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Journal articleSarwat S, Alen R, Wu Z, et al., 2026,
MTFP1 preserves β-cell cristae structure and bioenergetics to ensure insulin release and glucose homeostasis.
, bioRxivPancreatic β-cells are uniquely dependent on mitochondrial metabolism to couple glucose sensing to insulin secretion, a process impaired in diabetes. Mitochondrial fission process 1 (MTFP1) is an inner mitochondrial membrane protein that plays pleiotropic, tissue-specific roles in mitochondrial function and dynamics. Our previous work has identified Mtfp1 mRNA as a target for miR-125b, a microRNA that negatively regulates insulin secretion from β-cells. Nevertheless, the function of MTFP1 in these cells remained unexplored. Here, we show that MTFP1 is essential for normal glucose-stimulated insulin secretion (GSIS) in mouse and human cell lines and islets, and that mice with β-cell-specific elimination of MTFP1 develop glucose intolerance. Whereas β-cell survival and mitochondrial content were unaffected, oxidative phosphorylation and ATP production were sharply lowered. These changes were accompanied by disruption of mitochondrial cristae structure and a reduced contact surface with the endoplasmic reticulum, providing a mechanistic basis for defective stimulus-secretion coupling. Conversely, MTFP1 overexpression in mouse and human islets sufficed to improve mitochondrial respiration and GSIS. Finally, MTFP1 downregulation blocked the positive effects of miR-125b elimination in GSIS and mitochondrial respiration, unveiling MTFP1 as a downstream effector of miR-125b. Together, our findings identify MTFP1 as a critical regulator of β-cell mitochondrial architecture and function, necessary for efficient insulin secretion and glucose homeostasis, and a potential therapeutic target to enhance β-cell bioenergetic resilience in diabetes.
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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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Journal articleAnwar M, Sarkar M, Ford K, et al., 2026,
Human left ventricle circRNA-miRNA-mRNA network analyses reveal a novel proangiogenic role for circNPHP1 under ischemic conditions
, JACC: Basic to Translational Science, Vol: 11, ISSN: 2452-302XTherapies promoting microvascular flow and endothelial repair require effective identification of new targets in ischemic heart disease (IHD). The aim of this study was to unravel and functionally investigate circular RNA (circRNA)-microRNA (miRNA)-messenger RNA (mRNA) networks in endothelial cells in the context of IHD and Type 2 Diabetes Mellitus (T2DM). We performed RNA sequencing on left ventricle biopsies from patients with IHD, IHD and T2DM and non-IHD. Next, we created circRNA-miRNA-mRNA networks and mechanistically investigated the top circRNA-miRNA sponging interactions in endothelial cells (ECs). We found that circNPHP1 promotes angiogenesis via sponging of miR-221-3p and regulates its downstream target genes, VEGFA and BCL2 in IHD and T2DM.
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Journal articleBello SO, Singh C, Perbellini F, et al., 2026,
Mechanical unloading coupled with coronary reperfusion stimulates cardiomyocyte proliferation and prevents unloading-induced fibrosis after myocardial infarction
, Basic Research in Cardiology, Vol: 121, Pages: 43-57, ISSN: 0300-8428Percutaneous left ventricular assist devices (LVADs) have become essential tools during coronary reperfusion in high-risk PCI. Significant reduction in infarct propagation is observed when mechanical unloading is coupled with reperfusion, but little is known of the effect this reduction in wall stress and extracellular matrix with LVADs has on the heart's regenerative capacity. This study investigates the effect coronary reperfusion coupled with mechanical unloading has on myocardial fibrosis, and the impact of these changes in extracellular matrix on the heart's regenerative potential. MI was induced by coronary artery ligation in Lewis rats. Hearts underwent permanent coronary ligation (AMI) or were reperfused after 90 min (AMI/R). In each group, hearts were either loaded (AMI-L or AMI/R-L) or unloaded (AMI-U or AMI/R-U). In the unloaded subgroup, the infarcted hearts were explanted after 90 min and transplanted into the abdomen of healthy recipients via heterotopic abdominal heart–lung transplantation. The recipient’s heart acted as control. Hearts were analysed on day 7. 30 hearts were studied. In the permanent ligation group, fibrosis increased in both the loaded and unloaded hearts with no significant rise in cardiomyocyte proliferation. After coronary reperfusion, no increase in fibrosis was observed with mechanical unloading but cardiomyocyte proliferation rose significantly (AMI/R-L vs AMI/R-U p = 0.0001). Cardiomyocyte proliferative rate in the loaded and unloaded hearts was 0.6% and 3.7%, respectively, after permanent ligation, and 0.5% and 10.4%, respectively, after coronary reperfusion. These data show that coronary reperfusion coupled with mechanical unloading reduces myocardial fibrosis and upregulates cardiomyocyte proliferation after myocardial infarction.
