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AIMS: Different disease processes can combine to cause atrial fibrillation (AF). Their contribution to recurrent AF after ablation in patients is not known. Cardiovascular processes associated with recurrent AF after AF ablation were determined by quantifying biomolecules related to inflammation, metabolism, proliferation, fibrosis, shear stress, atrial pressure, and others in the AXAFA biomolecule study. METHODS AND RESULTS: Twelve circulating cardiovascular biomolecules (ANGPT2, BMP10, CA125, hsCRP, ESM1, FABP3, FGF23, GDF15, IGFBP7, IL6, NT-proBNP, and hsTnT) were quantified in plasma samples obtained prior to a first AF ablation using high-throughput, high-precision assays. Cox regression was used to identify biomolecules associated with recurrent AF during the first 3 months after AF ablation. In 433 patients (64 years [58, 70]; 33% women), baseline concentrations of ANGPT2, BMP10, hsCRP, FGF23, FABP3, GDF15, and NT-proBNP were elevated in patients with recurrent AF (120/433; 28%). After adjustment for 11 clinical features and randomized treatment, elevated NT-proBNP [hazard ratio (HR) 1.58, 95% confidence interval (1.29, 1.94)], ANGPT2 [HR 1.37, (1.12, 1.67)], and BMP10 [HR 1.24 (1.02, 1.51)] remained associated with recurrent AF. Concentrations of ANGPT2, BMP10, and NT-proBNP decreased in patients who remained arrhythmia free, but not in patients with recurrent AF, highlighting their connection to AF. The other eight biomarkers showed unchanged concentrations. CONCLUSION: Elevated concentrations of ANGPT2, BMP10, and NT-proBNP are associated with recurrent AF after a first AF ablation, suggesting that processes linked to disturbed cardiomyocyte metabolism, altered atrial shear stress, and increased load contribute to AF after AF ablation in patients.
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Fibrilação Atrial , Humanos , Feminino , Masculino , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Fibrilação Atrial/complicações , Proteína C-Reativa , Átrios do Coração , Peptídeo Natriurético Encefálico , Biomarcadores , Modelos de Riscos Proporcionais , Fragmentos de Peptídeos , Proteínas Morfogenéticas ÓsseasRESUMO
AIMS: Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4. METHODS AND RESULTS: We analysed the primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) and primary efficacy outcome (cardiovascular death, stroke, and hospitalization for worsening of heart failure (HF) or acute coronary syndrome) during SCB intake for patients with ERC (n = 1395) in EAST-AFNET 4. The protocol discouraged flecainide and propafenone in patients with reduced left ventricular ejection fraction and suggested stopping therapy upon QRS prolongation >25% on therapy. Flecainide or propafenone was given to 689 patients [age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with HF; 41 with prior myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention; 26 with left ventricular hypertrophy >15â mm; median therapy duration 1153 [237, 1828] days]. The primary efficacy outcome occurred less often in patients treated with SCB [3/100 (99/3316) patient-years] than in patients who never received SCB [SCBnever 4.9/100 (150/3083) patient-years, P < 0.001]. There were numerically fewer primary safety outcomes in patients receiving SCB [2.9/100 (96/3359) patient-years] than in SCBnever patients [4.2/100 (135/3220) patient-years, adjusted P = 0.015]. Sinus rhythm at 2 years was similar between groups [SCB 537/610 (88); SCBnever 472/579 (82)]. CONCLUSION: Long-term therapy with flecainide or propafenone appeared to be safe in the EAST-AFNET 4 trial to deliver effective ERC therapy, including in selected patients with stable cardiovascular disease such as coronary artery disease and stable HF. Clinical Trial Registration ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.
