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Journal articleHunt SE, Lemos D, Pericherla SR, et al., 2026,
Gene2Phenotype: A Database of Structured Human Monogenic Diseases and Pathomechanisms.
, J Mol Biol, Vol: 438To facilitate both disease research and personalised medicine, there is an urgent need for accessible, structured data models describing the molecular basis of genetically determined disease. Gene2Phenotype is a database of expert-curated monogenic gene-disease associations, which was established in 2012 to enable efficient prioritisation of likely diagnostic genomic variants. Initially focused on developmental disorders, it has since been extended to support cardiac, eye, skeletal and skin disorders and germline cancer predisposition. We have redesigned and extended Gene2Phenotype, which now openly shares standardised, structured models of rare monogenic diseases, detailing genotype, molecular mechanism and associated phenotypes, curated from scientific literature. The updated platform, which includes a new API, enabling programmatic access, improves the findability, accessibility, interoperability and reusability of detailed rare monogenic disease association data. These data have the potential to accelerate disease research, clinical diagnosis, treatment selection and the development of novel therapies. Gene2Phenotype is available at https://www.ebi.ac.uk/gene2phenotype/.
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Journal articleLuo Y, Ferreira PF, Wen K, et al., 2026,
Optimized Reduced Field of View and Fat Suppression Methods for Interleaved Multislice In Vivo Cardiac Diffusion Tensor Imaging.
, Magn Reson Med, Vol: 96, Pages: 1097-1110PURPOSE: Slice interleaving, a limited phase encode (PE) field of view (FOV), and effective fat suppression are vital for efficient cardiac diffusion tensor imaging (cDTI) with minimal artifacts. This study aimed to optimize reduced FOV and fat suppression methods for interleaved multislice cDTI to improve signal-to-noise ratio (SNR) and minimize artifacts. METHODS: Two-slice motion compensated spin echo datasets from 20 healthy volunteers were acquired. Four reduced PE FOV sequences were evaluated: 2DRF pulse; applying either 180 ° or 90 ° pulses in PE direction; and the proposed flip-back sequence with a nonselective 180 ° pulse after readout to restore inverted magnetization. Four fat suppression techniques were implemented: no fat suppression (standard); fat saturation; binomial water excitation and spectral attenuated inversion recovery (SPAIR). RESULTS: The proposed flip-back sequence with SPAIR achieved the highest median SNR, and its SNR values are significantly higher ( p < 0.01 ) than 2DRF with SPAIR as current state-of-the-art. SPAIR and water excitation demonstrated comparable performance when combined with the flip-back sequence, and both yielded superior image quality than with no suppression or fat saturation. SPAIR showed robust fat suppression across most subjects, whilst water excitation exhibited advantages in some subjects with a high body mass index. CONCLUSION: The proposed flip-back sequence with SPAIR enables efficient interleaved multislice imaging with reduced PE FOV and effective fat suppression, facilitating clinical translation of in vivo cDTI.
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Journal articleMazzarotto F, Ware J, 2026,
An updated evidence assessment of the genetic causes of dilated cardiomyopathy
, Circulation, ISSN: 0009-7322Background: Evidence of the diverse genetic architecture of dilated cardiomyopathy (DCM) continues to emerge and requires reassessment of the clinical relevance of implicated disease genes. Building on the 2019-2020 Clinical Genome Resource (ClinGen) evaluation, the DCM Gene Curation Expert Panel (GCEP) reconvened in 2024-2025 to conduct a reassessment of genes in DCM.Methods: The ClinGen semi-quantitative clinical validity classification framework was applied with specifications to DCM to classify genes into categories based upon strength of published evidence for a DCM phenotype. Previously curated genes were reassessed and newly reported gene-disease-mode of inheritance (MOI) relationships, termed “curations,” were evaluated.Results: Sixty-eight genes were evaluated, inclusive of 72 unique gene-disease-MOI relationships across 51 previously evaluated and 17 newly assessed genes. Thirty-five curations were classified as high evidence (16 Definitive, 10 Strong, 9 Moderate), increasing by 16 from the prior assessment. Nine newly assessed genes were classified as high evidence, including BAG5, FLII, LMOD2, MYLK3, MYZAP, NRAP, PPA2, PPP1R13L, and RPL3L. Twelve genes (11 newly appraised) were rated as high evidence with an autosomal recessive (AR) MOI. Five re-evaluated genes from 2019-2020 had clinically significant changes in classification. Except for JPH2, for which curation was modified to separate autosomal dominant (-AD) and -AR MOI curations, clinically significant changes involved upgrades from low to high evidence categories (PLEKHM2, PRDM16, TBX20, TNNI3K), demonstrating the robustness of the ClinGen gene curation process over time. An additional 29 gene-disease-MOI curations were classified as Limited, including six newly evaluated genes and one new MOI for a previously evaluated gene, MYBPC3-AR; four were classified as No Known Disease Relationship, and four remained Disputed. Four previously evaluated genes were curated for both AD and AR MOIs
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Journal articlePerotto M, Radesich C, Paldino A, et al., 2026,
Variant Site-Specific Natural History of Titin-Induced Cardiomyopathy: An International Multicenter Registry.
