BACKGROUND:Inflammation is associated with atrial fibrillation (AF), but its precise impact on the long-term progression of the AF substrate, also called atrial cardiomyopathy (ACM), remains debated. METHODS:Human atria specimens were used for spatial transcriptomic, histology, epicardial progenitor cell (EPDCs) culture and immunofluorescence. Atria removed from B6J mice fed a high fat diet (HFD) were evaluated at 2 and 4 months of diet with single-cell RNA sequencing, microscopy and flow cytometer. Lyve1-resident macrophages deficient and CCR2 (C-C chemokine receptor type 2) knockout mice and their wild type littermates were evaluated in terms of ACM, cardiac structure, metabolic diseases, histology, immune cells characterization and key molecular markers. Olink assay was performed to screen plasma samples and the cellular secretome for various cytokines. Primary THP1-derived macrophages were cocultured with EPDCs and evaluated for myofibroblast differentiation. RESULTS:Macrophage subpopulations were mainly confined in the EAT of human atria. In a mouse model of obesity and ACM, macrophage recruitment was associated with atrial adiposity. In addition, Lyve1+-resident and CCR2+ monocyte-derived macrophages were identified in obese mouse atria. Depleting Lyve1+-macrophages in mice prevented early fat expansion and led to myocardial dystrophy, while CCR2+-macrophage depletion prevented fibro-fatty remodeling, atrial dilation, and AF. CONCLUSIONS:These data highlight the pivotal role of macrophages in atrial adiposity, in particular that of Lyve1+-macrophages during adipose tissue expansion.

BACKGROUND:Echocardiography in patients with acute pulmonary embolism (PE) primarily focuses on right ventricular (RV) function. The involvement of other heart cavities have been less studied, especially regarding their potential effect on prognosis. In this study we assessed the additional prognostic value of 4-chamber myocardial strain beyond usual risk scores during follow-up. METHODS:This retrospective cohort study included 488 patients hospitalized for PE. RESULTS:During a median follow-up of 3.6 years, all-cause death (primary outcome) occurred in 93/488 patients (19.1%). At baseline, increasing PE severity across the 4 European Society of Cardiology (ESC) risk groups was significantly associated with reductions in left atrial (LA), right atrial (RA), and absolute values of biventricular strains (all P < 0.001, except RA contractile strain, P = 0.052). In multivariable analysis, left ventricular global longitudinal strain (> -19.1%), RV free wall strain (> -19.1%), RA reservoir strain (< 27.5%), RA conduit strain (< 16.0%), LA reservoir strain (< 36.4%), and LA conduit strain (< 16.6%) predicted all-cause death independently from body mass index, ESC risk score, and B-type natriuretic peptide and C-reactive protein levels. Using receiver-operating characteristic analysis, ESC risk score had the lowest area under the curve to predict all-cause mortality risk whereas a combined approach including clinical, biological, and echocardiography with strain parameters had the highest predictive value. CONCLUSIONS:Beyond RV remodelling and dysfunction, patients with acute PE might exhibit alterations in myocardial strain across all 4 cardiac chambers, which could serve as important predictors of all-cause mortality, in addition to conventional echocardiographic parameters.

