BACKGROUND:Titin truncating variants (TTNtv) represent the most common genotype underlying dilated cardiomyopathy but are also detected in the general population, exhibiting incomplete penetrance and marked phenotypic variability. This heterogeneity complicates clinical interpretation and risk stratification. Emerging molecular evidence suggests that truncating location within the gene may influence disease mechanisms. We aimed to investigate whether TTNtv location also affects clinical phenotype and prognosis. METHODS:We established an international multicenter registry of phenotypically affected carriers of pathogenic or likely pathogenic TTNtv. Patients were classified into 3 groups: A-band, Z/I-band, and M-band. A case-control study assessed the enrichment of TTNtv across regions. The primary outcome was a composite of all-cause mortality and heart transplantation. Secondary outcomes included: (1) sudden cardiac death or major ventricular arrhythmias and (2) heart failure-related death/heart transplantation/left ventricular assist device implantation. RESULTS:The study included 467 patients (81% probands, 73% male, median age 47 years, 81% dilated cardiomyopathy phenotype). Most carried TTNtv in the A-band (80% versus 15% Z/I-band and 5% M-band). All groups showed enrichment compared with GnomAD, with greater Bayesian-estimated penetrance for A-band variants. Over a median follow-up of 83 months, the primary end point was similar across groups. However, the risk of sudden cardiac death/major ventricular arrhythmias was significantly higher in M-band carriers (45% M-band versus 23% Z/I-band versus 12% A-band; P=0.001), especially as the first disease manifestation. Band location independently predicted sudden cardiac death/major ventricular arrhythmias risk, whereas left ventricular ejection fraction was predictive only in A- and Z/I-band groups. CONCLUSIONS:TTNtv are differently enriched across the gene in patients with dilated cardiomyopathy/nondilated left ventricular cardiomyopathy. Penetrance and risk of sudden cardiac death/major ventricular arrhythmias differ according to variant location, supporting the TTN truncation site as a parameter that should be considered for personalized risk stratification in TTN cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a prevalent inherited cardiac disorder characterized by left ventricular hypertrophy and contractile dysfunction. Mutations in sarcomeric genes, particularly cardiac myosin-binding protein C (MYBPC3), are a leading cause of HCM. Here, we generated two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells of patients carrying distinct MYBPC3 mutations (c.2490dupT and c.1800delA). Both lines displayed normal morphology, stable karyotypes, robust expression of pluripotency markers, and trilineage differentiation potential. These patient-specific iPSC lines provide a valuable platform for modeling MYBPC3-associated HCM and enable mechanistic and therapeutic studies of inherited cardiac disease

Induced pluripotent stem cells (iPSCs) are a valuable platform for studying human biology and developing patient-specific cellular models. However, individuals of African American ancestry remain underrepresented in existing iPSC repositories, limiting the diversity of available research resources. To address this gap, we generated and characterized two iPSC lines derived from healthy donors of African American ancestry. Both lines exhibited normal morphology, expression of pluripotency markers, trilineage differentiation potential, stable karyotypes, and absence of mycoplasma contamination. Short tandem repeat analysis confirmed donor identity. These well-characterized iPSC lines provide a valuable resource for future studies investigating ancestry-specific genetic and cellular mechanisms relevant to human disease.

