Atrial cardiomyopathy: From healthy atria to atrial failure. A clinical consensus statement of the Heart Failure Association of the ESC
The importance of atrial cardiomyopathy (AtCM) as a specific clinical entity is increasingly recognized. Past definitions have varied, and the lack of consistent cut-offs for imaging parameters and biomarkers have limited clinical utility to diagnose and track AtCM progression. While research has mainly focused on AtCM in the context of atrial fibrillation, emerging evidence underscores its relevance in remodelling and development of heart failure. The aim of this consensus document was to provide a contemporary framework for AtCM, evolve the definitions of AtCM and atrial failure for more widespread clinical use, and help to direct emerging research and future clinical trials. Supporting the work of early career researchers, this consensus document evaluates diagnostic markers and summarizes the underpinning mechanisms, clinical characteristics and prognostic impact of AtCM. Our objective was to bring together new translational scientific progress, catalyse future research and enable clinical application to facilitate better management, for example in patient groups where aggressive control of risk factors or comorbidities could prevent AtCM progression. We redefined AtCM as a graded disorder that includes electrical dysfunction of the atria along with evidence of either mechanical atrial dysfunction, atrial enlargement and/or atrial fibrosis. Atrial failure is the end-stage manifestation of AtCM, characterized by progressive structural, electrophysiological and functional changes. Earlier identification, risk stratification and ongoing research into therapeutic options have the potential to prevent the clinical consequences of AtCM and atrial failure, including adverse patient outcomes and poor quality of life associated with atrial fibrillation and heart failure.
Pericoronary Adipose Tissue Imaging and the Need for Standardized Measurement of Coronary Inflammation: Translating PCAT Attenuation Gradients Into FAI Score for Clinical Use
Antiarrhythmic drug use in atrial fibrillation among different European countries - as determined by a physician survey
There is limited knowledge of physicians' antiarrhythmic drug (AAD) treatment practices for patients with atrial fibrillation and adherence to guidelines in European countries.
A tailored substrate-based approach using focal pulsed field catheter ablation in patients with atrial fibrillation and advanced atrial substrate: Procedural data and 6-month success rates
Focal pulsed field ablation (F-PFA) integrated in electroanatomic mapping systems allows tailored lesion sets in patients with atrial fibrillation (AF).
Coronary inflammation and cardiovascular risk in breast cancer after radiotherapy
Inflammatory Biomarkers in Hypertension
Hypertension remains a leading modifiable risk factor for cardiovascular diseases, yet its underlying mechanisms are not fully understood. Emerging evidence suggests that inflammation plays a central role in the pathogenesis and progression of hypertension. This review explores the association between inflammatory biomarkers, such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), and hypertension. These biomarkers are not only indicators of inflammation but also active participants in the processes that elevate blood pressure, including endothelial dysfunction, oxidative stress, and immune system activation. Cytokines play a pivotal role in vascular remodeling and renal dysfunction, underscoring the inflammatory underpinnings of hypertension. Additionally, novel composite biomarkers like the monocyte-to-high-density lipoprotein ratio (MHR), systemic inflammation response index (SIRI), and systemic immune-inflammation index (SII) have been identified as valuable tools for assessing the inflammatory state in hypertensive patients. While renal denervation has emerged as a promising treatment for resistant hypertension, its impact on inflammatory biomarkers remains inconclusive, highlighting the need for further research.
Shivering, but not adipose tissue thermogenesis, increases as a function of mean skin temperature in cold-exposed men and women
Skin cooling results in the activation of heat-generating mechanisms to counteract heat lost to the environment. Here, we aim to understand the extent to which variations in cold-stimulated heat production may be driven by differences in the contribution of shivering and non-shivering thermogenesis (NST) and the interaction with biological sex. Using a novel mean skin temperature clamping technique in healthy men and women, our data show that cold-stimulated heat production rises with increasing shivering and myocardial oxidative metabolism in a skin temperature-dependent fashion. Shivering and myocardial thermogenesis were also moderately associated. By contrast, adipose tissue NST did not increase in a linear manner to reductions in skin temperature. Men and women displayed similar thermoregulatory responses, although women presented more pronounced shivering through a greater recruitment of lower-body muscles and a greater number of motor units recruited. Thus, shivering contributes proportionally to cold-induced thermogenesis, whereas adipose tissue thermogenesis displays an all-or-none response.
Short-term benefit of early rhythm control for atrial fibrillation: the EAST-AFNET 4 trial
Electrocardiogram-Based Artificial Intelligence to Identify Coronary Artery Disease
Coronary artery disease (CAD) results in substantial morbidity and mortality.
Feasibility and Prognostic Value of Stress Cardiovascular Magnetic Resonance in Patients With End-Stage Renal Disease
Patients with end-stage renal disease (ESRD) are at high cardiovascular risk. The safety and prognostic value of stress cardiovascular magnetic resonance (CMR) in ESRD patients remains unclear as data are lacking due to perceived contrast agent-related risk.
A Mid-Term Follow-Up in Patients with Symptomatic Moderate to Severe and Severe Degenerative Mitral Valve Regurgitation After Transapical NeoChord Implantation
The transapical off-pump NeoChord procedure is a recognized minimally invasive surgical approach for the treatment of severe degenerative mitral regurgitation. This study aims to report the initial Greek experience with the NeoChord procedure, presenting mid-term clinical and echocardiographic outcomes from a single cardiothoracic surgical center, with a median follow-up duration of 20 months. In this study, 42 symptomatic patients with moderate to severe and severe primary mitral regurgitation underwent mitral valve repair with the Neochord procedure between March 2018 and December 2024. All patients were evaluated clinically and echocardiographically by the Heart team preoperatively, after 1 month, and at the last follow-up (end of 2024). The primary endpoint was established as the presence of a major clinical event (all-cause mortality, reintervention due to deterioration of MR, and cardiac-related rehospitalization). The median age of patients was 69 [61.75-79.25] years, and 69% of patients were men. The median EuroScore II was 1.79 [1.32-2.48], and the STS-PROM MV repair score was 3.18 [2.28-4.66]. Regarding the preprocedural mitral valve anatomical evaluation, 35 patients had type A (83.3%),4 had type B(9.5%), whereas only two patients had type C and 1 with type D anatomy. The median of LAI was 1.2 [1.15-1.25], whereas the CI was 4 [2.15-5]. More than two neochordae were implanted in 34 patients (81%). MR severity improved at 1-month (
Regionalization of the atria for 3D electroanatomical mapping, cardiac imaging, and computational modelling: a clinical consensus statement of the European Heart Rhythm Association and the European Association of Cardiovascular Imaging of the ESC
This clinical consensus document proposes standardized atrial segments for 3D imaging, electroanatomical mapping and computational modelling, based on anatomical, electrophysiological and clinical considerations, with precise definitions of regional borders allowing for reproducible and automated regionalization. 3D imaging and high-resolution electroanatomical mapping have become an integral part of cardiac electrophysiology and the management of patients with arrhythmias. However, to perform regional quantitative analyses and intra- and inter-individual, as well as cross-modality comparisons, a universal definition of atrial regions and their boundaries is required. While for the left ventricle there is already an established standardized regionalization (AHA 17-segment model), there is no such consensus for the atria. In a multi-disciplinary writing group consisting of cardiologists, cardiac electrophysiologists, cardiovascular imaging specialists, and anatomists as well as specialists in computational cardiac modelling from European Heart Rhythm Association and European Association of Cardiovascular Imaging, a standardized regionalization based on a 15-segment bi-atrial model was elaborated. This clinical consensus document will enable consistent regional analyses and homogeneous data acquisition across different centres and modalities, and may thus have a significant impact on atrial arrhythmia research and personalized treatment approaches based on individual arrhythmia patterns and phenotypes.
Diabetes and Obesity and Treatment Effect of Early Rhythm Control vs Usual Care in Patients With Atrial Fibrillation: A Secondary Analysis of the EAST-AFNET 4 Randomized Clinical Trial
The EAST-AFNET 4 randomized clinical trial demonstrated that early rhythm control therapy added to anticoagulation therapy and therapy of concomitant conditions reduces the primary composite outcome of cardiovascular death, stroke, hospitalization because of heart failure, or acute coronary syndrome compared to usual care. However, the impact of body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) and diabetes on outcomes in EAST-AFNET 4 is not known.
Are There Pulmonary Veins Geometrical Features Associated with Reconnection after Pulsed-Field Ablation of Atrial Fibrillation?
Pulmonary vein (PV) isolation (PVI) using pulsed field ablation (PFA) is an emerging technique for the treatment of atrial fibrillation (AF). However, the recurrence rate of AF remains significant, and the durability of PVI insufficient.
Diagnostic and prognostic value of quantitative cardiac magnetic resonance imaging biomarkers in systemic lupus erythematosus: a systematic review and meta-analysis
The aim of this study was to compare CMR imaging biomarkers between SLE patients and matched controls.
Noninvasive quantification of aortic wave reflection timing indices in aging: a study combining MRI and applanation tonometry
To study associations of newly proposed noninvasive central arterial wave reflection timing indices with age and reference indices of reflection magnitude, using superimposed MRI aortic flow and applanation tonometry carotid pressure waveforms.
Atrial granules as acidic calcium stores in cardiomyocytes
Acidic calcium stores significantly influence basal calcium transient amplitude and β-adrenergic responses in cardiomyocytes. Atrial myocytes contain atrial granules (AGs), small acidic organelles that store and secrete atrial natriuretic peptide (ANP) and are absent in healthy ventricular myocytes. AGs are known to be acidic and calcium-rich, but their number and location relative to other signalling sites remain unexplored. Labelling of acidic organelles in adult guinea pig cardiomyocytes showed the presence of acidic puncta throughout the cytosol. Atrial myocytes exhibited an increased concentration of acidic organelles at the nuclear poles. Live cell fluorescent studies using 4-phenyl-3-butenoic acid (PBA) to inhibit peptidylglycine α-amidating monooxygenase, a crucial component of AGs membranes, effectively eliminated staining at the nuclear poles and most acidic puncta in atrial cells, but not in ventricular cells. Our immunofluorescent labelling also emphasizes the differences in acidic punctae between atrial and ventricular myocytes by showing minimal co-localization between AG-specific ANP and lysosomal-associated membrane protein. Electron microscopy studies on goat atrial fibrillation (AF) and sham control tissue allowed visualization of AGs. Quantitative analysis revealed that AGs were positioned significantly further away from the nearest sarcoplasmic reticulum and were closer to mitochondria in AF compared to sinus rhythm control tissue. We raise the question whether the positioning of AGs is strategic for communication with other calcium-containing organelles.
Visualization of monopolar biphasic focal pulsed-field ablation lesions three months after pulmonary vein isolation on high-resolution 3D dark-blood LGE CMR images
Dark-blood late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (CMR) is used to visualize ablation lesions after pulmonary vein isolation (PVI) by cryo- and radiofrequency ablation. The performance of dark-blood LGE CMR in visualizing chronic ablation lesions after PVI by monopolar biphasic focal pulsed field ablation (F-PFA) remains unclear.
Genomics reveals eleven obesity endotypes with distinct biological and phenotypic signatures
Obesity, a leading global risk factor for cardiometabolic conditions, arises from multifaceted and biologically complex mechanisms. To elucidate the full-dimensional genetic architecture underlying obesity, we conducted a multi-trait, multi-ancestry, genome-wide association study (GWAS) by combining genetic data on anthropometric traits (body mass index, waist circumference, waist-to-hip ratio, and hip circumference) from >2 million ancestrally diverse participants. We identified 743 significant loci, including 86 previously unreported loci, representing a 13% increase in locus discovery. We leveraged machine learning and multimodal data integration to identify the likely effector genes at obesity-associated loci. We performed genetic clustering on biologically enriched multi-trait GWAS data based on Bayesian non-negative matrix factorisation in the UK Biobank ( = 408,816) and identified 11 obesity clusters (endotypes). In addition to recapitulating the endotypes that drive classical metabolically healthy and unhealthy obesity phenotypes, we identified nine additional obesity endotypes driven by insulin physiology, beta cell compensation, immune dysregulation, neuroendocrine regulation, and lipid metabolism. Each cluster not only was characterised by unique biomarker features and clinical trajectories but also showed cluster-specific enrichment in tissue and single-cell regulatory regions. To facilitate the clinical and research adoption of obesity endotyping, we created partitioned polygenic scores for the 11 obesity endotypes, which we externally validated their performance using the Mass General Brigham Biobank ( = 48,377), and made publicly available in the PGS Catalog. This study marks a step forward in both the biological resolution and clinical translation of heterogeneity in obesity, implicating that obesity prevention and management should be as diverse as the condition itself.
Scalable screening for structural heart disease: promises from artificial intelligence-electrocardiogram tools
Ablation of cavotricuspid isthmus-dependent atrial flutter using a focal monopolar pulsed-field ablation catheter: Feasibility, periprocedural coronary spasms and conduction disorders
Pulsed-field ablation for the treatment of cavotricuspid isthmus (CTI)-dependent atrial flutter has been associated with coronary spasms (CS) and atrioventricular conduction disorders (CD).
