Journal of the American College of Cardiology

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 Current management of pediatric dilated cardiomyopathy (DCM) in children relies on guideline-directed medical therapy (GDMT) extrapolated from adult heart failure. However, due to small sample size, randomized trials of GDMT agents in children have failed to demonstrate efficacy and mortality benefits seen in adults, suggesting fundamental differences in disease mechanisms. We hypothesized that distinct age-dependent transcriptional programs underlie this therapeutic discordance. Methods We performed comparative transcriptomic profiling using bulk RNA sequencing on explanted left ventricular tissue from pediatric (n=29) and adult (n=35) DCM patients (adult DCM from previously published data) compared with age-matched non-failing controls (n=22 pediatric, 14 adult). We analyzed differential gene expressions, pathway enrichment across disease etiologies, and the regulation of a conserved 430-gene {beta}1-adrenergic receptor gene signaling network ({beta}1-GSN) known to modulate remodeling in adult heart failure. Results Transcriptional signatures were profoundly distinct, with only 7.4% of differentially expressed genes shared between adult and pediatric cohorts. Pediatric DCM was characterized by transcriptional reprogramming and the activation of developmental pathways, including WNT/{beta}-catenin and Notch signaling. Conversely, adult DCM hearts were enriched for pathways associated with metabolic dysfunction, mitochondrial deficits, and inflammation. Crucially, while the {beta}1-GSN was desensitized and extensively remodeled in adults, the pathway remained activated in children, with only 4 of 430 network genes showing antithetical regulation. Conclusion The lack of pathological {beta}-adrenergic remodeling in children could provide a molecular explanation for the lack of clear efficacy of {beta}-blockers in this population. Collectively, these results suggest pediatric DCM represents a biologically distinct disease entity rather than an earlier manifestation of adult heart failure, and future therapeutic strategies must move beyond adult extrapolation to target pediatric-specific pathways.

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.

BackgroundGenetic studies using cardiac magnetic resonance (CMR) imaging have identified loci related to cardiac shape, but most focus on static morphology. The value of a dynamic cardiac shape atlas capturing both shape and function remains unknown. MethodsA dynamic shape atlas comprising CMR-derived shape models at end-diastole and end-systole was combined with genetic and outcome data in 36,992 UK Biobank participants. Dynamic shape principal components (PCs) describing >1% of variance were characterized, and tested for associations with prevalent and incident cardiometabolic diseases, including ischemic heart disease (IHD), heart failure (HF), significant atrioventricular block (AVB), and atrial fibrillation (AF), and independent predictive power alongside standard CMR measures. Genome-wide association studies (GWAS) were performed to identify candidate genes and biological pathways, and polygenic risk scores (PRS) were assessed for disease associations. Mendelian randomization (MR) was performed to test causality of observed disease associations. ResultsWe identified 14 dynamic cardiac shape PCs capturing 83.3% of total dynamic cardiac shape variance. These PCs captured distinct functional remodeling patterns such as variation in annular plane systolic excursion, while remaining only modestly correlated with standard CMR measures. All 14 PCs were associated with at least one incident cardiometabolic disease, with the strongest associations observed for incident IHD, HF, and AVB. Notably, incorporating dynamic shape PCs improved the prediction of incident IHD beyond standard CMR measures. GWAS identified 75 genetic loci associated with dynamic shape, including 14 variants previously unreported for cardiac traits, and candidate genes demonstrated enrichment in pathways related to cardiac development and contractile function. PRS derived from dynamic shape loci were significantly associated with multiple outcomes, most prominently HF. MR identified significant causal relationships between several PCs and cardiometabolic disease. ConclusionsDynamic cardiac shape features capture aspects of cardiac structure and function not fully represented by standard CMR measures. These features are strongly associated with incident cardiometabolic disease and provide new insights into the genetic architecture of cardiac remodeling. Clinical perspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIGenetic and outcome relationships with a dynamic statistical shape model capturing both left and right ventricles at end-diastole and end-systole. C_LIO_LIDemonstration of incremental value over existing cardiac shape models, through capture of functional remodeling not represented by standard imaging measures. C_LIO_LIIdentification of genetic susceptibility loci for dynamic cardiac shape, including 14 variants not previously reported for cardiac traits. C_LI What are the clinical implications?O_LIThe results enhance our understanding of the genetic architecture of dynamic cardiac shape and function in the general population and clarify their relationships with other cardiovascular endophenotypes and incident cardiometabolic diseases. C_LIO_LINewly identified candidate genes expand the biological pathways implicated in cardiac remodeling and provide targets for future functional and mechanistic studies. C_LIO_LIThe improved prediction of incident cardiometabolic disease, particularly ischemic heart disease, achieved by adding dynamic shape PCs to traditional CMR measures suggests potential value for their inclusion in evaluation of patients. C_LI