RATIONALE:Atrial fibrillation (AF) has roughly tripled in prevalence over the last 50 years. This disease disproportionately affects morbidity and mortality among older women. Increased physical activity has been associated with a lower incidence of new AF in some studies, but a higher incidence in others, especially among elite athletes. PRIMARY HYPOTHESIS:We designed a randomized trial within the Women's Health Initiative (WHI) Strong and Healthy (WHISH) trial to test the hypothesis that a pragmatic intervention consisting of multimodal messaging recommending physical activity levels consistent with national guidelines would decrease the incidence of AF among a cohort of older women. DESIGN:The present WHISH Silent Atrial Fibrillation Recording (WHISH STAR) trial randomized 29,758 postmenopausal women without baseline AF who were enrolled in Medicare Fee-for-Service to the aforementioned intervention or comparison group, with a planned 7-year follow-up to assess the primary outcome of incident clinical AF, namely those identified in Medicare claims. We also designed a sub-study of 1,257 women at high-risk for AF (with a CHARGE-AF score ≥5%) to undergo serial, 7-day electrocardiogram (ECG) patch monitoring to detect screened AF. We will use Cox proportional hazards models to compare the incidence of clinical AF in the participants assigned to physical activity intervention and the participants assigned to usual care groups. We will also compare the incidence of screened AF in the intervention and comparison groups detected on patch ECG monitors in the sub-study of women who underwent serial ECG patch monitoring. The WHISH STAR trial will rigorously evaluate the effect of a pragmatic physical activity intervention on the development of AF in a large, diverse, well-characterized cohort of older women. SITES:The WHISH trial is embedded within the nationwide WHI study, enrolling postmenopausal women from 40 United States clinical centers. ENROLLMENT DATES:Participants were enrolled in 2015 per the parent WHISH trial. CURRENT STATUS:WHISH STAR is in the analysis phase. TRIAL REGISTRATION:WHISH STAR has been registered on www. CLINICALTRIALS:gov (NCT05366803).

Background Gene replacement and gene editing therapies for cardiomyopathies are in early-phase clinical trials. However, limited data exist on patient perspectives. We assessed adult familial cardiomyopathy patient perspectives towards the clinical implementation of somatic genetic therapies. Methods Patients completed a demographic survey and semi-structured interview. A codebook was developed deductively and inductively, and thematic analysis was performed. Results Twenty-one participants with genetic and clinical diagnoses of either hypertrophic cardiomyopathy (17) or dilated cardiomyopathy (4) completed interviews. Participants ranged from age 38 to 80 (mean 57) and were 57% female. Four main themes influence participants’ decision-making for hypothetical pursuit of genetic therapies: 1) perceived clinical severity 2) potential for impact on quality of life 3) treatment details - safety, mechanism, and delivery 4) ethical and societal considerations. Those who described a severe clinical presentation expressed increased interest in genetic therapies and an increased willingness to accept risks for potential quality of life improvement, particularly if the therapy targeted the root cause and halted condition progression. Participants voiced uncertainties about the safety and long-term consequences of these therapies. Many participants believed that clinical severity should be prioritized for genetic therapies regardless of age; some felt younger individuals benefit more, avoiding lifelong treatment. Family members’ negative experiences with cardiomyopathies also influenced the decision-making process. A majority ranked genetic therapies over other treatment options, with 29% expressing hypothetical interest in participating in clinical trials or early adoption post-FDA approval. Ethical and societal concerns included misuse of these therapies, their egalitarian distribution, and loss of beneficial genetic traits. Conclusion Patients' support for and concerns about genetic therapies for cardiomyopathies highlight the need for clear communication of benefits, risks, uncertainties, and potential impact on quality of life. Including patients in discussions about the ethical and societal impacts of these therapies is essential.