Semi-supervised motion flow and myocardial strain estimation in cardiac videos using distance maps and memory networks
Myocardial strain plays a crucial role in diagnosing heart failure and myocardial infarction. Its computation relies on assessing heart muscle motion throughout the cardiac cycle. This assessment can be performed by following key points on each frame of a cine Magnetic Resonance Imaging (MRI) sequence. The use of segmentation labels yields more accurate motion estimation near heart muscle boundaries. However, since few frames in a cardiac sequence usually have segmentation labels, most methods either rely on annotated pairs of frames/volumes, greatly reducing available data, or use all frames of the cardiac cycle without segmentation supervision. Moreover, these techniques rarely utilize more than two phases during training. In this work, a new semi-supervised motion estimation algorithm using all frames of the cardiac sequence is presented. The distance map generated from the end-diastolic segmentation label is used to weight loss functions. The method is tested on an in-house dataset containing 271 patients. Several deep learning image registration and tracking algorithms were retrained on our dataset and compared to our approach. The proposed approach achieves an average End Point Error (EPE) of 1.02mm, against 1.19mm for RAFT (Recurrent All-Pairs Field Transforms). Using the end-diastolic distance map further improves this metric to 0.95mm compared to 0.91 for the fully supervised version. Correlations in systolic peak were 0.83 and 0.90 for the left ventricular global radial and circumferential strain respectively, and 0.91 for the right ventricular circumferential strain.
Performance of SCORE2, QRISK3 and PREVENT equations in systemic lupus erythematosus
BackgroundAssessment of contemporary cardiovascular risk scores using clinically relevant endpoints is lacking in systemic lupus erythematosus (SLE).AimThis study aimed to assess and compare the performances of SCORE2, QRISK3 and PREVENT equations in SLE.MethodsSLE patients with no prior atherosclerotic cardiovascular disease (ASCVD) who underwent a baseline cardiovascular risk assessment including coronary artery calcium (CAC) scoring at the French national SLE reference center between 2014 and 2024 were retrospectively included. The primary outcome was incident ASCVD events defined as coronary artery disease (CAD), stroke and peripheral artery disease (PAD). The secondary outcome was CAC presence (CAC score >0). Discrimination and calibration were respectively assessed by areas under the curve (AUCs) and observed-to-predicted risk ratios.ResultsA total of 143 patients were included (91% female, median age 51 years [46-60], SLE duration 15 years [8-22]). After a median follow-up of 7 years [3-9], 12 patients (8%) had incident ASCVD events (7 CAD, 4 strokes, 1 PAD). AUCs were 0.81 for SCORE2, 0.76 for QRISK3 and 0.80 for PREVENT and did not significantly differ (all > .05). Optimal thresholds for clinical events prediction were 3.9% for SCORE2, 9.4% for QRISK3 and 4.3% for PREVENT. Mean observed-to-predicted ratios were 3 for SCORE2, 0.85 for QRISK3 and 2.8 for PREVENT. Similar results were obtained when using CAC as the main outcome.ConclusionRisk scores demonstrated similar and fair discriminative performances but were poorly calibrated except for QRISK3. Application of lower thresholds and use of QRISK3 may improve cardiovascular risk stratification in SLE but requires confirmation from larger studies.
Polygenic prediction of body mass index and obesity through the life course and across ancestries
Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.6% African ancestry, 14.4% American ancestry, 8.4% East Asian ancestry, 71.1% European ancestry and 1.5% South Asian ancestry) from the GIANT consortium and 23andMe, Inc., we developed ancestry-specific and multi-ancestry PGSs. The multi-ancestry score explained 17.6% of BMI variation among UK Biobank participants of European ancestry. For other populations, this ranged from 16% in East Asian-Americans to 2.2% in rural Ugandans. In the ALSPAC study, children with higher PGSs showed accelerated BMI gain from age 2.5 years to adolescence, with earlier adiposity rebound. Adding the PGS to predictors available at birth nearly doubled explained variance for BMI from age 5 onward (for example, from 11% to 21% at age 8). Up to age 5, adding the PGS to early-life BMI improved prediction of BMI at age 18 (for example, from 22% to 35% at age 5). Higher PGSs were associated with greater adult weight gain. In intensive lifestyle intervention trials, individuals with higher PGSs lost modestly more weight in the first year (0.55 kg per s.d.) but were more likely to regain it. Overall, these data show that PGSs have the potential to improve obesity prediction, particularly when implemented early in life.
Fibroblast-Restricted Inflammasome Activation Promotes Atrial Fibrillation and Heart Failure With Diastolic Dysfunction
Atrial fibrillation (AF) often coexists with heart failure, both involving inflammatory signaling and cardiac fibroblasts. To understand the role of fibroblast NLR family pyrin domain containing 3 (NLRP3) inflammasome in cardiac function, we found that NLRP3 was up-regulated in atrial fibroblasts from AF patients. Fibroblast-specific activation of NLRP3 in mice induced AF-promoting atrial myopathy and heart failure with diastolic dysfunction, accompanied by increased fibrosis, and reduced conduction velocity. Knockdown of NLRP3 prevented the AF-promoting atrial substrate and cardiomyopathy in the context of NLRP3 activation in fibroblasts. We identify the fibroblast NLRP3 inflammasome as a key pathway governing the promotion of proarrhythmic fibrosis in AF and cardiomyopathy.
Computational modelling of the pro- and antiarrhythmic effects of atrial high rate-dependent trafficking of small-conductance calcium-activated potassium channels
Small-conductance calcium-activated potassium (SK) channels are promising targets for atrial-specific antiarrhythmic therapies, with evidence suggesting tachycardia-dependent SK-channel upregulation. However, the dynamics of SK-channel gating and trafficking in human atrial electrophysiology remain unclear because of experimental limitations, including the availability of human cardiomyocytes and long patch clamp experiments. Although computational models help explore these mechanisms, none integrate SK-channel trafficking. In the present study, we expanded our K11.1 trafficking model to simulate rate-dependent SK-channel trafficking in a human atrial cardiomyocyte model. Calibrated against experimental data, our model replicates time- and rate-dependent SK-channel function, allowing simulations of SK-channel trafficking and its effects on action potentials. Tachypacing at 5 Hz increased SK-channel density, enhancing SK current and shortening action potential duration, with or without calcium buffering. Two-dimensional tissue simulations with physiological calcium handling showed that tachycardia increased re-entry duration and ectopic activity. SK-channel inhibition reduced re-entry duration but promoted ectopic activity, suggesting a reduction in atrial fibrillation burden rather than complete elimination. Our novel computational model highlights SK channels' role in re-entry-promoting effects of short atrial tachycardia episodes, offering insights into early atrial fibrillation progression and potential antiarrhythmic strategies. KEY POINTS: Small-conductance calcium-activated potassium (SK) channels have emerged as potential targets for atrial-specific antiarrhythmic therapies, especially in atrial fibrillation (AF). Emerging evidence suggests that tachycardia-induced SK-channel trafficking can regulate cardiac cellular electrophysiology over minutes, but investigating its impact on arrhythmogenesis in humans is experimentally challenging. We adapted our recent in silico K11.1 trafficking model to simulate SK-channel trafficking and incorporated it into a human atrial cardiomyocyte model, which was calibrated based on experimental results. Tachypacing at 5 Hz led to a substantial increase in SK channel-density at the membrane, resulting in enhanced SK current and a reduction in action potential duration. 2-D tissue simulations demonstrated that rapid pacing promoted both re-entry and ectopic (triggered) activity. Blocking SK channels reduced re-entry duration but increased ectopic activity, suggesting that SK channel inhibition could decrease AF burden, but may not eliminate AF per se.
From lipids and inflammation to artificial intelligence-driven therapeutics: the 93rd European atherosclerosis society (EAS) congress 2025 in focus
Identifying a Heterogeneous Effect of Atrial Fibrillation Screening in Older Adults: A Secondary Analysis of the VITAL-AF Trial
One-time atrial fibrillation (AF) screening trials in older adults have produced mixed results. In a secondary analysis of the VITAL-AF trial, we aimed to identify a subset of people in whom such screening is effective, using effect-based and risk-based approaches.
Nicotinic acid increases adipose tissue dietary fatty acid trapping and reduces postprandial hepatic and cardiac fatty acid uptake in prediabetes
Increased adipose tissue (AT) dietary fatty acids (DFA) trapping limits fatty acid exposure to lean organs in the face of elevated postprandial nonesterified fatty acid (NEFA) flux from excess AT intracellular lipolysis in prediabetes. We hypothesized that pharmacological inhibition of postprandial AT intracellular lipolysis using short-acting nicotinic acid (NA) would increase AT DFA trapping and limit AT NEFA spillover to lean organs in subjects with prediabetes. Twenty subjects with impaired glucose tolerance and 19 individuals with normal glucose tolerance underwent four postprandial studies with positron emission tomography/computed tomography with radio-labeled fatty acid tracers and stable isotopic palmitate tracers. Over the 6-h postprandial period, NA increased AT DFA partitioning with reciprocal reduction in liver and in muscle. NA also robustly reduced cardiac and liver total (DFA + NEFA) postprandial fatty acid uptake. Short-acting NA administered postprandially thus enhances AT DFA trapping and markedly reduces postprandial hepatic and cardiac fatty acid uptake. (clinicaltrials.gov NCT02808182).
Efficacy and Safety of Intravascular Lithotripsy in the Management of Underexpanded Stents: A Systematic Review and Meta-Analysis
Stent underexpansion significantly heightens the risk of major adverse cardiac events (MACE), and available treatment options for this condition remain limited. Intravascular Lithotripsy (IVL) technology disrupts superficial and deep calcium by using localized pulsative sonic pressure waves, emerges as a promising tool for underexpanded stents.
Sex and sex hormonal regulation of the atrial inward rectifier potassium current (IK1): insights into potential pro-arrhythmic mechanisms
Pronounced sex-differences are known in the incidence of atrial fibrillation (AF). In this study, we aimed to investigate the atrial electrophysiological properties that may underlie sex-differences in AF incidence in the younger population, focusing on IK1, a cardiac ion current important for action potential (AP) stability and triggered activity.
Management of dyslipidaemia in patients with comorbidities-facing the challenge: type 1 diabetes mellitus
Type 1 diabetes is associated with excess cardiovascular risk. In contrast to type 2 diabetes, however, age at the onset of type 1 diabetes and sex are major predictors of cardiovascular risk, while the role of low-density lipoprotein cholesterol (LDL-C) and lipid-lowering therapy is less clear. Since most data on the effects of lipid-lowering treatments are obtained from randomized clinical trials that included very predominantly patients with type 2 diabetes, it is almost impossible to specifically discern endpoints in type 1 diabetes. Inversely, most data specific for type 1 diabetes are obtained from real world findings. Consequently, the evidence on efficacy and safety of lipid-lowering therapies available from randomized clinical trials arises very predominantly from type 2 diabetes. Thus, this specific review summarizes the evidence of lipid-lowering drug classes in reducing cardiovascular risk in patients with type 1 diabetes.
Critical medications in cardiology: strategic policy of the European Medicines Agency
The Role of NLRP3 Inflammasome in Type 2 Diabetes Mellitus and Its Macrovascular Complications
Diabetes Mellitus (DM) is among the most common non-infectious causes of death globally, with Type 2 DM (T2DM) representing the majority of cases. T2DM is primarily characterized by insulin resistance, leading to hyperglycemia and compensatory hyperinsulinemia. Rapid changes in lifestyle, technological advancement, and societal evolution have fueled a global rise in T2DM, making it a major public health concern. The condition is associated with numerous complications-both macrovascular and microvascular-including coronary artery disease, heart failure, chronic kidney disease, and diabetic retinopathy, all of which contribute to increased morbidity and early mortality. Chronic tissue inflammation is now recognized as a key factor in the development of T2DM, with elevated inflammatory markers serving as predictors of the disease. In particular, the NLRP3 inflammasome complex has emerged as a central player in this inflammatory process. NLRP3 acts as an intracellular sensor for danger signals and tissue injury, triggering inflammatory responses and contributing to endothelial dysfunction and T2DM pathogenesis. Its role in linking metabolic stress to inflammation has positioned it as a promising therapeutic target. This review focuses on the mechanisms underlying NLRP3 inflammasome activation and its role in T2DM and related vascular complications. Additionally, it highlights emerging therapies that target NLRP3, offering new potential strategies for the prevention and treatment of T2DM.
Impact of a clinical atrial fibrillation risk estimation tool on cardiac rhythm monitor utilization following acute ischemic stroke: A prepost clinical trial
Detection of undiagnosed atrial fibrillation (AF) after ischemic stroke through extended cardiac monitoring is important for preventing recurrent stroke. We evaluated whether a tool that displays clinically predicted AF risk to clinicians caring for stroke patients was associated with the use of extended cardiac monitoring.
Cardiomyopathy-Associated Gene Variants in Atrial Fibrillation
Patients with atrial fibrillation (AF), a common morbid arrhythmia, are more likely to carry rare genetic variants associated with inherited cardiomyopathies. Prior studies on rare pathogenic variants in AF relied on small, hospital referral populations, and knowledge on clinical outcomes remains limited.
Successful pulsed field ablation of pulmonary veins in an atrial fibrillation patient with situs inversus totalis
Situs inversus (situs transversus) is a rare congenital anomaly with an incidence of ∼0.01% in the general population. Catheter ablation of atrial fibrillation (AF) in patients with situs inversus totalis poses technical challenges. Here, the first case of successful pulsed field ablation (PFA) using the circular array catheter (PulseSelect™ PFA System; Medtronic) in an AF patient with situs inversus totalis is presented.
Ceramides in cardiovascular disease - emerging role as independent risk predictors and novel therapeutic targets
Ceramides are bioactive lipid mediators involved in apoptosis, inflammation, and fibrosis. This narrative review provides a concise overview of the emerging role of ceramides in cardiovascular disease with emphasis on atherosclerotic vascular disease and heart failure, suggesting a potential use of ceramides in risk stratification and as putative therapeutic targets. Recent developments based on observational evidence and genetic associations, including Mendelian randomization studies in humans, are summarized and put into context with experimental evidence for the role of ceramides in human and animal models of disease. Emerging scores composed of ceramides and phosphatidylcholines that are based on the length and desaturation of the N-acyl chains are discussed in the light of novel data demonstrating age- and sex-specific differences. Also reviewed is the structural heterogeneity of the sphingoid bases, including non-conventional sphingolipids that are increasingly recognized for their importance in health and disease. Lastly, novel targets and potential modalities for tissue-specific transfer of drugs are discussed.
