Incidence and progression of atrial fibrillation in patients with and without heart failure using mineralocorticoid receptor antagonists: a meta-analysis.

BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) have emerged as potential therapy to target the underlying arrhythmogenic substrate in atrial fibrillation (AF). Nevertheless, there have been inconsistent results on the impact of MRAs on AF. OBJECTIVE: We sought to evaluate the effect of MRAs on AF incidence and progression in patients with and without heart failure. METHODS: Electronic databases were searched up to September, 2022 for randomized controlled trials (RCTs) that evaluated MRA use and reported AF outcomes. Primary outcome was a composite of new-onset or recurrent AF. Safety outcomes included hyperkalemia and gynecomastia risks. A random-effects meta-analysis estimated pooled odds ratios (OR) and 95% confidence intervals (CI). RESULTS: 12 RCTs, comprising 11,419 patients treated with various MRAs were included [5960 (52%) on MRA]. On follow-up (6-39 months), 714 (5.5%) patients developed AF. MRA therapy was associated with a 32% reduction in the risk of new-onset or recurrent AF [OR 0.68 (95% CI 0.51-0.92), I2 = 40%]. On subgroup analysis, the greatest benefit magnitude was demonstrated in reducing AF recurrence [OR 0.50 (95% CI 0.30-0.83)] and among patients with left ventricular dysfunction [OR 0.59 (95% CI 0.40-0.85)]. Gynecomastia, but not hyperkalemia, was associated with MRA use. Meta-regression analysis demonstrated that therapy duration was a significant interaction factor driving the effect size (Pinteraction = 0.013). CONCLUSION: MRA use is associated with a reduction in AF risk, especially AF progression. A prominent effect is seen in patients with heart failure, further augmented by therapy duration. Prospective trials are warranted to evaluate MRA use as upstream therapy for preventing this common arrhythmia.

Intermedin 1-53 Ameliorates Atrial Fibrosis and Reduces Inducibility of Atrial Fibrillation via TGF-ß1/pSmad3 and Nox4 Pathway in a Rat Model of Heart Failure.

OBJECTIVE: New drugs to block the occurrence of atrial fibrillation (AF) based on atrial structural remodeling (ASR) are urgently needed. The purpose of this study was to study the role of intermedin 1-53 (IMD1-53) in ASR and AF formation in rats after myocardial infarction (MI). MATERIAL AND METHODS: Heart failure was induced by MI in rats. Fourteen days after MI surgery, rats with heart failure were randomized into control (untreated MI group, n = 10) and IMD-treated (n = 10) groups. The MI group and sham group received saline injections. The rats in the IMD group received IMD1-53, 10 nmol/kg/day intraperitoneally for 4 weeks. The AF inducibility and atrial effective refractory period (AERP) were assessed with an electrophysiology test. Additionally, the left-atrial diameter was determined, and heart function and hemodynamic tests were performed. We detected the area changes of myocardial fibrosis in the left atrium using Masson staining. To detect the protein expression and mRNA expression of transforming growth factor-ß1 (TGF-ß1), α-SMA, collagen Ⅰ, collagen III, and NADPH oxidase (Nox4) in the myocardial fibroblasts and left atrium, we used the Western blot method and real-time quantitative polymerase chain reaction (PCR) assays. RESULTS: Compared with the MI group, IMD1-53 treatment decreased the left-atrial diameter and improved cardiac function, while it also improved the left-ventricle end-diastolic pressure (LVEDP). IMD1-53 treatment attenuated AERP prolongation and reduced atrial fibrillation inducibility in the IMD group. In vivo, IMD1-53 reduced the left-atrial fibrosis content in the heart after MI surgery and inhibited the mRNA and protein expression of collagen type Ⅰ and III. IMD1-53 also inhibited the expression of TGF-ß1, α-SMA, and Nox4 both in mRNA and protein. In vivo, we found that IMD1-53 inhibited the phosphorylation of Smad3. In vitro, we found that the downregulated expression of Nox4 was partly dependent on the TGF-ß1/ALK5 pathway. CONCLUSIONS: IMD1-53 decreased the duration and inducibility of AF and atrial fibrosis in the rats after MI operation. The possible mechanisms are related to the inhibition of TGF-ß1/Smad3-related fibrosis and TGF-ß1/Nox4 activity. Therefore, IMD1-53 may be a promising upstream treatment drug to prevent AF.