IMPORTANCE Valsartan has been shown to attenuate phenotypic progression among individuals with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Myocardial tissue characterization by cardiac magnetic resonance (CMR) imaging may enhance mechanistic insights, but whether valsartan influences these parameters remains uncertain. OBJECTIVE To evaluate the treatment effects of valsartan on myocardial structure, function, and tissue parameters in early-stage sarcomeric HCM. DESIGN, SETTING, AND PARTICIPANTS This prespecified CMR substudy of the VANISH (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) randomized clinical trial evaluated treatment effects of valsartan vs placebo on myocardial structure, function, and tissue parameters and was conducted from April 2014 through July 2019 at 17 international sites. Individuals aged 8 to 45 years with early-stage HCM aged between 8 and 45 years and with no or minimal symptoms were eligible for inclusion. INTERVENTIONS Treatment with placebo or valsartan (80 mg per day for children weighing <35 kg, 160 mg per day for children weighing >= 35 kg, or 320 mg per day for adults aged 18 years or older). MAIN OUTCOMES AND MEASURES The primary outcome was mean change in CMR parameters between baseline and year 2, including indexed extracellular volume (iECV), indexed intracellular volume (iICV), and late gadolinium enhancement (LGE). Mean between-group differences in CMR parameters between baseline and year 2 were evaluated using multivariable mixed-effects linear regression models. RESULTS Overall, 137 of 178 VANISH participants (77.0%) underwent CMR imaging at baseline and year 2. Among these participants, mean (SD) age was 23 (10) years, and 51 participants (37.2%) were female. Baseline characteristics and CMR parameters were well balanced between treatment groups. Higher LGE, iECV, and iICV at baseline were associated with higher cardiac biomarker levels and more pronounced cardiac remodeling. Between baseline and year 2, valsartan appeared to increase left ventricular (LV) end-diastolic volume index (mean difference [MD], 3.3 mL/m(2); 95% CI, 0.4-6.2; P = .03), suggesting treatment benefit, but did not significantly impact LV mass index (MD, -2.9 g/m(2); 95% CI, -6.1 to 0.2; P = .07) or LV ejection fraction. Similarly, valsartan appeared to reduce decline in right ventricular volumes. Valsartan appeared to significantly reduce iICV progression (MD, -5.0 mL/m(2); 95% CI, -9.7 to -0.4; P = .03), but did not impact iECV (MD, 0.0 mL/m(2); 95% CI, -1.4 to 1.3; P = .95) or LGE progression (MD, 0.5%; 95% CI, -0.4 to 1.3; P = .30). CONCLUSIONS AND RELEVANCE These findings enhance mechanistic insights into the effect of valsartan in early-stage HCM, showing potential benefits on biventricular remodeling and myocardial intracellular volume. Further research to identify cellular mechanisms of valsartan on HCM progression is needed.

Background: Atrial fibrillation (AF) is the most common arrhythmia in dilated cardiomyopathy (DCM) and is associated with adverse outcomes. Characterization of AF in DCM by genotype and clinical features remains limited. Aims: To describe AF prevalence and incidence in DCM stratified by genotype and disease gene, and to identify clinical and genetic predictors of incident AF. Methods: Using the multicenter Sarcomeric Human Cardiomyopathy Registry (SHaRe), we included 3117 DCM patients who had genetic testing. AF prevalence, incidence, clinical characteristics and genotype (genotype-positive [G+], defined by the presence of a pathogenic/likely pathogenic [P/LP] variant in a DCM gene or genotype-negative [G-]) were assessed and further stratified by disease gene. Predictors of incident AF were identified with uni- and multivariable analyses. Covariates for the multivariable model were selected based on clinical relevance and discriminative performance (C-index 0.74), and included age at first site visit, sex, genotype, prior heart failure (HF) hospitalization and left atrial (LA) diameter. Results: Of 3117 patients with DCM (mean age 48±15 years, 39% female, 35% G+), 12.3% (n=384) had prevalent AF. Among 2491 patients without prevalent AF, 12.5% (n=312) developed incident AF during a median follow-up of 4.5 years (IQR 1.6-9.0). AF burden varied by disease gene (Figure 1). Patients with P/LP LMNA variants had the highest AF prevalence (56.7%) and incidence (7.6/100 patient-years), with AF typically preceding left ventricular systolic dysfunction, and LMNA was the only gene independently associated with incident AF in multivariable analysis (HR 7.10, 95% CI 4.44-11.36; p<0.001). In contrast, those with P/LP TTN variants had lower AF burden (prevalence 24.4%, incidence 2.1/100 patient-years), comparable to G- patients, despite having the largest LA diameter (41±7mm). Patients with P/LP DSP variants were the 3 rd largest gene group (n=156) but had the lowest AF prevalence (7.4%) and incidence (0.8/100 patient-years). Additional independent predictors of incident AF included male sex, prior HF hospitalization, older age at first visit, and larger LA diameter (Table 1). Conclusion: In this multicenter cohort study of genotyped patients with DCM, LMNA had the strongest genetic association with AF, while TTN had lower AF rates despite larger LA diameter. Genotype-based risk stratification may help guide AF surveillance and management in DCM patients.

