiac phases. SOX5, a transcription factor involved in extracellular matrix development, showed significant genome-wide association exclusively with mid-diastolic velocities. Mendelian randomization implicated RABGAP1L as a candidate causal mediator of early diastolic velocity (IVW {beta} = -0.255 per NPX for early diastolic right ventricular inner circumferential velocity; p = 5.49 x 10^-22), nominating a calcium-handling pathway in diastolic dysfunction. Conclusion: Genetic and causal-inference evidence implicates intracellular calcium handling and extracellular matrix remodeling as candidate mechanisms underlying diastolic dysfunction. Together, this work establishes deep-learning-enabled cardiac motion phenotyping as a scalable approach to interrogate the molecular basis of HFpEF and nominates candidate targets for therapeutic development.

ImportanceCardiovascular disease remains the leading cause of mortality worldwide. Although machine learning models have demonstrated strong predictive performance, limited attention has been given to uncertainty quantification and gender-specific risk factor identification, which are essential for clinically trustworthy artificial intelligence. ObjectiveTo develop and evaluate an interpretable and uncertainty-aware machine learning framework for cardiovascular disease prediction that integrates an association study on biomarkers, explainable artificial intelligence, and gender-stratified risk assessment. Design, Setting, and ParticipantsThis retrospective observational study utilized the UCI Heart Disease dataset comprising 918 participants, including 725 males and 193 females. Demographic, clinical, laboratory, and exercise-related variables were analyzed. Missing values were addressed using a hybrid imputation strategy combining MICE and supervised Random Forest imputation. MethodsAn ensemble machine learning imputation strategy was developed to address missingness. Then advanced machine learning models were developed and evaluated using stratified training/testing partitions and 5-fold cross-validation. Predictive performance was assessed using several evaluation metrics. Uncertainty was quantified through bootstrap resampling, predictive entropy, and mutual information. Linear Double machine learning and Causal Forest double machine learning were applied to estimate gender-specific averages and association studies for risk factors. ResultsRandom Forest achieved the strongest and most stable predictive performance across male and female cohorts, with ROC-AUC values exceeding 0.90 and robust cross-validation performance. Hybrid imputation improved classification performance, increasing the F1-score from 0.87 to 0.89 and ROC-AUC from 0.90 to 0.92. The causal association study analyzes identified the number of major vessels, ST-segment slope, thalassemia, and exercise-induced angina as the strongest determinants of heart disease, with notable differences observed between male and female subgroups. Conclusions and RelevanceIntegrating predictive modeling, uncertainty quantification, and association study machine learning provides a robust and clinically interpretable framework for cardiovascular disease risk assessment. The proposed approach improves prediction reliability while identifying gender-specific causally important risk factors, supporting precision cardiovascular medicine and trustworthy clinical artificial intelligence.

Background: Tirzepatide and semaglutide improve functional status and heart failure (HF) events in patients with obesity and HF with preserved ejection fraction. Tirzepatide has been associated with greater control of cardiometabolic risk factors in patients with obesity compared to semaglutide. Whether tirzepatide is associated with lower risk of new-onset HF than semaglutide in patients with obesity is underexplored. Methods: A retrospective cohort study was conducted using data pooled from the TriNetX platform. Patients with obesity who initiated therapy with tirzepatide or semaglutide during the period Jun 4, 2021 to Aug 13, 2026 were identified and 1:1 propensity-score matched to produce two study cohorts. The one-year incidence of new-onset HF was calculated and compared between the two cohorts. Secondary outcomes included new-onset systolic HF, new-onset diastolic heart failure, new-onset atrial fibrillation or flutter, all-cause mortality, and hospital encounters. Cox proportional hazards models were fitted to calculate hazard ratios (HR) along with 95% confidence intervals (CI). Results: Two well-matched cohorts (N=424,269 in each) were formed. The incidence of new-onset HF was lower in the tirzepatide group (1.0% vs. 1.3%; absolute risk difference -0.3%, 95% CI -0.35 to -0.26; HR 0.9, 95% CI 0.86[boxh]0.93). The tirzepatide group were also at lower risk of all-cause mortality (HR, 95% CI: 0.8, 0.77[boxh]0.91) and new-onset systolic HF (0.8, 0.79[boxh]0.92). All other secondary outcomes occurred at similar rates in both study groups. Conclusion: Among patients with obesity, tirzepatide therapy was associated with lower risk of new-onset HF compared to semaglutide although the effect sizes were modest.