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Antiarrítmicos , Flecainida , Bloqueadores dos Canais de Sódio , Humanos , Idoso , Masculino , Feminino , Resultado do Tratamento , Pessoa de Meia-Idade , Flecainida/uso terapêutico , Flecainida/efeitos adversos , Antiarrítmicos/uso terapêutico , Antiarrítmicos/efeitos adversos , Bloqueadores dos Canais de Sódio/uso terapêutico , Bloqueadores dos Canais de Sódio/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Fatores de Tempo , Frequência Cardíaca/efeitos dos fármacos , Acidente Vascular CerebralRESUMO
Developed in partnership with the European Heart Rhythm Association (EHRA), (a registered branch of the European Society of Cardiology (ESC)) the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin America Heart Rhythm Society (LAHRS).
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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.
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Fibrilação Atrial , Acidente Vascular Cerebral , Humanos , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Risco , Hemorragia , Anticoagulantes/uso terapêuticoAssuntos
Anticoagulantes , Fibrilação Atrial , Humanos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Feminino , Masculino , Administração Oral , Fatores Etários , Idoso , Fatores Sexuais , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/epidemiologia , Comorbidade , Resultado do Tratamento , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/epidemiologiaRESUMO
OBJECTIVE: Repetitive atrial activation patterns (RAAPs) during complex atrial tachycardia could be associated with localized mechanisms that can be targeted. Clinically available electroanatomical mapping systems are limited by either the spatial coverage or electrode density of the mapping catheters, preventing the adequate visualization of transiently occurring RAAPs. This work proposes a technique to overcome this shortcoming by stitching spatially overlapping conduction patterns together to a larger image- called a composite map. METHODS: Simulated stable mechanisms and meandering reentries are sequentially mapped (4x4 grid, 3mm spacing) and then reconstructed back to the original sizes with the proposed recurrence plot-based algorithm. RESULTS: The reconstruction of single linear waves presents minimal errors (local activation time (LAT) difference: 3.2 [1.6-4.9] ms, conduction direction difference: 5.2 [2.3-8.0] degrees). Errors significantly increase (p<0.05) for more complex patterns, being the highest with unstable reentries (LAT difference: 10.3 [3.5-16.2] ms, conduction direction difference: 18.2 [6.7-29.7] deg). In a second part of the analysis, 111 meandering reentries are reconstructed. Mapping 30 locations overlappingly around each reentry core was found to be the optimal mapping strategy. For this optimal setting, LAT, conduction direction, and core localization errors are low (6.1 [4.2-8.6] ms, 11.2 [8.6-15.5] deg and 4.1 [2.9-4.9] mm, respectively) and are weakly correlated with the degree of the meander ( ρ=0.41, ρ=0.40 and ρ=0.20, respectively). CONCLUSION: Our findings underline the feasibility of generating composite maps by stitching spatially overlapping recordings. SIGNIFICANCE: Composite maps can be instrumental in personalized ablation strategies.
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BACKGROUND: Postoperative atrial fibrillation (POAF) is a frequent complication after cardiac surgery that is associated with late atrial fibrillation (AF) recurrences (late-POAF) and increased morbidity and long-term mortality. OBJECTIVES: This study sought to determine device-detected POAF incidence and to identify clinical variables associated with POAF, both in patients with and without preoperative AF history. METHODS: A total of 133 consecutive patients undergoing cardiac surgery were prospectively enrolled and continuously monitored with an implantable loop recorder for 2.5 years after surgery. Preoperative transthoracic echocardiography, 12-lead electrocardiogram, blood biomarkers, and clinical data were analyzed to develop prediction models for early- and late-POAF. RESULTS: In patients without preoperative AF history, early-POAF within the first 90 postoperative days occurred in 41 (47.1%) of 87 patients. Late-POAF after the first 90 postoperative days occurred in 22 (25%) of 87 patients, and 20 of these patients also had early-POAF during the first 90 days (20 of 22 [91%]). Increased right atrial minimum volume indexed for body surface area (RAVImin) and early-POAF were independently associated with late-POAF. A prediction model for late-POAF, which included RAVImin >11 mL/m2, age >65 years, and early-POAF, achieved an area under the curve of 0.82 (95% CI: 0.72-0.92). For patients with preoperative AF-history, late-POAF recurrences were frequent (22 of 33 [67%]). Increased RAVImin was independently associated with a higher incidence of late-POAF. CONCLUSIONS: In patients with and without AF history, late-POAF recurrences are frequent, including in patients undergoing surgical AF ablation. In patients with no history of AF, late-POAF might be predicted with excellent accuracy by using a combination of preoperative variables. In patients with a history of AF, signs of advanced AF substrate (eg, increased right atrial volumes) were associated with long-term AF recurrences. [Reappraisal of Atrial Fibrillation: Interaction Between Hypercoagulability, Electrical Remodeling, and Vascular Destabilisation in the Progression of AF; NCT03124576].