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. Hypertrophic cardiomyopathy (HCM) is a clinically variable disease in terms of onset and progression. Pathogenic MYBPC3 variants account for a substantial proportion of HCM diagnoses. This study sought to identify protein biomarkers associated with HCM severity. Methods. Olink-assayed plasma proteins of 144 MYBPC3 pathogenic variant carriers were tested for associations with HCM severity based on HCM diagnostic criteria (unaffected, mildly, or severely affected). The UK Biobank was used to replicate the identified proteins through considering time to onset of HCM (67 cases), cardiomyopathy (156 cases),and associations with cardiac MRI derived left ventricular maximum wall thickness (6,492 participants). Replicated proteins were further prioritised based on cardiac tissue expression and druggability, and annotated using pathway enrichment and association with onset of: heart failure (HF), dilated cardiomyopathy (DCM), sudden cardiac arrest (SCA), and ventricular arrhythmias (VA). Results. Among pathogenic MYBPC3 variant carriers, we identified 27 proteins associated with HCM severity. We independently replicated 21 proteins in the UK Biobank. Of the five prioritised proteins (NT-proBNP, GDF-15, FGF-23, ADM, and NCAM1), all but NT-proBNP were targeted by drugs with repurposing potential. The replicated proteins additionally associated with the incidence of HF (n=5), DCM (n=4), SCA (n=4), and VA (n=4). Conclusion. This study replicated 21 and prioritised five proteins associated with HCM severity in pathogenic MYBPC3 variant carriers. Replication in unselected HCM suggests the prioritised proteins are associated with HCM independent of genotype, providing important leads for plasma-based markers for diagnoses, disease monitoring, and drug targets.

BackgroundHypertrophic (HCM) and dilated (DCM) cardiomyopathy constitute the principal phenotypes of primary cardiomyopathy, yet both lack sufficient therapeutic options. Integrating genetic insights with detailed cardiac phenotyping offers a promising strategy to prioritize targets and elucidate their mechanisms of action. MethodsWe conducted an three-stage analysis. First, drug-target Mendelian randomization (MR) was performed using cis-acting protein (pQTL) and expression (eQTL) quantitative trait loci as genetic instruments for potential drug targets. Second, we examined causal associations between 82 cardiac magnetic resonance (CMR)-derived imaging traits and HCM/DCM risk in a CMR-based MR analysis. Third, mediation MR was employed to quantify the proportion of the genetic effect of prioritized drug targets on cardiomyopathy risk that was mediated through specific CMR phenotypes. ResultsOur analyses identified 19 and 13 potential therapeutic targets for HCM and DCM, respectively. CMR-based MR revealed that HCM risk was causally associated with increased right ventricular ejection fraction (RVEF) and greater left ventricular wall thickness, whereas DCM risk was linked to ventricular dilation, impaired myocardial strain, and altered aortic dimensions. Critically, mediation analysis established that these CMR traits served as significant intermediate pathways. The protective effect of ALPK3 on HCM risk was mediated through a reduction in myocardial wall thickness. Conversely, the effects of PDLIM5, HSPA4, and FBXO32 on DCM risk were exerted in part via alterations in aortic dimensions. ConclusionThis integrative genetic and imaging study systematically identify candidate therapeutic targets for HCM and DCM and delineates the specific CMR phenotypes through which they likely exert their causal effects. Our findings advance the understanding of disease pathogenesis and highlight new possibilities for improving the diagnosis and management of cardiomyopathy.