Background Several disease-modifying agents for transthyretin amyloid cardiomyopathy (ATTR-CM) have been investigated, but differences in trial design and background stabilizer use complicate interpretation of their efficacy. This meta-analysis assessed their efficacy overall and by background stabilizer use. Methods PubMed, Embase, and the Cochrane Library were searched through September 2026 for phase III randomized, placebo-controlled trials of disease-modifying therapy in ATTR-CM. Primary endpoints were all-cause mortality, 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), pooled with a random-effects model. Treatment effects were compared between the monotherapy and baseline stabilizer strata using a mixed-effects model. Results Five trials (ATTR-ACT, APOLLO-B, ATTRibute-CM, HELIOS-B, CARDIO-TTRansform; N=3497) were included. Disease-modifying therapy reduced all-cause mortality (risk ratio, 0.76; 95% confidence interval [CI], 0.66-0.87; I2=0%) and improved 6MWD (pooled standardized mean difference [SMD], 0.43; 95% CI, 0.20-0.67), KCCQ-OS score (SMD, 0.37; 95% CI, 0.19-0.55), and NT-proBNP (SMD, -0.53; 95% CI, -0.89 to -0.18). The mortality benefit was similar whether therapy was given alone or added to a background stabilizer (pooled risk ratio, 0.77 vs. 0.71; P for interaction = 0.59), but treatment effects on 6MWD (pooled SMD, 0.49 vs. 0.14), KCCQ-OS score (0.44 vs. 0.07), and NT-proBNP (-0.65 vs. -0.13) were smaller among patients receiving a background stabilizer (P for interaction = 0.012, <0.001, and 0.029, respectively). Conclusion Disease-modifying treatments reduced all-cause mortality and favored functional capacity, health status, and NT-proBNP outcomes in patients with ATTR-CM. Exploratory subgroup analyses showed smaller treatment effects on 6MWD, KCCQ-OS score, and NT-proBNP among patients receiving a background stabilizer, with no statistically significant difference in the mortality effect according to baseline stabilizer use.

Background: Coronary perivascular fat attenuation index score (FAI-Score) on coronary computed tomography angiography (CCTA) quantifies vascular inflammation and predicts cardiac mortality in symptomatic cohorts. However, its prevalence, anatomical distribution, and clinical correlates in asymptomatic primary prevention populations remain uncharacterized. Methods: In an IRB-approved prospective study across two clinical sites, 84 consecutive asymptomatic adults (mean age 53.7 {+/-} 8.6 years; 63.1% men) with no prior coronary artery disease underwent screening CCTA and comprehensive clinical, metabolic, and biomarker profiling. AI-standardized FAI-Score was quantified across three epicardial vessels (LAD, LCx, RCA). High and very high perivascular inflammation were pre-specified as any vessel [&ge;]75th and [&ge;]90th percentiles, respectively. Luminal stenosis and plaque were graded using CAD-RADS 2.0. Results: Elevated FAI-Score ([&ge;]75th percentile) was present in 42.9% of participants (36/84; 95% CI 32.8% - 53.5%), with 17.9% (15/84; 95% CI 11.1% - 27.4%) exhibiting very high inflammation ([&ge;]90th percentile). Multi-vessel inflammation was identified in 17.9% (15/84), with the RCA most frequently involved ([&ge;]90th percentile in 13.1%). Standard circulating biomarkers, including ApoB, non-HDL-C, HbA1c, and PREVENT-ASCVD 10-year risk showed no association with binary inflammation. Systemic hs-CRP (median 0.8 mg/L) exhibited an inverse correlation with maximum vessel FAI-Score (Spearman {rho}=-0.27, p=0.014). Men demonstrated higher rates of elevated FAI-Score than women (52.8% vs. 25.8%, p=0.016; [&ge;]90th percentile: 26.4% vs. 3.2%, p=0.007). Strikingly, 46.2% (30/65) of participants with normal luminal anatomy (CAD-RADS 0) and 47.2% (25/53) with zero plaque burden harbored elevated FAI-Score; all 15 individuals with very high FAI-Score had CAD-RADS 0 (Fisher's exact p=0.018). Body mass index was the sole secondary correlate surviving false discovery rate correction (AUC = 0.71, p=0.001, all-test FDR q=0.028). Regularized multivariable models showed modest out-of-sample discrimination for FAI-Score elevation (cross-validated AUC = 0.71). Conclusions: Coronary perivascular inflammation is common among asymptomatic adults and frequently uncouples from structural plaque and luminal stenosis. Routine circulating biomarkers and clinical risk calculators fail to identify inflamed vessels, highlighting FAI-Score as an independent dimension of primary cardiovascular risk assessment.