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Fibrilação Atrial , Procedimentos Cirúrgicos Cardíacos , Complicações Pós-Operatórias , Humanos , Fibrilação Atrial/epidemiologia , Masculino , Feminino , Idoso , Estudos Prospectivos , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Ecocardiografia , Fatores de Risco , Incidência , Eletrocardiografia , RecidivaRESUMO
BACKGROUND: We aimed to evaluate the association between atrial fibrillation (AF) burden, duration and number of episodes with healthcare utilisation and quality of life in patients with early paroxysmal AF without a history of AF. METHODS: In this observational cohort study, we included 417 patients with paroxysmal AF from the Reappraisal of Atrial Fibrillation: interaction between hyperCoagulability, Electrical remodelling and Vascular destabilisation in the progression of AF (RACE V) Study. Patients were monitored with an insertable cardiac monitor for 1 year. Outcomes collected were healthcare utilisation, and quality of life assessed using the Atrial Fibrillation Severity Scale and EuroQol EQ-5D-5L questionnaires. RESULTS: During 1 year of follow-up, 63 973 AF episodes were detected in 353 (85%) patients. The median AF burden was 0.7% (IQR 0.1-4.0%). AF ablation was performed more frequently in patients with intermediate-to-high AF burdens (>0.2%) (16.2% vs 5.9%, p=0.01) and longer AF episode duration (>1 hour) (15.8% vs 2.0%, p=0.01), whereas cardioversions were more frequent in patients with longer episode duration (>1 hour) (9.5% vs 0%, p=0.04) and intermediate (0.2-1.9%) (but not high) AF burdens (13.6% vs 4.2%, p=0.01). Patients with many episodes (>147) reported higher symptom severity (p=0.001). No differences in symptom severity nor in EQ-5D-5L scores according to AF burden or duration were observed. CONCLUSION: In patients with early paroxysmal AF, higher AF burden and longer episode duration were associated with increased rates of healthcare utilisation but not with symptoms and quality of life. Patients with a higher number of episodes experienced more severe symptoms. TRIAL REGISTRATION NUMBER: NCT02726698.
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Fibrilação Atrial , Qualidade de Vida , Humanos , Fibrilação Atrial/terapia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Fatores de Tempo , Ablação por Cateter/estatística & dados numéricos , Índice de Gravidade de Doença , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Cardioversão Elétrica/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Early postoperative AF (POAF) is common after cardiac surgery and is associated with late-POAF recurrences. However, little is known about the burden of POAF, and its potential impact on long-term outcomes after cardiac surgery, particularly on the risk for late-POAF recurrences. OBJECTIVE: To establish the distribution of POAF burden and to determine the association between early-POAF burden and late-POAF recurrences during 2.5 years of continuous rhythm monitoring after cardiac surgery in patients with and without preoperative history of AF. METHODS: Patients undergoing cardiac surgery were prospectively enrolled and postoperatively continuously monitored with an implantable loop recorder (ILR) for 2.5 years. All patients underwent extensive clinical assessment at baseline. During the follow-up all AF episodes were registered, and AF-associated metrics, such as burden, were calculated for different time intervals. Early-POAF was defined as AF within first 90 postoperative days and late-POAF as AF after this interval. RESULTS: A total of 98 consecutive patients were included. POAF burden during the early postoperative phase was significantly higher as compared to the late postoperative phase (p<0.001). The longest individual POAF episode was strongly associated with increased POAF burden after adjusting for age, sex, and AF-history (standardized Beta: 0.91, p<0.001). Also, early-POAF burden was associated with late-POAF (re)occurrence after adjusting for age, sex, AF-history (adjusted Hazard Ratio=1.93, 95%CI: 1.42-2.62, p<0.001). CONCLUSION: POAF burden was significantly associated with the longest individual POAF episode duration. Additionally, greater early-POAF burden was associated with increased late-POAF incidence, highlighting its potential in estimating the risk for long-term POAF recurrences.