Análisis del tratamiento para mantener el ritmo sinusal en pacientes con fibrilación auricular prescrito en los servicios de urgencias: subanálisis del estudio HERMES-AF / Emergency department prescription of sinus rhythm maintenance therapy for patients treated for atrial fibrillation: a secondary analysis of the HERMES-AF study

Objetivo. El mantenimiento del ritmo sinusal (RS) con fármacos antiarrítmicos (FAA) y/o tratamiento del remodelado (TRM) es parte fundamental en la estrategia de control del ritmo en la fibrilación auricular (FA). Este estudio analiza estas estrategias y su adecuación en los servicios de urgencias hospitalarios (SUH). Método. Análisis secundario del estudio multicéntrico observacional transversal HERMES-AF, desarrollado en 124 SUH representativos del sistema sanitario español en 2011. Se incluyeron pacientes consecutivos con FA que revirtieron a RS y fueron dados de alta desde urgencias. Resultados. Se incluyeron 449 pacientes: 204 (45,4%) ya realizaban tratamiento para mantenimiento del RS. De los 245 restantes se prescribió tratamiento en el SUH a 107 (43,7%): 41 con FAA, 19 TRM y en 47 ambas terapias. En 10 casos (11,8%) la selección del FAA no era acorde a las recomendaciones de las guías. La prescripción de FAA se asoció a FA previa [odds ratio (OR) 2,024, IC 95%: 1,196-3,424, p = 0,009], frecuencia cardiaca > 110 lpm (OR 2,147, IC 95%: 1,034-4,456, p = 0,040) y anticoagulación al alta (OR 1,862, IC 95%: 1,094-3,170, p = 0,022). El TRM se asoció a frecuencia cardiaca > 110 lpm (OR 2,187, IC 95%: 1,005-4,757, p = 0,018). En total, al alta del SUH 311 pacientes (69,2%) recibían tratamiento para mantenimiento del RS (87 con FAA, 117 con TRM y 107 con ambas terapias). Conclusiones. La prescripción de tratamiento para evitar las recurrencias de la FA es insuficiente en los SUH. Extender esta prescripción y mejorar la adecuación del tratamiento antiarrítmico son áreas de mejora de la estrategia de control del ritmo en los SUH.

Background and objective. The maintenance of sinus rhythm by means of antiarrhythmic drugs and/or upstream therapy to counter cardiac remodeling is fundamental to the management of atrial fibrillation (AF). This study aimed to analyze this approach and its appropriateness in the setting of hospital emergency departments. Methods. Secondary analysis of data from the multicenter observational cross-sectional HERMES-AF study carried out in 124 hospitals representative of the Spanish national health service in 2011. Included were consecutive patients with AF restored to sinus rhythm who were discharged home from emergency care. Results. A total of 449 patients were included; 204 (45.4%) were already on sinus rhythm maintenance therapy. Of the 245 remaining patients, 107 (43.67%) were prescribed maintenance treatment in the emergency department, as follows: 41, an antiarrhythmic drug; 19, upstream therapy; and 49, both treatments. The selection of an antiarrhythmic drug did not follow guideline recommendations in 10 patients (11.8%). Antiarrhythmic drug prescription was associated with having had a prior episode of AF (odds ratio [OR], 2.024; 95% CI, 1.196-3.424; P = .009); a heart rate of more than 110 beats/min (OR, 2.147; 95% CI, 1.034-4.456, P = 0.40); and prescription of anticoagulation on discharge (OR, 1.862; 95% CI, 1.094-3.170; P = .022). Upstream therapy prescription was associated only with a heart rate over 110 beats/min (OR, 2.187; 95% CI, 1.005-4.757; P = .018). In total, 311 patients (69.23%) were discharged from the emergency department with sinus rhythm maintenance therapy: 87 with an antiarrhythmic drug, 117 with an upstream therapy, and 107 with both. Conclusions. Treatment to prevent the recurrence of AF is underprescribed in emergency departments. Increasing such prescription and ensuring the appropriateness of antiarrhythmic therapy prescribed are points emergency departments can improve in the interest of better sinus rhythm maintenance.