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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 articleSaleh K, Hadadi R, Liang Y, et al., 2026,
AI-ECG classification for Brugada syndrome: A study of machine learning techniques to optimise for limited datasets.
, PLOS Digit Health, Vol: 5Deep neural networks can classify ECGs with high accuracy when training data is abundant. Rare conditions like Brugada syndrome, an inherited arrhythmia syndrome predisposing to sudden death, pose challenges due to data scarcity hindering model training. We evaluated multiple machine learning (ML) approaches to optimise a Brugada ECG classification model using limited training data. The baseline model was trained on a dataset comprising 176 Brugada, 176 right bundle branch block (RBBB) and 352 normal ECGs from Zhongshan Hospital (Zhongshan-baseline dataset), framed as a binary classification task to distinguish Brugada from non-Brugada ECGs. A 25%-75% train-test split was used to exacerbate data scarcity. To enhance training, we incorporated three additional datasets: (i) a different, labelled ECG dataset from Zhongshan Hospital including normal and RBBB ECGs (Zhongshan-pretrain), (ii) an unlabelled ECG dataset from Hammersmith Hospital including Brugada and non-Brugada ECGs (Imperial), (iii) an open-access labelled ECG dataset (PTB-XL). Three strategies were tested: (1) supervised pretraining, (2) self-supervised pretraining with data augmentation, and (3) oversampling using SMOTE (synthetic minority oversampling technique). Each model was evaluated on the unseen internal test set and an external Brugada mimic dataset. The models were re-trained using an 80%-20% train-test split as a secondary analysis. The baseline model achieved 92.2% accuracy, F1-score 0.837, and area under the Receiver Operating Characteristic curve (AUC) 0.962. Supervised pretraining significantly improved performance when training data was scarce, with the best model pretrained on the Zhongshan-pretrain dataset boosting accuracy (+3.2%), F1-score (+0.071) and AUC + 0.019), with consistent cross-validation performance. Self-supervised pretraining produced smaller and more variable gains, although select models better mitigated against false positives on the Brugada mimic dataset.
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Journal articleSamways JW, Cheng T, Chow J-J, et al., 2026,
Ventricular repolarization is improved by His resynchronization therapy but not biventricular pacing.