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BACKGROUND: Dark-blood late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) has better correlation with bipolar voltage (BiV) to define ablation scar in the left atrium (LA) compared to conventional bright-blood LGE CMR. OBJECTIVES: This study sought to determine the optimal signal intensity threshold of dark-blood LGE CMR to identify LA ablation scar. METHODS: In 54 patients scheduled for atrial fibrillation ablation, image intensity ratios (IIRs) were derived from preprocedural dark-blood LGE CMR. In 26 patients without previous ablation, the upper limit of normal was derived from the 95th and 98th percentiles of pooled IIR values. In 28 patients with previous atrial fibrillation ablation, BiV was compared with the corresponding IIR. Receiver-operating characteristics analyses were employed to determine the optimal IIR threshold (ie, the point with the smallest distance to the upper left corner of the receiver-operating characteristics) for LA ablation scar (BiV ≤0.15 mV). RESULTS: Upper limit of normal corresponded to IIR values 1.16 and 1.21, yielding low sensitivities of 0.32 and 0.09 to detect LA ablation scar. Receiver-operating characteristics analysis of IIR and BiV comparison achieved a median area under the curve of 0.77. Median optimal IIR threshold for LA ablation scar was 1.09, with an average sensitivity of 0.73, specificity of 0.75, and accuracy of 0.71. Median IIR thresholds of 1.00 and 1.10 corresponded to 80% sensitivity and 80% specificity, respectively. There was considerable interpatient variability: optimal IIR thresholds per patient ranged from 1.01 to 1.22. CONCLUSIONS: The optimal IIR threshold to identify LA ablation scar by dark-blood LGE CMR is 1.09. Because of interpatient variability, the investigators recommend using a lower (1.00) and upper (1.10) threshold to prevent over- or underestimation of ablation scar.
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BACKGROUND: Serum bone morphogenetic protein 10 (BMP10) blood levels are a marker for history of atrial fibrillation (AF) and for major adverse cardiovascular events in patients with AF, including stroke, AF recurrences after catheter ablations, and mortality. The predictive value of BMP10 in patients undergoing cardiac surgery and association with morphologic properties of atrial tissues are unknown. OBJECTIVES: This study sought to study the correlation between BMP10 levels and preoperative clinical traits, occurrence of early and late postoperative atrial fibrillation (POAF), and atrial fibrosis in patients undergoing cardiac surgery. METHODS: Patients with and without preoperative AF history undergoing first cardiac surgery were included (RACE V, n = 147). Preoperative blood biomarkers were analyzed, left (n = 114) and right (n = 125) atrial appendage biopsy specimens were histologically investigated after WGA staining, and postoperative rhythm was monitored continuously with implantable loop recorders (n = 133, 2.5 years). RESULTS: Adjusted multinomial logistic regression indicated that BMP10 accurately reflected a history of persistent AF (OR: 1.24, 95% CI: 1.10-1.40, P = 0.001), similar to NT-pro-BNP. BMP10 levels were associated with increased late POAF90 occurrence after adjustment for age, sex, AF history, and early POAF occurrence (HR: 1.07 [per 0.1 ng/mL increase], 95% CI: 1.00-1.14, P = 0.041). Left atrial endomysial fibrosis (standardized ß = 0.22, P = 0.041) but not overall fibrosis (standardized Β = 0.12, P = 0.261) correlated with circulating BMP10 after adjustment for age, sex, AF history, reduced LVF, and valvular surgery indication. CONCLUSIONS: Increased BMP10 levels were associated with persistent AF history, increased late POAF incidence, and LAA endomysial fibrosis in a diverse sample of patients undergoing cardiac surgery.
