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Journal articleTayal P, 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, ISSN: 0735-1097 -
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 CommunAtrial 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 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 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 articleHCMR Investigators, Kramer CM, Kolm P, et al., 2026,
Predictors of Long-Term Outcomes in Hypertrophic Cardiomyopathy: The NHLBI HCM Registry.
, JAMAIMPORTANCE: 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 articleStroeks SLVM, Bart NK, Rossano J, et al., 2026,
Sex and Age Specific Genetic Risk Across the Dilated and Arrhythmogenic Cardiomyopathy Spectrum
, JACC, ISSN: 0735-1097 -
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 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, ISSN: 0735-1097 -
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 MedPURPOSE: 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 ° $$ {180}^{{}^{\circ}} $$ or 90 ° $$ {90}^{{}^{\circ}} $$ pulses in PE direction; and the proposed flip-back sequence with a nonselective 180 ° $$ {180}^{{}^{\circ}} $$ 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 $$ p<0.01 $$ ) 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 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 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 CardiolIMPORTANCE: 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 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 articleHunt SE, Lemos D, Pericherla SR, et al., 2026,
Gene2Phenotype: A Database of Structured Human Monogenic Diseases and Pathomechanisms.
, J Mol BiolTo 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 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 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 RhythmBACKGROUND: 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 articleKhalique Z, Scott AD, Ferreira PF, et al., 2026,
Diffusion Tensor CMR Assessment of the Microstructural Response to Dobutamine Stress in Health and Comparison With Patients With Recovered Dilated Cardiomyopathy.
, Circ Cardiovasc Imaging, Vol: 19BACKGROUND: Contractile reserve assessment assesses myocardial performance and prognosis. The microstructural mechanisms that facilitate increased cardiac function have not been described, but can be studied using diffusion tensor cardiovascular magnetic resonance. Resting microstructural contractile function is characterized by reorientation of aggregated cardiomyocytes (sheetlets) from wall-parallel in diastole to a more wall-perpendicular configuration in systole, with the diffusion tensor cardiovascular magnetic resonance parameter E2A defining their orientation, and sheetlet mobility defining the angle through which they rotate. We used diffusion tensor cardiovascular magnetic resonance to identify the microstructural response to dobutamine stress in healthy volunteers and then compared with patients with recovered dilated cardiomyopathy (rDCM). METHODS: In this first-of-its-kind prospective observational study, 20 healthy volunteers and 32 patients with rDCM underwent diffusion tensor cardiovascular magnetic resonance at rest, during dobutamine, and on recovery. RESULTS: In healthy volunteers, both diastolic and systolic E2A increased with dobutamine stress (13±3° to 17±5°; P<0.001 and 59±11° to 65±7°; P=0.002). Sheetlet mobility remained unchanged (45±11° to 49±10°; P=0.19), but biphasic mean E2A increased (36±6° to 41±4°; P<0.001). In rDCM, diastolic E2A at rest was higher than in healthy volunteers (20±8° versus 13±3°, P<0.001), and sheetlet mobility was reduced (34±12° versus 45±11°; P<0.001). During dobutamine stress, rDCM diastolic and systolic E2A increased compared with rest (20±8° to 24±10°; P=0.001 and 54±13° to 63±11°; P=0.005). However, sheetlet mobility in patients with rDCM failed to increase with dobutamine to healthy levels (39±13° versus 49±
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Journal articleArdissino M, Morley AP, Truong B, et al., 2026,
Genetic Association of Circulating Proteins and Gene Transcripts With Spontaneous Coronary Artery Dissection.
, Circ Genom Precis Med, Vol: 19BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an uncommon cause of myocardial infarction that disproportionately affects women, particularly during pregnancy and the peripartum period. Limited understanding of its underlying pathophysiology hinders the development of effective preventive and therapeutic strategies. METHODS: This study investigated associations between genetically predicted circulating proteins and tissue-specific RNA levels with genetically predicted SCAD risk using Mendelian randomization and Bayesian colocalization. Genetic scores for >1500 circulating proteins were derived from the UK Biobank (N=34 557) and deCODE (N=35 559). Scores for 13 848 gene transcripts in arterial and fibroblast tissues were generated from Genotype-Tissue Expression data. Associations between these scores and SCAD were assessed in a genome-wide association study meta-analysis of 1917 individuals with SCAD and 9292 controls. Findings were validated in vitro using mass spectrometry-based proteomic analysis of extracellular vesicles from 50 patients with SCAD and 50 healthy controls. RESULTS: Genetic associations of 4 circulating proteins with SCAD (AFAP1 [actin filament-associated protein 1], ECM1 [extracellular matrix protein 1], SPON1 [spondin 1], and STAT6 [signal transducer and activator of transcription 6]) were identified. Two were supported by gene expression data (AFAP1 and ECM1), and one by tissue-specific Bayesian colocalization analyses (ECM1). Protein interaction mapping identified potential shared pathways through the JAK-STAT (Janus kinases and signal transducers and activators of transcription) signaling pathway and inflammatory regulation. Mass spectrometry-based proteomic analysis demonstrated that ECM1 was significantly upregulated in SCAD cases versus controls. CONCLUSIONS: Integrative analysis of proteomic, transcriptomic, and experimental data revealed 4 circulating proteins genetically associated with SCAD risk, w
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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, 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 articleKramarenko DR, Haydarlou P, Powell GJ, et al., 2026,
Leveraging the shared and opposing genetic mechanisms in the heritable cardiomyopathies.