, Circ Genom Precis MedBACKGROUND: 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
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Journal articleTänzer M, Lim EJ, Qiu HH, et al., 2026,
Simultaneous multi-slice Cardiac Diffusion Tensor Imaging with variable CAIPIRINHA shifts and artefact-aware AI.
, Med Image Anal, Vol: 112Cardiac Diffusion Tensor Imaging (cDTI) provides unique insights into myocardial microstructure in-vivo but requires averaging multiple repetitions for adequate signal quality, leading to prohibitively long acquisition times. Standard acceleration strategies, such as reducing repetitions and employing simultaneous multi-slice (SMS) imaging, are limited by low signal-to-noise ratio (SNR) and inter-slice leakage artefacts, respectively. We introduce ORCAS, a unified framework that synergistically combines a novel variable CAIPIRINHA acquisition with an artefact-aware AI reconstruction to overcome these challenges. The variable CAIPIRINHA scheme decoheres SMS artefacts across repetitions, while our dual-domain deep learning model simultaneously suppresses these artefacts and combats the low SNR from fewer repetitions. The model is guided by patient-specific single-band auxiliary data to preserve anatomical fidelity. Validated on ex-vivo hearts with and without anomalies, ORCAS achieves an over 18-fold acceleration by combining these strategies, reducing a whole-heart scan from over two hours to under 7 min. This is accomplished while reducing errors in key biomarkers, such as Fractional Anisotropy, by up to 64%. The framework preserves essential microstructural properties and the delineation of abnormalities, representing a significant step towards the clinical translation of whole-heart cDTI.
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Journal articleMcGurk K, Halliday B, O'Regan D, 2026,
Left ventricular non-compaction: time to retire a flawed diagnosis
, Journal of the American College of Cardiology, Vol: 87, ISSN: 0735-1097 -
Journal articleStroeks SLVM, Bart NK, Rossano J, et al., 2026,
Sex and age specific genetic risk across the dilated and arrhythmogenic cardiomyopathy spectrum: insights from the SHaRe registry
, Journal of the American College of Cardiology, Vol: 87, Pages: 3573-3588, ISSN: 0735-1097BackgroundDilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) are progressive cardiac muscle disorders with phenotypic and genetic overlap. Although a male predominance is noted in DCM/ACM, it remains unclear whether this extends to specific genetic subtypes or reflects variation in disease stage and whether sex influences age-dependent disease onset across pediatric and adult groups.ObjectivesThe aim of this study was to define sex-based differences in genetic architecture and age at diagnosis of DCM/ACM across pediatric and adult populations.MethodsGenetically tested adult and pediatric DCM/ACM patients and asymptomatic genotype-positive relatives enrolled in the multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Sex distribution across 27 DCM- and ACM-associated genes was evaluated using logistic regression. Age at diagnosis was compared across sex and genes using Kaplan-Meier cumulative incidence estimates.ResultsAmong 3,410 patients, a 61% male predominance was present across subgroups of genotype positive, genotype negative, and variants of uncertain significance (P = 0.008), with significant gene-specific variation. TTN truncating variants (TTNtv) were less common in females (OR: 0.42 [95% CI: 0.33-0.54]; P < 0.01), while DSP (OR: 3.3 [95% CI: 2.35-4.78]; P < 0.01) and grouped non-TTN sarcomeric variants (ACTC1, TNNT2, MYH7, TNNC1, TNNI3, and TPM1) were more common (OR: 1.68 [95% CI: 1.15-2.47]; P < 0.001) in females compared with males with DCM/ACM. Age at diagnosis was comparable between sexes, except in TTNtv carriers, among whom males exhibited earlier disease onset compared with females (median age 45 years [Q1-Q3: 33-55 years] vs 51 years [Q1-Q3: 38-60 years]; P = 0.003). Pediatric-onset (diagnosis at <18 years) cases (n = 174) also demonstrated a male predominance (60% male) but had distinct genetic characteristics, with non-TTN sarcomeric and PKP2 variants being more prevalent compared with adult-o
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Journal articleVerdonschot JAJ, van Spaendonck-Zwarts KY, Hellebrekers DMEI, et al., 2026,
Genetic counselling implementation in dilated cardiomyopathy.