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Fibrilação Atrial , Procedimentos Cirúrgicos Cardíacos , Complicações Pós-Operatórias , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Apêndice Atrial/cirurgia , Fibrilação Atrial/sangue , Fibrilação Atrial/epidemiologia , Biomarcadores/sangue , Proteínas Morfogenéticas Ósseas , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Fibrose , Átrios do Coração/patologia , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/epidemiologiaRESUMO
Introduction: The mechanisms leading to the conversion of atrial fibrillation (AF) to sinus rhythm are poorly understood. This study describes the dynamic behavior of electrophysiological parameters and conduction patterns leading to spontaneous and pharmacological AF termination. Methods: Five independent groups of goats were investigated: (1) spontaneous termination of AF, and drug-induced terminations of AF by various potassium channel inhibitors: (2) AP14145, (3) PA-6, (4) XAF-1407, and (5) vernakalant. Bi-atrial contact mapping was performed during an open chest surgery and intervals with continuous and discrete atrial activity were determined. AF cycle length (AFCL), conduction velocity and path length were calculated for each interval, and the final conduction pattern preceding AF termination was evaluated. Results: AF termination was preceded by a sudden episode of discrete activity both in the presence and absence of an antiarrhythmic drug. This episode was accompanied by substantial increases in AFCL and conduction velocity, resulting in prolongation of path length. In 77% ± 4% of all terminations the conduction pattern preceding AF termination involved medial to lateral conduction along Bachmann's bundle into both atria, followed by anterior to posterior conduction. This finding suggests conduction block in the interatrial septum and/or pulmonary vein area as final step of AF termination. Conclusion: AF termination is preceded by an increased organization of fibrillatory conduction. The termination itself is a sudden process with a critical role for the interplay between spatiotemporal organization and anatomical structure.
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Endolysosomes (EL) are known for their role in regulating both intracellular trafficking and proteostasis. EL facilitate the elimination of damaged membranes, protein aggregates, membranous organelles and play an important role in calcium signaling. The specific role of EL in cardiac atrial fibrillation (AF) is not well understood. We isolated atrial EL organelles from AF goat biopsies and conducted a comprehensive integrated omics analysis to study the EL-specific proteins and pathways. We also performed electron tomography, protein and enzyme assays on these biopsies. Our results revealed the upregulation of the AMPK pathway and the expression of EL-specific proteins that were not found in whole tissue lysates, including GAA, DYNLRB1, CLTB, SIRT3, CCT2, and muscle-specific HSPB2. We also observed structural anomalies, such as autophagic-vacuole formation, irregularly shaped mitochondria, and glycogen deposition. Our results provide molecular information suggesting EL play a role in AF disease process over extended time frames.
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AIMS: Atrial fibrillation (AF) and concomitant cardiometabolic disease processes interact and combine to lead to adverse events, such as stroke, heart failure, myocardial infarction, and cardiovascular death. Circulating biomolecules provide quantifiable proxies for cardiometabolic disease processes. The aim of this study was to test whether biomolecule combinations can define phenotypes in patients with AF. METHODS AND RESULTS: This pre-specified analysis of the EAST-AFNET 4 biomolecule study assigned patients to clusters using polytomous variable latent-class analysis based on baseline concentrations of 13 precisely quantified biomolecules potentially reflecting ageing, cardiac fibrosis, metabolic dysfunction, oxidative stress, cardiac load, endothelial dysfunction, and inflammation. In each cluster, rates of cardiovascular death, stroke, or hospitalization for heart failure or acute coronary syndrome, the primary outcome of EAST-AFNET 4, were calculated and compared between clusters over median 5.1 years follow-up. Findings were independently validated in a prospective cohort of 748 patients with AF (BBC-AF; median follow-up 2.9 years).Unsupervised biomolecule analysis assigned 1586 patients (71 years old, 46% women) into four clusters. The highest risk cluster was dominated by elevated bone morphogenetic protein 10, insulin-like growth factor-binding protein 7, N-terminal pro-B-type natriuretic peptide, angiopoietin 2, and growth differentiation factor 15. Patients in the lowest risk cluster showed low concentrations of these biomolecules. Two intermediate-risk clusters differed by high or low concentrations of C-reactive protein, interleukin-6, and D-dimer. Patients in the highest risk cluster had a five-fold higher cardiovascular event rate than patients in the low-risk cluster. Early rhythm control was effective across clusters (Pinteraction = 0.63). Sensitivity analyses and external validation in BBC-AF replicated clusters and risk gradients. CONCLUSION: Biomolecule concentrations identify cardiometabolic subphenotypes in patients with AF at high and low cardiovascular risk.