, Heart Rhythm, Vol: 23, Pages: e220-e229BACKGROUND: Biventricular pacing (BVP) delivered cardiac resynchronization therapy (CRT) modestly improves activation synchrony in patients with heart failure and left bundle branch block (LBBB) but can trigger ventricular arrhythmias. His bundle pacing (HBP) can correct LBBB as an alternative CRT method, producing superior ventricular activation synchrony and hemodynamics. OBJECTIVE: The aim of the study was to investigate the relative effects of HBP-CRT and BVP-CRT on ventricular repolarization. METHODS: Patients with LBBB referred for BVP-CRT underwent intra-procedural non-invasive epicardial mapping during atrial pacing (intrinsic LBBB), BVP-CRT, and temporary HBP. When HBP corrected LBBB, changes from baseline (LBBB) in overall and left ventricular (LV) repolarization dispersion (ΔVRT, ΔLVRT), repolarization gradient (ΔVRG, ΔLVRG) and activation-recovery interval (ARI) dispersion (ΔVARI, ΔLVARI) were measured. RESULTS: 17 patients had full datasets. BVP-CRT had no effect on global repolarization dispersion, gradient steepness or ARI (ΔVRT -1.5 ms, 95% confidence interval [CI] -15.4 to +12.4, P = .82; ΔVRG -0.00549 ms/mm, -0.106 to +0.0954, P = .9; ΔVARI -5.0 ms, -24.3 to +14.3, P = .59) and worsened the parameters in the LV (ΔLVRT +14.5 ms, +0.05 to +28.9, P = .049; ΔLVRG +0.0931 ms/mm, -0.0635 to +0.25, P = .226, ΔLVARI +28.6 ms, 95% CI +6.0 to +51.2, P = .02). HBP-CRT significantly improved global repolarization dispersion, gradient steepness and ARI (ΔLVRT +14.5 ms, +0.05 to +28.9, P = .049; ΔLVRG +0.0931 ms/mm, -0.0635 to +0.25, P = .226; ΔVARI -49.5 ms, -69.0 to -29.9, P < .0001) and within the LV (ΔLVRT -38.2 ms, -48.7 to -27.6, P < .001; ΔLVRG -0.228 ms/mm, -0.334 to -0.122, P = .0003; ΔLVARI -37.2 ms, -59.4 to -15.0, P = .003). CONCLUSION: HBP-CRT improves LBBB-induced repolarization abnormalities through improved activation synchrony and AR
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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 articleVenkatakrishnan A, Srinivasan D, Malik A, et al., 2026,
Effect of estrogen and testosterone on cardiac electrophysiology and atrial fibrillation.
, Heart Rhythm O2, Vol: 7, Pages: 393-403The prevalence and treatment outcomes of atrial fibrillation (AF) differ between sexes, yet the mechanisms underlying these differences remain poorly understood. Given that estrogen and testosterone are the major sex hormones, they may be involved in altering cardiac electrophysiology and risk of AF. Preclinical studies demonstrate that estrogen and testosterone alter ion currents and cardiomyocyte calcium (Ca2+) handling via receptor-mediated mechanisms, but with opposite effects. Estrogen prolongs action potential duration (APD), whereas testosterone shortens it. A longer APD has antiarrhythmic effects in the atria, whereas a shorter APD is proarrhythmic. Testosterone also accelerates repolarization and enhances contractility, further increasing AF risk. However, most laboratory studies were done in animal ventricular models, limiting direct translation to human atrial physiology owing to species-specific electrophysiological differences. Human population studies suggest that decreased exposure to endogenous estrogen increases AF risk in women. In males, there is no similar consensus for the relationship between endogenous testosterone exposure and AF risk in men. Evidence from hormone replacement, testosterone replacement, and androgen deprivation therapies is similarly inconclusive, reflecting confounding factors, variation in hormone formulations, and reliance on single hormone measurements. This review provides novel insights into how estrogen and testosterone differentially influence cardiac electrophysiology and risk of AF in men and women. These findings underscore the need for personalized sex- and hormone-specific treatment strategies in AF management, addressing a critical gap in current clinical practices.
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Journal articleSimader FA, Rajkumar CA, Foley MJ, et al., 2026,
Association Between Age and PCI Effectiveness in Stable CAD: Secondary Analysis of ORBITA-2.
