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Journal articleNasilli G, Lin X, Swiatlowska P, et al., 2026,
Decreasing Microtubule Detyrosination Improves Cardiac Mechanics and Sodium Channel Function in Arrhythmogenic Cardiomyopathy.
, Circ Arrhythm Electrophysiol, Vol: 19BACKGROUND: Alterations in microtubule dynamics have been shown to affect cardiomyocyte membrane stiffness and modulate ion channels, including the cardiac sodium channel. While conditions, such as heart failure and Duchenne muscular dystrophy, are associated with increased detyrosination of microtubules and reduced sodium current, a potential role for microtubule detyrosination in arrhythmogenic cardiomyopathy has not been explored. We here investigated the impact of microtubule detyrosination on membrane stiffness, cardiac sodium channel distribution, and function in mouse and human models of arrhythmogenic cardiomyopathy. METHODS: Isolated ventricular cardiomyocytes from mice with cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 (plakophilin-2), as well as PKP2-c.2013delC, and isogenic control human-induced pluripotent stem cell-derived-cardiomyocytes were incubated for 2 to 4 hours with compounds known to decrease microtubule detyrosination (parthenolide, 10 µmol/L; EpoY, 20 µmol/L) or vehicle (dimethyl sulfoxide). Immunocytochemistry, mechano-scanning ion conductance microscopy, patch-clamp analysis, and stochastic optical reconstruction microscopy were performed. RESULTS: Cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes displayed increased microtubule detyrosination and membrane stiffness, which were both attenuated by parthenolide treatment. Parthenolide significantly increased whole-cell sodium current density in cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes, with macropatch measurements demonstrating that this increase occurred both at the intercalated disc and lateral membrane. Stochastic optical reconstruction microscopy analysis revealed that parthenolide increased cardiac sodium channel cluster density at the intercalated disc of cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes. In contrast, parthenolide had no effect on sodium c
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Journal articleKappadan V, Hua Z, Tonko JB, et al., 2026,
Combined emission ratiometry and motion tracking for optical mapping of contracting hearts: Validation with monophasic action potentials.
, J Physiol, Vol: 604, Pages: 5758-5776Cardiac optical mapping in fully contracting hearts is limited by motion artefacts, leading most investigations to rely on excitation-contraction uncoupling despite its impact on physiological relevance. Although motion tracking and ratiometric imaging have each been used to reduce motion artefacts, and their combined use has been demonstrated with excitation ratiometry, systematic validation of emission ratiometry combined with motion tracking against an established electrophysiological reference remains limited. In this study, we integrated emission ratiometry with two-dimensional, marker-free motion tracking to suppress motion-related artefacts during optical mapping of Langendorff-perfused rabbit hearts, leveraging the advantage that emission ratiometry derives both signals from the same excitation pathway and thereby reduces sensitivity to motion-related photometric fluctuations in fluorescence intensity. Motion-corrected optical action potentials were quantitatively validated against simultaneously recorded monophasic action potentials (MAPs), with optical signals extracted from regions adjacent to the MAP electrode. Compared with raw recordings and with either method applied alone, the combined approach produced the closest agreement with MAP-derived repolarization measurements. Bland-Altman analysis indicated no systematic bias at APD70 and APD80, with bias confidence intervals including zero. Cumulative probability analysis revealed a marked improvement in precision following combined motion correction, with the proportion of optical action potential duration (APD) measurements within ±10 ms of MAP increasing from 16.9%, 29.2% and 26.2% in raw recordings to 75.4%, 87.7% and 80% for APD50, APD70 and APD80, respectively. Collectively, these findings establish the integrated motion-correction strategy as a validated framework for accurate quantification of action potentials in contracting hearts, supporting more physiologically relevant optical map
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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 articleKailey B, Bola H, Wright I, et al., 2026,
Ripple mapping demonstrates putative signals identifying the right inferior nodal extension to the lower nodal bundle during AVNRT.