Background: Glucagon-like peptide-1 receptor agonists (GLP1-RA) improve cardiovascular outcomes in patients with type 2 diabetes (T2D) and obesity, and more recently they have been shown to be beneficial in patients with obesity and heart failure with preserved ejection fraction. Their role in patients with heart failure and reduced ejection fraction (HFrEF) and T2D remains underexplored. Methods: A retrospective cohort study was conducted using data pooled from the TriNetX platform. Patients with T2D and HFrEF who were initiated on GLP1-RA therapy during the period May-13-2026 to Jun-6-2026 were identified. One:one propensity-score matching with controls was performed. Time-to-event analysis was conducted to compare the one-year incidences of all-cause mortality and a primary composite outcome of acute myocardial infarction, ischemic stroke and acute heart failure, between the two matched-cohorts. Secondary outcomes included individual components of the primary composite outcome and any inhospital encounter. Results: Two well-matched cohorts with 38,879 patients in each were formed. Patients treated with GLP1-RAs had a lower incidence of all-cause mortality (4.2% vs. 12%; absolute risk difference [ARD] -7.8, 95% CI -8.17 to -7.41; HR 0.4, 95% CI 0.34[boxh]0.38) and the primary composite outcome (32.5% vs. 48.3%; ARD -15.8, 95% CI -16.47 to -15.11; HR 0.6, 95% CI 0.57[boxh]0.60) compared to the control group. The GLP1-RA group were also at lower risk of all secondary outcomes compared to the control group. Conclusion: In a real-world study, GLP1-RA therapy was associated with lower risk of all-cause mortality and cardiovascular outcomes in patients with T2D and HFrEF.

Background Cardiovascular prevention is organized around target metrics. Blood pressure, LDL cholesterol, and A1c define treatment targets, quality metrics, and, implicitly, who is considered safe. Yet a value below a cutoff is a correlative measurement, not an outcome. We tested whether social context recorded before the measurement separated subsequent cardiovascular events among people whose numbers already met the cutoff. Methods In this retrospective cohort study, we analyzed All of Us participants without recorded cardiovascular disease and with low comorbidity in three separately indexed cohorts: systolic blood pressure (SBP), LDL cholesterol, and A1c. A preindex score combined household income, education, food security, physical activity, and ZIP-linked deprivation, standardized against a fixed pooled reference of 325,652 eligible people. The outcome was first myocardial infarction, ischemic stroke, or heart failure. A sensitivity analysis indexed participants at only events recorded in inpatient or emergency settings. Results The SBP, LDL, and A1c cohorts included 19,525, 16,578, and 18,539 participants with 144, 129, and 191 events. Each one-SD more favorable score was associated with lower hazard: HR 0.611 (95% CI 0.498-0.749), 0.631 (0.512-0.778), and 0.544 (0.457-0.648), respectively. Below each study cutoff (SBP <140 mmHg, LDL <100 mg/dL, A1c <8%), less favorable context had event rates of 3.39 versus 1.68, 7.16 versus 2.05, and 8.67 versus 2.34 per 1,000 person-years. In a one-year analysis restricted to 2019-2023 index dates, the corresponding adjusted HRs were 0.530, 0.336, and 0.365. In the sensitivity cohorts (54,338, 41,451, and 33,607 participants; 493, 288, and 316 events), HRs were 0.732 (0.657-0.815), 0.660 (0.573-0.761), and 0.631 (0.552-0.722). Conclusions A biomarker below the study cutoff did not identify a uniform, low-risk population. Social context recorded before the measurement separated cardiovascular events after adjustment for the measured value and clinical factors. Risk assessment that stops at the number misses this variation.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a pan-ethnic disease, at least as common in Black as in White Americans, yet Black patients reach specialist care later, undergo septal reduction less often, and die sooner. Whether the defining trials enrolled representatively is unknown. We sought to measure Black participation in the landmark HCM trials against three expectations of increasing stringency, and to test whether trial site geography or quantitative eligibility thresholds account for the shortfall. METHODS: Of 197 registered interventional HCM trials, 32 met prespecified landmark tiers; demographics were extracted for 16 and 13 reported race. The Black share of Black plus White participants was pooled by random-effects meta-analysis and compared with the US adult population, with each trial?s own site counties, and with a disease-referenced echocardiographic expectation. Site geography and eligibility thresholds were tested using site addresses, census data, and NHANES. RESULTS: Across 13 trials, 70 of 1,780 Black or White participants were Black. The pooled Black share was 3.98% (95% CI 2.68-5.86), against a population expectation of 16.5%, giving a participation-to-prevalence ratio (PPR) of 0.24 (95% CI 0.16-0.36), the lowest of any racial and/or ethnic minority group. The clinical trial site network reached 63.7% of Black and 47.5% of White US adults, with geospatial analysis predicting 26.4% Black enrollment; however, every trial fell below this expectation. Quantitative eligibility thresholds closed only 2.0% of the enrollment gap. CONCLUSIONS: Black participation was about one quarter of the population expectation. Neither site geography nor eligibility thresholds explain it.