, Res SqDilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are heart muscle diseases with largely opposing structural and functional phenotypes. Yet, both may lead to the same devastating outcomes of advanced heart failure and life-threatening arrhythmias. Using genome-wide association data from 9,365 DCM cases, 5,900 HCM cases, and over 1.2 million controls, we show that DCM and HCM are largely inversely associated across multiple genomic levels. Modeling both disorders as opposing genetic entities, in case-case GWAS approaches, we identify 100 loci (17 novel) underlying the cardiomyopathy spectrum. Several loci map to potential therapeutic targets (e.g., ADM, CACNA2D2), and polygenic risk scores derived from these data show strong discrimination between DCM and HCM patients in external datasets (AUC 0.78-0.84; AUPRC ~ 0.85). The pervasive opposing associations suggest that cardiomyocyte-directed therapies may often have opposite effects in DCM versus HCM. Nevertheless, a shared-effect analysis reveals a single locus - near the calcium-buffering gene CASQ2 - and also identifies a concordant genomic component associated with cardiometabolic health and extracardiac risk factors. By leveraging the shared and opposing genetic mechanisms of DCM and HCM, our work defines the genomic architecture of major cardiomyopathy subtypes and suggests new directions for therapeutics and precision medicine in heart failure.
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Journal articleMohal JS, Whinnett ZI, Mohiddin SA, et al., 2026,
Electromechanically Optimized Right Ventricular Pacing for Obstructive Hypertrophic Cardiomyopathy: The EMORI-HCM Trial.
, J Am Coll Cardiol, Vol: 87, Pages: 124-139BACKGROUND: Many patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) have devices capable of right ventricular pacing (RVP). Although pacing can reduce left ventricular outflow tract gradient (LVOTg), it can also reduce cardiac output, so its net effect is variable. OBJECTIVES: We tested whether electromechanical optimization of the programmed atrio-ventricular delay (AVD) allows RVP to achieve a net benefit on symptoms. METHODS: EMORI-HCM (Electromechanically Optimized Right Ventricular Pacing in Obstructive Hypertrophic Cardiomyopathy) is a multicenter, blinded, randomized, crossover trial of AVD-optimized RVP in patients with symptomatic oHCM with resting or provoked gradient of at least 30 mm Hg. Patients with existing dual-chamber devices were randomized to either 3 months of continuous AVD-optimized RVP (intervention) followed by 3 months of backup-only RVP (control), or vice versa. AVD was optimized using a high-precision multiple-alternation protocol assessing acute change in beat-by-beat blood pressure while varying AVD. The primary outcome was symptoms measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. Secondary outcomes include patient-reported daily symptom data collected using a dedicated smartphone application (ORBITA-app), dichotomous patient preference, EQ-5D, exercise capacity, and LVOTg. Patients were blinded to treatment allocation. Symptom assessments were self-administered. Outcome measures were recorded at baseline, crossover, and completion. Analysis was by Bayesian ordinal mixed modeling. RESULTS: Between October 2021 and October 2024, 117 screened patients met the inclusion criteria, of whom 60 were randomized. AVD-optimized RVP improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (+4.5; 95% credible interval [CrI]: 1.3-8.1; probability of benefit [Prbenefit] = 0.997) and daily symptom scores (OR: 1.29; 95% CrI: 0.98-1.68; Prbenefit: 0.969) compared with backup-only pacin
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Journal articleHalliday BP, Owen R, Ragavan A, et al., 2026,
A double-blind, randomized placebo-controlled trial examining the effect of MitoQ on myocardial energetics in patients with dilated cardiomyopathy
, European Heart Journal-Cardiovascular Imaging, Vol: 27, Pages: 74-77, ISSN: 2047-2404 -
Journal articleRjoob K, McGurk K, Zheng S, et al., 2026,
A multi-modal vision knowledge graph of cardiovascular disease
, Nature Cardiovascular Research, Vol: 5, Pages: 18-33, ISSN: 2731-0590Understanding gene–disease associations is important for uncovering pathological mechanisms and identifying potential therapeutic targets. Knowledge graphs can represent and integrate data from multiple biomedical sources, but lack individual-level information on target organ structure and function. Here we develop CardioKG, a knowledge graph that integrates over 200,000 computer vision-derived cardiovascular phenotypes from biomedical images with data extracted from 18 biological databases to model over a million relationships. We used a variational graph auto-encoder to generate node embeddings from the knowledge graph to predict gene–disease associations, assess druggability and identify drug repurposing strategies. The model predicted genetic associations and therapeutic opportunities for leading causes of cardiovascular disease, which were associated with improved survival. Candidate therapies included methotrexate for heart failure and gliptins for atrial fibrillation, and the addition of imaging data enhanced pathway discovery. These capabilities support the use of biomedical imaging to enhance graph-structured models for identifying treatable disease mechanisms.
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