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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 -
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 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 articleVissing CR, Axelsson Raja A, Helms AS, et al., 2026,
Differences in Disease Trajectory, Comorbidities, and Mortality in Sarcomeric and Nonsarcomeric Hypertrophic Cardiomyopathy.
, CirculationBACKGROUND: 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 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 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 -
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 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 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 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 articleRjoob K, McGurk K, Zheng S, et al., 2025,
A multi-modal vision knowledge graph of cardiovascular disease
, Nature Cardiovascular Research, 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 multiplebiomedical sources, but lack individual-level information on target organ structure and function. Here wedevelop 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 overa million relationships. We used a variational graph auto-encoder to generate node embeddings from theknowledge graph to predict gene-disease associations, assess druggability and identify drug repurposing strategies. The model predicted genetic associations and therapeutic opportunities for leading causesof cardiovascular disease, which were associated with improved survival. Candidate therapies includedmethotrexate for heart failure and gliptins for atrial fibrillation, and the addition of imaging data enhancedpathway discovery. These capabilities support the use of biomedical imaging to enhance graph-structuredmodels for identifying treatable disease mechanisms.
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Journal articlePouliopoulos J, Imran M, Anthony C, et al., 2025,
Cardiovascular magnetic resonance feature tracking for rejection surveillance after cardiac transplantation.
, J Cardiovasc Magn Reson, Vol: 28BACKGROUND: Endomyocardial biopsy (EMB) is the standard invasive method for monitoring acute cardiac allograft rejection (ACAR); however, non-invasive alternatives are increasingly proving to be dependable. OBJECTIVES: We aimed to identify and validate dependable cardiovascular magnetic resonance (CMR) strain indices for ACAR detection. METHODS: We analyzed 160 CMR scans, including long- and short-axis cines, as well as T1/T2 maps from 54 transplant recipients. Uniparametric and multiparametric models integrating left ventricular strain metrics and tissue characteristics were developed to classify histological rejection grades (0, 1 R, ≥2 R) and evaluate therapeutic response. RESULTS: Regression analysis using generalized linear mixed-models identified significant differences between rejection groups, with global radial strain (GRS) (z-value = 3.1, p = 0.002) and global circumferential strain (GCS) (z-value = 2.5 p<0.008) outperforming global longitudinal strain (GLS) in discriminating ≥2 R from 1 R rejection. Diagnostic performance for detecting ≥2 R rejection was excellent, particularly for GCS (AUC = 0.852, negative predictive value [NPV] = 98.3%) and GRS (AUC = 0.826, NPV = 95.8% (95.8/100)), with enhanced accuracy in the anterolateral mid-basal segments (AUC>0.886, NPV>97.9%). Strain metrics effectively monitored recovery post-therapy for ≥2 R rejection, showing significant improvements (GRS Δ24.5±7.1%, GCS Δ15.9±4.6%, GLS Δ27.4±11.8%, all p<0.02). Furthermore, as strained-based detection of ≥2 R rejection correlated with increases in edema detected using T1/T2 mapping (all p<0.001), integrating strain with T1/T2 mapping significantly enhanced diagnostic accuracy, with T2+GRS (AUC = 0.931, NPV = 98.2) and T1+T2+GCS (AUC = 0.943, NPV = 97.5) as the most effective models. CONCLUSION: Segmental CMR strain analysis demonstrates excellent diagn
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Journal articleLakdawala NK, Hershberger RE, Garcia-Pavia P, et al., 2025,
Danicamtiv, a Selective Agonist of Cardiac Myosin, for Dilated Cardiomyopathy: A Phase 2 Open-Label Trial.