Emergency department prescription of sinus rhythm maintenance therapy for patients treated for atrial fibrillation: a secondary analysis of the HERMES-AF study / Análisis del tratamiento para mantener el ritmo sinusal en pacientes con fibrilación auricular prescrito en los servicios de urgencias: subanálisis del estudio HERMES-AF

OBJECTIVES: The maintenance of sinus rhythm by means of antiarrhythmic drugs and/or upstream therapy to counter cardiac remodeling is fundamental to the management of atrial fibrillation (AF). This study aimed to analyze this approach and its appropriateness in the setting of hospital emergency departments. MATERIAL AND METHODS: Secondary analysis of data from the multicenter observational cross-sectional HERMES-AF study carried out in 124 hospitals representative of the Spanish national health service in 2011. Included were consecutive patients with AF restored to sinus rhythm who were discharged home from emergency care. RESULTS: A total of 449 patients were included; 204 (45.4%) were already on sinus rhythm maintenance therapy. Of ,the 245 remaining patients, 107 (43.67%) were prescribed maintenance treatment in the emergency department, as follows: 41, an antiarrhythmic drug; 19, upstream therapy; and 49, both treatments. The selection of an antiarrhythmic drug did not follow guideline recommendations in 10 patients (11.8%). Antiarrhythmic drug prescription was associated with having had a prior episode of AF (odds ratio [OR], 2.024; 95% CI, 1.196-3.424; P = .009); a heart rate of more than 110 beats/min (OR, 2.147; 95% CI, 1.034-4.456, P = 0.40); and prescription of anticoagulation on discharge (OR, 1.862; 95% CI, 1.094-3.170; P = .022). Upstream therapy prescription was associated only with a heart rate over 110 beats/min (OR, 2.187; 95% CI, 1.005-4.757; P = .018). In total, 311 patients (69.23%) were discharged from the emergency department with sinus rhythm maintenance therapy: 87 with an antiarrhythmic drug, 117 with an upstream therapy, and 107 with both. CONCLUSION: Treatment to prevent the recurrence of AF is underprescribed in emergency departments. Increasing such prescription and ensuring the appropriateness of antiarrhythmic therapy prescribed are points emergency departments can improve in the interest of better sinus rhythm maintenance.

OBJETIVO: El mantenimiento del ritmo sinusal (RS) con fármacos antiarrítmicos (FAA) y/o tratamiento del remodelado (TRM) es parte fundamental en la estrategia de control del ritmo en la fibrilación auricular (FA). Este estudio analiza estas estrategias y su adecuación en los servicios de urgencias hospitalarios (SUH). METODO: Análisis secundario del estudio multicéntrico observacional transversal HERMES-AF, desarrollado en 124 SUH representativos del sistema sanitario español en 2011. Se incluyeron pacientes consecutivos con FA que revirtieron a RS y fueron dados de alta desde urgencias. RESULTADOS: Se incluyeron 449 pacientes: 204 (45,4%) ya realizaban tratamiento para mantenimiento del RS. De los 245 restantes se prescribió tratamiento en el SUH a 107 (43,7%): 41 con FAA, 19 TRM y en 47 ambas terapias. En 10 casos (11,8%) la selección del FAA no era acorde a las recomendaciones de las guías. La prescripción de FAA se asoció a FA previa [odds ratio (OR) 2,024, IC 95%: 1,196-3,424, p = 0,009], frecuencia cardiaca > 110 lpm (OR 2,147, IC 95%: 1,034-4,456, p = 0,040) y anticoagulación al alta (OR 1,862, IC 95%: 1,094-3,170, p = 0,022). El TRM se asoció a frecuencia cardiaca > 110 lpm (OR 2,187, IC 95%: 1,005-4,757, p = 0,018). En total, al alta del SUH 311 pacientes (69,2%) recibían tratamiento para mantenimiento del RS (87 con FAA, 117 con TRM y 107 con ambas terapias). CONCLUSIONES: La prescripción de tratamiento para evitar las recurrencias de la FA es insuficiente en los SUH. Extender esta prescripción y mejorar la adecuación del tratamiento antiarrítmico son áreas de mejora de la estrategia de control del ritmo en los SUH.

Deciphering mechanism of the herbal formula WuShen in the treatment of postinfarction heart failure.