, Eur Heart J, Vol: 47, Pages: 3040-3051Genetic testing has become an integral part of the diagnostic workup of patients with dilated cardiomyopathy (DCM). While the initial goal of genetic testing was to identify family members at risk, recent advances have now extended their relevance to clinical decision-making. Our knowledge of the genetic architecture of DCM has expanded significantly, promoting a shift from the monogenic dogma towards a broader polygenic spectrum. However, current genetic testing strategies still primarily rely on the model of monogenic inheritance with an incomplete penetrance. Large studies have shown a yield varying from 8% to 36% of genetic testing in patients with DCM, depending on aetiology or family history. Genetic testing is generally warranted for every patient with DCM where genetic results could have an impact on risk stratification, the prognosis or the treatment of the patient, or its family members with an opportunity for reassurance or early disease detection. There are various strategies for genetic testing including broad multigene panels, or more targeted panels limited to specific disease-associated genes. Identified variants are classified by genetic laboratories, where pathogenic or likely pathogenic variants often have actionable clinical implications. It is crucial to interpret these variants in the context of the individual patient considering the phenotype and other contributing factors. When the genetic results are consistent with the patients' broader phenotype, potential clinical implications may include decision for device therapy, recommendations for family screening, and reproductive options. A comprehensive approach to integrate genetic testing in the clinical care of patients with DCM is proposed.
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Journal articleMarwaha SK, Basu J, Bhatia R, et al., 2026,
Unravelling the grey zone: submaximal-to-peak stress echocardiography enhances diagnostic accuracy in differentiating early dilated cardiomyopathy from physiological adaptation.
, Echo Res Pract, Vol: 13, ISSN: 2055-0464BACKGROUND: Participation in regular endurance exercise may be associated with physiological left ventricular (LV) dilatation and concomitant low resting LV ejection fraction (LVEF), a phenotype indistinguishable from early dilated cardiomyopathy (DCM) on resting imaging alone and termed the "grey zone". Stress echocardiography has emerged as a potential arbiter and has been proposed to resolve this dilemma. OBJECTIVES: We evaluated the diagnostic accuracy of stress echocardiography in distinguishing physiological from pathological LV dilatation and assessed whether incorporating submaximal-to-peak contractile reserve improved discriminatory value in athletes in the grey zone. METHODS: Of the 182 athletic individuals, 62 control athletes with an enlarged LV and normal LVEF, 58 athletic DCM individuals, and 62 grey zone athletes underwent stress echocardiography using a semi-supine bicycle. In addition to the ability to augment LVEF ≥ 10% from rest to maximal exercise, we evaluated the ability to augment LVEF from submaximal exercise (80% of maximal heart rate) to peak exercise. RESULTS: Resting LV dimensions did not differ significantly amongst the groups. Control athletes had higher resting LVEF than grey zone athletes and DCM individuals (62.1% vs 52.1% and 53.1%; p=<0.001). Control and grey zone athletes showed greater ΔLVEF from rest to peak exercise than DCM individuals (21% and 19.2% vs 4.9%; p < 0.001). Most control (98.3%) and grey-zone athletes (90.3%) achieved a ΔLVEF ≥ 10% from rest to peak exercise compared with 20.6% of athletic DCM individuals. Control and grey zone athletes also revealed a mean increase in LVEF from submaximal to peak exercise of 7.5% and 3.8%, respectively, whereas DCM individuals showed a mean LVEF decline of -4.3% (p < 0.001). Although 20.6% of DCM individuals demonstrated a ΔLVEF ≥ 10% from rest to peak, only a singl
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Journal articleHCMR Investigators, Kramer CM, Kolm P, et al., 2026,
Predictors of Long-Term Outcomes in Hypertrophic Cardiomyopathy: The NHLBI HCM Registry.
, JAMA, Vol: 335, Pages: 1959-1969IMPORTANCE: Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. OBJECTIVE: To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. DESIGN, SETTING, AND PARTICIPANTS: A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. EXPOSURES: Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. MAIN OUTCOMES AND MEASURES: The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy-related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. RESULTS: Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percenta
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Journal articleCraig NJ, Loganath K, Everett RJ, et al., 2026,
Myocardial Fibrosis and Early Intervention in Asymptomatic Patients With Severe Aortic Stenosis: Insights From the EVOLVED Randomized Clinical Trial.