Right ventricular-pulmonary arterial coupling and outcomes in cardiac amyloidosis: systematic review and meta-analysis
Using pericoronary fat attenuation to guide management after coronary interventions
Comparison of two genetic strategies for diagnostic work-up of hypertrophic cardiomyopathy: impact on the diagnosis of Fabry disease or transthyretin amyloidosis
Diagnostic work-up of patients with hypertrophic cardiomyopathy is crucial for appropriate management. However, the optimal genetic strategy remains debatable. We compared two strategies: targeted testing based on careful examination of clinical red flags versus large multigene panel analysis without gene prioritization. We applied the strategy to the diagnosis of Fabry disease or Hereditary Transthyretin Amyloidosis (GLA or TTR genes respectively).
Computational modelling of cardiac fibroblast signalling reveals a key role for Ca in driving atrial fibrillation-associated fibrosis
Atrial fibrillation (AF) is the most common arrhythmia, characterized by irregular atrial electrical activity resulting in asynchronous atrial contraction. AF is accompanied by extensive structural remodelling of atria, including extracellular matrix expansion (fibrosis), which affects both AF maintenance and treatment outcomes. However, no fibrosis-specific therapies are currently available for AF. To identify the prominent pathways in atrial fibroblasts (Fb) that modulate atrial fibrosis and arrhythmogenesis, we developed the first atrial Fb signalling network model. This expands on the well-established ventricular model by integrating atrial-relevant elements involved in fibrogenesis and/or differentially expressed in chronic AF (vs. normal sinus rhythm) patients and connections based on experimental evidence in an Fb-related context. Our findings indicate that under high profibrotic signals, e.g. angiotensin-II (AngII) and transforming growth factor β, inhibition of Ca fluxes reduced the abundance of key fibrotic markers such as collagen I, collagen III, periostin, plasminogen activator inhibitor-1, connective tissue growth factor and α-smooth muscle actin, via modulation of the Ca/calmodulin-dependent protein kinase II/Smad3 pathway and extra domain A of fibronectin via the calcineurin pathway. Mechanistically, we found that the Ca-dependent regulation of collagen I and III is primarily at the level of gene transcription, with collagen I and collagen III exhibiting similar dynamics in the Fb model. Overall, our study highlights the pivotal role of Ca signalling in the evolution of AF-associated fibrogenesis and provides novel insights into potential anti-AF therapeutic strategies targeting fibrotic responses. Future work will investigate in greater detail the upstream mechanisms driving Ca increases in atrial Fbs during AF. KEY POINTS: A fibroblast signalling network was developed incorporating new atrial-informed elements and reactions to identify the prominent pathways that modulate atrial fibrosis and associated arrhythmogenesis, including atrial fibrillation (AF). The model was validated against experimental data in cardiac fibroblasts. For atrial-specific validation, we focused on the model responses to AF-relevant profibrotic inputs, i.e. angiotensin-II (AngII) and transforming growth factor β (TGFβ). The analysis underscores the critical role of Ca signalling in mediating profibrotic responses under AF-relevant stimuli, AngII and TGFβ and shows that Ca/calmodulin-dependent protein kinase II/Smad3 and calcineurin mediate the Ca-dependent upregulation of key fibrotic markers.
Epidemiological Profile and Mortality of Infective Endocarditis Over the Past Decade: A Systematic Review and Meta-Analysis of 133 Studies
Infective endocarditis (IE) is an increasingly prevalent condition with relatively high mortality, whose epidemiology has become more complex with an aging population, an increased number of comorbidities, and an increasing incidence of health-care associated IE. Epidemiological data on the causative microorganisms of IE, prevalence of involvement of the different cardiac valves, and IE-associated mortality are clinically relevant. Eligible studies were identified through a systematic search of PubMed/MEDLINE database from 2010 to 2020, and a random effects model meta-analysis was conducted. 133 studies comprising 132,584 patients from six continents were included in this systematic review. The most common causative agents were Staphylococci species in 36% of cases, followed by Streptococci species (26%) and Enterococci species (10%). Out of studies that provided further speciation, the predominant species was Staphylococcus aureus with an incidence of 29%, followed by Viridans group Streptococcus (12%). The short-term mortality rate (defined as in-hospital or 30-day mortality) was 17%. The highest mortality was reported in studies from Latin America with a mean mortality rate of 33% and the lowest mortality was reported in studies from Oceania at 13%. The aortic valve was the most commonly affected valve (46%), followed closely by the mitral valve (43%). The prevalence of tricuspid valve IE was 7% and multivalvular IE occurred in 14% of cases. Our study highlights a shift in epidemiological profile of IE over the last decade with S. aureus identified as the most common causative microorganism of IE. PROTOCOL REGISTRATION: PROSPERO CRD42024602342.
Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis
Semaglutide, a glucagon-like peptide-1 receptor agonist, is a candidate for the treatment of metabolic dysfunction-associated steatohepatitis (MASH).
Machine Learning-Based Plasma Protein Risk Score Improves Atrial Fibrillation Prediction Over Clinical and Genomic Models
Clinical factors discriminate incident atrial fibrillation (AF) risk with moderate accuracy, with only modest improvement after incorporation of polygenic risk scores. Whether emerging large-scale proteomic profiling can augment AF risk estimation is unknown.
Diabetes and atrial fibrillation: Causality is still a black-box
Early postoperative atrial fibrillation is associated with late mortality after cardiac surgery: a systematic review and reconstructed individual patient data meta-analysis
Early postoperative atrial fibrillation (early-POAF) is the most common complication after cardiac surgery. Although prior studies have demonstrated an association between early-POAF and late outcomes, it is questionable whether these long-term adverse events result from early-POAF or from comorbidities that underlie the development of early-POAF. Therefore, the aim of this study was to investigate the association of early-POAF with late mortality and stroke after adjustment for age and cardiovascular comorbidities.
Association of atrial fibrillation burden and clinical profile with blood biomarkers: Results from the ISOLATION Ablation Cohort
Advances have been made in identifying biomarkers for atrial fibrillation (AF) outcomes.
Right ventricular-pulmonary arterial coupling in transcatheter structural heart interventions
Right ventricular-pulmonary arterial (RV-PA) coupling describes the interaction between right ventricular contractility and pulmonary arterial afterload, offering a comprehensive assessment of right heart function. In the context of structural heart interventions such as transcatheter aortic valve implantation (TAVI), transcatheter edge-to-edge mitral repair (TEER), and transcatheter tricuspid therapies, RV-PA coupling has emerged as a powerful prognostic indicator. Impaired coupling, typically defined using echocardiographic surrogates such as the tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) ratio, is consistently associated with increased mortality and heart failure hospitalization. RV-PA coupling also demonstrates dynamic behavior, with potential for improvement following intervention-though persistent uncoupling portends worse outcomes. Despite its clinical promise, significant limitations exist. Commonly used non-invasive indices, while practical, only moderately correlate with gold-standard invasive pressure-volume loop assessments and are subject to measurement variability and lack of standardization. Furthermore, current surrogates do not distinguish between the underlying drivers of uncoupling-whether impaired contractility or increased afterload-each with distinct therapeutic implications. As structural heart interventions expand to broader patient populations, a more refined understanding of RV-PA coupling may enhance risk stratification, procedural planning, and long-term management. Future research should focus on standardizing assessment techniques and establishing evidence-based thresholds to support its routine clinical use.
Safety and efficacy of amiodarone and dronedarone for early rhythm control in EAST-AFNET 4
Concerns exist about the safety of amiodarone and dronedarone. We assessed the long-term outcome of both drugs for early rhythm control (ERC) in the EAST-AFNET 4 trial.
Rare genetic variation in PTPRB is associated with central serous chorioretinopathy, varicose veins and glaucoma
Central serous chorioretinopathy is an eye disease characterized by fluid buildup under the central retina whose etiology is not well understood. Abnormal choroidal veins in central serous chorioretinopathy patients have been shown to have similarities with varicose veins. To identify potential mechanisms, we analyzed genotype data from 1,477 patients and 455,449 controls in FinnGen. We identified an association for a low-frequency (allele frequency = 0.5%) missense variant (rs113791087) in PTPRB, the gene encoding vascular endothelial protein tyrosine phosphatase (odds ratio=2.85, P = 4.5 × 10). This was confirmed in a meta-analysis of 2,452 patients and 865,767 controls from 4 studies (odds ratio=3.06, P = 7.4 × 10). Rs113791087 was associated with a 56% higher prevalence of retinal abnormalities (35.3% vs 22.6%, P = 8.0 × 10) in 708 UK Biobank participants and, surprisingly, with increased risk of varicose veins (odds ratio=1.31, P = 2.3 × 10) and reduced risk of glaucoma (odds ratio=0.82, P = 6.9 × 10). Predicted loss-of-function variants in PTPRB, though rare in number, were associated with central serous chorioretinopathy in All of Us (odds ratio=17.09, P = 0.018). These findings highlight the significance of vascular endothelial protein tyrosine phosphatase in diverse ocular and systemic veno-vascular diseases.
Genome-Wide Assessment of Pleiotropy Across >1000 Traits from Global Biobanks
Large-scale genetic association studies have identified thousands of trait-associated risk loci, establishing the polygenic basis for common complex traits and diseases. Although prior studies suggest that many trait-associated loci are pleiotropic, the extent to which this pleiotropy reflects shared causal variants or confounding by linkage disequilibrium remains poorly characterized. To define a set of candidate loci with potentially pleiotropic associations, we performed genome-wide association study (GWAS) meta-analyses of up to 1,167 clinically relevant traits and diseases across 1,789,365 diverse individuals genetically similar to Admixed American (AMR, N = 60,756), African (AFR, N = 128,361), East Asian (EAS, N = 307,465), European (EUR, N = 1,283,907), and South Asian (SAS, N = 8,876) reference populations from the VA Million Veteran Program (MVP), UK Biobank (UKB), FinnGen, Biobank Japan (BBJ), Tohoku Medical Megabank (ToMMo), and Korean Genome and Epidemiology Study (KoGES). We identified 27,193 genome-wide significant locus-trait pairs (1MB region with P < 5 × 10) in within-population analysis and 29,139 in multi-population analysis (P < 5 × 10). Among these, 11.5% (n = 3,149) of locus-trait pairs in population-wise and 6.4% (n = 1,875) in multi-population analyses did not reach genome-wide significance in previously published GWAS. In aggregate, the genome-wide significant loci fell within 2,624 non-overlapping autosomal genomic windows on average ~600kb in size. Each locus contained genome-wide significant signals for a median of 6 traits (IQR 2 to 18), including 2,110 (80%) pleiotropic loci associated with >1 trait. Multi-trait colocalization identified 1,902 (72%) loci with high-confidence (posterior probability > 0.9) evidence of a shared causal variant across two or more traits. Variants in pleiotropic loci were significantly enriched for a broad spectrum of functional annotations compared to non-pleiotropic counterparts. Polygenic scores (PGS) developed from these data generally improved prediction compared to existing PGS, and were broadly associated with both primary and pleiotropic phenotypes. These results provide a contemporary map of genetic pleiotropy across the spectrum of human traits/diseases and diverse genetic backgrounds.
A short history of the atrial NLRP3 inflammasome and its distinct role in atrial fibrillation
Inflammasomes are multiprotein complexes of the innate immune system that mediate inflammatory responses to infection and to local and systemic stress and tissue injury. The principal function is to facilitate caspase-1 auto-activation and subsequently maturation and release of the effectors interleukin (IL)-1β and IL-18. The atrial-specific NLRP3 inflammasome is a unifying causal feature of atrial fibrillation (AF) development, progression and recurrence after ablation. Many AF-associated risk factors and co-morbidities converge mechanistically on the activation of this central inflammatory signaling platform. This review presents the historical conceptual development of a distinct atrial inflammasome and its potential causal involvement in AF. We follow the early observations linking systemic and local inflammation with AF, to the emergence of an atrial-intrinsic NLRP3 inflammasome operating within not just immune cells but also in resident atrial fibroblasts and cardiomyocytes. We outline the key developments in understanding how the atrial NLRP3 inflammasome and its effector IL-1β contribute causally to cellular and tissue-level arrhythmogenesis in different pathological settings, and outline candidate therapeutic concepts verified in preclinical models of atrial cardiomyopathy and AF.
A 3D Genome Atlas of Genetic Variants and Their Pathological Effects in Cancer
The hierarchical organization of the eukaryotic genome is crucial for nuclear activities and cellular development. Genetic aberrations can disrupt this 3D genomic architecture, potentially driving oncogenesis. However, current research often lacks a comprehensive perspective, focusing on specific mutation types and singular 3D structural levels. Here, pathological changes from chromosomes to nucleotides are systematically cataloged, including 10 789 interchromosomal translocations (ICTs), 18 863 structural variants (SVs), and 162 769 single nucleotide polymorphisms (SNPs). The multilayered analysis reveals that fewer than 10% of ICTs disrupt territories via potent 3D interactions, and only a minimal fraction of SVs disrupt compartments or intersect topologically associated domain structures, yet these events significantly influence gene expression. Pathogenic SNPs typically show reduced interactions within the 3D genomic space. To investigate the effects of variants in the context of 3D organization, a two-phase scoring algorithm, 3DFunc, is developed to evaluate the pathogenicity of variant-gene pairs in cancer. Using 3DFunc, IGHV3-23's critical role in chronic lymphocytic leukemia is identified and it is found that three pathological SNPs (rs6605578, rs7814783, rs2738144) interact with DEFA3. Additionally, 3DGAtlas is introduced, which provides a highly accessible 3D genome atlas and a valuable resource for exploring the pathological effects of genetic mutations in cancer.