La cardiomyopathie atriale est un concept physiopathologique correspondant à une anomalie du substrat et de la fonction atriales, définie par une dilatation, une altération de la fonction des myocytes et une fibrose atriale, constituant un milieu thrombogène. Une cardiomyopathie atriale précoce, suivie secondairement de la fibrillation atriale (FA), pourrait être à l’origine des accidents vasculaires cérébraux (AVC), d’insuffisance cardiaque à FEVG préservée et de régurgitations atrioventriculaires. La cardiomyopathie atriale peut être due à une pathologie primitive, y compris génétique, sans autre anomalie cardiaque initiale significative ou être secondaire à une pathologie ventriculaire et/ou valvulaire préexistante. À l’instar de la cardiomyopathie ventriculaire, elle présente un spectre de gravité variable et la combinaison de différents marqueurs indique un risque accru de progression. La cardiomyopathie atriale peut se manifester par des anomalies de la géométrie, de la structure et de la fonction atriale. Cependant, il n’existe pas de seuils universellement acceptés et documentés pour la prédiction de la gravité et de la constance de ces anomalies. De plus, les valeurs de référence ne sont disponibles que pour un nombre limité de marqueurs. Un électrocardiogramme à 12 dérivations doit être systématiquement réalisé, à la recherche d’une anomalie de l’onde P. Les extrasystoles atriales fréquentes identifient les patients susceptibles de développer une FA, et sont associées à un risque accru de survenue d’AVC et de mortalité. L’échocardiographie transthoracique est l’examen de routine pour déterminer le volume atrial gauche indexé et la déformation ou strain longitudinal de l’oreillette gauche, paramètre précis et validé de la fonction atriale. Un milieu thrombogène atrial, défini par la présence d’un thrombus atrial gauche ou dans l’auricule gauche, d’un contraste échocardiographique spontané, et de faibles vitesses de remplissage et de vidange auriculaire gauche, a été décrit en échocardiographie transœsophagienne, mais cet examen semi-invasif est surtout réalisé chez les patients en FA ou au décours d’un AVC de cause indéterminée. L’IRM cardiaque est un outil validé pour l’évaluation de la morphologie et des volumes de l’oreillette gauche et constitue la méthode de référence pour évaluer l’étendue de la fibrose atriale (rehaussement tardif), prédicteur indépendant de la FA, de la dysfonction atriale et des événements cérébrovasculaires. La tomodensitométrie cardiaque permet de mesurer les volumes de l’oreillette gauche, d’analyser l’anatomie et la taille de l’auricule gauche, y compris la présence d’un thrombus, et constitue l’examen de référence pour la caractérisation morphologique de l’auricule gauche. Les biomarqueurs circulants (NT-proBNP, BNP, troponines) peuvent refléter une inflammation et une fibrose atriales. L’objectif thérapeutique principal doit être la prévention ou l’inversion du remodelage atrial délétère, basé d’abord sur le contrôle des facteurs de risque sous-jacents, incluant l’hypertension artérielle, le diabète, l’obésité et leurs conséquences. Plusieurs classes médicamenteuses peuvent constituer des thérapies « d’amont » (upstream), en raison de leurs propriétés anti-fibrosantes et anti-inflammatoires, tels les inhibiteurs du système rénine–angiotensine–aldostérone, les inhibiteurs du SGLT2 et les agonistes des récepteurs du GLP-1, et d’autres molécules dont l’évaluation est en cours.

BACKGROUND:Transcriptional dysregulation, possibly affected by genetic variation, contributes to disease development. Due to dissimilarities in development, function, and remodeling during disease progression, transcriptional differences between the left atrial (LA) and right atrial (RA) may provide insight into diseases such as atrial fibrillation. METHODS:Lateral differences in atrial transcription were evaluated in CATCH ME (Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly) using a 2-stage discovery and replication design. The design took advantage of the availability of 32 paired samples, for which both LA and RA tissue were obtained, as a discovery cohort, and 98 LA and 69 RA unpaired samples utilized as a replication cohort. RESULTS:A total of 714 transcripts were identified and replicated as differentially expressed (DE) between LA and RA, as well as 98 exons in 55 genes. Approximately 50% of DE transcripts were colocated with another frequently correlated DE transcript (PFDR ≤0.05 for 579 regions). These transcription disequilibrium blocks contained examples including side-specific differential exon usage, such as the PITX2 locus, where ENPEP showed evidence of differential exon usage. Analysis of this region in conjunction with BMP10 identified rs9790621 as associated with ENPEP transcription in LA, while rs7687878 was associated with BMP10 expression in RA. In RA, BMP10 and ENPEP were strongly correlated in noncarriers, which was attenuated in risk-allele carriers, where BMP10 and PITX2 expression were strongly correlated. CONCLUSIONS:These results significantly expand knowledge of the intricate, tissue-specific transcriptional landscape in human atria, including DE transcripts and side-specific isoform expression. Furthermore, they suggest the existence of blocks of transcription disequilibrium influenced by genetics.