, JAMA Cardiol, Vol: 11, Pages: 599-605IMPORTANCE: Myocardial fibrosis burden has been associated with adverse clinical outcomes in symptomatic patients with aortic stenosis. OBJECTIVE: To determine whether midwall myocardial fibrosis burden is associated with adverse clinical outcomes in asymptomatic patients and whether those with more fibrosis derive greater benefit from early intervention. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of a randomized clinical trial was conducted between August 2017 and October 2022. The trial took place at 24 cardiac centers across the United Kingdom and Australia. Participants included asymptomatic patients with severe aortic stenosis and midwall fibrosis on cardiac magnetic resonance. These data were analyzed from October 2024 through June 2025. INTERVENTION: Early intervention with transcatheter or surgical aortic valve replacement. MAIN OUTCOMES AND MEASURES: Primary outcome was all-cause death or unplanned aortic stenosis-related hospitalization. Secondary outcomes included the individual components of the primary outcome. RESULTS: In 224 trial participants (mean [SD] age, 73 [9] years; 63 women and 161 men, and mean [SD] aortic valve peak velocity 4.3 [0.5] m per second) with a median follow-up of 42 months, fibrosis burden (per 1% increase) was associated with an increase in the primary end point (hazard ratio [HR], 1.23; 95% CI, 1.08-1.37) and its component of unplanned aortic stenosis-related hospitalizations (HR, 1.22; 95% CI, 1.03-1.40) but not all-cause death (HR, 1.17; 95% CI, 0.98-1.35). There were no interactions between randomization arm and the midwall fibrosis burden for the primary (P for interaction = .39) or secondary end points. In patients with high fibrosis burden above the median, the primary end point occurred in 12 of 59 (20%) of those randomized to early intervention and 17 of 53 (32%) of those randomized to guideline-directed conservative management (HR, 0.62; 95% CI, 0.29-1.28). For the individual components, al
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Journal articlede Villiers C, Ormondroyd E, Thomson K, et al., 2026,
Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
, Heart Rhythm, Vol: 23, Pages: 1289-1299BACKGROUND: Filamin-C (FLNC) gene variants are associated with cardiac and skeletal muscle diseases including a clear role of loss-of-function variants in dilated cardiomyopathy. OBJECTIVE: This study aimed to assess the contribution of rare FLNC variants to hypertrophic cardiomyopathy (HCM)/restrictive cardiomyopathy (RCM). METHODS: Family-based studies in 2 specialist services and statistical modeling of rare FLNC missense variants were conducted, using a cohort of 3289 sarcomere-negative HCM cases and 122,348 genome aggregation database controls. RESULTS: Clinical evaluation of patients with HCM/RCM and a rare FLNC variant identified a distinct electrocardiographic (ECG) repolarization phenotype in 37% (19 of 51 individuals, from 12 families), which was observed in only 1.0% of a control HCM cohort (2 of 197). FLNC variant carriers with the characteristic ECG had smaller left ventricular cavity size, lower contractility, and more severe diastolic dysfunction and were more likely to have a restrictive phenotype. Heart failure death, transplant, or cardiac arrest occurred in at least 1 individual in 7 of the 12 families (58%) in the "ECG-positive" group, and musculoskeletal abnormalities were present in 4 families (33%). 5 of 12 variants (41.7%) in the "ECG-positive" group cosegregated, and 2 were apparently de novo. 11 variants were missense, and 1 splice site. Rare FLNC missense variant burden indicated a low case excess among all HCM cases (etiologic fraction, 0.45; 95% confidence interval, 0.36-0.54), but in "ECG-positive" cases the etiologic fraction was substantially higher (0.98; 95% confidence interval, 0.97-0.99). CONCLUSION: Pathogenic FLNC variants in patients with HCM/RCM are nontruncating and cause a discrete phenotype comprising a characteristic ECG, hypertrophic and restrictive features without hypercontractility, and extracardiac abnormalities.
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Journal articleStroeks SLVM, Bart NK, Rossano J, et al., 2026,
Sex and Age Specific Genetic Risk Across the Dilated and Arrhythmogenic Cardiomyopathy Spectrum
, JACC, Vol: 87, Pages: 3573-3588, ISSN: 0735-1097 -
Journal articleChan JH, Grace C, Mazidi M, et al., 2026,
Biobank-Scale Plasma Proteomics Identifies Novel Biomarkers in Hypertrophic Cardiomyopathy.
, Circ Genom Precis Med, Vol: 19BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by substantial heterogeneity in both clinical phenotype and risk of adverse outcomes, including heart failure and sudden cardiac death. This highlights the need for robust biomarkers for risk stratification, and while previous studies have identified the role of select plasma proteins, comprehensive large-scale proteomic analyses have been limited in HCM. METHODS: We performed a case-control analysis of 2922 plasma proteins in 49 588 UK Biobank participants (100 HCM cases) to identify proteins associated with HCM. External replication analyses were performed in the deCODE Genetics Icelandic study (51 cases/38 904 controls) and All of Us (546 cases/41 049 controls) data sets. Associations with adverse clinical outcomes and cardiac endophenotypes of disease severity were further identified, and causal relationships were evaluated using Mendelian randomization. Relative biomarker importance was also assessed by joint modeling via machine learning. RESULTS: We identified novel associations of ANGPT2 (angiopoietin-2) and LTBP2 (latent transforming growth factor-beta binding protein 2) with HCM, with both also showing prognostic utility for heart failure-related outcomes in HCM cases. We also confirmed the associations of established biomarkers (eg, NT-proBNP [N-terminal pro-B-type natriuretic peptide], troponins I and T) with HCM cases, cardiac imaging markers of disease severity, and adverse outcomes. Mendelian randomization analyses supported a causal effect of HCM on increasing NT-proBNP and troponin T levels. CONCLUSIONS: This biobank-scale plasma proteomic study in HCM identified ANGPT2 and LTBP2 as novel HCM biomarkers with potential diagnostic and prognostic utility. These findings highlight the potential for plasma proteomics to improve risk prediction and provide insight into HCM pathobiology.