While there is ongoing debate about the role of the 12‑lead Electrocardiogram (ECG) in the routine screening of young athletes during pre-participation evaluations, studies continue to support the use of ECG within properly organized settings. This paper aims to offer considerations for enhancing the International ECG recommendations for the interpretation of the ECGs of young athletes through an emphasis on 1) percentile outliers, 2) computerized ECG technology and 3) clarification of terminology. We specifically highlight criteria for early repolarization, left atrial abnormality, right bundle branch block, ST shifts, and high and low voltage QRS.

Background: Diffuse myocardial fibrosis is a hallmark of heart failure progression. T1 mapping MRI quantifies fibrosis, but conventional mean-T1 metrics blur regional patterns characteristic of distinct biological pathways (Fig. 1). Objective: To retrieve regional fibrosis signatures at the population scale and identify molecular drivers with therapeutic potential. Methods: Native-T1 maps from 50,239 CMRs were U-Net-segmented (Dice 0.85) and encoded by a 16-D variational autoencoder (VAE) (SSIM 0.92). We derived global T1 scalars—mean, SD, and 5th–95th percentiles—and latent features (LD1-LD16); gradient-based attention linked each factor to specific myocardial regions. Prognosis was tested with Kaplan–Meier curves and covariate-adjusted Cox models. Scalar and latent traits entered GWAS, rare-variant burden screens, and 3,000-plex Olink PWAS. Causal analysis combined cis-eQTL/pQTL COLOC, Mendelian randomisation, and SMR-HEIDI to flag druggable genes (Fig. 2). Results: Clinical impact T1 75th percentile showed highest heritability (10.3%) and mortality prediction (p=0.004). VAE dimension 12 had the strongest mortality association (p<0.0001), while dimension 8 predicted non-ischemic heart disease with superior discrimination to T1 scalar metrics. Genomics: Seven loci reached significance: iron-homeostasis (HFE p=2.6×10 -13 , TMPRSS6), growth-factor (IGF1R), sarcomere (ALPK3/SYNPO2L), and spatial-specific DLG2 (p=1.9×10 -8 ). Rare-variant testing implicated 914 genes, enriching inflammatory/metabolic pathways. Proteomics: Leptin dominated (p=1.1×10 -73 ) with FABP4/oxytocin. Dimension 8 identified stronger leptin association (p=1.13×10 -73 ) plus inflammatory (TNFRSF1A), neuronal (RTN4R), and vascular (ADM) drivers. Causal Inference: Cis-pQTL MR nominated eight proteins led by FOLH1 (β=0.17 SD, p=3.4×10 -13 ), with HEIDI confirming pleiotropy. Colocalization confirmed LRRC37A2 (pp_h4>0.99), PDE5A (pp_h4=0.933), CTSS (pp_h4=0.80). eQTL SMR identified LMF1 (p=8.3×10 -5 ), JMJD6 (p=1.7×10 -4 ), RIT1 (p=3.96×10 -4 ). Targets with existing inhibitors include CTSS (VBY-036, RO5459072), PDE5A (sildenafil, tadalafil), and ENPP2 (ONO-8430506, PF-8380, IOA-289). Conclusions: AI-derived spatial fibrosis phenotypes using VAE decomposition of T1 maps reveal hidden prognostic information and region-specific biological drivers invisible to conventional mean T1 analysis, identifying causal protein targets (FOLH1, ENPP2, CTSS, PDE5A) amenable to existing inhibitors for precision anti-fibrotic therapies.