, Heart Rhythm, Vol: 23, Pages: e1080-e1092BACKGROUND: Mapping wavefronts within the triangle of Koch is challenging owing to multiple small and large amplitude signals within a short time interval. Ripple mapping was designed to overcome these limitations. OBJECTIVE: We tested the feasibility of delineating wavefronts within the triangle of Koch during slow-fast atrioventricular nodal reentrant tachycardia (AVNRT). METHODS: Patients undergoing electrophysiological studies were recruited. Right atrial CARTO maps were collected during atrial pacing, ventricular pacing, and typical AVNRT. Using ripple mapping, we marked His activation during atrial pacing, the earliest retrograde atrial activation during ventricular pacing, the earliest signal during AVNRT (E-AVNRT), and the earliest retrograde right atrial activation during AVNRT. RESULTS: 72 patients were recruited, with typical AVNRT in 40 patients and a full mapping protocol in 30 patients (6327 ± 948 points collected). The E-AVNRT was 14.7 ± 5.3 mm inferior to the earliest His identified during atrial pacing. A wavefront consistent with slow pathway activation started at E-AVNRT taking 22.2 ± 4.8 ms to reach the His cloud with a line of block demarcating the atrial side. This same line formed the ventricular border of atrial activation during atrial pacing, consistent with slow pathway activation over the right inferior nodal extension. These wavefront signals became sharper approaching His but consistently activated a region inferior to the His cloud, consistent with the right inferior nodal extension activating the lower nodal bundle. Earliest retrograde fast pathway-mediated right atrial activation during AVNRT was 57.3 ± 27.1 ms later and 11.7 ± 6.0 mm from E-AVNRT and distinct from the earliest atrial activation during ventricular pacing (7.0 ± 3.2 mm). Successful ablation sites were closer to E-AVNRT than unsuccessful sites (6.4 ± 3.0 vs 14.8 ± 5.6 mm; 95% confidence interval 5.2-7.6 vs 12.2-17
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Journal articleBalycheva M, Reilly-O'Donnell B, Alvarez-Laviada A, et al., 2026,
Downregulation of L-type Ca2+ current in patients with atrial fibrillation results from altered channel gating and disruption of membrane microdomains.
, Heart Rhythm, Vol: 23, Pages: e1170-e1182BACKGROUND: Atrial fibrillation (AF) is associated by alterations in cardiomyocyte membrane microdomain organization that can modify the distribution and biophysical properties of L-type Ca2+ channels (LTCCs), contributing to downregulation of the L-type Ca2+ current (ICa,L). OBJECTIVE: This study aimed to examine the role of cellular microarchitecture and microdomain-specific changes of single LTCCs in ICa,L remodeling in chronic AF. METHODS: Right atrial (RA) and left atrial (LA) biopsies from patients in sinus rhythm (SR, n = 51) and AF (n = 61) were analyzed to assess cardiomyocyte microarchitecture and microdomain-specific remodeling of single LTCCs and ICa,L. Computational modeling estimated the contributions of different cellular components in ICa,L reduction. RESULTS: In AF, ICa,L was reduced in RA (∼32%, P < .05) and LA (∼71%, P < .01). In RA, this was associated with preserved transverse (T)-tubular LTCCs (T-LTCCs) density and decreased extra-tubular (crest, C-LTCCs) density. In LA-AF, densities of both T- and C-LTCCs were reduced. These changes paralleled T-tubule downregulation in both atria and an LA-specific decrease in caveolin-3 expression. In AF, the open probabilities of T- and C-LTCCs in both atria were 3-5-fold higher than in SR and accompanied by 2-fold increase in protein kinase A and phosphorylated Ca2+/calmodulin kinase II activities. However, computational simulations showed that enhanced LTCC open probability did not compensate for reduced channel density. Caveolin-3 overexpression in LA-AF cardiomyocytes increased CaV1.2 membrane expression, partially restoring ICa,L. CONCLUSION: ICa,L downregulation in AF is driven by chamber-specific degradation of membrane structures and loss of functional LTCCs, not offset by increased channel activity. Caveolin-3 is crucial for maintaining functional LTCCs at the sarcolemma.
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Journal articleHong W, Zhang Z, Li A, et al., 2026,
A Correlative SICM-OPM Platform for Surface and Volumetric Imaging in Live Cells.