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Journal articlePaul S, Munoz C, Ferreira P, et al., 2026,
Motion compensated spin echo cardiac diffusion tensor imaging in multiple cardiac phases using an ultrahigh gradient strength scanner
, Journal of Cardiovascular Magnetic Resonance, Vol: 28, ISSN: 1097-6647BackgroundCardiac diffusion tensor imaging (cDTI) has traditionally relied on inefficient stimulated echo techniques to robustly assess microstructural changes over the cardiac cycle. Ultrahigh gradient strength systems (>80mT/m) allow shorter motion compensated diffusion encoding. This study compares the ability of high and ultrahigh strength gradient systems to provide systolic and diastolic motion compensated spin echo (MCSE) cDTI.MethodsSecond order MCSE sequences were developed for a research-only Siemens 3T Connectom (300mT/m maximum gradient amplitude per axis) and breath hold cDTI was acquired at peak systole and end diastole. Acquisitions used the maximum achievable gradient strength (GUH, 116mT/m) and also limited to typical high gradient strengths (GH, 66mT/m based on 80mT/m maximum allowable), giving TE=48ms and 58ms respectively. Data were acquired at 2.8x2.8x8mm3, b=500s/mm2 (8 averages) and b=150s/mm2 (2 averages) in 6 encoding directions.Results22 healthy subjects were recruited. 20/21 and 21/22 systolic acquisitions at GUH and GH respectively met the >50% criteria of the circumferential myocardium showing the expected transmural variation in helix angle. For GUH and GH (16/20) 80% and (16/22) 73% of diastolic acquisitions were successful respectively. SNR was increased using GUH compared to GH (median [IQR]: 112.9 [3.8] vs. 9.6 [2.9], p=0.0002 diastole, 15.6 [5.9] vs. 12.5 [6.7], p=0.006 systole). Using GUH fractional anisotropy was lower in systole (0.349 [0.040] vs. 0.373 [0.019], p=0.002) and GUH transmural helix angle gradient (HAG) was steeper in diastole (-0.70 [0.17] vs. -0.55 [0.12] ˚/%, p=0.04). At both GUH and GH, sheetlet angle (|E2A|) was higher in systole than in diastole (30.7 [7.3] vs. 21.3 [6.7]˚ p=10-4 and 32.6 [10.9] vs. 26.0 [7.4]˚, p=0.03 respectively). Differences in HAG between phases were only apparent with GH (-0.88 [0.23] vs. -0.55 [0.15], p=10-4) and differences in the mean diffusivity only with GUH (1.64 [0.11] vs
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Journal articleOwais A, Chen H, Farooq H, et al., 2026,
Gene-gene interactions between a LMNA variant and common polymorphisms drive early-onset atrial fibrillation.
, Nat Commun, Vol: 17Atrial fibrillation (AF), the most common sustained arrhythmia, has a complex genetic basis; however, the molecular mechanisms linking rare and common variants remain poorly understood. Polygenic risk score (PRS) analysis in the UK Biobank and All of Us cohorts reveals that carriers of protein-altering LMNA variants (PAVs) have a significantly higher risk of incident AF than predicted by PRS alone, supporting an additive effect of common polymorphisms and LMNA variants. Induced pluripotent stem cell derived atrial cardiomyocytes (iPSC-aCMs) from individuals carrying the pathogenic missense variant p.S143P in LMNA exhibit widespread disruption of chromatin architecture and perturbation of atrial gene regulatory networks, particularly at loci harboring AF-associated variants and transcription factors essential for atrial rhythm control and contractility. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based epigenetic editing validates the function of several AF-associated regulatory elements and their downstream targets. Notably, reduced accessibility at an intronic SCN10A enhancer harboring the AF-associated SNP rs6801957 is associated with reduced sodium current in p.S143P iPSC-aCMs. These findings are reproduced in iPSC-aCMs derived from an additional individual carrying a distinct pathogenic LMNA variant, supporting a broader mechanism in which rare LMNA variants and common polymorphisms converge on shared regulatory networks to influence AF susceptibility and highlighting the value of integrating both in arrhythmia risk assessment.