, J Am Coll Cardiol, Vol: 86, Pages: 2598-2612BACKGROUND: Precision therapies for dilated cardiomyopathy (DCM) are lacking despite diverse manifestations and clinical trajectories based on underlying etiology. DCM-associated pathogenic variants in cardiac beta-myosin heavy chain (MYH7) and titin (TTN) can impair the function/availability of cardiac myosin. Danicamtiv is a novel investigational small molecule that selectively enhances cardiac myosin function. OBJECTIVES: The study sought to translationally evaluate danicamtiv in the setting of myosin dysfunction, from in vitro assessments to a clinical trial exploring its safety and efficacy in DCM due to MYH7 or TTN variants, or other causes (either positive or negative genetic results). METHODS: The danicamtiv effects on DCM-variant cardiac myosin enzyme activity and skinned left ventricular (LV) fiber force generation were assessed in vitro. A phase 2a, baseline-controlled, open-label trial enrolled individuals with DCM into cohorts by variants (MYH7 or TTN) or other causes. In the week of treatment period (TP)1, participants received oral danicamtiv 25 mg twice daily with dose adjustment in TP2 to 10 or 50 mg twice daily. The primary endpoint was safety/tolerability; secondary endpoints included echocardiography-assessed changes in cardiac structure/function. RESULTS: In vitro, danicamtiv increased the activity of wild-type and DCM myosin, increasing force production in cardiac fibers. Forty-one participants were enrolled in the trial (mean age 49.6 ± 13 years; mean baseline LV ejection fraction 33.4% ± 8.0%). Twelve had MYH7 variants, 14 had TTN variants, and 15 had other cause DCM. Treatment-emergent adverse events were reported in 22 (53.7%) of 41 participants (all mild or moderate; 1 discontinuation); an asymptomatic increase in cardiac troponin was detected in 3 participants in the other causes cohort. After TP2, the MYH7 and TTN cohorts showed improvements from baseline in LV ejection fraction (MYH7: 8.8% [95% CI: 5.03%-12.64%]; TTN: 5.9%
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Journal articleJohnson R, Fletcher RA, Peters S, et al., 2025,
Titin-related familial dilated cardiomyopathy: factors associated with disease onset.
, Eur Heart J, Vol: 46, Pages: 5240-5257BACKGROUND AND AIMS: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. METHODS: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. RESULTS: A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80-30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06-5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27-3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35-9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08-.23). CONCLUSIONS: Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.
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Journal articleArdissino M, Nicolaides K, Conti-Ramsden F, et al., 2025,
Polygenic Risk Scores for Preeclampsia Prediction Beyond Gold-Standard Clinical Models in Multiethnic Populations
, JOURNAL OF THE AMERICAN HEART ASSOCIATION, Vol: 14 -
Journal articleTänzer M, Scott AD, Khalique Z, et al., 2025,
Accelerating cDTI with deep learning-based tensor de-noising and breath hold reduction. a step towards improved efficiency and clinical feasibility
, Journal of Cardiovascular Magnetic Resonance, Vol: 27, ISSN: 1097-6647BackgroundCardiac Diffusion Tensor Imaging (cDTI) non-invasively provides unique insights into cardiac microstructure. Current protocols require multiple breath-hold repetitions to achieve adequate signal-to-noise ratio, resulting in lengthy scan times. The aim of this study was to develop a cDTI de-noising method that would enable the reduction of repetitions while preserving image quality.MethodsWe present a novel de-noising framework for cDTI acceleration centred on three fundamental advances: (1) a paradigm shift from image-based to tensor-space de-noising that better preserves structural information, (2) an ensemble of Vision Transformer-based models specifically optimised for tensor processing through adversarial training, and (3) a sophisticated data augmentation strategy that maximises training data utilisation through dynamic repetition selection.ResultsOur approach reduces scan times by a factor of up to 4 while achieving a 20% reduction in cDTI maps errors over existing de-noising methods (Table 1) and preserving anatomical features such as infarct characterisation and transmural cardiomyocyte orientation patterns. Crucially, our proposed method succeeds in clinical cases where other algorithms previously failed.ConclusionsThis demonstrates substantial improvements in cDTI acquisition efficiency, achieving up to 4-fold scan time reduction (3-5 breath-holds) while maintaining diagnostic accuracy across diverse cardiac pathologies.
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Journal articlePatlatzoglou K, Pastika L, Barker J, et al., 2025,
The cost of explainability in artificial intelligence-enhanced electrocardiogram models
, npj Digital Medicine, ISSN: 2398-6352Artificial intelligence-enhanced electrocardiogram (AI-ECG) models have shown outstanding performance in diagnostic and prognostic tasks, yet their black-box nature hampers clinical adoption. Meanwhile, a growing demand for explainable AI in medicine underscores the need for transparent, trust-worthy decision-making. Moving beyond post-hoc explainability techniques that have shown unreliable results, we focus on explicit representation learning using variational autoencoders (VAE), to capture inherently interpretable ECG features. While VAEs have demonstrated potential for ECG interpretability, the presumed performance-explainability trade-off remains underexplored, with many studies relying on complex, non-linear methods that obscure the morphological information of the features. In this work, we present a novel framework (VAE-SCAN) to model bi-directional, interpretable associations between ECG features and clinical factors. We also investigate how different representations affect ECG decoding performance across models with varying levels of explainability. Our findings demonstrate the cost introduced by intrinsic ECG interpretability, based on which we discuss potential implications and directions.