, Adv Sci (Weinh), Vol: 13Live-cell imaging of cell surface topography and intracellular architecture is essential for understanding cellular function. However, conventional approaches often involve trade-offs between resolution, invasiveness, and volumetric coverage. Here, we present an integrated Scanning Ion Conductance Microscope and single-objective Oblique Plane Microscope (SICM-OPM) system that enables simultaneous non-contact topographical imaging and volumetric fluorescence imaging within the same live cell without sample translation. Beyond correlative live imaging, the platform supports nanomechanical mapping with tens-of-nanometers resolution, fluorescence-guided localized molecular delivery via the SICM, and benefits from reduced photobleaching due to light-sheet excitation. We demonstrate this platform's capabilities by visualizing imipramine-induced transverse-tubule (TT) remodeling in live cardiomyocytes, revealing pronounced detubulation of internal TT invaginations while surface TT opening characteristics remain largely preserved, and capturing high-speed correlative volumetric images of clathrin-mediated endocytosis in Cos-7 cells. Additionally, we show precision delivery of fluorescent cargos, including dextrans and α-synuclein, into mammalian cells and diatoms, alongside localized stiffness mapping to evaluate mechanical responses of mammalian cells. We believe this technique opens new avenues for correlative structural, functional, and biophysical studies in live cells, with broad relevance to cell biology, neurodegeneration, and mechanobiology.
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Journal articleJones OS, Linton N, Bissett S, et al., 2026,
Tau20-RETROmapping System Identifies Driver-Like Activation Patterns in Real Time During Persistent Atrial Fibrillation.
, Circ Arrhythm Electrophysiol, Vol: 19BACKGROUND: Conventional activation mapping of atrial fibrillation (AF) during clinical procedures is limited by low-amplitude, fractionated electrograms and cycle length variability. The Tau20-RETROmapping stimulator-recorder system (TauRhythm Therapies, United Kingdom) is an investigational device used to identify nonpulmonary vein AF drivers by real-time, high-density activation mapping of uniform wavefronts during AF. We validated the accuracy of the system and applied it to left atrial mapping for evidence of AF drivers. METHODS: Left atrial geometry was acquired using a 3-dimensional electroanatomic mapping system with high-density mapping catheters (CARTO 3 with Optrell, or EnSite X with HD Grid). Electrograms were recorded for 30 seconds at multiple left atrial sites. The Tau20-RETROmapping system generates activation maps of organized wavefronts. System performance was manually validated against randomly sampled local electrograms using a grid sweep of thresholds to identify Pareto-optimal parameters in sinus rhythm, atrial pacing, atrial tachycardia (AT), and AF. The system was then applied to identify putative driver activation patterns during persistent AF. RESULTS: We studied 24 patients undergoing pulmonary vein isolation for AF. Six patients presented in sinus rhythm or AT, in whom the system demonstrated a sensitivity of 100.0% (95% CI, 80.5%-100.0%) and a specificity of 100.0% (85.2%-100.0%). Eighteen patients were mapped in AF: the system had a sensitivity of 94.4% (86.2%-98.4%) and a specificity of 97.1% (89.9%-99.6%) when identifying organized AF wavefronts, and accurately identified the earliest activation in 89.6% (79.7%-95.7%) of waves. Stable propagation originating from the left atrial appendage (LAA) was observed in 3/18 patients, while 8/18 demonstrated competing propagation toward and away from the LAA. Conduction away from the LAA was detected along the anterior (8/18 patients), lateral (8/18 patients), and posterior (7/18 patients) wall
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Journal articleMcGurk K, Halliday B, O'Regan D, 2026,
Left ventricular non-compaction: time to retire a flawed diagnosis
, Journal of the American College of Cardiology, Vol: 87, ISSN: 0735-1097 -
Journal articleStroeks SLVM, Bart NK, Rossano J, et al., 2026,
Sex and age specific genetic risk across the dilated and arrhythmogenic cardiomyopathy spectrum: insights from the SHaRe registry