Background This study presents reference ranges for cardiovascular magnetic resonance (CMR)-derived myocardial strain from the Healthy Hearts Consortium, while evaluating variations by demographic characteristics (age, sex, and ethnicity) and technical factors (scanner vendor, magnetic field strength). We derived reference ranges and centile-based categories for ventricular, atrial, and rapid strain parameters. The prognostic relevance of these categories was assessed by examining their associations with incident cardiovascular events. Methods The dataset included 9,088 CMR studies. Automated image analysis pipelines were established using suiteHEART (NeoSoft Inc.) and cvi42 (Circle Cardiovascular Imaging). A three-step quality control framework was applied including exclusion of incomplete data, visual assessment of image and segmentation quality, and statistical outlier removal. Ventricular strain and strain rate were measured using both software solutions. Additional cvi42 derived metrics included velocity and displacement, annular plane systolic excursion metrics, and rapid strain parameters. Age- and sex-specific reference ranges were generated using lambda-mu-sigma (LMS) modeling with penalized splines. Reference ranges were defined as values between the 2.5th and 97.5th percentiles. For lower-tail classification, values below the 2.5th percentile were considered mildly out-of-range and values below the 0.5th percentile at least moderately out-of-range. Differences across scanner vendors (Siemens, Philips, GE) and magnetic field strengths (1.5 T vs. 3 T) were evaluated using adjusted linear models. The prognostic relevance of selected cvi42-derived categories was evaluated in approximately 45,000 UK Biobank participants using Cox regression adjusted for age, sex, and body mass index. Results After quality control, 8,975 CMR examinations (cvi42) and 8,992 (suiteHEART) were available for analysis; these represent software-specific analytic cohorts. Most exclusions occurred during visual quality control. Women had higher absolute ventricular and atrial strain values than men across all age groups. Left ventricular (LV) longitudinal strain and strain rate were slightly lower in older ages, whereas circumferential and radial parameters remained largely stable. Left atrial strain was also lower in older age groups, while right atrial strain did not vary by age. Annular plane systolic excursion and rapid strain metrics showed similar sex-specific patterns, with modestly lower atrial and displacement values in older groups. Ethnicity-related differences were modest, heterogeneous, and substantially smaller in magnitude than age- and sex-related differences. Technical effects were parameter specific. While LV longitudinal and circumferential strains were largely unaffected, radial strain was higher at 3 T and showed vendor-related differences. LMS-derived reference ranges and centile thresholds were applied both across all ethnicities and within ethnicity-specific analyses, and are presented stratified by age and sex. In the prognostic analysis, centile categories were most consistently associated with incident heart failure. LV longitudinal, circumferential, and radial strain below the 0.5th centile were associated with significantly increased risk of incident heart failure (HRs: 9.9 to 12.4, 95% CIs 7.00-13.90 to 8.49-18.06). Conclusion This study provides age- and sex-specific reference ranges and centile-based categories for CMR-derived strain parameters in a large reference population. Age and sex represent the primary determinants of myocardial deformation, whereas scanner-related effects are parameter-specific. Values in the lower extremes of the healthy reference distribution, particularly for LV strain, are associated with increased risk of incident heart failure. These findings enable standardized, centile-based classification of myocardial strain, facilitating consistent interpretation and improving risk stratification in research and clinical practice.