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Journal articlePrzybylski R, Norrish G, Claggett B, et al., 2026,
The Natural History of Massive Left Ventricular Hypertrophy in Pediatric Hypertrophic Cardiomyopathy: A Multiregistry Analysis.
, Circulation, Vol: 153, Pages: 1463-1476BACKGROUND: Massive left ventricular hypertrophy (LVH) is a risk factor for sudden cardiac death in children with hypertrophic cardiomyopathy (HCM), but little is understood about its natural history. METHODS: Patients with pediatric-onset HCM identified from 2 registries (SHaRe [Sarcomeric Human Cardiomyopathy Registry] and IPHCC [International Paediatric Hypertrophic Cardiomyopathy Consortium]) with or without massive LVH were compared. Massive LVH was defined as absolute maximal left ventricular wall thickness (MLVWT) ≥30 mm or MLVWT z score ≥+20 at <18 years of age. Data from SHaRe and IPHCC include encounters from January 1960 through March 2024 and January 1970 through March 2024, respectively. Demographic, clinical, and serial MLVWT data were collected. Composite outcomes included major ventricular arrhythmia event (sudden cardiac death, aborted sudden cardiac death, or appropriate implantable cardioverter defibrillator therapy); heart failure (HF) event (left ventricular ejection fraction <50%, New York Heart Association class III or IV, transplant, or HF-related death); major adverse cardiac event (stroke or any major ventricular arrhythmia or HF outcome aside from left ventricular ejection fraction <50%); and HCM-related mortality (sudden cardiac death or HF-related death). Time-to-event analyses were performed using Cox proportional hazards models. RESULTS: We identified 587 patients (54 female [30%]). In 186 children with massive LVH, age at diagnosis was younger (median, 9.2 years [interquartile range, 2.1-13.1 years]) versus 13.6 years (9.7-15.5 years; P<0.001) and sarcomeric genetic variants more prevalent (72% versus 61%; P=0.034), as was HCM-related mortality (unadjusted hazard ratio, 3.3 [95% CI,1.2-9.7]; P=0.026), major adverse cardiac events (hazard ratio, 2.6 [1.7-3.9]; P<0.001), major ventricular arrhythmia (hazard ratio, 3.1 [1.8-5.2]; P<0.001), and HF (hazard ratio, 1.9 [1.1-3.1]; P=0.013). These associations remained
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Journal articleBenfield N, Thami PK, Ware J, et al., 2026,
GWAS reveals common SLX4 variants associated with telomere length and hypertension in individuals of African ancestry.
, Genes Genomics, Vol: 48, Pages: 673-682BACKGROUND: Cardiovascular disease (CVD) and its risk factors are highly prevalent in the UK, with incidence differing by ethnicity. Black individuals have an increased prevalence of heart failure, stroke and hypertension compared to White individuals. Telomere length has been associated with many age-related conditions, with shorter telomeres associated with increased CVD risk. However, Black individuals have longer telomeres on average compared to White individuals, which should be protective against CVDs. The increased incidence of CVD in this population indicates a paradoxical association. OBJECTIVES: To investigate the relationship between telomere length and cardiovascular disease risk across ethnic groups and to identify genetic variants that may explain observed differences. METHODS: Using the UK Biobank cohort, we assessed telomere length in Black and White populations and performed GWAS analysis to identify ethnicity-specific variants associated with telomere length. RESULTS: We report that Black individuals had significantly longer telomeres than White individuals (0.9035 vs 0.8301, p < 0.0001). Contrary to published reports, Black individuals showed lower incidence of most CVD subtypes compared to White individuals. However, hypertension was more prevalent in Black individuals despite longer telomeres. GWAS analysis identified 12 ethnicity-specific variants at genome-wide significance associated with longer telomeres in Black populations. Notably, 3 variants in SLX4 were significantly more common in Black individuals and associated with both longer telomere length and hypertension risk. High BMI and lower household income were found to influence hypertension risk, overriding the protective effect of longer telomeres in Black populations. CONCLUSIONS: The increased rate of hypertension in Black populations, as well as longer telomere length, may be influenced by common genetic variants. The protective effect of longer telomeres against CV
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Journal articleMukhopadhyay S, Cheng L, Jones RE, et al., 2026,
Prevalence and Clinical Importance of Right Ventricular Involvement in Mild Dilated Cardiomyopathy.
, J Am Heart Assoc, Vol: 15 -
Journal articleVissing CR, Axelsson Raja A, Helms AS, et al., 2026,
Differences in Disease Trajectory, Comorbidities, and Mortality in Sarcomeric and Nonsarcomeric Hypertrophic Cardiomyopathy.