, J Am Coll Cardiol, Vol: 87, Pages: 253-265BACKGROUND: ORBITA-2 (Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) was the first randomized placebo-controlled trial to show the efficacy of percutaneous coronary intervention (PCI) in patients with stable angina and single- or multivessel coronary artery disease without background antianginal medication. Whether the effect is consistent across age groups is unknown. OBJECTIVES: The authors sought to evaluate the interaction between age and symptom and stenosis severity, and the efficacy of PCI on the ORBITA-2 primary and secondary endpoints. METHODS: All patients from the primary ORBITA-2 trial contributed data to this post hoc analysis. For daily symptoms, a bayesian longitudinal Markov model was constructed. For treadmill exercise time, stress echocardiography, and questionnaires, a bayesian ordinal proportional odds model was used, including the prerandomization value and treatment arm, which were allowed to interact with age. RESULTS: The mean age was 64 ± 9 years, ranging from 40 to 82 years. There was little relationship between age and symptom and stenosis severity. In older patients, PCI was more effective for symptom relief (OR: 2.03; 95% CrI: 1.67-2.45; Pr > 0.99) than in younger patients (OR: 1.70; 95% CrI: 1.38-2.15; Pr > 0.99; Pr [interaction] = 0.99). In contrast, the effect of PCI on treadmill exercise time was far greater in younger than in older patients (50-year-old: +125 s [95% CrI: 35.8-215.0 s; Pr > 0.99]; 70-year-old: +31.9s [95% CrI: -12.6 to 78.3; Pr = 0.92]; Pr [interaction] = 0.96). CONCLUSIONS: PCI was effective across all ages in reducing angina frequency. Notably, there was limited improvement in treadmill exercise time in the elderly, challenging its role as a primary endpoint in many antianginal trials. These data should inform cardiovascular clinical trial design to ensure applicability across all ages. (Objective Randomized Blinded Investigation With Optimal
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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 articleMonguillon V, Kelly PJ, O'Donoghue ML, et al., 2026,
Efficacy and Safety of Very Low Achieved LDL Cholesterol in Patients With Previous Ischemic Stroke.
, Circulation, Vol: 153, Pages: 86-93BACKGROUND: Patients with previous ischemic stroke are at high risk for recurrent stroke and other major adverse cardiovascular events. The benefits of achieving very low levels of low-density lipoprotein cholesterol (LDL-C) in such patients is unclear. METHODS: We analyzed patients with previous ischemic stroke enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), a randomized placebo-controlled trial studying evolocumab in patients with stable atherosclerotic cardiovascular disease (median follow-up, 2.2 years), and through the open-label extension (FOURIER-OLE) period (additional median follow-up, 5 years), to examine the relationship between achieved LDL-C and the long-term incidence of the primary end point (cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization) and stroke-related end points. RESULTS: The analysis included 5291 patients with previous ischemic stroke (>4 weeks). Of these, 666 (12.6%), 1410 (26.6%), 586 (11.1%), 508 (9.6%), and 2121 (40.1%) patients achieved LDL-C values of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. The incidence of the primary end point, all stroke, and ischemic stroke each decreased in a monotonic fashion with lower achieved LDL-C levels on a continuous scale (Ptrend<0.001, 0.002, and 0.002, respectively). Compared with patients with LDL-C ≥70 mg/dL, those who achieved levels <40 mg/dL had incidence rate ratios of 0.69 (95% CI, 0.57-0.84), 0.73 (95% CI, 0.53-0.99), and 0.75 (95% CI, 0.54-1.05) for the outcomes of the primary end point, all stroke, and ischemic stroke, respectively. Hemorrhagic strokes were infrequent and unrelated to achieved LDL-C (Ptrend=0.85). CONCLUSIONS: In patients with previous ischemic stroke, it appeared that the lower the LDL-C, down to levels <40 mg/dL, the lower the risk of major adverse cardiovascular events, includi
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Journal articleTorre E, Faure M, Bidaud I, et al., 2026,
L-Type Cav1.3 and HCN Channels Mediate Heart Rate Acceleration by Catecholamines.