Background: Whether ethnoracial differences in cerebral small vessel disease (cSVD) appear in multimarker burden, particular MRI manifestations, or both, and how they relate to Life's Essential 8 (LE8) cardiovascular health and cognition, remain unclear. Methods: This cross-sectional study included 44,982 participants and an age- and sex-matched subsample of 1,426 with reviewed lacune and cerebral microbleed (CMB) ratings. White, South Asian, Black, Chinese and Mixed participants were compared on 0-2 (white matter hyperintensity [WMH]/enlarged perivascular space [ePVS]) and 0-4 (adding CMB and lacunes) composite scores and each marker. LE8 was related to WMH and composite burden, and cognitive means were compared by group. Models were age-, sex- and center-adjusted with false-discovery-rate correction. Results: Both composite scores differed across groups (0-2: P=0.00010; 0-4: P=0.0011), with greater burden in Black than South Asian (0-4: OR 1.66; 95% CI, 1.21-2.28) and Chinese participants (OR 2.36; 1.51-3.70), whereas Black-White contrasts were not detected. Black participants had higher WMH volume than White participants (=0.209; 0.110-0.308), robust to deprivation adjustment and segmentation method; South Asian participants had fewer ePVS (0.82; 0.72-0.93). No ethnoracial-group differences in lacune or CMB counts were detected after correction. Higher LE8 was associated with lower WMH volume (0.13 per SD; 0.17 to 0.09) and lower two-marker burden (OR 0.89 per SD; 0.87-0.91) without detected ethnoracial moderation. Black participants, who had the least favorable LE8 scores, and South Asian participants had lower global cognition than White participants (z 0.76 and 0.57 versus 0.24) despite differing WMH profiles; the pooled WMH-cognition association was null. Conclusions: Ethnoracial differences in multimarker cSVD burden were evident but marker-dependent: WMH showed the clearest Black-White difference; focal-lesion contrasts were inconclusive. Better cardiovascular health related to lower WMH and aggregate cSVD burden across groups, whereas cognitive differences did not track cSVD burden, supporting prospective prevention and cognition studies.

Background: Racial disparities in incident heart failure (HF) are well documented, yet the extent to which systemic inflammatory burden-shaped by structural determinants of environmental exposure-accounts for these disparities remains unquantified in multi-ethnic prospective cohorts. Methods: Among 6785 participants in the Multi-Ethnic Study of Atherosclerosis (enrolled 2000-2002; 4 racial/ethnic groups) followed for approximately 16 years, we estimated associations of 4 prespecified baseline inflammatory and hemostatic biomarkers (interleukin-6 [IL-6], C-reactive protein [CRP], fibrinogen, and D-dimer; per 1-SD increment) with incident HF (485 events) using Cox proportional hazards models. A composite inflammatory burden index was derived by principal components analysis. Race x biomarker multiplicative interactions were tested with Holm correction. Sequential biomarker adjustment quantified the percentage of the Black-White log-hazard difference explained relative to a clinical-only model. Robustness to ambient air pollution (PM2.5, NO2) was assessed in a geocoded subcohort. Results: All 4 biomarkers were independently associated with incident HF (IL-6: hazard ratio [HR], 1.20 [95% CI, 1.08-1.34]; D-dimer: 1.18 [1.06-1.30]; CRP: 1.14 [1.02-1.27]; fibrinogen: 1.13 [1.02-1.24]). The composite index (first principal component, 53.7% of variance explained) yielded an HR of 1.25 (1.12-1.39) per 1-SD increase. No multiplicative race x biomarker interaction was detected (all Holm-corrected P=1.0), indicating that the per-SD inflammatory hazard was directionally consistent across groups. Sequential biomarker adjustment reduced the Black-White log-hazard difference by 57.5%, a pattern consistent with-but not sufficient to prove-attenuation by inflammatory pathways. Associations were robust to PM2.5/NO2 co-adjustment. Conclusions: Inflammatory and hemostatic burden partially explains the Black-White disparity in incident HF. The null multiplicative interaction pattern indicates that per-unit biological risk is equitable across groups, consistent with differential structural exposure-rather than differential susceptibility-as a primary driver of disparity. Key Words: heart failure; inflammation; health equity; structural determinants; MESA; biomarkers