, Circulation, Vol: 153, Pages: 1104-1116BACKGROUND: Sarcomere gene variants are a key cause of hypertrophic cardiomyopathy (HCM), and have been associated with worse prognosis. However, it is unclear how comorbidities influence clinical trajectories, the timing of events, and causes of death in sarcomeric and nonsarcomeric HCM. METHODS: We conducted a multicenter longitudinal cohort study of genotyped patients with HCM in the Sarcomeric Human Cardiomyopathy registry (SHaRe). Patients were classified as sarcomeric HCM (pathogenic/likely pathogenic sarcomere variant) or nonsarcomeric HCM (genetically elusive). The influence of genetic classification and comorbidities on the sequence of cardiovascular events were assessed in time-varying Cox proportional hazards models. RESULTS: Among 6120 patients (40% women; 87% probands; 50% sarcomeric HCM), followed for a median of 5.3 years, sarcomeric HCM (n=3082) was associated with a younger age at diagnosis (median 38.1 versus 54.3 years; P<0.001), a higher proportion of women and less obesity, hypertension, and left ventricular (LV) obstruction. After age standardization, sarcomeric HCM was associated with a higher burden of atrial fibrillation (age-standardized incidence [ASI] ratio, 1.28 [CI, 1.16-1.40]), LV systolic dysfunction (ASI ratio, 1.31 [CI, 1.15-1.48]), and ventricular arrhythmias (ASI ratio, 1.37 [CI, 1.17-1.52]) than nonsarcomeric HCM. All-cause mortality was similar (10.4% versus 9.4%; P=0.20); however, patients with sarcomeric HCM died younger (mean 7.8 years; P<0.001), with model-based survival-analysis estimating 3.5 life-years lost between ages 44 and 85. Sarcomeric HCM was also associated with higher HCM-related mortality (hazard ratio [HR], 1.61 [CI, 1.18-2.20]). Temporal analysis identified atrial fibrillation as the strongest disease-modifier, increasing the risk of LV systolic dysfunction (HR, 2.54 [CI 2.07-3.11]), ventricular arrhythmias (HR, 3.13 [CI, 2.36-4.20]), and mortality (HR, 1.94 [CI, 1.64-2.31]) in both groups. Genotype-inte
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Journal articleda Rocha GL, Feiner J, Lazarte J, et al., 2026,
Cardiomyopathy Gene Variants and Polygenic Risk Scores in Atrial Fibrillation: Evidence for an Atrial-First Phenotype.
, J Am Coll Cardiol, Vol: 87, Pages: 1279-1299BACKGROUND: Atrial fibrillation (AF) is heritable and its complex underlying genetic substrate is gradually being unraveled. OBJECTIVES: We sought to explore the impact of disease-causing cardiomyopathy variants on the risk of AF after adjustment for incident ventricular cardiomyopathy and clinical heart failure in 2 cohort studies (UK Biobank [UKB] and All of Us [AoU]) and evaluate the utility of polygenic risk scores (PRS) to further discern the risk of atrial and ventricular phenotypes in carriers. METHODS: Cox regression was used to evaluate for associations between disease-causing variants within genes for 3 cardiomyopathies (dilated cardiomyopathy [DCM], hypertrophic cardiomyopathy [HCM], and arrhythmogenic right ventricular cardiomyopathy) and AF. Disease-specific PRSs for AF, DCM, and HCM stratified study participants into quintiles. A HR random-effects meta-analysis was performed using the DerSimonian-Laird method. The Kaplan-Meier method was used to ascertain cumulative incidence from birth to 75 years of age. RESULTS: Among 655,796 individuals from UKB and AoU, presence of a disease-causing variant was associated with an increased AF hazard (HR: 1.73; 95% CI: 1.59-1.89; P < 0.001), including after adjustment for incident ventricular cardiomyopathy or clinical heart failure (adjusted to HR: 1.55; 95% CI: 1.46-1.64, P < 0.001). The cumulative AF risk for study participants with a putative disease-causing rare variant and a PRSAF within the top-risk quintile ranged from 32.5% (UKB) to 32.4% (AoU) relative to 9.8% (UKB) and 11.0% (AoU) for individuals without a putative disease-causing variant and a PRSAF within the lowest-risk quintile. The absolute cumulative cardiomyopathy risk among study participants with both a putative disease-causing variant and a disease-specific PRS within the top-risk quintile ranged from 5.9% (UKB) to 15.2% (AoU) for DCM and from 11.7% (UKB) to 19.1% (AoU) for HCM. CONCLUSIONS: Genetic variants that cause cardiomyopathy also
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Journal articleInciardi RM, Halliday B, Lombardi CM, et al., 2026,
Ethnicity and Disparities in Heart Failure: Hunt for an Equity Paradigm.