Macrophage-mediated IL-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation
Postoperative atrial fibrillation (poAF) is AF occurring days after surgery, with a prevalence of 33% among patients undergoing open-heart surgery. The degree of postoperative inflammation correlates with poAF risk, but less is known about the cellular and molecular mechanisms driving postoperative atrial arrhythmogenesis. We performed single-cell RNA-seq comparing atrial nonmyocytes from mice with and without poAF, which revealed infiltrating CCR2+ macrophages to be the most altered cell type. Pseudotime trajectory analyses identified Il-6 as a gene of interest driving in macrophages, which we confirmed in pericardial fluid collected from human patients after cardiac surgery. Indeed, macrophage depletion and macrophage-specific Il6ra conditional knockout (cKO) prevented poAF in mice. Downstream STAT3 inhibition with TTI-101 and cardiomyocyte-specific Stat3 cKO rescued poAF, indicating a proarrhythmogenic role of STAT3 in poAF development. Confocal imaging in isolated atrial cardiomyocytes (ACMs) uncovered what we believe to be a novel link between STAT3 and CaMKII-mediated ryanodine receptor-2 (RyR2)-Ser(S)2814 phosphorylation. Indeed, nonphosphorylatable RyR2S2814A mice were protected from poAF, and CaMKII inhibition prevented arrhythmogenic Ca2+ mishandling in ACMs from mice with poAF. Altogether, we provide multiomic, biochemical, and functional evidence from mice and humans that IL-6-STAT3-CaMKII signaling driven by infiltrating atrial macrophages is a pivotal driver of poAF, which portends therapeutic utility for poAF prevention.
Opportunities and challenges for the use of human samples in translational cardiovascular research: a scientific statement of the ESC Working Group on Cellular Biology of the Heart, the ESC Working Group on Cardiovascular Surgery, the ESC Council on Basic Cardiovascular Science, the ESC Scientists of Tomorrow, the European Association of Percutaneous Cardiovascular Interventions of the ESC, and the Heart Failure Association of the ESC
Animal models offer invaluable insights into disease mechanisms but cannot entirely mimic the variability and heterogeneity of human populations, nor the increasing prevalence of multi-morbidity. Consequently, employing human samples-such as whole blood or fractions, valvular and vascular tissues, myocardium, pericardium, or human-derived cells-is essential for enhancing the translational relevance of cardiovascular research. For instance, myocardial tissue slices, which preserve crucial structural and functional characteristics of the human heart, can be used in vitro to examine drug responses. Human blood serves as a rich source of biomarkers, including extracellular vesicles, various types of RNA (miRNA, lncRNA, and circRNAs), circulating inflammatory cells, and endothelial colony-forming cells, facilitating detailed studies of cardiovascular diseases. Primary cardiomyocytes and vascular cells isolated from human tissues are invaluable for mechanistic investigations in vitro. In cases where these are unavailable, human induced pluripotent stem cells serve as effective substitutes, albeit with specific limitations. However, the use of human samples presents challenges such as ethical approvals, tissue procurement and storage, variability in patient genetics and treatment regimens, and the selection of appropriate control samples. Biobanks are central to the efficient use of these scarce and valuable resources. This scientific statement discusses opportunities to implement the use of human samples for cardiovascular research within specific clinical contexts, offers a practical framework for acquiring and utilizing different human materials, and presents examples of human sample applications for specific cardiovascular diseases, providing a valuable resource for clinicians, translational and basic scientists engaged in cardiovascular research.
GDF15 links adipose tissue lipolysis with anxiety
Psychological stress changes both behaviour and metabolism to protect organisms. Adrenaline is an important driver of this response. Anxiety correlates with circulating free fatty acid levels and can be alleviated by a peripherally restricted β-blocker, suggesting a peripheral signal linking metabolism with behaviour. Here we show that adrenaline, the β3 agonist CL316,243 and acute restraint stress induce growth differentiation factor 15 (GDF15) secretion in white adipose tissue of mice. Genetic inhibition of adipose triglyceride lipase or genetic deletion of β-adrenergic receptors blocks β-adrenergic-induced increases in GDF15. Increases in circulating GDF15 require lipolysis-induced free fatty acid stimulation of M2-like macrophages within white adipose tissue. Anxiety-like behaviour elicited by adrenaline or restraint stress is eliminated in mice lacking the GDF15 receptor GFRAL. These data provide molecular insights into the mechanisms linking metabolism and behaviour and suggest that inhibition of GDF15-GFRAL signalling might reduce acute anxiety.
Benchmarking Photon-Counting Computed Tomography Angiography Against Invasive Assessment of Coronary Stenosis: Implications for Severely Calcified Coronaries
Clinical guidelines do not recommend coronary computed tomographic angiography (CTA) in elderly patients or in the presence of heavy coronary calcification. Photon-counting coronary computed tomographic angiography (PCCTA) introduces ultrahigh in-plane resolution and multienergy imaging, but the ability of this technology to overcome these limitations is unclear.
Management of patients with congenital bleeding disorders and cardiac indications for antithrombotic therapy
Cardiologists have only had rare exposure to haemophilia patients and patients with other congenital bleeding disorders during the last decades, as these patients had a reduced life expectancy and were partly protected against thrombosis due to the bleeding disorder. With the availability of effective and safe replacement therapies of clotting factors, the average life expectancy in these populations of patients has significantly increased, and thrombotic complications may occur.
New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2024
Despite substantial advances in cardiovascular pharmacotherapy and devices in recent years, prevention and treatment of many cardiovascular diseases (CVDs) remain limited, thus reflecting the need for more effective and safer pharmacological strategies. In this review, we summarize the most relevant studies in cardiovascular pharmacotherapy in 2024, including the approval of first-in-class drugs for the treatment of resistant hypertension and pulmonary arterial hypertension, label expansions for bempedoic acid and semaglutide, and the results of major randomized clinical trials (RCTs) that have met the pre-specified primary endpoints, thereby filling some gaps in knowledge and opening new perspectives in the management of CVD, and those RCTs whose results did not confirm the proposed research hypotheses. We also include a section on drug safety, where we describe the newest data on adverse reactions and drug-drug interactions that may complicate treatment and/or reduce drug adherence with the consequent decrease in drug effectiveness. Finally, we present the most important ongoing phase 2 and phase 3 clinical trials assessing the efficacy and safety of cardiovascular drugs for the prevention and treatment of CVD.
Comparison of cardiac troponin assays reveals assay-specific sensitivities in a clinical model of very acute myocardial injury
High-sensitivity cardiac troponin (hs-cTn) assays indicating myocardial injury are critical for the diagnosis of acute myocardial infarction (AMI), but their use to differentiate between acute and chronic myocardial injury is limited. This study aimed to assess the differential utility of three hs-cTn assays, targeting different troponin epitopes (proximal and/or central), to detect myocardial injury in a clinical model of acute myocardial injury by left-atrial ablation.
New Threshold for Defining Mild Aortic Stenosis Derived From Velocity-Encoded MRI in 60,000 Individuals
Mild aortic stenosis (AS) is associated with adverse outcomes but is incompletely defined.
Cardiac MRI-based Subclinical Cardiac Dysfunction during 2 Years after Breast Cancer Irradiation: The MEDIRAD EARLY-HEART Study
Purpose To evaluate the relationship between cardiac radiation doses and subclinical changes in cardiac function using cardiac MRI during 2 years of follow-up in patients with breast cancer treated with radiation therapy without chemotherapy after lumpectomy. Materials and Methods This prospective multicenter study (NCT03297346) enrolled female individuals with breast cancer treated with radiation therapy between December 2017 and September 2019. Participants underwent cardiac MRI at baseline, 6 months, and 24 months. Cardiac radiation doses were assessed for the whole heart (WH) and right and left ventricles (LV). A persistent decrease in LV global longitudinal strain (GLS) from baseline to the other two measurement points over the 2-year follow-up was considered an adverse subclinical change in cardiac function. Statistical analysis included Wilcoxon tests for continuous variables and odds ratios for risk assessment. Results The study included 138 female participants (mean age, 58.4 years ± 8.0 [SD]). Mean WH and LV doses were 1.42 Gy (IQR, 1.03-2.01) and 1.46 Gy (IQR, 0.64-2.34). At the 2-year follow-up, all participants had reduced LV end-diastolic volume (EDV) (-4.0% ± 13.2; < .001) and stroke volume (-3.4% ± 15.2; < .001), preserved LV ejection fraction, and increased LV remodeling (LV mass/EDV ratio) (4.2% ± 18.1; < .04) without associated symptoms. Twenty-three (16.6%) participants showed a persistent decrease in LV GLS and received higher mean WH and LV doses compared with participants without persistent decrease in LV GLS (WH: 2.09 Gy [IQR, 1.50-2.45] vs 1.36 Gy [IQR, 1.01-1.87], < .001; LV: 2.40 Gy [IQR, 1.09-2.88] vs 1.34 Gy [IQR, 0.63-2.02], = .002). The relative changes in LV EDV and LV mass/EDV were -12.7% ± 9.0 versus -2.2% ± 13.3 ( < .001) and 14.2% ± 15.5 versus 2.2% ± 18.1 ( = .002), respectively, in participants with and without a persistent decrease in LV GLS. A higher WH cardiac radiation dose was associated with a higher risk of a persistent decrease in LV GLS (odds ratio, 1.09 [95% CI: 1.02, 1.16]). Conclusion In participants with recent breast cancer radiation therapy, a modest but persistent reduction in LV GLS over a 2-year follow-up period was associated with the cardiac radiation dose. Radiotherapy, Magnetic Resonance Imaging, Cardiotoxicity, Strain Clinical trial registration no. NCT03297346 © RSNA, 2025.
Computed tomography-derived myocardial radiomics for detection of transthyretin amyloidosis in patients with severe aortic stenosis
We explored the value of myocardial radiomics by computed tomography angiography (CTA) for detection of transthyretin amyloidosis cardiomyopathy (ATTR-CM).
Timing and trajectory of BCR::ABL1-driven chronic myeloid leukaemia
Mutation of some genes drives uncontrolled cell proliferation and cancer. The Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer. However, little is known about the trajectory to CML, the rate of BCR::ABL1 clonal expansion and how this affects disease. Using whole-genome sequencing of 1,013 haematopoietic colonies from nine patients with CML aged 22 to 81 years, we reconstruct phylogenetic trees of haematopoiesis. Intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR, requiring exon skipping to derive BCR::ABL1, were also noted. Apart from ASXL1 and RUNX1 mutations, extra myeloid gene mutations were mostly present in wild-type cells. We inferred explosive growth attributed to BCR::ABL1 commencing 3-14 years (confidence interval 2-16 years) before diagnosis, with annual growth rates exceeding 70,000% per year. Mutation accumulation was higher in BCR::ABL1 cells with shorter telomere lengths, reflecting their excessive cell divisions. Clonal expansion rates inversely correlated with the time to diagnosis. BCR::ABL1 in the general population mirrored CML incidence, and advanced and/or blast phase CML was characterized by subsequent genomic evolution. These data highlight the oncogenic potency of BCR::ABL1 fusion and contrast with the slow and sequential clonal trajectories of most cancers.
Atrial cardiomyocyte-restricted cleavage of gasdermin D promotes atrial arrhythmogenesis
Enhanced inflammatory signalling causally contributes to atrial fibrillation (AF) development. Gasdermin D (GSDMD) is an important downstream effector of several inflammasome pathways. However, the role of GSDMD, particularly the cleaved N-terminal (NT)-GSDMD, in non-immune cells remains elusive. This study aimed to elucidate the function of NT-GSDMD in atrial cardiomyocytes (ACMs) and determine its contribution to atrial arrhythmogenesis.
Predicting Atrial Fibrillation After Stroke by Combining Polygenic Risk Scores and Clinical Features
Because treatment with anticoagulants can prevent recurrent strokes, identification of patients at risk for incident atrial fibrillation (AF) after stroke is crucial. We aimed to investigate whether the addition of AF polygenic risk scores (PRSs) to existing clinical risk predictors could improve prediction of AF after stroke.
Baseline right ventricular-to-pulmonary artery coupling and outcomes after transcatheter aortic valve replacement: a systematic review and meta-analysis
Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes
Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.
Population-Scale Studies of Protein S Abnormalities and Thrombosis
Clinical decision-making in thrombotic disorders is impeded by long-standing uncertainty regarding the magnitude of venous and arterial thrombosis risk associated with low protein S. Population-scale multiomic datasets offer an unprecedented opportunity to answer questions regarding the epidemiology and clinical impacts of protein S deficiency.
Non-neuronal ventricular cardiomyocyte-located nicotinergic acetylcholine receptors cause remodelling and arrhythmias
Epidemiology of hospitalized heart failure in France based on national data over 10 years, 2012-2022
We aim to describe the incidence of HF hospitalization in France in the post-pandemic era, the prevalence of HF cases and patients' characteristics, management and outcomes while focusing on sex, age and socio-economic differences and to analyse time-trends between 2012 and 2022.