Abstract Routine blood tests can be used to calculate several inflammation-related ratios, including the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and platelet-to-lymphocyte ratio (PLR). These indices are widely reported as markers of cardiovascular risk, but it is unclear whether they provide comparable information or whether SII, which is derived from platelet count and NLR, adds anything beyond NLR. We analyzed two independent samples from the National Health and Nutrition Examination Survey (NHANES): 15,141 adults from 2005-2010 (development cohort) and 15,392 adults from 2011-2016 (validation cohort), each with complete blood count data and linked mortality follow-up. Survey-weighted Cox models, restricted cubic splines, multiple imputation, and model comparison were used, and the development model was applied to the validation cohort. During a median follow-up of 11.4 years, 795 cardiovascular deaths occurred in the development cohort; the validation cohort recorded 364 cardiovascular deaths over 5.75 years. In the development cohort, hazard ratios per 1-SD increase were 1.32 (95% CI 1.21-1.44) for NLR, 1.21 (1.12-1.32) for SII, and 1.13 (1.04-1.22) for PLR. When NLR and SII were entered together, only NLR remained associated (HR 1.49, 1.23-1.81). The validation cohort showed the same pattern: NLR was strongest (HR 1.35, 1.22-1.49), and neither SII nor PLR remained significant after mutual adjustment. The frozen model showed good discrimination (C-index 0.8991 to 0.9023) and calibration (slope 0.96). Adding NLR produced only a small improvement in discrimination, and reclassification results were inconsistent between cohorts.

Background: CADASIL caused by cysteine-altering NOTCH3 variants, the most frequent hereditary cerebral small vessel disease worldwide, is characterized by marked phenotypic variability. Mutation location within the EGFr domains of the NOTCH3 receptor has emerged as a key determinant of this variability. We investigated phenotypic variability and potential modifiers of CADASIL expression by comparing individuals harbouring the same pathogenic NOTCH3 variant across distinct recruitment settings in three European countries. Methods: We compared clinical features, MRI markers, and cardiovascular risk factors among individuals harbouring the p.Arg1231Cys NOTCH3 mutation across three distinct recruitment settings: a multigenerational founder population from Cilento, Italy (CILCAD), a population-based cohort from the UK Biobank (UKB), and a clinically referred cohort from a national referral centre in Lariboisiere Hospital, Paris, France (LRB). In addition, CILCAD carriers were compared with NON-Carriers from the same population. The NOTCH3 locus was finally analysed to define the shared haplotype in CILCAD and explore potential genetic contributions to phenotypic variability. Findings: By comparing populations from three European countries, this study showed marked context-dependent phenotypic variability associated with the sole pathogenic p.Arg1231Cys NOTCH3 variant. In CILCAD, a multigenerational founder population, the haplotype carrying the NOTCH3 mutation also predisposes to decreased LDL levels, resulting in an unusually low LDL cholesterol profile in this sample. Strikingly, these very low LDL levels were associated with a higher likelihood of stroke. Interpretation: In European carriers of NOTCH3 p.Arg1231Cys, factors beyond mutation location, including genetic background, may substantially shape disease expression, while exceptionally low LDL levels could paradoxically be associated with greater disease severity.