, Journal of the American College of Cardiology, Vol: 87, Pages: 3573-3588, ISSN: 0735-1097BackgroundDilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) are progressive cardiac muscle disorders with phenotypic and genetic overlap. Although a male predominance is noted in DCM/ACM, it remains unclear whether this extends to specific genetic subtypes or reflects variation in disease stage and whether sex influences age-dependent disease onset across pediatric and adult groups.ObjectivesThe aim of this study was to define sex-based differences in genetic architecture and age at diagnosis of DCM/ACM across pediatric and adult populations.MethodsGenetically tested adult and pediatric DCM/ACM patients and asymptomatic genotype-positive relatives enrolled in the multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Sex distribution across 27 DCM- and ACM-associated genes was evaluated using logistic regression. Age at diagnosis was compared across sex and genes using Kaplan-Meier cumulative incidence estimates.ResultsAmong 3,410 patients, a 61% male predominance was present across subgroups of genotype positive, genotype negative, and variants of uncertain significance (P = 0.008), with significant gene-specific variation. TTN truncating variants (TTNtv) were less common in females (OR: 0.42 [95% CI: 0.33-0.54]; P < 0.01), while DSP (OR: 3.3 [95% CI: 2.35-4.78]; P < 0.01) and grouped non-TTN sarcomeric variants (ACTC1, TNNT2, MYH7, TNNC1, TNNI3, and TPM1) were more common (OR: 1.68 [95% CI: 1.15-2.47]; P < 0.001) in females compared with males with DCM/ACM. Age at diagnosis was comparable between sexes, except in TTNtv carriers, among whom males exhibited earlier disease onset compared with females (median age 45 years [Q1-Q3: 33-55 years] vs 51 years [Q1-Q3: 38-60 years]; P = 0.003). Pediatric-onset (diagnosis at <18 years) cases (n = 174) also demonstrated a male predominance (60% male) but had distinct genetic characteristics, with non-TTN sarcomeric and PKP2 variants being more prevalent compared with adult-o
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Journal articleVerdonschot JAJ, van Spaendonck-Zwarts KY, Hellebrekers DMEI, et al., 2026,
Genetic counselling implementation in dilated cardiomyopathy.
, Eur Heart J, Vol: 47, Pages: 3040-3051Genetic testing has become an integral part of the diagnostic workup of patients with dilated cardiomyopathy (DCM). While the initial goal of genetic testing was to identify family members at risk, recent advances have now extended their relevance to clinical decision-making. Our knowledge of the genetic architecture of DCM has expanded significantly, promoting a shift from the monogenic dogma towards a broader polygenic spectrum. However, current genetic testing strategies still primarily rely on the model of monogenic inheritance with an incomplete penetrance. Large studies have shown a yield varying from 8% to 36% of genetic testing in patients with DCM, depending on aetiology or family history. Genetic testing is generally warranted for every patient with DCM where genetic results could have an impact on risk stratification, the prognosis or the treatment of the patient, or its family members with an opportunity for reassurance or early disease detection. There are various strategies for genetic testing including broad multigene panels, or more targeted panels limited to specific disease-associated genes. Identified variants are classified by genetic laboratories, where pathogenic or likely pathogenic variants often have actionable clinical implications. It is crucial to interpret these variants in the context of the individual patient considering the phenotype and other contributing factors. When the genetic results are consistent with the patients' broader phenotype, potential clinical implications may include decision for device therapy, recommendations for family screening, and reproductive options. A comprehensive approach to integrate genetic testing in the clinical care of patients with DCM is proposed.
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Journal articleHoward JP, Stevenson A, 2026,
Native T1 and Exercise Capacity After COVID-19: A Question of Causality.
, J Cardiovasc Magn Reson -
Journal articleMarwaha SK, Basu J, Bhatia R, et al., 2026,
Unravelling the grey zone: submaximal-to-peak stress echocardiography enhances diagnostic accuracy in differentiating early dilated cardiomyopathy from physiological adaptation.