Selecting variant masks to improve power and replicability of gene-level burden tests
Rare coding variant association studies typically perform gene-level association tests in which variants are filtered (or "masked") and aggregated based on functional annotation and allele frequency. As there is little research and no consensus regarding masking strategies to use, we investigated the impact of masking strategies on gene-level burden tests, the most widely used and interpretable type of aggregate association test. A systematic review of 234 studies catalogued 664 masks and masking strategies that rarely repeated across studies. Analyzing 54 traits within 189,947 UK Biobank exomes, we show that the number of significant associations greatly depends on the masking strategy employed (ranging from 58 to 2,523 associations) and, consequently, separate published analyses of this dataset report minimally overlapping associations (<30%). By empirically determining mask combinations that maximize the number of significant associations, we propose masking strategies that detect twice as many significant low-frequency and rare variant associations as the "average" strategies previously employed, with consistent performance across many traits. Our analyses demonstrate the inconsistency of previously used variant masking strategies and provide a simple solution to increase power and replicability in future studies.
Genetic Predisposition to Low-Density Lipoprotein Cholesterol and Incident Type 2 Diabetes
Treatment to lower high levels of low-density lipoprotein cholesterol (LDL-C) reduces incident coronary artery disease (CAD) risk but modestly increases the risk for incident type 2 diabetes (T2D). The extent to which genetic factors across the cholesterol spectrum are associated with incident T2D is not well understood.
Gut Microbiota in Heart Failure-The Role of Inflammation
Heart failure (HF) has become an immense health concern affecting almost 1-2% of the population globally. It is a complex syndrome characterized by activation of the sympathetic nervous system and the Renin-Angiotensin-Aldosterone (RAAS) axis as well as endothelial dysfunction, oxidative stress, and inflammation. The recent literature points towards the interaction between the intestinal flora and the heart, also called the gut-heart axis. The human gastrointestinal tract is naturally inhabited by various microbes, which are distinct for each patient, regulating the functions of many organs. Alterations of the gut microbiome, a process called dysbiosis, may result in systemic diseases and have been associated with heart failure through inflammatory and autoimmune mechanisms. The disorder of intestinal permeability favors the translocation of microbes and many metabolites capable of inducing inflammation, thus further contributing to the deterioration of normal cardiac function. Besides diet modifications and exercise training, many studies have revealed possible gut microbiota targeted treatments for managing heart failure. The aim of this review is to demonstrate the impact of the inflammatory environment induced by the gut microbiome and its metabolites on heart failure and the elucidation of these novel therapeutic approaches.
Endothelial Function and Pro-Inflammatory Cytokines as Prognostic Markers in Acute Coronary Syndromes
Endothelial dysfunction and inflammation are associated with the progression of coronary artery disease (CAD) and the pathophysiology of acute coronary syndrome (ACS). We examined the prognostic role of endothelial function and pro-inflammatory cytokines in patients admitted with ACS. The study population consisted of 864 subjects. From 663 subjects who presented with chest pain, ACS was diagnosed in 460. We additionally recruited 201 consecutive patients with stable CAD. Endothelial function was assessed using flow-mediated dilatation (FMD). Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) levels were measured via ELISA. Subjects with ACS were followed up for major adverse cardiovascular events (MACE), defined as cardiovascular death, cardiac arrest, myocardial infarction, stroke, nonfatal stroke, other arterial thrombotic events, and hospitalization due to cardiovascular conditions. There was a stepwise impairment in FMD, logTNF-α, and logIL-6 in patients with chest pain of non-epicardial CAD etiology compared to patients with stable CAD and those with ACS ( < 0.001 for all). Moreover, patients who presented with chest pain had increased odds of ACS in accordance with the increasing levels of TNF-α, IL-6, and impaired FMD ( < 0.05 for all). Interestingly, from all these markers, in patients with ACS, we found that only TNF-α levels above 5.19 pg/mL had a 2.5-times-increased risk of MACE compared to patients with TNF-α levels below 5.19 pg/mL, independently of other confounders. In the current study, we found that patients who presented with ACS had impaired endothelial function and increased levels of IL-6 and TNF-α.
Ventricular arrhythmias in acute heart failure. A clinical consensus statement of the Association for Acute CardioVascular Care (ACVC), the European Heart Rhythm Association (EHRA) and the Heart Failure Association (HFA) of the ESC
Patients presenting with or alerting emergency networks due to acute heart failure (AHF) form a diverse group with a plethora of symptoms, risks, comorbidities, and aetiologies. During AHF, there is an increased risk of destabilizing the functional substrate and modulatory adding to the risk of ventricular arrhythmias (VAs) already created by the structural substrate. New VAs during AHF have previously identified patients with higher in-hospital and 60-day morbidity and mortality. Risk stratification and criteria/best time point for coronary intervention and implantable cardioverter-defibrillator implantation, however, are still controversial topics in this difficult clinical setting. The characteristics and logistics of pre-hospital emergency medicine, as well as the density of centres capable of treating AHF and VAs, differ massively throughout Europe. Scientific guidelines provide clear recommendations for the management of arrhythmias in chronic heart failure patients. However, the incidence, significance, and management of arrhythmias in patients with AHF have been less studied. This consensus paper aimed to address the identification and treatment of VAs that complicate the course of patients who have AHF, including cardiogenic shock.
Endothelial cell-related genetic variants identify LDL cholesterol-sensitive individuals who derive greater benefit from aggressive lipid lowering
The role of endothelial cell (EC) dysfunction in contributing to an individual's susceptibility to coronary atherosclerosis and how low-density lipoprotein cholesterol (LDL-C) concentrations might modify this relationship have not been previously studied. Here, from an examination of genome-wide significant single nucleotide polymorphisms associated with coronary artery disease (CAD), we identified variants with effects on EC function and constructed a 35 single nucleotide polymorphism polygenic risk score comprising these EC-specific variants (EC PRS). The association of the EC PRS with the risk of incident cardiovascular disease was tested in 3 cohorts: a primary prevention population in the UK Biobank (UKBB; n = 348,967); a primary prevention cohort from a trial that tested a statin (JUPITER, n = 8,749); and a secondary prevention cohort that tested a PCSK9 inhibitor (FOURIER, n = 14,298). In the UKBB, the EC PRS was independently associated with the risk of incident CAD (adjusted hazard ratio (aHR) per 1 s.d. of 1.24 (95% CI 1.21-1.26), P < 2 × 10). Moreover, LDL-C concentration significantly modified this risk: the aHR per 1 s.d. was 1.26 (1.22-1.30) when LDL-C was 150 mg dl but 1.00 (0.85-1.16) when LDL-C was 50 mg dl (P = 0.004). The clinical benefit of LDL-C lowering was significantly greater in individuals with a high EC PRS than in individuals with low or intermediate EC PRS, with relative risk reductions of 68% (HR 0.32 (0.18-0.59)) versus 29% (HR 0.71 (0.52-0.95)) in the primary prevention cohort (P = 0.02) and 33% (HR 0.67 (0.53-0.83)) versus 8% (HR 0.92 (0.82-1.03)) in the secondary prevention cohort (P = 0.01). We conclude that EC PRS quantifies an independent axis of CAD risk that is not currently captured in medical practice and identifies individuals who are more sensitive to the atherogenic effects of LDL-C and who would potentially derive substantially greater benefit from aggressive LDL-C lowering.
Feasibility of repeated on-demand smartphone app-based approximation of time spent with atrial fibrillation and symptoms in patients after catheter ablation: Data from the ISOLATION study
The preferred outcome after atrial fibrillation (AF) ablation is reducing AF burden, reflected by time spent with AF. Digital tools provide novel strategies to approximate time spent with AF.
"Weekend Warrior" Physical Activity and Adipose Tissue Deposition
Attaining guideline-recommended levels of physical activity is associated with substantially lower risk of cardiometabolic diseases.
Atrial fibrillation burden in clinical practice, research, and technology development: a clinical consensus statement of the European Society of Cardiology Council on Stroke and the European Heart Rhythm Association
Atrial fibrillation (AF) is one of the most common cardiac diseases and a complicating comorbidity for multiple associated diseases. Many clinical decisions regarding AF are currently based on the binary recognition of AF being present or absent with the categorical appraisal of AF as continued or intermittent. Assessment of AF in clinical trials is largely limited to the time to (first) detection of an AF episode. Substantial evidence shows, however, that the quantitative characteristic of intermittent AF has a relevant impact on symptoms, onset, and progression of AF and AF-related outcomes, including mortality. Atrial fibrillation burden is increasingly recognized as a suitable quantitative measure of intermittent AF that provides an estimate of risk attributable to AF, the efficacy of antiarrhythmic treatment, and the need for oral anticoagulation. However, the diversity of assessment methods and the lack of a consistent definition of AF burden prevent a wider clinical applicability and validation of actionable thresholds of AF burden. To facilitate progress in this field, the AF burden Consensus Group, an international and multidisciplinary collaboration, proposes a unified definition of AF burden. Based on current evidence and using a modified Delphi technique, consensus statements were attained on the four main areas describing AF burden: Defining the characteristics of AF burden, the recording principles, the clinical relevance in major clinical conditions, and implementation as an outcome in the clinic and in clinical trials. According to this consensus, AF burden is defined as the proportion of time spent in AF expressed as a percentage of the recording time, undertaken during a specified monitoring duration. A pivotal requirement for validity and comparability of AF burden assessment is a continuous or near-continuous duration of monitoring that needs to be reported together with the AF burden assessment. This proposed unified definition of AF burden applies independent of comorbidities and outcomes. However, the disease-specific actionable thresholds of AF burden need to be defined according to the targeted clinical outcomes in specific populations. The duration of the longest episode of uninterrupted AF expressed as a time duration should also be reported when appropriate. A unified definition of AF burden will allow for comparability of clinical study data to expand evidence and to establish actionable thresholds of AF burden in various clinical conditions. This proposed definition of AF burden will support risk evaluation and clinical treatment decisions in AF-related disease. It will further promote the development of clinical trials studying the clinical relevance of intermittent AF. A unified approach on AF burden will finally inform the technology development of heart rhythm monitoring towards validated technology to meet clinical needs.
Systemic immune inflammation index as a predictor for atrial fibrillation recurrence after catheter ablation
Atrial fibrillation (Afib) is a common arrhythmia with significant public health implications, affecting millions of individuals worldwide. Catheter ablation (CA) is an established treatment for drug-resistant Afib, yet recurrence remains a major concern, impacting quality of life in a significant portion of patients. Inflammation plays a critical role in the recurrence of Afib after ablation, with systemic inflammatory markers such as C-reactive protein being linked to higher recurrence rates. In this editorial, we discuss the study by Wang , published in the latest issue, which investigates the predictive role of the systemic immune inflammation index (SII) in Afib recurrence following radiofrequency CA. Elevated pre-ablation SII levels are identified as an independent predictor of recurrence, significantly enhancing the predictive power of the APPLE score. Integration of SII improved the APPLE score's predictive performance, as shown by enhanced area under the curve, net reclassification improvement, and integrated discrimination improvement. This combined model highlights the importance of both structural and inflammatory factors in Afib recurrence, offering a more personalized approach to patient management. Additionally, the affordability and accessibility of SII enhance its practicality in clinical workflows. The study by Wang underscores the potential of integrating SII with existing scoring systems to refine risk stratification and optimize treatment strategies. Future research should validate these findings across diverse populations, explore limitations such as the potential influence of comorbidities on SII reliability, and investigate additional biomarkers to enhance predictive accuracy.
Antilipolytic Insulin Sensitivity Indices Measured during an Oral Glucose Challenge: Associations with Insulin-Glucose Clamp and Central Adiposity in Women without Diabetes
Tissue overexposure to non-esterified fatty acids (NEFA) contributes to the development of metabolic conditions, with insulin-mediated suppression of lipolysis being an important mechanism in limiting this overexposure. We investigated which dynamic NEFA insulin-suppression indices derived from the oral glucose tolerance test (OGTT) were best associated with those derived from the insulin-glucose clamp, as well as with central adiposity and glucoregulatory parameters.
Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk
Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.
Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases
Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.
Multimorbidity Is Associated With Symptom Severity and Disease Progression in Patients with Paroxysmal Atrial Fibrillation-Data From the RACE V Study
Multimorbidity is common among patients with atrial fibrillation (AF) and is associated with worse outcomes. We aimed to investigate the association between multimorbidity, AF progression and AF symptom severity in patients with paroxysmal AF.
Inhibiting atrial natriuretic peptide clearance reduces myocardial fibrosis and improves cardiac function in diabetic rats
Natriuretic peptides (NPs) exert pleiotropic effects through the recruitment of cyclic guanosine monophosphate (cGMP) signalling pathways depending on their bioavailability, which is regulated by clearance receptors and peptidases. Here, we tested the hypothesis that increasing myocardial bioavailability of NP has a beneficial effect on heart failure. We studied the effects of a mutated NP, M-atrial natriuretic peptide (MANP), resistant to neprilysin in a model of diabetic cardiomyopathy characterized by marked myocardial fibrosis.
The diagnostic role of pharmacological provocation testing in cardiac electrophysiology: a clinical consensus statement of the European Heart Rhythm Association and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC, the ESC Working Group on Cardiovascular Pharmacotherapy, the Association of European Paediatric and Congenital Cardiology (AEPC), the Paediatric & Congenital Electrophysiology Society (PACES), the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS)
The pharmacological provocation test is a pivotal tool in cardiac electrophysiology for the diagnosis of potential causes of sudden cardiac death, sudden cardiac arrest (SCA), arrhythmias, symptoms, or ECG abnormalities. The 2022 European Society of Cardiology Guidelines for the Treatment of Ventricular Arrhythmias and Prevention of Sudden Cardiac Death offered guidance on provocation testing but did not describe the indications and requirements in depth. This clinical consensus statement, led by the European Heart Rhythm Association and approved by major international stakeholders, aims to advise the general cardiologist and the arrhythmia expert who to test and when, where, and how to do it. The statement focuses on current practice for the diagnosis of subclinical arrhythmia syndromes and the causes of SCA, building upon the recommendations of the Guidelines. We address the sodium channel blocker provocation test for patients suspected of Brugada syndrome as well as the use of epinephrine, isoproterenol, adenosine, ergonovine, and acetylcholine.