, J Am Coll Cardiol, Vol: 87, Pages: 1257-1260 -
Journal articleHatipoglu S, Voges I, Pushparajah K, et al., 2026,
Stress imaging in paediatric and congenital heart disease patients.
, Eur Heart J Cardiovasc Imaging, Vol: 27, Pages: 567-581Stress imaging in paediatric cardiology and congenital heart disease patients has an increasing role for functional assessment. Indications include coronary artery anomalies and disease in association with anomalous aortic origin of coronary arteries, Kawasaki disease or surgical manipulation of the coronary ostia, as well as assessment of elevated filling pressures, dynamic left ventricular outflow obstruction or significance of valvular heart disease. This review provides practical guidance focused on commonly used stress echocardiography and stress cardiovascular magnetic resonance in context of their clinical indications for this age group.
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Journal articleStroeks SLVM, Oko-Osi S, Arasu A, et al., 2026,
Sex differences in dilated cardiomyopathy: evidence gaps and future directions
, JACC, Vol: 87, Pages: 723-735, ISSN: 0735-1097Dilated cardiomyopathy (DCM), which affects 1 in 250 people, is a leading global cause of heart failure and the most common indication for heart transplantation. Evidence suggests that DCM is more prevalent in men, but whether this reflects biological differences or underdiagnosis in women remains uncertain. This review explores the impact of sex on DCM, examining differences in epidemiology, etiology, clinical presentation, treatment response, and outcomes. Women often present with less severe cardiac phenotypes, including lower levels of fibrosis and better left ventricular function, yet the long-term prognosis of DCM in women is less clear. Through a systematic review and meta-analysis, we found that male DCM patients with variants in PLN, DSP, and LMNA had higher arrhythmic event rates compared with TTNtv and BAG3 carriers. In female patients with DCM, those with RBM20, DSP, and PLN variants faced the highest arrhythmic risk, and TTNtv carriers the lowest. PLN and LMNA variants had the highest heart failure risk in both sexes, whereas BAG3, RBM20, and TTN variants had lower heart failure rates in female compared with male carriers. These findings highlight the influence of sex and genotype on clinical outcomes. Current risk-stratification tools, such as those used for implantable cardioverter-defibrillators, may undertreat women owing to reliance on sex-neutral thresholds. We highlight the role of genetic, environmental, and reproductive factors in shaping these disparities, including the influence of pregnancy, pregnancy complications, and menopause. This review identifies key gaps in knowledge and calls for expanded representation of women in DCM studies and the development of sex-specific risk models. Addressing these gaps is essential to improving outcomes and advancing equitable personalized care for all DCM patients.
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Journal articleSau A, Sieliwonczyk E, Barker J, et al., 2026,
Prediction of incident atrial fibrillation: a comprehensive evaluation of conventional and artificial intelligence-enhanced approaches
, Heart Rhythm, Vol: 23, Pages: E183-E191, ISSN: 1547-5271BackgroundMultiple risk scores and biomarkers have been proposed for the prediction of atrial fibrillation (AF), but it is unknown how these compare with each other and whether they could be combined.ObjectiveThis study aimed to evaluate and compare approaches for incident AF prediction.MethodsThe artificial intelligence-enhanced electrocardiogram risk estimator-AF (AIRE-AF), a convolutional neural network with a discrete-time survival loss function, was developed to predict incident AF. It was trained using a dataset of 1,163,401 electrocardiograms from 189,539 patients from the Beth Israel Deaconess Medical Center and externally validated in the UK Biobank (n = 38,892). AIRE-AF was compared with other risk prediction approaches including the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)-AF, a clinical risk score.ResultsIn the Beth Israel Deaconess Medical Center cohort, AIRE-AF predicted incident AF with a C-index of 0.750 (0.743–0.758). AIRE-AF was superior to CHARGE-AF, left atrial size, and N-terminal pro-B-type natriuretic peptide. The addition of CHARGE-AF and left atrial size provided a minor improvement in performance (C-index improvement 0.017). There was no additive value of N-terminal pro-B-type natriuretic peptide in combination with AIRE-AF. The single best-performing single predictor in the volunteer population (UK Biobank) was CHARGE-AF (C-index 0.750 [0.734–0.769]). The best-performing combination of 2 predictors was AIRE-AF and CHARGE-AF (C-index 0.768 [0.743–0.792]). The addition of a polygenic risk score to AIRE-AF and CHARGE-AF provided a further significant improvement in performance (C-index 0.791 [0.766–0.816]).ConclusionWe present the first comprehensive evaluation of methodologies for predicting incident AF. Risk prediction with a model including AIRE-AF and CHARGE-AF resulted in similar performance to more complex models.
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