Aims. It is unknown whether large language models (LLMs) can predict a trial's result at the design stage, from the information available when it is registered. We tested three LLMs prospectively on the Late-Breaking Science programme of the European Society of Cardiology (ESC) Congress 2026. Methods and results. Of 139 trials, 50 were selected by pre-specified criteria, and predictions were locked and registered on the Open Science Framework before the congress. Claude Fable 5, GPT-5.5 and Gemini 3.5 Flash, without web access, received each title and an investigator-compiled summary of the registered design. They gave the probability that the primary endpoint would be met, and a point estimate with an 80% prediction interval for a locked effect measure. Results were adjudicated from publications (19) or presenters' slides (31). Of 48 scorable trials, 28 (58%) were positive. The area under the receiver operating characteristic curve was 0.80 (95% CI 0.66-0.92) for Claude, 0.79 (0.66-0.91) for GPT and 0.74 (0.59-0.87) for Gemini, with accuracies of 73%, 71% and 67%. Among 26 trials whose effect was reported exactly as locked, the direction was correct in 88% of predictions and the median multiplicative error of ratio estimates was about 15%. The 80% prediction intervals contained the observed effect in 73.1% (Claude), 84.6% (GPT) and 57.7% (Gemini). Conclusion. From the registered design alone, LLMs showed statistically significant discrimination between positive and negative trials and usually predicted the direction and approximate size of the effect. Such predictions might help trial design, and further studies are needed.

Background: Mitral valve prolapse (MVP) causes mitral regurgitation (MR), leading to volume overload and maladaptive left ventricular (LV) remodelling. Objective: To comprehensively characterize markers of maladaptive LV remodelling across MR severity grades in MVP using cardiovascular magnetic resonance (CMR), and their association with functional status. Methods: Patients with MVP undergoing 1.5T CMR (2016-2025) were stratified by MR fraction: mild<20%, moderate 20-39%, and severe [&ge;]40%. Exclusion criteria were significant coronary artery disease, rheumatic valve disease, mitral stenosis, previous mitral valve procedures, endocarditis or signs of primary cardiomyopathy. Global native T1, T2, extracellular volume (ECV), indexed ECV (iECV), indexed intracellular volume (iICV), and late gadolinium enhancement (LGE) were quantified. Indexed LV end-diastolic volume (EDVI) and the EDV-to-LV mass ratio (EDV/LVM-ratio) were also calculated as indices of LV remodelling and adaptive hypertrophy. Functional status was assessed by NYHA class. Results: Among 112 MVP patients (23 mild, 48 moderate, 41 severe MR) and 20 controls, LGE prevalence (17% vs. 46% vs. 51% vs. 0%) and the proportion with LV dilatation (46% vs. 67% vs. 88% vs 15%) rose progressively with MR severity. Increased EDVI, prevalence of LGE, higher EDV/LVM-ratio, global native T1 and iECV showed the strongest associations with more severe MR, whereas EDV/LVM-ratio, iECV and global native T1 were independently related to NYHA class[&ge;]II. Conclusions: CMR markers of maladaptive LV remodelling were abnormal across all MR grades and increased markedly with MR severity. Global native T1, iECV and EDV/LVM-ratio correlated most strongly with symptom burden, rather than MR severity per se.

BackgroundClonal hematopoiesis of indeterminate potential (CHIP) is associated with ageing and atherosclerotic coronary artery disease (CAD), but evidence has largely come from peripheral blood. Whether somatic mutational profiles differ between arterial tissue and blood, and whether hematopoietic clones are represented in arterial tissue, remain poorly understood. MethodsWe performed deep whole-exome sequencing on 302 blood granulocytes and 263 arterial tissues from patients undergoing coronary artery bypass graft surgery, including 221 matched blood-tissue pairs, with mean sequencing depths of 130.5X and 120.8X, respectively. Somatic variants were identified using Mutect2. Associations with age and CAD complexity, assessed using SYNTAX score, were evaluated using multivariable regression. Primary analyses focused on variants with variant allele fractions of 10-25%. ResultsCHIP was detected in 24/302 (7.9%) blood granulocytes, predominantly involving DNMT3A, TET2, and ASXL1. In contrast, somatic mutations in CHIP-associated genes in arterial tissues showed a distinct profile dominated by CALR, SETDB1, and PDSS2. Somatic mutation carrier status increased with age in blood ({beta} = 0.07, p = 0.02) and arterial tissues ({beta} = 0.06, p = 0.04). Blood CHIP was associated with lower SYNTAX score ({beta} = -1.05, p = 2.66 x 10-3), partly driven by DNMT3A carriers ({beta} = -1.06, p = 0.04), whereas arterial CALR mutations were associated with higher SYNTAX score ({beta} = 1.14, p = 0.03). Among 221 matched pairs, only four identical variants, involving CHEK2, DNMT3A, GNB1, and SRSF1, were detected in both compartments. Genome-wide analyses showed compartment specificity, with bile acid metabolism enriched among arterial tissue-specific mutations (PAdj = 0.038). ConclusionBlood and arterial tissues in CAD harbour distinct somatic mutational landscapes with limited cross-compartment sharing. These findings suggest that cardiovascular somatic mutations may reflect both hematopoietic and arterial tissue-associated processes and motivate cell-resolved and spatial studies to define their origins and roles in cardiovascular ageing.