Arrhythmias and heart failure (HF) are common causes of morbidity and premature death worldwide, and patients who present with both conditions have particularly poor outcomes. Arrhythmia-induced cardiomyopathy (AIC) is a condition in which arrhythmias, often atrial fibrillation (AF), but also frequent atrial or ventricular ectopic beats, cause or aggravate HF. The hallmark of this condition is partial or complete reversibility of left ventricular systolic dysfunction after restoration of normal sinus rhythm. Differentiation between HF that causes arrhythmias and arrhythmias that cause HF remains challenging, leads to the underuse of rhythm-control therapy and, consequently, to the under-diagnosis of AIC. In this Review, we describe the various pathophysiological mechanisms of AIC, with a focus on AF as the underlying arrhythmia. We then discuss the epidemiology, clinical presentation and assessment of patients with AIC, with consideration of the complex interactions between AF and left ventricular dysfunction. We also present the therapeutic approach taken in patients presenting with suspected AIC, including restoration of sinus rhythm to unmask a diagnosis of AIC and treatment of HF. We conclude with a discussion of priorities for future research and the observation that there is an urgent need for objective, easily quantifiable parameters to identify patients with AIC. Arrhythmia-induced cardiomyopathy (AIC) refers to heart failure caused or exacerbated by arrhythmias, which resolves completely after restoration of sinus rhythm. In this Review, Fabritz and colleagues focus on atrial fibrillation as the cause of AIC, describing its pathophysiology, epidemiology and clinical presentation, and the various approaches to the diagnostic–therapeutic strategy of rhythm restoration.

Aims: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. Methods and results:Natriuretic peptides as well as sacubitril were delivered via osmotic mini-pumps to high-fat/streptozotocin-induced Type 2 diabetic (T2D) rats. Cardiac function was evaluated by echocardiography. Myocardial remodelling was studied by histological approaches, collagen phenotype, and atrial natriuretic peptide (ANP)/cGMP concentrations. Live-cell cGMP biosensing was conducted on cultured rat cardiac fibroblasts to investigate the biological effects of NP. Cyclic guanosine monophosphate signalling pathway was studied using multiple antibody arrays and biochemical assays in cardiac tissue and cultured fibroblasts. M-atrial natriuretic peptide exhibits superior efficacy than ANP in reducing left ventricular dysfunction and myocardial fibrosis with less extracellular matrix deposition. In vitro, MANP and ANP similarly generated cGMP and activated the protein kinase G (PKG) signalling pathway in cardiac fibroblasts, attenuating Mothers against decapentaplegic homolog 2 (SMAD) activation, collagen secretion, and cell proliferation. Nevertheless, in vivo, MANP specifically enhanced cardiac cGMP accumulation and was more potent than ANP in activating myocardial cGMP/PKG signalling and inhibiting the profibrotic SMAD, extracellular signal-regulated kinases 1/2, and nuclear factor of activated T cells 3 pathways. Endopeptidase inhibition using sacubitril also led to cardiac ANP/cGMP accumulation and reduced myocardial fibrosis. Conclusion:Myocardial bioavailability of ANP is a major determinant of peptide efficacy in reducing cardiac fibrosis and improving pump function during diabetic cardiomyopathy.

Background: The intercalated disc (ID) electromechanically couples adjacent cardiomyocytes. Alteration of this structure plays a central role in cardiac arrhythmias, notably arrhythmogenic cardiomyopathy (ACM), an inherited genetic disorder of desmosomes. Calcium/Calmodulin-Dependent Serine Protein Kinase (CASK), a costameric component of the lateral membrane, regulates cardiomyocyte protein trafficking. Here, we investigated CASK regulation of the organization of ID components in normal and pathological contexts. Here, we investigated CASK regulation of the organization of ID components in normal and pathological contexts. Methods: We studied the outcomes of CASK depletion in neonatal rat hearts using a cardiac-specific adeno-associated virus strategy. We used conventional and strain echocardiography, hemodynamics, electrocardiography, histology, and gene and protein expression studies to characterize adult rat hearts. We also studied the effects of CASK depletion in neonatal rat ventricular cardiomyocytes (NRVM), and control and ACM (PKP2+/-) IPS cell-derived CM (hIPS-CM) using proteomics, electron microscopy, high-resolution imaging, mechano-scanning ion conductance microscopy (mechano-SICM), and stress resistance tests. We studied cardiac CASK expression and localization in human ACM and non-transplantable control hearts. Results: Depletion of CASK in our multiple experimental models revealed that CASK regulates cardiomyocyte IDs. In rats, CASK depletion improved contractile reserve and compliance. In cultured rat cardiomyocytes, CASK knockdown increased localization of connexin 43 (Cx43) and PKP2 at IDs, resulting in increased contact stiffness. In PKP2+/- hIPS-CMs, CASK expression was increased. CASK depletion in these cells promoted PKP2 accumulation at cell contacts, formation of desmosome-like structures, and stress resistance. In the right ventricles of ACM patients, CASK protein level was also increased and CASK abnormally localized at the ID. Conclusion: CASK functions as a repressor of ID organization and tissue cohesion, suggesting novel mechanisms for regulating ID structure and function. These observations, along with CASK upregulation and mislocalization in ACM, open up new perspectives on understanding the pathophysiology of ACM and suggest innovative strategies for its treatment. ### Competing Interest Statement The authors have declared no competing interest.