BackgroundHypertrophic cardiomyopathy (HCM) is a heritable trait with marked variability in expression and outcomes. Our aims were to discover new genetic loci associated with HCM and to test the effect of a new polygenic risk score (PRS) on incidence, phenotype and outcomes, stratified by sarcomere genotype status. MethodsA discovery genome-wide association study (GWAS) was performed on 2,284 HCM cases and 4,525 controls. Two fixed-effects meta-analyses combined our discovery GWAS with single-trait and multi-trait results from a published study. Discovered loci underwent comprehensive bioinformatic analysis including functional and druggability annotations. A PRS using loci from the two meta-analyses was evaluated for association with: HCM diagnosis in 411,213 individuals from UK Biobank (UKBB); imaging phenotypes in individuals without HCM; a composite endpoint (including all-cause mortality and transplantation) and sudden cardiac death (SCD) in 1,756 HCM cases. PRS analyses were stratified by sarcomere genotype status. ResultsThree loci were found in the discovery GWAS (BAG3, FHOD3 and novel locus PPP1R3A). In the meta-analyses, 70 unique loci were identified, four novel (MYPN, YWHAE, NOS1AP and OBSCN). Bioinformatic analyses identified NOS1AP as a candidate HCM gene. A new PRS was significantly associated with HCM diagnosis (hazard ratio [HR] 3.19, 95% CI:2.46-4.14, for top 5% vs lower 95%; HR 1.88, 95% CI:1.72-2.06, per SD increase). Significant associations were found between PRS and greater left ventricular (LV) wall thickness and higher LV ejection fraction in UKBB participants without HCM. Sarcomere-negative HCM cases in the top 20% of the PRS distribution had an increased risk of SCD (HR 2.72, 95% CI:1.03-7.17). ConclusionsWe report novel HCM loci. A new PRS predicted the risk of HCM development and associated imaging characteristics in the UKBB and outcomes in an HCM cohort.

Cardiovascular diseases (CVDs) are highly heritable, but pathogenesis at the organ and physiological level is still poorly defined. Polygenic risk scores (PRSs), which estimate individual genetic susceptibility to a disease, may allow for the identification of associated abnormal organ structures. Ultimately, identifying where cardiovascular polygenic risk manifests can guide early interventions, shape mechanistic hypotheses, and motivate prevention trials for cardiac remodelling. This study investigated the association between PRSs for five common CVDs [heart failure (HF), coronary artery disease (CAD), atrial fibrillation (AF), abdominal aortic aneurysm (AAA) and ischaemic stroke (IS)] and 28 imaging-derived phenotypes (IDPs) from cardiac magnetic resonance imaging of ~62,000 participants in UK Biobank. To investigate the cardiac features associated with elevated polygenic risk of CVDs, we tested CVD PRSs against cardiac IDPs and identified 97 significant associations (FDR [&le;] 0.05). We further identified 32 significant putative mediators between CVD PRSs and incident disease events, revealing that across CVDs, polygenic risk manifested as distinct patterns in cardiac structures. HF implicated all cardiac chambers, including left ventricular and left atrial dysfunction alongside enlarged aorta. AF was characterised by biatrial enlargement and reduced ejection fractions, most prominently in the left atrium but also involving left ventricular wall thickness. IS exhibited left ventricular hypertrophy and left atrial dysfunction, while CAD predominantly involved left ventricular hypertrophy. AAA was primarily characterised by enlarged descending aorta. Overall, cardiac IDPs mediated a substantial proportion of polygenic risk for CVDs, in particular for HF. Taken together, our results show that cardiac structure and function lie on the pathway between polygenic risk and cardiovascular events.