Background: Left ventricular hypertrophy is a common electrocardiographic (ECG) finding in athletes, but existing amplitude-based criteria often generate false positives. Objective: The purpose of this study was to reevaluate ECG criteria for screening athletes for left ventricular hypertrophy by considering QRS amplitude measurements and demographic factors, using data from an extensive digital ECG database. Methods: A retrospective analysis of digitized ECG records from 9254 young athletes aged 12-35 years underwent a preparticipation examination between 2010 and 2021. Univariate and multivariate analyses assessed R- and S-wave amplitudes by applying the 99th percentile for R waves and the 1st percentile for S waves and examined the Sokolow-Lyon (SL) precordial lead score and the limb lead (LL) score, adjusting for sex, sport, age, class (athlete classification [college, grade school, high school, and professional]), body mass index, and heart rate. Results: Our findings demonstrate significant sex differences in R- and S-wave voltages, with the highest R-wave voltages observed at the 99th percentile in lead V-4, V-5, or V-6 (4.4 mV for males and 3.3 mV for females). Multivariate analyses demonstrated that male athletes had significantly higher SL and LL scores than did females. While age, sport, ethnicity, and body mass index influenced SL and LL scores, their effect was much weaker than those of sex and impractical for general use. Conclusion: Our findings demonstrate that the 99th percentile values for sex-specific QRS voltage criteria (SL score of >6.8 mV for males and >4.7 for females; LL score of >2.3 mV for males and >1.9 mV for females) can enhance ECG criteria in athletes by increasing sensitivity for pathological hypertrophy with modest decreases in specificity.

BACKGROUND:Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity. METHODS:Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5x10(-5) in the Genome Aggregation Database, gnomAD) and (2) moderate enrichment (>2x) in patients with HCM compared with gnomAD. LowSVs were examined for their association with disease severity and clinical outcomes. Functional effects of selected LowSVs were assessed using induced pluripotent stem cell-derived cardiomyocytes. Association of LowSVs with HCM-adjacent traits in the general population was tested using UK Biobank cardiac magnetic resonance imaging data. RESULTS:Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; P<0.001). An intermediate functional impact was validated for 2 specific LowSVs-MYBPC3 c.442G>A (partial splice gain) and TNNT2 c.832C>T (intermediate effect on contractile mechanics). Cardiac magnetic resonance imaging analysis of the general population revealed 5 of 12 LowSVs were significantly associated with HCM-adjacent traits without overt HCM. CONCLUSIONS:This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM.

Tandem repeats are a highly polymorphic class of genomic variation that play causal roles in rare diseases but are notoriously difficult to sequence using short-read techniques1,2. Most previous studies profiling tandem repeats genome-wide have reduced the description of each locus to the singular value of the length of the entire repetitive locus3,4. Here we introduce a comprehensive database of 3.6 billion tandem repeat allele sequences from over one thousand individuals using HiFi long-read sequencing. We show that the previously identified pathogenic loci are among the most variable tandem repeat loci in the genome, when incorporating nucleotide resolution sequence content to measure the longest pure motif segment. More broadly, we introduce a novel measure, 'tandem repeat constraint', that assists in distinguishing potentially pathogenic from benign loci. Our approach of measuring variation as 'the length of the longest pure segment' successfully prioritizes pathogenic repeats within their previously published linkage regions. We also present evidence for two novel pathogenic repeat expansion candidates. In summary, this analysis significantly clarifies the potential for short tandem repeat pathogenicity at over 1.7 million tandem repeat loci and will aid the identification of disease-causing repeat expansions.