AIMS:The concept of "atrial cardiomyopathy" (AtCM) had been percolating through the literature since its first mention in 1972. Since then, publications using the term were sporadic until the decision was made to convene an expert working group with representation from four multinational arrhythmia organizations to prepare a consensus document on atrial cardiomyopathy in 2016 (EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication). Subsequently, publications on AtCM have increased progressively. METHODS AND RESULTS:The present consensus document elaborates the 2016 AtCM document further to implement a simple AtCM staging system (AtCM stages 1-3) by integrating biomarkers, atrial geometry, and electrophysiological changes. However, the proposed AtCM staging needs clinical validation. Importantly, it is clearly stated that the presence of AtCM might serve as a substrate for the development of atrial fibrillation (AF) and AF may accelerates AtCM substantially, but AtCM per se needs to be viewed as a separate entity. CONCLUSION:Thus, the present document serves as a clinical consensus statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asian Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS) to contribute to the evolution of the AtCM concept.

BACKGROUND AND AIMS:In patients with atrial fibrillation (AF), recurrent AF and sinus rhythm during follow-up are determined by interactions between cardiovascular disease processes and rhythm control therapy. Predictors of attaining sinus rhythm at follow-up are not well known. METHODS:To quantify the interaction between cardiovascular disease processes and rhythm outcomes, 14 biomarkers reflecting AF-related cardiovascular disease processes in 1586 patients in the EAST-AFNET 4 biomolecule study (71 years old, 45% women) were quantified at baseline. Mixed logistic regression models including clinical features were constructed for each biomarker. Biomarkers were interrogated for interaction with early rhythm control. Outcome was sinus rhythm at 12 months. Results were validated at 24 months and in external datasets. RESULTS:Higher baseline concentrations of three biomarkers were independently associated with a lower chance of sinus rhythm at 12 months: angiopoietin 2 (ANGPT2) (odds ratio [OR] .76 [95% confidence interval .65-.89], P < .001), bone morphogenetic protein 10 (BMP10) (OR .83 [.71-.97], P = .017), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (OR .73 [.60-.88], P < .001). Analysis of rhythm at 24 months confirmed the results. Early rhythm control interacted with the predictive potential of NT-proBNP (Pinteraction = .033). The predictive effect of NT-proBNP was reduced in patients randomized to early rhythm control (usual care: OR .64 [.51-.80], P < .001; early rhythm control: OR .90 [.69-1.18], P = .453). External validation confirmed that low concentrations of ANGPT2, BMP10, and NT-proBNP predict sinus rhythm during follow-up. CONCLUSIONS:Low concentrations of ANGPT2, BMP10, and NT-proBNP identify patients with AF who are likely to attain sinus rhythm during follow-up. The predictive ability of NT-proBNP is attenuated in patients receiving rhythm control.

Aims Recent trial data demonstrate beneficial effects of active rhythm management in patients with atrial fibrillation (AF) and support the concept that a low arrhythmia burden is associated with a low risk of AF-related complications. The aim of this document is to summarize the key outcomes of the 9th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). Methods and results Eighty-three international experts met in Münster for 2 days in September 2023. Key findings are as follows: (i) Active rhythm management should be part of the default initial treatment for all suitable patients with AF. (ii) Patients with device-detected AF have a low burden of AF and a low risk of stroke. Anticoagulation prevents some strokes and also increases major but non-lethal bleeding. (iii) More research is needed to improve stroke risk prediction in patients with AF, especially in those with a low AF burden. Biomolecules, genetics, and imaging can support this. (iv) The presence of AF should trigger systematic workup and comprehensive treatment of concomitant cardiovascular conditions. (v) Machine learning algorithms have been used to improve detection or likely development of AF. Cooperation between clinicians and data scientists is needed to leverage the potential of data science applications for patients with AF. Conclusions Patients with AF and a low arrhythmia burden have a lower risk of stroke and other cardiovascular events than those with a high arrhythmia burden. Combining active rhythm control, anticoagulation, rate control, and therapy of concomitant cardiovascular conditions can improve the lives of patients with AF.