, Circ Res, Vol: 138BACKGROUND: The ionic mechanism by which catecholamines increase the heart rate is incompletely understood. In this study, we have assessed the roles of sinoatrial node L-type Cav1.3 (α1D) Ca2+ channels, phosphorylation of L-type channel regulatory partner protein Rad (Ras-related RGK GTP-binding protein), and cAMP-dependent regulation of hyperpolarization-activated HCN (hyperpolarization-activated cyclic nucleotide-gated) channels. METHODS: We studied β-adrenergic regulation of heart rate and sinoatrial pacemaker activity in mice lacking Cav1.3 channels and in mice expressing dihydropyridine-insensitive L-type Cav1.2 channels alone or concomitantly expressing cAMP-insensitive HCN4 subunits in a heart-specific and time-controlled manner. We also studied the chronotropic response to sympathomimetics of sinoatrial pacemaker myocytes under conditions of specific inhibition of cAMP-dependent regulation of HCN4 by the cyclic dinucleotide cyclic di-(3',5')-GMP and ablation of PKA (protein kinase A)-dependent phosphorylation of Rad. RESULTS: Mutant mice with knockout of Cav1.3 and cAMP-insensitive HCN4 subunits in the heart lacked diurnal variation in heart rate and failed to increase their heart rate after administration of catecholamines or during physical activity. Selective pharmacological inhibition of Cav1.3 prevented the enhancement of pacemaker activity by sympathomimetics or by direct activation of adenylate cyclase, as well as by phosphodiesterase inhibitors, when cAMP-dependent regulation of HCN was simultaneously silenced. Upregulation of Cav1.3 and HCN-mediated funny current (If) accounted for the total change in diastolic current on activation of β-adrenoceptors, explaining the loss of chronotropic effect of catecholamines. Preventing PKA phosphorylation of Rad abrogated the chronotropic response to sympathomimetics of intact hearts under HCN blockade, or in pacemaker myocytes on preventing cAMP-dependent regulation of HCN4, respectively. CONC
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Journal articleJenkins A, Rainbow E, Jaimoukha I, et al., 2026,
Fair and Skill-Diverse Student Group Formation: A graph-theoretic approach
, IEEE Signal Processing Magazine, Vol: 43, Pages: 83-97, ISSN: 1053-5888In modern education, collaborative learning plays a crucial role in fostering problem-solving skills and innovation. However, traditional student group formation methods, such as random assignment, self-selection, or instructor intuition, often fail to optimize learning outcomes. Existing algorithmic methods for student grouping, while sophisticated, draw from general approaches for team formation and thus rely on predefined skill categories or subjective student assessments, constraining group effectiveness from the outset. This article provides a comprehensive review of existing team formation strategies and proceeds to address the formation of student groups that are internally skill diverse yet fair across groups, maximizing intra-group heterogeneity while ensuring inter-group homogeneity. Graph-theoretic methods provide a unified framework for this challenge, encoding student similarities while enabling both skill discovery and constrained optimization. Prior graph-based approaches, however, predominantly optimized structural properties alongside skill coverage requirements. This article demonstrates the ability of correlation-based Laplacian eigenmaps to discover latent skills from academic records, and how constrained graph partitioning can optimize student group composition according to education-relevant criteria. The resulting variable neighborhood search (VNS) heuristic achieves near-optimal solutions, within 0.25% of theoretical optimum, with polynomial time complexity. Deployment at Imperial College London validated practical viability, with 80%–93.4% of students reporting maintained or improved collaborative learning dynamics across all three metrics compared to random assignment. It is our hope that such a domain-informed graph-based strategy will offer educators practical tools for objective data-driven group formation while promoting student engagement and enhancing learning outcomes.