The Role of Calcified Nodules in Acute Coronary Syndrome: Diagnosis and Management
Calcified nodules (CNs) are increasingly recognized as critical contributors to the pathophysiology of acute coronary syndrome (ACS). This review provides a comprehensive synthesis of the recent literature, focusing on the prevalence of CNs, their underlying mechanisms, and their implications for the clinical management of coronary artery disease (CAD). CNs are characterized by unique pathophysiological processes, and the diagnosis and treatment of CNs during percutaneous coronary interventions (PCIs) underscore the importance of advanced intravascular imaging techniques, such as optical coherence tomography (OCT) and intravascular ultrasound (IVUS), for precise identification and prognostic evaluation. Current therapeutic strategies aim to modulate CN characteristics, enhance arterial wall stability, and reduce the risk of ACS and sudden cardiac death. This review highlights the impact of CNs in ACS, the role of intravascular imaging in diagnosis, and the importance of targeted interventions to improve clinical outcomes, as by bridging diagnostic insights with emerging atherectomy modalities, this review also seeks to advance the understanding and management of CNs in PCI, fostering improved patient outcomes.
Assessing the impact of COmorbidities and Sociodemographic factors on Multiorgan Injury following COVID-19: rationale and protocol design of COSMIC, a UK multicentre observational study of COVID-negative controls
SARS-CoV-2 disease (COVID-19) has had an enormous health and economic impact globally. Although primarily a respiratory illness, multi-organ involvement is common in COVID-19, with evidence of vascular-mediated damage in the heart, liver, kidneys and brain in a substantial proportion of patients following moderate-to-severe infection. The pathophysiology and long-term clinical implications of multi-organ injury remain to be fully elucidated. Age, gender, ethnicity, frailty and deprivation are key determinants of infection severity, and both morbidity and mortality appear higher in patients with underlying comorbidities such as ischaemic heart disease, hypertension and diabetes. Our aim is to gain mechanistic insights into the pathophysiology of multiorgan dysfunction in people with COVID-19 and maximise the impact of national COVID-19 studies with a comparison group of COVID-negative controls.
Practical Compendium of Antiarrhythmic Drugs: A Clinical Consensus Statement of the European Heart Rhythm Association of the ESC
The EHRA Practical Compendium of Antiarrhythmic Drugs (AADs) offers advice on these drugs, focusing on their clinical use and the global impact of cardiac arrhythmias. This document aims to provide practical instructions to clinicians in arrhythmia management through pharmacological strategies. The compendium highlights persistent challenges in arrhythmia treatment, including clinical constraints, procedural risks, and the complexity of certain arrhythmias. Notably, atrial fibrillation is highly prevalent, and the demand for invasive treatment often surpasses the capacity of existing healthcare systems. As a result, pharmacological management remains essential. This is particularly relevant for patients with cardiac implantable electronic devices or channelopathies, where ablation is often not a suitable option. AADs play a pivotal role in these scenarios. The compendium introduces the ABC framework for AAD therapy: A (Appropriate therapy), for patients in whom AADs are the best therapeutic option, B (Backup therapy), as adjunctive treatment to invasive procedures, such as catheter ablation, and C (Complementary therapy), in combination with other therapies. The document provides detailed insights into the mechanisms of action, efficacy, safety profiles, and drug interactions of each class of AADs. Additionally, the compendium covers practical considerations, including initiation, combination strategies, monitoring, follow-up, special populations, and adverse effect management, with an emphasis on proarrhythmia risk mitigation. It also explores the integration of AADs with other therapeutic modalities, promoting a synergistic approach to optimize patient outcomes. In summary, this compendium serves as an indispensable resource for clinicians, offering practical advice and evidence-based insights to navigate the complexities of arrhythmia management effectively.
Single cell transcriptomic analyses of human heart failure with preserved ejection fraction
Heart failure with preserved ejection fraction (HFpEF) is a poorly understood, multi-system disease with high morbidity and mortality. To improve our understanding of its underlying biology, we used single-nucleus RNA sequencing (snRNA-seq) to characterize cell-specific gene expression patterns in human HFpEF myocardium.
Cardiac Remodeling and Arrhythmic Burden in Pre-Transplant Cirrhotic Patients: Pathophysiological Mechanisms and Management Strategies
: Chronic liver disease (CLD) and cirrhosis contribute to approximately 2 million deaths annually, with primary causes including alcohol-related liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and chronic hepatitis B and C infections. Among these, MASLD has emerged as a significant global health concern, closely linked to metabolic disorders and a leading cause of liver failure and transplantation. : This review aims to highlight the interplay between cirrhosis and cardiac dysfunction, emphasizing the pathophysiology, diagnostic criteria, and management of cirrhotic cardiomyopathy (CCM). : A comprehensive literature review was conducted to evaluate the hemodynamic and structural cardiac alterations in cirrhosis. : Cirrhosis leads to portal hypertension and systemic inflammation, contributing to CCM, which manifests as subclinical cardiac dysfunction, impaired contractility, and electrophysiological abnormalities. Structural changes, such as increased left ventricular mass, myocardial fibrosis, and ion channel dysfunction, further impair cardiac function. Vasodilation in the splanchnic circulation reduces peripheral resistance, triggering compensatory tachycardia, while the activation of the renin-angiotensin-aldosterone system (RAAS) promotes fluid retention and increases cardiac preload. Chronic inflammation and endotoxemia exacerbate myocardial dysfunction. The 2005 World Congress of Gastroenterology (WCG) and the 2019 Cirrhotic Cardiomyopathy Consortium (CCC) criteria provide updated diagnostic frameworks that incorporate global longitudinal strain (GLS) and tissue Doppler imaging (TDI). Prolonged QT intervals and arrhythmias are frequently observed. Managing heart failure in cirrhotic patients remains complex due to intolerance to afterload-reducing agents, and beta-blockers require careful use due to potential systemic hypotension. The interaction between CCM and major interventions, such as transjugular intrahepatic portosystemic shunt (TIPS) and orthotopic liver transplantation (OLT), highlights the critical need for thorough preoperative cardiac evaluation and vigilant postoperative monitoring. : CCM is a frequently underdiagnosed yet significant complication of cirrhosis, impacting prognosis, particularly post-liver transplantation. Early identification using echocardiography and thorough evaluations of arrhythmia risk in cirrhotic patients are critical for optimizing management strategies. Future research should focus on targeted therapeutic approaches to mitigate the cardiac burden in cirrhotic patients and improve clinical outcomes.
FGF21 Analogues in Patients With Metabolic Diseases: Systematic Review and Meta-Analysis of Randomised Controlled Trials
Liver-related complications are frequent in patients with metabolic diseases, with limited treatment options currently available. This systematic review and meta-analysis aimed to assess the effect of fibroblast growth factor-21 (FGF21) analogues on hepatic steatosis, inflammation and fibrosis in patients with metabolic diseases.
Sex and atrial fibrillation-associated risk estimation and management
Raw photoplethysmogram waveforms versus peak-to-peak intervals for machine learning detection of atrial fibrillation: Does waveform matter?
Machine learning-based analysis can accurately detect atrial fibrillation (AF) from photoplethysmograms (PPGs), however the computational requirements for analyzing raw PPG waveforms can be significant. The analysis of PPG-derived peak-to-peak intervals may offer a more feasible solution for smartphone deployment, provided the diagnostic utility is comparable.
Correction: Thrombin receptor PAR4 cross-activates the tyrosine kinase c-met in atrial cardiomyocytes
Using artificial intelligence to spot heart failure from ECGs: is it prime time?
Epicardial adipose tissue from computed tomography: a missing link in premature coronary artery disease?
Epicardial adipose tissue (EAT) could contribute to the specific atherosclerosis profile observed in premature coronary artery disease (pCAD) characterized by accelerated plaque burden (calcified and non-calcified), high-risk plaque (HRP) features, and ischaemic recurrence. Our aims were to describe EAT volume and density in pCAD compared with asymptomatic individuals matched on cardiovascular risk factors and to study their relationship with coronary plaque severity extension and vulnerability.
Type 2 diabetes genetic risk and incident diabetes across diabetes risk enhancers
To evaluate the predictive value of a contemporary type 2 diabetes (T2D) polygenic score (PGS) in detecting incident diabetes across a range of diabetes risk factors.
Management of dyslipidaemia in patients with comorbidities-facing the challenge
This review aims to examine the evidence on the benefits and risks of lipid-lowering drugs in patients with liver disease. Elevated liver enzyme levels often lead to cautious discontinuation of these drugs, potentially withholding from patients their benefit in reducing cardiovascular disease morbidity and mortality. Using a literature search of PubMed, we examine the efficacy and safety profiles of various lipid-lowering agents, including statins, ezetimibe, bempedoic acid, PCSK9 inhibitors, fibrates, and icosapent ethyl, focusing particularly on their potential side effects related to liver health. A major challenge in the assessment of drug-induced hepatotoxicity is the fact that it relies heavily on case reports rather than real-world evidence. There is currently a lack of robust evidence on lipid-lowering therapy in people with pre-existing liver disease. Nevertheless, we have attempted to summarize the available data for all the drugs mentioned in order to provide guidance for the treatment of patients with liver dysfunction. This review highlights the need for further research to optimize treatment strategies for patients with coexisting liver and cardiovascular disease.
The effect of altered sleep timing on glycaemic outcomes: Systematic review of human intervention studies
Alterations in sleep timing can lead to disturbances in glycaemic control, although the evidence is inconsistent. Therefore, this systematic review summarizes results from human intervention studies of altered sleep timing on glycaemic outcomes.
A deep learning digital biomarker to detect hypertension and stratify cardiovascular risk from the electrocardiogram
Hypertension is a major risk factor for cardiovascular disease (CVD), yet blood pressure is measured intermittently and under suboptimal conditions. We developed a deep learning model to identify hypertension and stratify risk of CVD using 12-lead electrocardiogram waveforms. HTN-AI was trained to detect hypertension using 752,415 electrocardiograms from 103,405 adults at Massachusetts General Hospital. We externally validated HTN-AI and demonstrated associations between HTN-AI risk and incident CVD in 56,760 adults at Brigham and Women's Hospital. HTN-AI accurately discriminated hypertension (internal and external validation AUROC 0.803 and 0.771, respectively). In Fine-Gray regression analyses model-predicted probability of hypertension was associated with mortality (hazard ratio per standard deviation: 1.47 [1.36-1.60], p < 0.001), HF (2.26 [1.90-2.69], p < 0.001), MI (1.87 [1.69-2.07], p < 0.001), stroke (1.30 [1.18-1.44], p < 0.001), and aortic dissection or rupture (1.69 [1.22-2.35], p < 0.001) after adjustment for demographics and risk factors. HTN-AI may facilitate diagnosis of hypertension and serve as a digital biomarker of hypertension-associated CVD.
Comparing Phenotypes for Acute and Long-Term Response to Atrial Fibrillation Ablation Using Machine Learning
It is difficult to identify patients with atrial fibrillation (AF) most likely to respond to ablation. While any arrhythmia patient may recur after acutely successful ablation, AF is unusual in that patients may have long-term arrhythmia freedom despite a lack of acute success. We hypothesized that acute and chronic AF ablation outcomes may reflect distinct physiology and used machine learning of multimodal data to identify their phenotypes.
The Efficacy and Safety of Direct Oral Anticoagulants Compared to Warfarin in Morbidly Obese Patients on Anticoagulation: A Systematic Review and Meta-Analysis
Current guidelines and consensus statements advise caution in using direct oral anticoagulants (DOACs) for morbidly obese patients with body mass index (BMI) >40 kg/m2, indicating warfarin as the most studied treatment.
Cold-induced thermogenesis requires neutral-lipase-mediated intracellular lipolysis in brown adipocytes
Long-chain fatty acids (FAs) are the major substrates fueling brown adipose tissue (BAT) thermogenesis. Investigation of mouse models has previously called into question the contribution of brown adipocyte intracellular lipolysis to cold-induced non-shivering thermogenesis. Here, we determined the role of the lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in BAT thermogenesis. Brown fat from mice with inducible brown-adipocyte-specific deletion of ATGL and HSL (BAHKO) is hypertrophied with increased lipid droplet size and preserved mitochondria area and density. Maintenance of body temperature during cold exposure is compromised in BAHKO mice in the fasted but not in the fed state. This altered response to cold is observed in various thermal and nutritional conditions. Positron emission tomography-computed tomography using [C]-acetate and [C]-palmitate shows abolished cold-induced BAT oxidative activity and impaired FA metabolism in BAHKO mice. Our findings show that brown adipocyte intracellular lipolysis is required for BAT thermogenesis.
The inflammatory and nutritional status in patients with dilated cardiomyopathy: Different impact for distinct phenogroups?
Time-dependent Mitochondrial Remodeling in Experimental Atrial Fibrillation and Potential Therapeutic Relevance
Changes in mitochondria have been implicated in atrial fibrillation (AF), but their manifestations and significance are poorly understood. Here, we studied changes in mitochondrial morphology and function during AF and assessed the effect of a mitochondrial-targeted intervention in a large animal model.
Atrial fibrillation does not equal atrial fibrillation: The important prognostic implications of new-onset atrial fibrillation
A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies
Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis.