Atrial fibrillation (AF) causes progressive structural and electrical changes in the atria that can be summarized within the general concept of atrial remodeling. In parallel, other clinical characteristics and comorbidities may also affect atrial tissue properties and make the atria susceptible to AF initiation and its long-term persistence. Overall, pathological atrial changes lead to atrial cardiomyopathy with important implications for rhythm control. Although there is general agreement on the role of the atrial substrate for successful rhythm control in AF, the current classification oversimplifies clinical management. The classification uses temporal criteria and does not establish a well-defined strategy to characterize the individual-specific degree of atrial cardiomyopathy. Better characterization of atrial cardiomyopathy may improve the decision-making process on the most appropriate therapeutic option. We review current scientific evidence and propose a practical characterization of the atrial substrate based on 3 evaluation steps starting with a clinical evaluation (step 1), then assess outpatient complementary data (step 2), and finally include information from advanced diagnostic tools (step 3). The information from each of the steps or a combination thereof can be used to classify AF patients in 4 stages of atrial cardiomyopathy, which we also use to estimate the success on effective rhythm control.

La fibrillation auriculaire nécessite un substratum qui permet la formation de microcircuits de réentrée de l’influx électrique, les rotors, et des zones gâchette localisées principalement à l’abouchement des veines pulmonaires qui déclenche l’arythmie. Les mécanismes moléculaires et cellulaires qui aboutissent à ce complexe arythmogène sont maintenant connus réalisant une véritable cardiomyopathie atriale qui s’aggrave à chaque épisode d’arythmie et favorisée par de nombreux facteurs locaux et systémiques. Ainsi, la fibrillation auriculaire n’est pas une simple arythmie mais l’expression clinique d’une maladie complexe impliquant l’immunité, le métabolisme local et systémique et le génome, autant de facteurs qui devront être pris en compte pour une médecine de précision et personnalisée de la FA.

Atrial fibrillation (AF) causes progressive structural and electrical changes in the atria that can be summarized within the general concept of atrial remodeling. In parallel, other clinical characteristics and comorbidities may also affect atrial tissue properties and make the atria susceptible to AF initiation and its long-term persistence. Overall, pathological atrial changes lead to atrial cardiomyopathy with important implications for rhythm control. Although there is general agreement on the role of the atrial substrate for successful rhythm control in AF, the current classification oversimplifies clinical management. The classification uses temporal criteria and does not establish a well-defined strategy to characterize the individual-specific degree of atrial cardiomyopathy. Better characterization of atrial cardiomyopathy may improve the decision-making process on the most appropriate therapeutic option. We review current scientific evidence and propose a practical characterization of the atrial substrate based on 3 evaluation steps starting with a clinical evaluation (step 1), then assess outpatient complementary data (step 2), and finally include information from advanced diagnostic tools (step 3). The information from each of the steps or a combination thereof can be used to classify AF patients in 4 stages of atrial cardiomyopathy, which we also use to estimate the success on effective rhythm control.

Usually, the occurrence of the atrial fibrillation needs a substrate necessary for the formation of microcircuits of reentries of the electrical impulse together with targets most often arising from the junction between pulmonary veins and the atrial wall. Molecular and cellular basis of this arrhythmogenic scenario have been largely described and referred as to the atrial cardiomyopathy. The atrial cardiomyopathy gets worse with each episode of atrial fibrillation but also with hypertension, ageing, heart failure, metabolic disorders such as obesity and diabetes. Indeed, atrial fibrillation is no more considered as just a cardiac arrhythmia due to local electrical disturbances but as the clinical expression of a complex disease also involving metabolism, immunity, genotypes, ageing. Precision and personalized medicine of atrial fibrillation must take into count all these pathogenic factors. (c) 2024 l' Acad & eacute;mie nationale de m & eacute;decine. Published by Elsevier Masson SAS. All rights reserved.