Background Functional mitral regurgitation results from interacting mechanisms whose relative contributions vary between atrial and ventricular subtypes and shift dynamically within each heartbeat, producing temporal patterns that static analyses cannot capture. Objectives To identify which structural determinants predict mitral regurgitation variability beat to beat using Granger causality within vector autoregression, focusing on papillary muscle dynamics across subtypes. Methods Frame-level echocardiographic time series from 41 patients (21 atrial, 20 ventricular; 1,959 frames) were z-score standardised within patient. Individual (lag 3) and pooled (lag 2) vector autoregression models tested whether left ventricular volume, left atrial volume, papillary muscle length, and annulus diameter Granger-predict mitral regurgitation area. Results Individual models revealed marked heterogeneity. In pooled analysis, left ventricular volume was the strongest Granger predictor at short lags (atrial p=0.011; ventricular p=0.006), while left atrial volume emerged at longer lags (lag 7: atrial p=0.043; ventricular p=0.011). Systolic papillary muscle length was not predictive. Full-cycle analysis revealed a subtype-specific dissociation: papillary muscle length Granger-predicted regurgitation only in the ventricular subtype (p=0.001), while regurgitation predicted papillary muscle displacement only in the atrial subtype (p<0.001). Left ventricular volume dominated within-beat prediction but lost cross-beat relevance in the ventricular subtype, while left atrial volume gained cross-beat predictive relevance in the atrial subtype. No structural determinant correlated with severity cross-sectionally. Conclusions Beat-to-beat vector autoregression and Granger modelling reveals heterogeneous, subtype-specific temporal patterns with distinct temporal windows of predictability for ventricular loading and papillary geometry. This framework may support patient-specific temporal phenotyping of functional mitral regurgitation.

Background. Adults with congenital heart disease (CHD) are a growing population and face unique challenges as they age. Unlike acquired diseases that disrupt a previously healthy baseline, CHD is developmentally embedded. Allostatic load, the multi-system biological "wear and tear" exacted by the continuous cost of coping, offers a framework for indexing this lifelong psychophysiological stress. Methods. We analyzed 14,469 adults from the All of Us Research Program: non-syndromic CHD (n = 6,810), acquired heart disease (AHD; n = 2,264), non-cardiac chronic illness (n = 4,331), and a general population comparison cohort (GP; n = 1,064). Using a standardized operationalization, allostatic load was scored across five biomarker domains (AL5, range 0-5). A pre-specified primary test compared adjusted AL5 between CHD and GP. Exploratory analyses examined clinical predictor of this gap and whether baseline subjective health predicted prospective AL5 change, utilizing strictly matched biomarkers across timepoints to prevent substitution artifacts. Results. Adults with CHD carried significantly higher allostatic load than the general population comparison cohort (adjusted difference +0.30 AL5 units, 95% CI 0.24-0.37, p < .001). Cumulative comorbidity and cardiac medication burden explained most of this gap. Congenital anatomical complexity did not independently predict this burden. In a prospective subsample (n = 8,031, mean follow-up 2.7 years), worse baseline mental health predicted increases in allostatic load over time in CHD. Baseline physical health showed no such prospective association. The general population and acquired heart disease cohorts demonstrated the inverse dissociation: subjective physical health predicted these longitudinal physiological changes. Conclusions. Adults with CHD carry an elevated allostatic burden dictated by the cumulative cost of acquired medical and treatment intensity. The original congenital anatomy does not predict this accumulation. Furthermore, subjective mental health prospectively tracks future increases in allostatic load in CHD. This dissociation is absent in adult-onset acquired heart disease, suggesting that the mental aspects of coping with CHD may impact outcomes above and beyond those with acquired heart disease. These findings position psychological care as a potentially physiologically consequential intervention.