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Book chapterD'Souza A, Dobrzynski H, Hart G, et al., 2026,
Electrophysiology of the atrioventricular node
, Cardiac Conduction System Evolution Development and Therapeutic Potential, Pages: 155-188The atrioventricular node serves as the sole pathway for normal electrical conduction from the atria to the ventricles, regulating cardiac timing to optimize ventricular filling and output. The atrioventricular node's complex anatomy features multiple pathways with distinct cellular characteristics, creating the foundation for normal function but also vulnerability to dysfunction. This specialized structure possesses unique electrophysiological properties that enable both slow conduction and backup pacemaker function when the primary pacemaker fails. Atrioventricular node impairment increases with aging and is associated with athletic training, heart failure, diabetes and genetic factors. Research reveals that dysfunction stems from remodeling of ion channels and gap junctions, is influenced by circadian rhythms, and may be driven by an inflammatory response. In this chapter, we will examine the electrophysiology of the atrioventricular node, explore its role in normal conduction and arrhythmogenesis, and discuss the molecular mechanisms underlying dysfunction in various clinical conditions as well as potential therapeutic approaches.
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Journal articleKappadan V, Hua Z, Efstathiou P, et al., 2026,
Differential response to acute ischemia between isolated contracting hearts and hearts perfused with excitation-contraction uncouplers.
, Am J Physiol Heart Circ Physiol, Vol: 330, Pages: H75-H88Acute myocardial ischemia triggers electrophysiological changes, including altered cardiac action potential and conduction slowing. Optical mapping is widely used to study these changes, but most experiments use excitation-contraction uncouplers to suppress contractile motion and motion artifacts. We hypothesized that contraction suppression with these uncouplers masks ischemic effects, leading to misleading results. We compared Langendorff-perfused, noncontracting hearts treated with blebbistatin to contracting hearts under acute ischemic conditions. Optical mapping with emission ratiometry and motion-tracking postprocessing minimized motion artifacts, whereas ischemia was induced by ligating the obtuse marginal branch of the left circumflex coronary artery. Contracting hearts exhibited faster and more pronounced reductions in action potential duration (APD) and action potential triangulation (2 min vs. 14 min), along with an increased incidence of spatially discordant alternans (SDA). They also displayed steeper APD restitution slopes, whereas these slopes were flattened in noncontracting hearts. These differences may stem from reduced metabolic demands and the absence of mechanoelectric feedback in noncontracting hearts. In contrast, contracting hearts, with higher metabolic activity and mechanical feedback, experienced more severe ischemic changes. These findings highlight the limitations of using blebbistatin-treated, noncontracting hearts in electrophysiological research, as critical ischemic effects may be underestimated. This study underscores the need to integrate mechanical and electrical dynamics in preclinical models to accurately replicate ischemic conditions, enhancing the translational relevance of experimental cardiac research.NEW & NOTEWORTHY This study highlights key differences in acute ischemic responses between contracting and blebbistatin-treated noncontracting rabbit hearts. Contracting hearts showed faster, more severe action potential du
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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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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 articleAvezzú A, Longobardi S, Alvarez-Laviada A, et al., 2026,
A model for the human fetal ventricular myocyte electrophysiology.
, PLoS Comput Biol, Vol: 22Fetal cardiac arrhythmias can lead to stillbirth, but direct studies on the human fetal heart are challenging. To address this, we developed a computational model of human fetal ventricular myocyte (hfVM) electrophysiology, focusing on early gestation (10 weeks). This model incorporates major ionic currents, including fetal-specific T-type calcium and funny currents, and is calibrated using mRNA expression data and experimental measurements. The hfVM model replicates key electrophysiological features, such as a shorter action potential duration and a more positive resting membrane potential compared to adult cells. Global sensitivity analysis reveals that the resting membrane potential is primarily influenced by the funny current and IK1, while action potential repolarisation depends mainly on IKr. Additionally, the sarcoplasmic reticulum contributes to calcium release, but less so than in adults; instead, the T-type calcium current and the sodium-calcium exchanger are more prominent in initiating calcium transients. This is the first human fetal ventricular myocyte model available for studying fetal cardiac physiology, pathology, and potential pharmacological interventions. It provides novel insights into the dominant ion channels governing fetal electrophysiology and calcium dynamics, offering a foundation for understanding arrhythmias and guiding therapeutic strategies.
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