Introduction COVID-19 combines in its severe forms pneumonia, damage to many organs, including the cardiovascular system, with major inflammation. As most cardiovascular cells express the SARS-CoV-2 receptor ACE2, cell damage from direct viral infection could also be involved. However, most experimental studies have been carried out in mouse models expressing hACE2 only in epithelial cells. Virus binding to ACE2 could affect vascular cell functions directly or by decreasing ACE2 levels and activity thereby increasing angiotensin 2 levels. Objective We aimed to characterize the cardiovascular alterations during SARS-CoV-2 infection in a hACE2 transgenic mouse model and to decipher the relative role of inflammation and direct cardiovascular cell infection. Method We used transgenic mice expressing epithelial hACE2 (K18 promoter) and mice with hACE2 replacing mouse ACE2 gene (hACE2-KI). K18-hACE2 and hACE2-KI mice were infected with different doses of SARS-CoV-2 and studied at 5 or 21 days. Lung tissues were examined for SARS-CoV-2 presence and pulmonary vessel remodeling by immunofluorescence. Effects of Spike protein administration on pulmonary arterial pressure were studied. Results K18-hACE2 showed high sensitivity to SARS-CoV-2 infection with rapid weakening and death at low virus doses, whereas hACE2-KI mice only showed minor effects. Human ACE2 expression analysis in K18-hACE2 showed expression only in alveolar epithelial cells. In hACE2-KI mice, hACE2 was highly expressed in epithelial alveolar cells and vascular smooth muscle cells. 21 days after infection of hACE2-KI mice, a significant neomuscularization of pulmonary vessels was observed whereas it was not significant in the lungs of surviving infected K18-hACE2 mice. This remodeling in hACE2-KI mice was inhibited by losartan, a blocker of angiotensin 2 receptors. Surprisingly, pulmonary angiotensin 2 levels were highly decreased from day 1 to day 7 post-infection confirming observations in humans. Intranasal administration of Spike protein led to a rapid increase in right ventricular systolic pressure of hACE2-KI mice suggesting a vasoconstriction effect of the virus despite the decrease in Angiotensin 2 levels. Conclusion Our results suggest that pulmonary vascular remodeling after infection may be dependent on hACE2 vascular expression leading to vasoconstriction and not on inflammation.

Aims:The growing interest in epicardial adipose tissue (EAT) as a biomarker of atrial fibrillation is limited by the difficulties in isolating EAT from other paracardial adipose tissues. We tested the feasibility and value of measuring the pure EAT contained in the atrioventricular groove (GEAT) using cardiovascular magnetic resonance (CMR) imaging in patients with distinct metabolic disorders. Methods and results:CMR was performed on 100 patients from the MetaCardis cohort: obese (n = 18), metabolic syndrome (MSD) (n = 25), type-2 diabetes (T2D) (n = 42), and age- and gender-matched healthy controls (n = 15). GEAT volume measured from long-axis views was obtained in all patients with a strong correlation between GEAT and atrial EAT (r = 0.95; P < 0.0001). GEAT volume was higher in the three groups of patients with metabolic disorders and highest in the MSD group compared with controls. GEAT volume, as well as body mass and body fat, allowed obese, T2D, and MSD patients to be distinguished from controls. GEAT T1 relaxation and peak longitudinal left atrial (LA) strain in CMR were decreased in T2D patients. Logistic regression and random forest machine learning methods were used to create an algorithm combining GEAT volume, GEAT T1, and peak LA strain to identify T2D patients from other groups with an area under curve (AUC) of 0.81 (Se: 77%, Spe: 80%; 95% confidence interval 0.72-0.91, P < 0.0001). Conclusion:Atrioventricular groove adipose tissue characteristics measured during routine CMR can be used as a proxy of atrial EAT and integrated in a multi-parametric CMR biomarker for early identification of atrial cardiomyopathy.

Aims Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation (AF). PITX2 is restricted to left atrial cardiomyocytes (aCMs) in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy, and AF are not fully understood.Methods and results To identify mechanisms linking PITX2 deficiency to AF, we generated and characterized PITX2-deficient human aCMs derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganized sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared with isogenic controls. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with AF compared with 43 patients with sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria.Conclusion PITX2 deficiency causes atrial mitochondrial dysfunction and a metabolic shift to glycolysis in human aCMs. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria. Graphical Abstract Deficiency in PITX2, a gene with left atrial and skeletal muscle expression in adults leads to mitochondrial dysfunction. PITX2 deficiency is likely to underlie the genomic basis for atrial fibrillation (AF). Reduced PITX2 in atrial cardiomyocytes (aCMs) conveys electrical changes and structural alterations. The cellular mechanisms linking PITX2 deficiency to AF are not fully understood. PITX2 deficiency increases cellular and functional heterogeneity in human iPSC-derived aCMs. These experiments show that PITX2 alters mitochondrial function and metabolism by altering gene and protein expression in aCMs, creating a metabolic shift away from respiration towards glycolysis. Left atrial tissue from patients with AF shows similar changes in gene expression patterns of mitochondrial genes and their association with PITX2. Figure was generated using BioRender.com.