Background: The clinical significance of sarcomere variants of uncertain significance (VUS) in hypertrophic cardiomyopathy (HCM) remains unclear, and VUS are currently regarded as clinically non-actionable despite their increasing prevalence. This study aimed to evaluate genotype?phenotype and genotype?outcome associations according to variant pathogenicity in patients with HCM, with a particular focus on the clinical relevance of sarcomere VUS. Methods: This multicenter retrospective cohort study included 438 patients with HCM who underwent next-generation sequencing-based genetic testing at two tertiary hospitals. Patients were classified into three groups: pathogenic or likely pathogenic (P/LP) variants, VUS, and no sarcomere mutations. Clinical characteristics, imaging phenotypes, and outcomes were compared across groups. The primary endpoint was a composite of cardiovascular death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator therapy, and heart transplantation. Time-to-event analyses were performed using Kaplan-Meier methods and Cox proportional hazards models with Firth's penalized partial likelihood approach. Results: P/LP variants were identified in 171 patients (39.0%) and sarcomere VUS in 159 patients (36.3%). Patients with VUS demonstrated intermediate clinical and phenotypic features between P/LP carriers and genotype-negative patients. Kaplan?Meier analysis showed a graded difference in event-free survival across variant classifications. While VUS were not independently associated with adverse outcomes when modeled as a categorical variable, increasing pathogenicity from genotype-negative to VUS and P/LP variants was associated with a stepwise increase in risk of the primary endpoint (hazard ratio 2.05, 95% confidence interval 1.11?4.16 p=0.019). Identified VUS were preferentially enriched in Z-disc and giant sarcomere scaffolding proteins. Conclusion: Sarcomere VUS represent intermediate characteristics along a continuum of sarcomere dysfunction, associated with distinct phenotypic features and clinical outcomes compared with both P/LP variants and the absence of sarcomere mutations. These findings suggest that sarcomere VUS may not be entirely clinically neutral and should be interpreted within a broader genetic and structural context in patients with HCM.

IntroductionSpontaneous coronary artery dissection (SCAD) is frequently accompanied by persistent symptoms of unknown pathogenesis after the index event. Autonomic dysfunction is a plausible mechanism for these but has not been systematically characterized. We quantified antecedent and contemporary autonomic symptoms in survivors of SCAD and examined their associations with cardiac and extra-cardiac symptoms and health-related quality of life. MethodsThis cross-sectional study recruited 227 volunteers from multiple countries with a self-reported history of SCAD. Participants completed validated patient-reported measures, including the Composite Autonomic Symptom Score-31 (COMPASS-31), Anxiety Sensitivity Index-3 (ASI-3), and EuroQol-5 Dimension-5L (EQ-5D-5L). They also completed an internally derived retrospective autonomic predisposition score assessing symptoms during adolescence and early adulthood. ResultsParticipants were predominantly female (97.8%), median age 53 (47-58) years, and were surveyed a median of 3 (1-5) years after their index SCAD event. 21.6% reported SCAD recurrence. Moderate autonomic symptom burden (COMPASS-31 [&ge;]20) was present in 56.4% and severe burden ([&ge;]40) in 16.3%. History of antecedent autonomic symptoms was the strongest independent predictor of contemporary autonomic symptom burden after adjustment for demographic and clinical covariates ({beta}=0.514; P <0.001). Greater autonomic symptom burden independently predicted lower EQ-5D health utility ({beta}=-0.150; P=0.029) and was associated with the ASI-3 physical concerns ({beta}=0.232; P <0.001), but not social concerns domain. Autonomic symptoms were not associated with SCAD recurrence. ConclusionSymptoms of autonomic dysregulation are common in survivors of SCAD and are associated with reduced quality of life. Their association with antecedent dysautonomic features during adolescence and early adulthood suggests a longstanding predisposition, the significance of which warrants further evaluation. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LISelf-reported antecedent and current autonomic symptoms are common in survivors of spontaneous coronary artery dissection and are associated with poorer health-related quality of life, greater fatigue, and greater psychological distress. C_LI What Are the Clinical Implications?O_LIAutonomic symptoms warrant clinical recognition in patients with prior spontaneous coronary artery dissection, not only as a post-event complaint but also as a potential marker of pre-existing autonomic vulnerability that may influence recovery experience. C_LIO_LIGreater awareness of autonomic symptom burden may support more personalized follow-up, patient counseling, and rehabilitation planning to help patients return more safely and confidently to daily activities, work, and family life. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/26351434v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1589559org.highwire.dtl.DTLVardef@b5423forg.highwire.dtl.DTLVardef@103b97org.highwire.dtl.DTLVardef@1b8378f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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: 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.