BACKGROUND: Because of the high mortality rate associated with fulminant myocarditis (FM), there is limited evidence regarding the prognostic efficacy of endomyocardial biopsy (EMB). In this study, we aimed to evaluate the influence of EMB in the early phase after admission on treatment and prognosis in FM using a large-scale nationwide registry in Japan. METHODS: Patients with FM who required catecholamine or mechanical circulatory support between 2012 and 2017 from 235 hospitals across Japan were included. The primary outcome of death or heart transplantation within 90 days according to performance of early EMB were determined using Kaplan-Meier and Cox regression analyses. Factors associated with performance of early EMB, and subsequent medical treatment were analyzed. RESULTS: The median age of 736 patients with clinical FM was 56 years, and 407 patients (55%) received EMB. Most EMB (89%) were performed during the early phase (within 5 days of admission) and 63% were performed on the first day of admission. The prognosis of FM patients who underwent EMB was more favorable than that of those who did not based on the landmark analysis (log-rank test, P=0.04). Factor analysis demonstrated that FM patients who underwent EMB had a lower left ventricular ejection fraction, higher incidence of cardiogenic shock on admission, and higher rate of early mechanical circulatory support, as well as early initiation of corticosteroids and guideline-directed medical therapy (GDMT) for heart failure. Absence of any GDMT was associated with a less favorable prognosis on multivariate analysis (hazard ratio, 4.34 [95% CI, 3.14?6.01]; P<0.0001). CONCLUSIONS: Although performing EMB in the early phase after admission depends on disease severity in FM patients, it is associated with early initiation of advanced medical treatment and may contribute to improving the prognosis.

Background Cardiac amyloidosis is an increasingly recognized cause of heart failure in older adults, yet Colombian data, and data from the southwest of the country in particular, remain scarce. We describe the clinical, diagnostic, imaging and outcome profile of patients with cardiac amyloidosis at two high-complexity institutions in Cali. Methods Observational, descriptive, retrospective, two-center study. Patients were identified in the institutional registries of both centers using ICD-10 codes for amyloidosis, and clinical data were abstracted manually from medical records. Continuous variables are reported as median (interquartile range) and categorical variables as counts and percentages over the number of patients with available data. Results Thirty-two patients were analyzed (median age 77 years; 68.8% men). Heart failure (90.6%), atrial fibrillation (46.9%) and carpal tunnel syndrome (31.2%) were frequent. The etiological classification depended on the test considered: bone scintigraphy was positive (Perugini 2-3) in 23 of 26 patients studied (88.5%), but a monoclonal protein was screened for in only 22, and the full non-invasive criteria for ATTR were met in 16 of 32 (50.0%). Genetic testing was positive in 9 of 18 tested, and the variant was Val142Ile in all 8 patients in whom it was characterized. The working diagnosis was ATTR in 26 patients (81.2%) and AL in 6 (18.8%). Tafamidis was used in 37.5%. Eleven of the 31 patients with known vital status died (35.5%), and NT-proBNP was markedly higher among those who died (6640 vs 1186 pg/mL; p=0.003). Conclusions In this southwestern Colombian cohort, cardiac amyloidosis presented as the classic transthyretin phenotype, with the Val142Ile variant in all 8 patients in whom it was characterized. Bone scintigraphy was frequently positive, but screening for a monoclonal protein was often omitted, so only half the cohort met the full non-invasive criteria for ATTR. Mortality was high and closely associated with NT-proBNP.