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Fibrilação Atrial , Biomarcadores , Fatores de Risco Cardiometabólico , Fenótipo , Humanos , Feminino , Masculino , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/sangue , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/epidemiologia , Idoso , Biomarcadores/sangue , Medição de Risco , Pessoa de Meia-Idade , Estudos Prospectivos , Valor Preditivo dos Testes , Prognóstico , Fatores de Tempo , Idoso de 80 Anos ou mais , Europa (Continente)/epidemiologiaRESUMO
AIM: Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation. PITX2 is restricted to left atrial cardiomyocytes in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy and atrial fibrillation are not fully understood. METHODS AND RESULTS: To identify mechanisms linking PITX2 deficiency to atrial fibrillation, we generated and characterized PITX2-deficient human atrial cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganised sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared to the control. 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 atrial fibrillation compared to 43 patients in sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. CONCLUSIONS: In summary, PITX2 deficiency causes mitochondrial dysfunction and a metabolic shift to glycolysis in human atrial cardiomyocytes. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.
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BACKGROUND: Sex differences in atrial fibrillation (AF) are observed in terms of comorbidities, symptoms, therapies received, AF progression and cardiovascular complications. METHODS: We assessed the differences in prevalence and the determinants of AF progression, as well as the clinical characteristics and quality of life (QoL), between women and men with paroxysmal AF included in the RACE V (Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF) study. At baseline, extensive phenotyping was done. To assess AF progression, implantable loop recorder (ILR) monitoring was used throughout follow-up. AF progression was defined as (1) progression to persistent or permanent AF or (2) progression of paroxysmal AF (>3% burden increase). RESULTS: 417 patients were included, 179 (43%) of whom were women. Women were older (median 67 years vs 63 years, p<0.001), less often had coronary artery disease (n=11 (6%) vs n=36 (16%), p=0.003), had more obesity (n=57 (32%) vs n=50 (21%), p=0.013), had less epicardial and pericardial fat (median 144 (interquartile range [IQR] 94-191) mL vs 199 (IQR 146-248) mL, p<0.001; and median 89 (ICQ 61-121) mL vs 105 (IQR 83-133) mL, p<0.001, respectively) and had more impaired left atrial function. The median follow-up was 2.2 (1.6-2.8) years. 51 of 417 patients (5.5% per year) showed AF progression (15/179 (8.4%) women and 36/238 (15.1%) men, p=0.032). Multivariable analysis showed tissue factor pathway inhibitor, N-terminal prohormone brain natriuretic peptide (NT-proBNP) and PR interval being associated with AF progression in women and factor XIIa:C1 esterase, NT-proBNP and proprotein convertase subtilisin/kexin type 9 in men. QoL was not different between sexes. CONCLUSION: Despite older age, the incidence of AF progression was lower in women. Parameters associated with AF progression varied in part between sexes, suggesting different underlying pathophysiological mechanisms.
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Fibrilação Atrial , Humanos , Masculino , Feminino , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/complicações , Qualidade de VidaRESUMO
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