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

BackgroundHeart failure with reduced ejection fraction is a leading cause of death worldwide, characterized by impaired left ventricular systolic function. Contractile, structural, and electrophysiological changes underpin this impairment, but how these changes collectively determine ventricular function remains unclear. We hypothesize that their integrated action involves a complex mechanical interplay at the myocardial mesoscale level, intermediate between individual cardiomyocytes and the global left ventricle. MethodsWe acquired high-resolution magnetic resonance images of healthy individuals and patients with myocardial infarction, and developed an analytical method to characterize in vivo contraction patterns in millimeter-sized myocardial units (i.e., at the mesoscale). Furthermore, we employed computational models to examine how mesoscale contraction patterns relate to the contraction mechanism, structure, and electrophysiology of the left ventricle. ResultsAt the left ventricular mesoscale, we observed that weakly contracting myocardial units are transiently elongated by the contraction of adjacent, more strongly contracting units. These mesoscale interactions generate a "tug-of-war" that pervades the left ventricle in healthy hearts and becomes particularly prominent following myocardial infarction. This behavior is macroscopically invisible as the contraction patterns of opposing units cancel each other out, but it nevertheless shapes the efficiency of mechanical performance. In the healthy heart, recruitment of more uniformly contracting units (i.e., reduction in tug-of-war) supports augmented contractility during acute stress. However, following myocardial infarction, excessive tug-of-war contributes to impaired contractile efficiency and performance. Computational modelling showed that the ventricular contraction mechanism, structure, and electrophysiology underpin this behavior in healthy hearts and exacerbate it in disease. ConclusionLeft ventricular systolic function is characterized by a myocardial tug-of-war at the mesoscale, which contributes to the hearts adaptability in health and its vulnerability in disease. These findings introduce a new concept for understanding left ventricular function and a novel analytical approach for investigating its failure.

BackgroundSodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a cornerstone of heart failure (HF) therapy, yet the totality of randomized evidence -- including smaller trials -- has not been comprehensively synthesized. We aimed to evaluate the efficacy and safety of SGLT2 inhibitors across the full spectrum of HF. MethodsWe searched PubMed, Cochrane CENTRAL, ClinicalTrials.gov, and WHO ICTRP from inception to March 2026 for randomized controlled trials comparing any SGLT2 inhibitor with placebo or standard care in adults with HF. Primary outcomes were all-cause mortality (ACM) and HF hospitalization (HFH). We used random-effects models with Mantel-Haenszel risk ratios and Hartung-Knapp-Sidik-Jonkman confidence intervals. Certainty of evidence was assessed using GRADE. The protocol was registered prospectively (PROSPERO CRD420251167908). ResultsOf 6,239 records identified, 114 studies met inclusion criteria and 59 RCTs (29,692 participants) were included in quantitative synthesis. SGLT2 inhibitors significantly reduced ACM (RR 0.90 [0.83, 0.98], p = 0.016; 26 trials; I2 = 0%; low certainty) and HFH (RR 0.74 [0.69, 0.79], p < 0.001; 15 trials; I2 = 0%; moderate certainty). The composite of CVD and HFH was reduced (RR 0.80 [0.75, 0.85], p < 0.001; high certainty). Genital infections were significantly increased (RR 3.75 [1.72, 8.19], p = 0.007). Results were robust across 12 sensitivity analyses and 4 alternative statistical models. ConclusionsSGLT2 inhibitors reduce all-cause mortality, HF hospitalization, cardiovascular death, and serious adverse events in adults with HF, with an acceptable safety profile apart from increased genital infections. These findings support the use of SGLT2 inhibitors as a foundational therapy across the HF spectrum.