, Echo Res Pract, Vol: 13, ISSN: 2055-0464BACKGROUND: Participation in regular endurance exercise may be associated with physiological left ventricular (LV) dilatation and concomitant low resting LV ejection fraction (LVEF), a phenotype indistinguishable from early dilated cardiomyopathy (DCM) on resting imaging alone and termed the "grey zone". Stress echocardiography has emerged as a potential arbiter and has been proposed to resolve this dilemma. OBJECTIVES: We evaluated the diagnostic accuracy of stress echocardiography in distinguishing physiological from pathological LV dilatation and assessed whether incorporating submaximal-to-peak contractile reserve improved discriminatory value in athletes in the grey zone. METHODS: Of the 182 athletic individuals, 62 control athletes with an enlarged LV and normal LVEF, 58 athletic DCM individuals, and 62 grey zone athletes underwent stress echocardiography using a semi-supine bicycle. In addition to the ability to augment LVEF ≥ 10% from rest to maximal exercise, we evaluated the ability to augment LVEF from submaximal exercise (80% of maximal heart rate) to peak exercise. RESULTS: Resting LV dimensions did not differ significantly amongst the groups. Control athletes had higher resting LVEF than grey zone athletes and DCM individuals (62.1% vs 52.1% and 53.1%; p=<0.001). Control and grey zone athletes showed greater ΔLVEF from rest to peak exercise than DCM individuals (21% and 19.2% vs 4.9%; p < 0.001). Most control (98.3%) and grey-zone athletes (90.3%) achieved a ΔLVEF ≥ 10% from rest to peak exercise compared with 20.6% of athletic DCM individuals. Control and grey zone athletes also revealed a mean increase in LVEF from submaximal to peak exercise of 7.5% and 3.8%, respectively, whereas DCM individuals showed a mean LVEF decline of -4.3% (p < 0.001). Although 20.6% of DCM individuals demonstrated a ΔLVEF ≥ 10% from rest to peak, only a singl
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Journal articleBoubekki A, Patlatzoglou K, Barker J, et al., 2026,
Explaining deep learning for ECG using time-localized clusters.
, IEEE Trans Biomed Eng, Vol: PPOBJECTIVE: Deep learning has advanced electrocardiogram (ECG) analysis but remains difficult to interpret, limiting clinical adoption and electrophysiological insight. We propose a post-hoc explainability method for convolutional neural networks (CNNs) applied to ECG. METHODS: The method clusters the feature activations of the last three residual blocks of a 1D-ResNet, segmenting each ECG into a sequence of clusters and quantifying assignment entropy as a per-timestamp uncertainty. It is evaluated on PTB-XL super-class classification under 10-fold cross-validation and on CODE-15% age regression. RESULTS: Cluster proportions correlate with predicted labels and align with P/QRS/T/TP landmarks. A random forest trained on cluster proportions reproduces the CNN's predictions at $94.9 \pm 0.5\%$ and matches its accuracy and AUROC on the true labels (88.2 vs. $88.4\%$; 79.6 vs. $81.4\%$). Encoder uncertainty surfaces class-dependent representational stability not visible to Grad-CAM. CONCLUSION: Time-localized clusters recover physiologically aligned structure from CNN activations and faithfully summarize the encoder's discriminative information. SIGNIFICANCE: The method provides a post-hoc, architecture-light tool to audit CNN-based ECG models and surface label-quality issues.
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Journal articleHCMR Investigators, Kramer CM, Kolm P, et al., 2026,
Predictors of Long-Term Outcomes in Hypertrophic Cardiomyopathy: The NHLBI HCM Registry.
, JAMA, Vol: 335, Pages: 1959-1969IMPORTANCE: Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. OBJECTIVE: To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. DESIGN, SETTING, AND PARTICIPANTS: A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. EXPOSURES: Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. MAIN OUTCOMES AND MEASURES: The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy-related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. RESULTS: Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percenta
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Journal articleAhmed-Jushuf F, Foley MJ, Chotai S, et al., 2026,
Determining the Physiological Threshold for Angina (ORBITA-FIRE): A Double-Blind, Randomized, Placebo-Controlled Study.