Introduction: Exercise is a cornerstone of cardiovascular health, yet not all individuals can engage in sufficient physical activity. Identifying pharmacological agents that mimic exercise-induced molecular adaptations offers a promising strategy for disease prevention. Here, we integrate transcriptomic data from the Molecular Transducers of Physical Activity Consortium (MoTrPAC)—a multi-omics effort characterizing exercise responses—including human skeletal muscle after acute exercise (0-24h), and both acute and endurance training (1-8 weeks) in rat heart and skeletal muscle. These are combined with the Library of Integrated Network-Based Cellular Signatures (LINCS), which catalogs drug-induced transcriptional responses in 292 human cell lines exposed to 20,272 compounds. Through this integrative approach, we aim to identify compounds that replicate transcriptional effects of endurance exercise. Methods: To address transcriptomic differences between tissues and cell lines, we developed a pipeline combining functional and regulatory analyses. We assessed pathway enrichment via FGSEA and inferred transcription factor (TF) activity using VIPER and DoRothEA (Figure 1A). Shared pathways and upstream regulators were integrated into a mimetic score ranking candidate drugs by their functional and regulatory similarity to exercise. Results: We identified between 600–800 candidate mimetics for skeletal muscle in acute human and rat responses, as well as during endurance training. Notably, predicted mimetics aligned well between species (Figure 1B). Among top hits, midodrine, an α1-adrenergic agonist investigating for its cardioprotective properties, matched 24h post-exercise signatures in both species and activated TFs linked to mitochondrial function, vascular remodeling, and metabolism (FOXP1, CREB1). PD-0325901, a MEK inhibitor, showed strong similarity to early phases (15–45 min), inducing early-response TFs (FOS, HIF1A, RELA), and reflected endurance training upregulation of oxidative phosphorylation. Mimetic profiles from rat heart clustered with muscle at matched timepoints, highlighting the potential to extend heart-based predictions to humans via conserved signatures (Figure 1C). Conclusion: This integrative analysis identifies candidate compounds that mimic distinct phases of exercise-induced molecular remodeling. Ongoing validation in cardiac models aims to translate these findings into cardiovascular contexts.

BACKGROUND:Left ventricular noncompaction (LVNC), or hypertrabeculation, is a myocardial condition that remains challenging to diagnose and differentiate from other cardiomyopathies. This study evaluated the ability of cardiac CT to differentiate between LVNC, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and controls using fractal analysis of LV trabeculae. METHODS:Subjects with LVNC, HCM, DCM, as well as controls, who underwent coronary CT angiography were included. LV trabecular structure was quantified using fractal analysis on a stack of 15 short-axis CT images. For each subject, maximum (FDmax) and average (FDglobal) fractal dimensions were reported. A subset of subjects also had clinically acquired cardiac MRI (CMR) exams for comparison. One-way ANOVA, Pearson correlation, and Bland-Altman analysis were used for statistical analysis. RESULTS:The study included 313 subjects (median age: 58.8 [48.1-68.0] years, 153 male) categorized into Control (89), LVNC (46), HCM (106), and DCM (72) cohorts. FDmax was significantly higher in LVNC (1.379 ​± ​0.047) than in Control (1.305 ​± ​0.033), HCM (1.321 ​± ​0.040), and DCM (1.344 ​± ​0.054) cohorts; all p ​< ​0.001. Similarly, FDglobal was significantly higher in LVNC (1.279 ​± ​0.041) than in the other cohorts; all p ​< ​0.05. In a subset of 132 subjects with both CT and CMR exams, fractal dimensions from the two modalities were strongly correlated (r ​= ​0.63, p ​< ​0.0001), with CT-derived values being higher (1.337 ​± ​0.049 vs. 1.262 ​± ​0.045, p ​< ​0.0001). CONCLUSIONS:CT-derived fractal dimensions of LV trabecular structure were significantly higher in LVNC compared to control subjects, HCM, and DCM. CT-derived fractal dimensions strongly correlated with, but were higher than, those from cardiac MRI in the same subjects.