A multi-modal computational fluid dynamics model of left atrial fibrillation haemodynamics validated with 4D flow MRI
Atrial fibrillation (AF) is characterized by rapid and irregular contraction of the left atrium (LA). Impacting LA haemodynamics, this increases the risk of thrombi development and stroke. Flow conditions preceding stroke in these patients are not well defined, partly due the limited resolution of 4D flow magnetic resonance imaging (MRI). In this study, we combine a high-resolution computed tomography (CT) LA reconstruction with motion and pulmonary inflows from 4D flow MRI to create a novel multimodal computational fluid dynamics (CFD) model, applying it to five AF patients imaged in sinus rhythm (24 ± 39 days between acquisitions). The dynamic model was compared with a rigid wall equivalent and the main flow structures were validated with 4D flow MRI. Point-by-point absolute differences between the velocity fields showed moderate differences given the sensitivity to registration. The rigid wall model significantly underestimated LA time-averaged wall shear stress (TAWSS) (p = 0.02) and oscillatory shear index (OSI) (p = 0.02) compared to the morphing model. Similarly, in the left atrial appendage (LAA), TAWSS (p = 0.003) and OSI (p < 0.001) were further underestimated. The morphing model yielded a more accurate mitral valve waveform and showed low TAWSS and high OSI in the LAA, both associated with thrombus formation. We also observed a positive correlation between indexed LA volume and endothelial cell activation potential (ECAP) (R = 0.83), as well as LAA volume and LAA OSI (R = 0.70). This work demonstrates the importance of LA motion in modelling LAA flow. Assessed in larger cohorts, LAA haemodynamic analysis may be beneficial to refine stroke risk assessment for AF.
Cardiac magnetic resonance imaging in patients with suspected myocarditis from immune checkpoint inhibitor therapy - A real-world observational study
Cardiotoxicity from immune checkpoint inhibitor (ICI) therapy is a challenge in clinical practice, and the assessment of ICI-related myocarditis (ICI-M) is often complicated by a variable phenotype. Cardiac magnetic resonance imaging (CMR) is used frequently, but evidence is poor. Here, we aim to assess the role of CMR in the assessment of suspected ICI-M in a real-world clinical setting.
Lateral Atrial Expression Patterns Provide Insights into Local Transcription Disequilibrium Contributing to Disease Susceptibility
Transcriptional dysregulation, possibly affected by genetic variation, contributes to disease etiology. Due to dissimilarities in development, function, and remodeling during disease progression, transcriptional differences between the left atrium (LA) and right atrium (RA) may provide insight into diseases such as atrial fibrillation.
Inflammatory cardiovascular events and coronary artery disease - Authors' reply
Mineralocorticoid axis activity and cardiac remodeling in patients with ACTH-dependent Cushing's syndrome
Arterial hypertension and left ventricular hypertrophy and remodeling are independent cardiovascular risk factors in patients with Cushing's syndrome. Changes in the renin-angiotensin system and in the mineralocorticoid axis activity could be involved as potential mechanisms in their pathogenesis, in addition to cortisol excess.
Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome
A well-balanced ion channel trafficking machinery is paramount for the normal electromechanical function of the heart. Ion channel variants and many drugs can alter the cardiac action potential and lead to arrhythmias by interfering with mechanisms like ion channel synthesis, trafficking, gating, permeation, and recycling. A case in point is the Long QT syndrome (LQTS), a highly arrhythmogenic disease characterized by an abnormally prolonged QT interval on ECG produced by variants and drugs that interfere with the action potential. Disruption of ion channel trafficking is one of the main sources of LQTS. We review some molecular pathways and mechanisms involved in cardiac ion channel trafficking. We highlight the importance of channelosomes and other macromolecular complexes in helping to maintain normal cardiac electrical function, and the defects that prolong the QT interval as a consequence of variants or the effect of drugs. We examine the concept of "interactome mapping" and illustrate by example the multiple protein-protein interactions an ion channel may undergo throughout its lifetime. We also comment on how mapping the interactomes of the different cardiac ion channels may help advance research into LQTS and other cardiac diseases. Finally, we discuss how using human induced pluripotent stem cell technology to model ion channel trafficking and its defects may help accelerate drug discovery toward preventing life-threatening arrhythmias. Advancements in understanding ion channel trafficking and channelosome complexities are needed to find novel therapeutic targets, predict drug interactions, and enhance the overall management and treatment of LQTS patients.
Unsupervised deep learning of electrocardiograms enables scalable human disease profiling
The 12-lead electrocardiogram (ECG) is inexpensive and widely available. Whether conditions across the human disease landscape can be detected using the ECG is unclear. We developed a deep learning denoising autoencoder and systematically evaluated associations between ECG encodings and ~1,600 Phecode-based diseases in three datasets separate from model development, and meta-analyzed the results. The latent space ECG model identified associations with 645 prevalent and 606 incident Phecodes. Associations were most enriched in the circulatory (n = 140, 82% of category-specific Phecodes), respiratory (n = 53, 62%) and endocrine/metabolic (n = 73, 45%) categories, with additional associations across the phenome. The strongest ECG association was with hypertension (p < 2.2×10). The ECG latent space model demonstrated more associations than models using standard ECG intervals, and offered favorable discrimination of prevalent disease compared to models comprising age, sex, and race. We further demonstrate how latent space models can be used to generate disease-specific ECG waveforms and facilitate individual disease profiling.
Improving antiarrhythmic therapy for patients with atrial fibrillation using common genetic variants
Contemporary Burden of Cardiovascular Disease in Pregnancy: Insights from a Real-World Pregnancy Electronic Health Record Cohort
Cardiovascular disease (CVD) is the leading cause of maternal morbidity and mortality, however the contemporary burden and secular trends in pregnancy-related CV complications are not well characterized.
Genomic Drivers of Coronary Artery Disease and Risk of Future Outcomes After Coronary Angiography
Disease characteristics of genetically mediated coronary artery disease (CAD) on coronary angiography and the association of genomic risk with outcomes after coronary angiography are not well understood.
Emerging debates and resolutions in brown adipose tissue research
Until two decades ago, brown adipose tissue (BAT) was studied primarily as a thermogenic organ of small rodents in the context of cold adaptation. The discovery of functional human BAT has opened new opportunities to understand its physiological role in energy balance and therapeutic applications for metabolic disorders. Significantly, the role of BAT extends far beyond thermogenesis, including glucose and lipid homeostasis, by releasing mediators that communicate with other cells and organs. The field has made major advances by using new model systems, ranging from subcellular studies to clinical trials, which have also led to debates. In this perspective, we identify six fundamental issues that are currently controversial and comprise dichotomous models. Each side presents supporting evidence and, critically, the necessary methods and falsifiable experiments that would resolve the dispute. With this collaborative approach, the field will continue to productively advance the understanding of BAT physiology, appreciate the importance of thermogenic adipocytes as a central area of ongoing research, and realize the therapeutic potential.
Transcriptional profile of the rat cardiovascular system at single-cell resolution
We sought to characterize cellular composition across the cardiovascular system of the healthy Wistar rat, an important model in preclinical cardiovascular research. We performed single-nucleus RNA sequencing (snRNA-seq) in 78 samples in 10 distinct regions, including the four chambers of the heart, ventricular septum, sinoatrial node, atrioventricular node, aorta, pulmonary artery, and pulmonary veins, which produced 505,835 nuclei. We identified 26 distinct cell types and additional subtypes, with different cellular composition across cardiac regions and tissue-specific transcription for each cell type. Several cell subtypes were region specific, including a subtype of vascular smooth muscle cells enriched in the large vasculature. We observed tissue-enriched cellular communication networks, including heightened Nppa-Npr1/2/3 signaling in the sinoatrial node. The existence of tissue-restricted cell types suggests regional regulation of cardiovascular physiology. Our detailed transcriptional characterization of each cell type offers the potential to identify novel therapeutic targets and improve preclinical models of cardiovascular disease.
Promising tools for future drug discovery and development in antiarrhythmic therapy
Arrhythmia refers to irregularities in the rate and rhythm of the heart, with symptoms spanning from mild palpitations to life-threatening arrhythmias and sudden cardiac death. The complex molecular nature of arrhythmias complicates the selection of appropriate treatment. Current therapies involve the use of antiarrhythmic drugs (class I-IV) with limited efficacy and dangerous side effects and implantable pacemakers and cardioverter-defibrillators with hardware-related complications and inappropriate shocks. The number of novel antiarrhythmic drugs in the development pipeline has decreased substantially during the last decade and underscores uncertainties regarding future developments in this field. Consequently, arrhythmia treatment poses significant challenges, prompting the need for alternative approaches. Remarkably, innovative drug discovery and development technologies show promise in helping advance antiarrhythmic therapies. In this article, we review unique characteristics and the transformative potential of emerging technologies that offer unprecedented opportunities for transitioning from traditional antiarrhythmics to next-generation therapies. We assess stem cell technology, emphasizing the utility of innovative cell profiling using multiomics, high-throughput screening, and advanced computational modeling in developing treatments tailored precisely to individual genetic and physiological profiles. We offer insights into gene therapy, peptide, and peptibody approaches for drug delivery. We finally discuss potential strengths and weaknesses of such techniques in reducing adverse effects and enhancing overall treatment outcomes, leading to more effective, specific, and safer therapies. Altogether, this comprehensive overview introduces innovative avenues for personalized rhythm therapy, with particular emphasis on drug discovery, aiming to advance the arrhythmia treatment landscape and the prevention of sudden cardiac death. SIGNIFICANCE STATEMENT: Arrhythmias and sudden cardiac death account for 15%-20% of deaths worldwide. However, current antiarrhythmic therapies are ineffective and have dangerous side effects. Here, we review the field of arrhythmia treatment underscoring the slow progress in advancing the cardiac rhythm therapy pipeline and the uncertainties regarding evolution of this field. We provide information on how emerging technological and experimental tools can help accelerate progress and address the limitations of antiarrhythmic drug discovery.
From Ca dysregulation to heart failure: β-adrenoceptor activation by RKIP postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant PLN by correction of aberrant Ca-handling
Impaired cardiomyocyte Ca handling is a central hallmark of heart failure (HF), which causes contractile dysfunction and arrhythmias. However, the underlying molecular mechanisms and the precise contribution of defects in Ca-cycling regulation in the development of HF are still not completely resolved. Here, we used transgenic mice that express a human mutation in the cardiomyocyte Ca-regulator phospholamban (PLN-tg) causing severe HF due to a reduction in Ca reuptake into the sarco(endo)plasmic reticulum (SR). PLN-induced HF is a rapidly progressing condition characterized by prominent Ca cycling and relaxation defects and premature death of mutation carriers. We found that endoplasmic reticulum (ER) and mitochondrial function are affected even before transition to overt HF. Early correction of aberrant Ca cycling by cardiac expression of the Raf kinase inhibitor protein (RKIP), an endogenous activator of β-adrenoceptors (βAR), delayed the cellular alterations, functional failure and prolonged lifespan. Our study highlights the importance of early and persistent correction of Ca dynamics, not only for excitation/contraction coupling, but also for the prevention of rather irreparable events on cardiac energetics and ER stress adaptations. The latter may even impede with later onset of Ca-related therapeutic interventions and should gain more focus for HF treatment.
The impact of common and rare genetic variants on bradyarrhythmia development
To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (r = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias.
Oxidative Stress Biomarkers in Hypertension
Arterial hypertension is a silent and progressive disease with deleterious vascular implications on all target organs, including the heart, the brain, the kidneys, and the eyes. Oxidative stress, defined as the overproduction of Reactive Oxygen Species (ROS) over antioxidants, is capable of deteriorating not only the normal endothelial but also the cellular function with further cardiovascular implications. Xanthine oxidase activity, NADPH oxidase overexpression, and ROS production lead to hypertension and high arterial tone, culminating in end-organ damage. The inactivation of NO by superoxide reduces vasodilation and promotes peroxynitrite formation, which damages cellular components. Activation of MMPs by oxidative stress contributes to pathological neovascularization and angiogenesis. Salucin-β-induced activation of Angiotensin-II and NADPH results in vascular remodeling and fibrosis, while lipid peroxidation and PARP- 1 activation further exacerbate cellular apoptosis and vascular calcification. Moreover, to reliably assess the oxidative status an emerging number of biomarkers are under investigation. Antioxidant therapy, alongside traditional antihypertensive agents such as beta-blockers and ACE inhibitors, offers the potential to mitigate oxidative stress and its detrimental effects. Additionally, polyphenols, found in plant-based foods, show promise in managing oxidative stress in hypertensive patients although this data has not been confirmed in randomized clinical trials. Understanding the intricate relationship between oxidative stress and hypertension underscores the importance of developing comprehensive therapeutic strategies to reduce cardiovascular risk and improve patient outcomes.
Kir2.1 mutations differentially increase the risk of flecainide proarrhythmia in Andersen Tawil Syndrome
Flecainide and other class-Ic antiarrhythmic drugs (AADs) are widely used in Andersen-Tawil syndrome type 1 (ATS1) patients. However, class-Ic drugs might be proarrhythmic in some cases. We investigated the molecular mechanisms of class-I AADs proarrhythmia and whether they might increase the risk of death in ATS1 patients with structurally normal hearts.
Towards improved detection of subclinical atrial fibrillation - Who could benefit from targeted screening?
Inflammatory gut-heart interactions: Is there a link between inflammatory bowel disease and atrial fibrillation?