, Circulation, Vol: 153, Pages: 1795-1812BACKGROUND: In stable coronary artery disease, the primary goal of percutaneous coronary intervention (PCI) is symptom relief. Fractional flow reserve (FFR) and nonhyperemic pressure ratios such as resting full-cycle ratio (RFR) are used to guide revascularization. Although these indices correlate with myocardial ischemia, they have never been validated against the onset of angina. The physiological thresholds for angina, FFRangina and RFRangina, angina (FFRangina at rest and during exercise remain undefined. METHODS: ORBITA-FIRE (Finding the Invasive Threshold for Symptom Relief in Exertional Angina) was a multicenter, double-blind, randomized, placebo-controlled study in patients with stable angina and single-vessel coronary artery disease. After imaging-guided PCI, an in-stent balloon was incrementally inflated until angina occurred at rest. This angina threshold was verified against placebo inflation, and corresponding FFRangina and RFRangina values were recorded at symptom onset. The protocol was repeated during low- and high-intensity exercise to assess changes in angina thresholds with increasing cardiac workload. RESULTS: Sixty-five patients were enrolled (mean age, 63.9±8.7 years; 74% male; 69% hypertensive; 23% diabetic; 91% with Canadian Cardiovascular Society class II-III angina). Median pre-PCI FFR was 0.59 (interquartile range [IQR], 0.46-0.70) and RFR was 0.61 (IQR, 0.40-0.82). Median FFRangina at rest was 0.29 (IQR, 0.23-0.35), increasing to 0.38 (IQR, 0.30-0.48) during low-intensity exercise and 0.45 (IQR, 0.36-0.55) during high-intensity exercise. RFRangina similarly increased from 0.22 (IQR, 0.16-0.30) at rest to 0.26 (IQR, 0.18-0.36) and 0.32 (IQR, 0.23-0.46) during low- and high-intensity exercise. All thresholds were significantly lower than clinical diagnostic cut points (P<0.001). Lower FFRangina and RFRangina thresholds were associated with greater symptom reproducibility across rest, low- and high-intensity exercise conditions (FF
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Journal articleGuichard J-B, Hupin D, Pichot V, et al., 2026,
Atrial cardiomyopathy as a multidomain disease: longitudinal evidence for autonomic remodelling.
, Europace, Vol: 28AIMS: Atrial cardiomyopathy (AtCM) is increasingly recognized as a substrate for atrial fibrillation (AF), yet its operationalization remains limited and largely marker-driven. Whether autonomic remodelling represents a longitudinally evolving domain within a multidomain framework of AtCM remains unclear. OBJECTIVES: To determine whether autonomic remodelling, assessed through static and longitudinal heart rate variability (HRV) abnormalities, defines a distinct domain of AtCM and contributes to atrial disease burden and clinical risk. METHODS AND RESULTS: We studied 670 individuals aged 65 years without prior AF or major cardiovascular disease from the prospective PROOF cohort with 24-h Holter ECGs at baseline and 5 years. Heart rate variability metrics, premature atrial contraction (PAC) burden, and left atrial (LA) size were assessed. Incident AF and cardiovascular outcomes were adjudicated over a median follow-up of 12.1 years. Seventy-two participants (10.7%) developed AF. Static HRV abnormalities and adverse 5-year HRV trajectories were independently associated with subsequent AF. Autonomic abnormalities showed limited concordance with PAC burden and LA enlargement, supporting their role as a distinct AtCM domain. Increasing involvement of remodelling domains was associated with higher risks of AF and cardiovascular outcomes. Participants with ≥2 domains exhibited higher risks of AF (HR 2.43; 95% CI 1.72-3.45), major adverse cardiovascular events (HR 1.42), and all-cause mortality (HR 1.35). CONCLUSION: Atrial cardiomyopathy is a cumulative, multidomain disease process in which structural, electrical, and autonomic abnormalities define atrial disease burden. Longitudinal autonomic remodelling constitutes an independent and evolving axis within this framework, shifting the focus from isolated arrhythmia detection towards progressive characterization of atrial substrate.