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Journal articleAkbari T, Hammersley DJ, May CY-Y, et al., 2025,
The impact of cardio-renal-metabolic profile in dilated cardiomyopathy
, Current Cardiology Reports, Vol: 27, ISSN: 1534-3170Purpose of ReviewDilated cardiomyopathy is an important contributor to heart failure burden worldwide. With an aging population and rising multimorbidity, in this review, we describe the prevalence of metabolic syndrome and renal failure in patients with dilated cardiomyopathy and focus on common underlying mechanisms, evaluate outcomes in these patients and highlight newer therapeutic strategies.Recent FindingsA significant proportion of patients with dilated cardiomyopathy has concomitant metabolic syndrome and renal disease. This combination of multimorbidity portends worse prognosis and often presents unique challenges in treatment given the complex interplay and shared pathophysiological pathways.SummaryOptimization of the cardio-renal-metabolic profile should be a key consideration in the management of patients with dilated cardiomyopathy. Therapeutic strategies targeting common pathophysiological pathways are needed in order to improve overall outcomes.
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Journal articleTeh I, Moulin K, Ferreira PF, et al., 2025,
Multi-center investigation of cardiac diffusion tensor imaging in healthy volunteers by the Society of Cardiovascular Magnetic Resonance Cardiac Diffusion Special Interest Group NETwork (SIGNET)
, Journal of Cardiovascular Magnetic Resonance, Vol: 27, ISSN: 1097-6647BackgroundCardiac diffusion tensor imaging (cDTI) is an emerging technique for microstructural characterization of the heart and has shown clinical potential in a range of cardiomyopathies. However, there is substantial variation reported for in vivo cDTI results across the literature, and sensitivity of cDTI to differences in imaging sites, scanners, acquisition protocols, and post-processing methods remains incompletely understood.MethodsSIGNET is a prospective multi-center, observational study in traveling and non-traveling healthy volunteers. The study was initiated by the executive board of the Society of Cardiovascular Magnetic Resonance (SCMR) Cardiac Diffusion Special Interest Group (SIG) as a follow-up to a previous multi-center study on phantom validation of cardiac DTI and a recently published SCMR consensus statement on cardiac diffusion MRI. The study has been developed by the Project Management Committee in consultation with the SCMR cardiac diffusion SIG, which includes international experts in cardiac diffusion MRI. To date, more than 20 international institutions have engaged with the study, including sites that are new to cardiac DTI, making this the largest collaborative effort in the field.DiscussionSIGNET will provide important information about the key sources of variation in cardiac DTI. This will help rationalize strategies for addressing and minimizing such variation. Harmonization of protocols in this and future studies will underpin efforts to translate cardiac DTI for clinical application.
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Journal articleAkbari T, Mach L, Hammersley DJ, et al., 2025,
Visually assessed ischaemia on cardiac magnetic resonance, but not quantitative perfusion metrics, predicts symptomatic improvement in coronary artery bypass
, Journal of Cardiovascular Magnetic Resonance, Vol: 27, ISSN: 1097-6647BackgroundSerial perfusion cardiovascular magnetic resonance (CMR) in symptomatic patients undergoing coronary artery bypass grafting (CABG) may provide mechanistic insight into dynamic abnormalities of the myocardium.ObjectivesTo assess how changes in cardiac reperfusion and remodelling associate with symptom improvement in patients undergoing CABGMethodsPatients awaiting elective CABG completed serial quality of life questionnaires and detailed CMR at baseline and at 6-12 months post CABG as per protocol. Automated fully quantitative stress and rest myocardial blood flow was calculated, alongside assessment of the visual ischaemic burden. Findings were correlated with changes in symptomatology.ResultsOf 40 patients who underwent serial evaluation with CMR (mean age 62.1±9.3, median LVEF 68% [IQR: 62-73%]), there was improvement in the median visual ischaemic burden (42% [IQR: 27-51] vs 18% [IQR: 11-21], P<0.001), mean global stress myocardial blood flow (1.34±0.5 ml/min/g vs 1.59±0.5 ml/min/g, P=0.002) and median global myocardial perfusion reserve (1.85±0.6 vs 2.4±0.9, P<0.001) following CABG. Greater improvement in the SAQ-7 summary score was associated with a greater decrease in the visual ischaemic burden following CABG (ρ=-0.38, P=0.02). Quantitative MBF metrics did not associate with baseline or change in SAQ-7 summary score.ConclusionSerial perfusion CMR identifies dynamic changes in markers of myocardial perfusion in patients following CABG. Greater reduction of visually assessed ischaemia associated with improvement in SAQ-7 score. Quantitative perfusion indices were not associated with symptom improvement in this study. The results also suggest residual inducible ischaemia post CABG requiring further studies to elucidate its clinical relevance.
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