Prognostic Value of Strain by Speckle Tracking Echocardiography in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy
Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic disorder associated with an elevated risk of life-threatening arrhythmias and progressive ventricular impairment. Risk stratification is essential to prevent major adverse cardiac events (MACE). Our study aimed to investigate the incremental value of strain measured by two-dimensional speckle-tracking echocardiography in predicting MACE in ARVC patients compared to conventional echocardiographic parameters. Methods and Results This was a retrospective, single-centre cohort study of 83 patients with ARVC (51% males, median age 37 years (IQR: 23, 53)) under the care of the Inherited Cardiac Conditions clinic at University Hospital Birmingham. MACE was defined as one of the following: sustained ventricular tachycardia (Sus VT), ventricular fibrillation (VF), appropriate implantable cardio-defibrillator (ICD) therapy [shock/anti-tachycardia pacing (ATP)], heart failure (defined as decompensated heart failure, cardiac index by heart catheter, HF medication, and symptoms), cardiac transplantation, or cardiac death. Echocardiography images were analysed by a single observer for right ventricle (RV) and left ventricular (LV) global longitudinal strain (GLS). Multivariable Cox regression was performed in combination with RV fractional area change and tricuspid annular plane systolic excursion. During three years of follow-up, 12% of patients suffered a MACE. ARVC patients with MACE had significantly reduced RV GLS (-13 ± 6% vs. -23 ± 6%, < 0.001) and RV free wall longitudinal strain (-15 ± 5% vs. -25 ± 7%, < 0.001) compared to those without MACE. Conclusions Right ventricular free wall longitudinal strain (RVFWLS) may be a more sensitive predictor of MACE than conventional echocardiographic parameters of RV function. Moreover, RV-free wall longitudinal strain may have superior predictive value compared to RV GLS.
Evolution in electrophysiology 100 years after Einthoven: translational and computational innovations in rhythm control of atrial fibrillation
In 1924, the Dutch physiologist Willem Einthoven received the Nobel Prize in Physiology or Medicine for his discovery of the mechanism of the electrocardiogram (ECG). Anno 2024, the ECG is commonly used as a diagnostic tool in cardiology. In the paper 'Le Télécardiogramme', Einthoven described the first recording of the now most common cardiac arrhythmia: atrial fibrillation (AF). The treatment of AF includes rhythm control, aiming to alleviate symptoms and improve quality of life. Recent studies found that early rhythm control might additionally improve clinical outcomes. However, current therapeutic options have suboptimal efficacy and safety, highlighting a need for better rhythm-control strategies. In this review, we address the challenges related to antiarrhythmic drugs (AADs) and catheter ablation for rhythm control of AF, including significant recurrence rates and adverse side effects such as pro-arrhythmia. Furthermore, we discuss potential solutions to these challenges including novel tools, such as atrial-specific AADs and digital-twin-guided AF ablation. In particular, digital twins are a promising method to integrate a wide range of clinical data to address the heterogeneity in AF mechanisms. This may enable a more mechanism-based tailored approach that may overcome the limitations of previous precision medicine approaches based on individual biomarkers. However, several translational challenges need to be addressed before digital twins can be routinely applied in clinical practice, which we discuss at the end of this narrative review. Ultimately, the significant advances in the detection, understanding, and treatment of AF since its first ECG documentation are expected to help reduce the burden of this troublesome condition.
MicroRNAs as Prognostic Biomarkers for Atrial Fibrillation Recurrence After Catheter Ablation: Current Evidence and Future Directions
Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice and is associated with significant morbidity and mortality. Even though catheter ablation has emerged as an available and effective treatment for AF, recurrence remains a significant challenge. This review presents the existing evidence on the prognostic role of microRNAs (miRNAs) in the prediction of AF recurrence after catheter ablation. We examined studies investigating the association between miRNA expression and post-ablation AF recurrence. Multiple miRNAs have been highlighted as potential biomarkers, which are involved in pathophysiological processes such as atrial remodeling, fibrosis, and inflammation. Despite some promising results, there has been significant heterogeneity across the studies. In this review, we demonstrate the potential miRNAs that can be routinely used as biomarkers of AF recurrence, and we identify areas that require further research to validate their clinical utility.
Cancer Therapy-Related Cardiac Dysfunction: A Review of Current Trends in Epidemiology, Diagnosis, and Treatment
Cancer therapy-related cardiac dysfunction (CTRCD) has emerged as a significant concern with the rise of effective cancer treatments like anthracyclines and targeted therapies such as trastuzumab. While these therapies have improved cancer survival rates, their unintended cardiovascular side effects can lead to heart failure, cardiomyopathy, and arrhythmias. The pathophysiology of CTRCD involves oxidative stress, mitochondrial dysfunction, and calcium dysregulation, resulting in irreversible damage to cardiomyocytes. Inflammatory cytokines, disrupted growth factor signaling, and coronary atherosclerosis further contribute to this dysfunction. Advances in cardio-oncology have led to the early detection of CTRCD using cardiac biomarkers like troponins and imaging techniques such as echocardiography and cardiac magnetic resonance (CMR). These tools help identify asymptomatic patients at risk of cardiac events before the onset of clinical symptoms. Preventive strategies, including the use of cardioprotective agents like beta-blockers, angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors have shown promise in reducing the incidence of CTRCD. This review summarizes the mechanisms, detection methods, and emerging treatments for CTRCD, emphasizing the importance of interdisciplinary collaboration between oncologists and cardiologists to optimize care and improve both cancer and cardiovascular outcomes.
Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.
His-Ventricular Interval and Incident Pacemaker Implant in Over 3000 Ambulatory Patients Undergoing Invasive Electrophysiologic Procedures
Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience
Dilated cardiomyopathy (DCM) is a heart muscle disease that represents an important cause of morbidity and mortality, yet causal mechanisms remain largely elusive. Here, we perform a large-scale genome-wide association study and multitrait analysis for DCM using 9,365 cases and 946,368 controls. We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis. Polygenic risk scores constructed from our genome-wide association study predict DCM across different ancestry groups, show differing contributions to DCM depending on rare pathogenic variant status and associate with systolic heart failure across various clinical settings. Mendelian randomization analyses reveal actionable potential causes of DCM, including higher bodyweight and higher systolic blood pressure. Our findings provide insights into the genetic architecture and mechanisms underlying DCM and myocardial function more broadly.
Publisher Correction: Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience
An economic evaluation of first-line cryoballoon ablation versus antiarrhythmic drug therapy for the treatment of paroxysmal atrial fibrillation from a German healthcare payer perspective
Three recent randomized controlled trials demonstrated that, in patients with symptomatic paroxysmal atrial fibrillation (PAF), first-line pulmonary vein isolation with cryoballoon catheter ablation reduces atrial arrhythmia recurrence compared to initial antiarrhythmic drug (AAD) therapy. This study aimed to evaluate the cost-effectiveness of first-line cryoablation compared to first-line AADs from a German healthcare payer perspective.
SGLT2 inhibitors in the prevention of diabetic cardiomyopathy: Targeting the silent threat
Heart failure (HF) is a major global health challenge, particularly among individuals with type 2 diabetes mellitus (T2DM), who are at significantly higher risk of developing HF. Diabetic cardiomyopathy, a unique form of heart disease, often progresses silently until advanced stages. Recent research has focused on sodium-dependent glucose transporter 2 inhibitors (SGLT2i), originally developed for hyperglycemia, which have shown potential in reducing cardiovascular risks, including HF hospitalizations, irrespective of diabetic status. In this editorial we comment on the article by Grubić Rotkvić published in the recent issue of the The investigators examined the effects of SGLT2i on myocardial function in T2DM patients with asymptomatic HF, finding significant improvements in stroke volume index and reductions in systemic vascular resistance, suggesting enhanced cardiac output. Additionally, SGLT2i demonstrated anti-inflammatory and antioxidant effects, as well as blood pressure reduction, though the study's limitations-such as small sample size and observational design-necessitate larger randomized trials to confirm these findings. The study underscores the potential of early intervention with SGLT2i in preventing HF progression in T2DM patients.
Intra-operative and post-operative management of conduits for coronary artery bypass grafting: a clinical consensus statement of the European Society of Cardiology Working Group on Cardiovascular Surgery and the European Association for Cardio-Thoracic Surgery Coronary Task Force
The structural and functional integrity of conduits used for coronary artery bypass grafting is critical for graft patency. Disruption of endothelial integrity and endothelial dysfunction are incurred during conduit harvesting subsequent to mechanical or thermal injury and during conduit storage prior to grafting, leading to acute thrombosis and early graft failure. Late graft failure, in particular that of vein grafts, is precipitated by progressive atherogenesis. Intra-operative management includes appropriate selection of conduit-specific harvesting techniques and storage solutions. Arterial grafts are prone to vasospasm subsequent to surgical manipulation, and application of intra-operative vasodilatory protocols is critical. Post-operative management includes continuation of oral vasodilator therapy and selection of antithrombotic and lipid-lowering agents to attenuate atherosclerotic disease progression in conduits. In this review, the scientific evidence underlying the key aspects of intra- and post-operative management of conduits for coronary artery bypass grafting is examined. Clinical consensus statements for best clinical practice are provided, and areas requiring further research are highlighted.
Deep learning-based segmentation and strain analysis of left heart chambers from long-axis CMR images
Feature tracking (FT) is increasingly used on dynamic cardiac magnetic resonance (CMR) images for myocardial strain evaluation but often requires manual initialization, which is tedious and source of variability, especially on the challenging long-axis (LAX) images. Accordingly, we designed a pipeline combining deep learning (DL) with FT for left ventricular (LV) and left atrial (LA) longitudinal myocardial strain estimation.
Selecting repetitive focal and rotational activation patterns with the highest probability of being a source of atrial fibrillation
Repetitive focal and rotational activation patterns are currently used as additional ablation targets for atrial fibrillation (AF). However, there is no evidence that all these detected targets are actual sources of AF. In this paper, we present an approach that detects and ranks AF activation patterns not only based on the degree of pattern repetitiveness but also on the extent to which they are able to entrain their vicinity. This new technique might enable selecting the site with the highest probability of being a source for AF.
A novel sequential endocardial mapping strategy for locating atrial fibrillation sources based on repetitive conduction patterns: An in-silico study
In persistent atrial fibrillation (AF), localized extra-pulmonary vein sources may contribute to arrhythmia recurrences after pulmonary vein isolation. This in-silico study proposes a high-density sequential mapping strategy to localize such sources.
Culturally responsive strategies and practical considerations for live tissue studies in Māori participant cohorts
Indigenous communities globally are inequitably affected by non-communicable diseases such as cancer and coronary artery disease. Increased focus on personalized medicine approaches for the treatment of these diseases offers opportunities to improve the health of Indigenous people. Conversely, poorly implemented approaches pose increased risk of further exacerbating current inequities in health outcomes for Indigenous peoples. The advancement of modern biology techniques, such as three-dimensional (3D) models and next generation sequencing (NGS) technologies, have enhanced our understanding of disease mechanisms and individualized treatment responses. However, current representation of Indigenous peoples in these datasets is lacking. It is crucial that there is appropriate and ethical representation of Indigenous peoples in generated datasets to ensure these technologies can be used to maximize the benefit of personalized medicine for Indigenous peoples.
From Atrial Small-conductance Calcium-activated Potassium Channels to New Antiarrhythmics
Despite significant advances in its management, AF remains a major healthcare burden affecting millions of individuals. Rhythm control with antiarrhythmic drugs or catheter ablation has been shown to improve symptoms and outcomes in AF patients, but current treatment options have limited efficacy and/or significant side-effects. Novel mechanism-based approaches could potentially be more effective, enabling improved therapeutic strategies for managing AF. Small-conductance calcium-activated potassium (SK or KCa2.x) channels encoded by have recently gathered interest as novel antiarrhythmic targets with potential atrial-predominant effects. Here, the molecular composition of smallconductance calcium-activated potassium channels and their complex regulation in AF as the basis for understanding the distinct mechanism of action of pore-blockers (apamin, UCL1684, ICAGEN) and modulators of calcium-dependent activation (NS8593, AP14145, AP30663) are summarised. Furthermore, the preclinical and early clinical evidence for the role of small-conductance calcium-activated potassium channel inhibitors in the treatment of AF are reviewed.
Coronary atherosclerotic plaque modification: the present and the future
Coronary atherosclerosis, marked by lipid deposition and inflammation, drives cardiovascular morbidity. Traditional treatments focus on lipid reduction, yet newer therapies target plaque composition, aiming to enhance stability and prevent coronary events.
Effect of timed exercise interventions on patient-reported outcome measures: A systematic review
Exercising at a specific time of day has the potential to mitigate the negative effects of disrupted circadian rhythms caused by irregular work and sleep schedules on the development of chronic diseases. Afternoon/evening exercise is postulated to be superior to morning exercise for various health outcomes, but patient acceptance of timed exercise remains unclear. The aim of this systematic review was to assess the impact of exercise timing on patient-reported outcomes (PROMs).
Sodium-Glucose Cotransporter 2 Inhibitors and Changes in Epicardial Adipose Tissue: A Systematic Literature Review And Meta-Analysis
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a groundbreaking class of antidiabetic medications renowned for their glucose-lowering effects and cardiovascular benefits. Recent studies have suggested that SGLT2 inhibitors may extend their influence beyond glycemic control to impact adipose tissue physiology, particularly within the epicardial adipose depot. Epicardial adipose tissue (EAT), an actively secretory organ surrounding the heart, has been implicated in the modulation of cardiovascular risk.
Imaging features of desmoplakin arrhythmogenic cardiomyopathy: A comparative cardiovascular magnetic resonance study
Arrhythmogenic cardiomyopathy (ACM) related to Desmoplakin (DSP) mutations is a distinct condition associated with particularly severe outcomes, more frequent left ventricular (LV) involvement, including fibrosis, dysfunction, and inflammatory episodes. Whether DSP-ACM is associated with specific imaging features remains elusive. This study aims to provide a comprehensive description of cardiovascular magnetic resonance (CMR) findings in patients with DSP-ACM and to compare them to RV-dominant ACM with LV involvement (LV+ right-dominant-ACM).