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Journal articleStefaniak E, Cui B, Yan X, et al., 2026,
Therapeutic peptide SS-31 modulates membrane binding and aggregation of α-synuclein and restores impaired mitochondrial function
, Chemical Biology and Drug Design, Vol: 107, ISSN: 1747-0277Membrane binding and aggregation properties of α-synuclein are closely associated with Parkinson's disease and a class of related syndromes named as synucleinopathy. This study explored the potential of SS-31 (Elamipretide), a therapeutic tetrapeptide with alternating cationic and aromatic residues and known properties of mitochondrial inner membrane binding and oxidative stress reduction, in modulating α-synuclein interaction with the lipid membranes and mitigating the impairment of mitochondrial function induced by α-synuclein oligomers. It was demonstrated by both fluorescence correlation spectroscopy and fluorescence anisotropy that SS-31 displaces both wild-type and N-terminal acetylated α-synuclein from negatively charged small unilamellar vesicles in a dose-dependent manner. Thioflavin-T assay and transmission electron microscopy showed that SS-31 inhibits membrane-induced α-synuclein aggregation and alters the morphology of α-synuclein fibrils. Moreover, MTT assay and Seahorse Mito Stress Test indicated that SS-31 enhances cell viability and restores impaired mitochondrial function in α-synuclein oligomer-treated neuroblastoma cells. Finally, confocal imaging revealed that SS-31 hinders cellular uptake of α-synuclein oligomers, possibly by modifying cell membrane electrostatics. These findings suggest that SS-31 potentially attenuates α-synuclein induced mitochondrial impairment via its interaction with the lipid membranes, justifying further development of a peptide-based intervention against α-synuclein mediated pathology.
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Journal articleSau A, Ng FS, 2026,
AI Electrocardiogram as a Potential Surrogate for Septal Fibrosis-Reply.
, JAMA Cardiol, Vol: 11 -
Journal articleNg FS, Shah A, Casadei B, 2026,
Interpreting AI-Enhanced ECG Performance in High-Risk, Resource-Limited Settings.
, JAMA Cardiol, Vol: 11 -
Journal articleCraig NJ, Loganath K, Everett RJ, et al., 2026,
Myocardial Fibrosis and Early Intervention in Asymptomatic Patients With Severe Aortic Stenosis: Insights From the EVOLVED Randomized Clinical Trial.
, JAMA Cardiol, Vol: 11, Pages: 599-605IMPORTANCE: Myocardial fibrosis burden has been associated with adverse clinical outcomes in symptomatic patients with aortic stenosis. OBJECTIVE: To determine whether midwall myocardial fibrosis burden is associated with adverse clinical outcomes in asymptomatic patients and whether those with more fibrosis derive greater benefit from early intervention. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of a randomized clinical trial was conducted between August 2017 and October 2022. The trial took place at 24 cardiac centers across the United Kingdom and Australia. Participants included asymptomatic patients with severe aortic stenosis and midwall fibrosis on cardiac magnetic resonance. These data were analyzed from October 2024 through June 2025. INTERVENTION: Early intervention with transcatheter or surgical aortic valve replacement. MAIN OUTCOMES AND MEASURES: Primary outcome was all-cause death or unplanned aortic stenosis-related hospitalization. Secondary outcomes included the individual components of the primary outcome. RESULTS: In 224 trial participants (mean [SD] age, 73 [9] years; 63 women and 161 men, and mean [SD] aortic valve peak velocity 4.3 [0.5] m per second) with a median follow-up of 42 months, fibrosis burden (per 1% increase) was associated with an increase in the primary end point (hazard ratio [HR], 1.23; 95% CI, 1.08-1.37) and its component of unplanned aortic stenosis-related hospitalizations (HR, 1.22; 95% CI, 1.03-1.40) but not all-cause death (HR, 1.17; 95% CI, 0.98-1.35). There were no interactions between randomization arm and the midwall fibrosis burden for the primary (P for interaction = .39) or secondary end points. In patients with high fibrosis burden above the median, the primary end point occurred in 12 of 59 (20%) of those randomized to early intervention and 17 of 53 (32%) of those randomized to guideline-directed conservative management (HR, 0.62; 95% CI, 0.29-1.28). For the individual components, al
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