Background: Cardiovascular-kidney-metabolic (CKM) syndrome is a leading driver of cardiovascular morbidity and mortality. Whole-body molecular imaging is well-positioned to phenotype such syndromes, yet no imaging biomarker quantifies cumulative CKM burden. Bone scintigraphy with 99mTc-labeled bisphosphonates is widely performed and expanding with transthyretin amyloidosis assessment, under which Perugini grade 0 (absent cardiac uptake) is considered clinically benign. Objective: We hypothesized that the soft tissue-to-bone ratio (STBR) on these scans captures CKM burden and is an independent prognostic biomarker. Methods: We retrospectively analyzed 8,769 consecutive patients without cardiac uptake on 99mTc-DPD whole-body planar scintigraphy. The primary endpoint was all-cause mortality. Secondary endpoints were major adverse cardiovascular events (MACE) and heart failure hospitalization. Cox models were adjusted for ten established cardiovascular risk factors. Imaging-phenotype association (IPA) analysis mapped STBR to 1,210 clinical traits. STBR distribution across CKM stages was assessed in four prespecified analyses, including a non-cancer subgroup. Results: During a median follow-up of 5.1 years (IQR 2.5-8.2), 2,418 deaths occurred. Patients with prespecified STBR >0.5 (n=772, 8.8%) had significantly higher mortality (adjHR 1.73, 95% CI 1.54-1.94, p<0.0001) with an adjHR of up to 3.42 at higher thresholds (95% CI 2.05-5.42, p<0.0001). Hazard increased monotonically with STBR. STBR >0.5 was independently associated with MACE (adjHR 1.51, 95% CI 1.11-2.05, p=0.008) and heart failure hospitalization (adjHR 1.31, 95% CI 1.02-1.67, p=0.03). The association was robust across all prespecified subgroups and sensitivity analyses, including continuous STBR and patients without renal insufficiency. IPA analysis identified significant associations with type 2 diabetes, chronic kidney disease, chronic ischaemic heart disease, heart failure, atrial fibrillation, liver disease, amyloidosis, and hypertension among binary traits, as well as with CRP, NT-proBNP, BUN, cholesterol (inverse), and hemoglobin (inverse) among continuous parameters. STBR increased monotonically across CKM stages in all sensitivity analyses (all p<0.0001). Conclusions: STBR derived from routine 99mTc-DPD bone scintigraphy in patients without cardiac uptake is an independent prognostic imaging biomarker associated with cumulative cardiovascular-kidney-metabolic burden. As an opportunistic measure from scans already acquired at scale, STBR could refine CKM risk stratification at no additional cost, radiation, or acquisition time.

Background: Treatment response in heart failure with reduced ejection fraction (HFrEF) is assessed predominantly through left ventricular (LV) functional recovery, while longitudinal changes in left atrial (LA) hemodynamic burden remain underexplored. The LA stiffness index (LASI), derived from E/e' and LA reservoir strain, integrates LV filling pressure and LA compliance. Objectives: We investigated longitudinal trajectories of LASI and their prognostic implications in HFrEF treated with angiotensin receptor-neprilysin inhibitor (ARNI)-based therapy. Methods: From the multicenter STRATS-HF-ARNI registry, 1,039 patients with HFrEF who underwent serial echocardiography at baseline and one-year follow-up were classified into four LASI trajectory patterns dichotomized at the cohort median (1.22): persistently compliant (Group A, 46.8%), reverse remodeling (B, 28.5%), progressive stiffening (C, 3.2%), and persistently stiff (D, 21.6%). Results: On multivariable Cox regression, Group D was independently associated with elevated risks of all-cause mortality (adjusted hazard ratio [aHR] 2.68, 95% CI 1.57-4.59), cardiovascular mortality (aHR 4.36, 1.97-9.64), and HF hospitalization (aHR 3.83, 2.22-6.60), whereas Group B showed outcomes comparable to Group A. One-year LASI progression independently predicted all three outcomes. LASI elevation at one year predicted adverse outcomes even among patients with recovered LV function, and LASI trajectory classification provided incremental prognostic discrimination beyond conventional diastolic and strain parameters. Among sinus-rhythm patients (n=786), Group C exhibited the highest risk of new-onset atrial fibrillation. Conclusions: In HFrEF treated with ARNI-based therapy, LASI trajectories identify distinct prognostic phenotypes. Persistent LA stiffness confers adverse outcomes independent of LV recovery, and serial LASI assessment may enhance risk stratification beyond LV-centric metrics.