BACKGROUND: Numerous clinical studies reported the effectiveness of herbal formula WuShen (WS) in treating cardiovascular diseases, yet relevant basic research was rarely conducted. METHODS AND RESULTS: Twelve main bioactive compounds of WS decoction were identified using the ultra-performance liquid chromatography-LTQ-Orbitrap mass spectrometer. A total of 137 active compounds with 613 targets were predicted by network pharmacology; their bioinformatic annotation and human microarray data suggested that wounding healing, inflammatory response, and gap junction were potentially the major therapeutic modules. A rat model of post-myocardial infarction (MI) heart failure (HF) was used to study the effects of WS on cardiac function, adverse cardiac remodeling, and experimental arrhythmias. Rats treated with WS led to a significantly improved pump function and reduced susceptibility to both ventricular tachycardia and atrial fibrillation, and restricted adverse cardiac remodeling partly via inhibiting TGFß1/SMADs mediated extracellular matrix deposition and Rac1/NOX2/CTGF/Connexin43 -involved gap junction remodeling. CONCLUSIONS: The present study highlights that WS can be applied to the treatment of heart failure and the upstream therapy for atrial fibrillation and ventricular tachycardia through its preventive effect on adverse cardiac remodeling.

Non-genetic risk factors for atrial fibrillation are equally important in both young and old age: A nationwide population-based study.

AIMS: There are several non-genetic risk factors for new-onset atrial fibrillation, including age, sex, obesity, hypertension, diabetes, and alcohol consumption. However, whether these non-genetic risk factors have equal significance among different age groups is not known. We performed a nationwide population-based analysis to compare the clinical significance of non-genetic risk factors for new-onset atrial fibrillation in various age groups. METHODS AND RESULTS: A total of 9,797,409 people without a prior diagnosis of atrial fibrillation who underwent a national health check-up in 2009 were included. During 80,130,090 person-years of follow-up, a total of 196,136 people were diagnosed with new-onset atrial fibrillation. The impact of non-genetic risk factors on new-onset atrial fibrillation was examined in different age groups. Obesity, male sex, heavy alcohol consumption, smoking, hypertension, diabetes and chronic kidney disease were associated with an increased risk of new-onset atrial fibrillation. With minor variations, these risk factors were consistently associated with the risk of new-onset atrial fibrillation among various age groups. Using these risk factors, we created a scoring system to predict future risk of new-onset atrial fibrillation in different age groups. In receiver operating characteristic curve analysis, the predictive value of these risk factors ranged between 0.556 and 0.603, and no significant trends were observed. CONCLUSIONS: Non-genetic risk factors for new-onset atrial fibrillation may have a similar impact on different age groups. Except for sex, these non-genetic risk factors can be modifiable. Therefore, efforts to control non-genetic risk factors might have relevance for both the young and old.

Therapeutic options for patients with advanced atrial fibrillation: from lifestyle and medication to catheter and surgical ablation.

Atrial fibrillation (AF) is part of a vicious cycle that includes multiple cardiovascular risk factors and comorbidity which can promote atrial remodelling and AF progression. Most AF-related risk factors-hypertension, diabetes, sleep apnoea, obesity and sedentary lifestyle-are in essence modifiable which may prevent AF development. Treatment of associated cardiovascular conditions may prevent both symptoms and future cardiovascular events. For advanced forms of symptomatic AF refractory to lifestyle management and optimal medication, invasive ablation therapies have become a cornerstone. Although electrical trigger isolation from the pulmonary veins is reasonably effective and safe, more potent energy sources including high output-short duration radiofrequency, ultra-low cryo-energy, and electroporation, as well as more sophisticated arrays, balloons, and lattice-tipped catheter tools, are on their way to eliminate existing pitfalls and simplify the procedure. Electroanatomical navigation and mapping systems are becoming available to provide real-time information on ablation lesion quality and the critical pathways of AF in the individual patient to guide more extensive ablation strategies that may enhance long-term outcome for freedom of advanced AF. Surgical techniques, either stand-alone or concomitant to structural cardiac repair, hybrid, or convergent, with novel less invasive access options are developing and can be helpful in situations unsuitable for catheter ablation.

Frequent drinking is a more important risk factor for new-onset atrial fibrillation than binge drinking: a nationwide population-based study.

AIMS: Heavy consumption of alcohol is a known risk factor for new-onset atrial fibrillation (AF). We aimed to evaluate the relative importance of frequent drinking vs. binge drinking. METHODS AND RESULTS: A total of 9 776 956 patients without AF who participated in a national health check-up programme were included in the analysis. The influence of drinking frequency (day per week), alcohol consumption per drinking session (grams per session), and alcohol consumption per week were studied. Compared with patients who drink twice per week (reference group), patients who drink once per week showed the lowest risk [hazard ratio (HR) 0.933, 95% confidence interval (CI) 0.916-0.950] and those who drink everyday had the highest risk for new-onset AF (HR 1.412, 95% CI 1.373-1.453), respectively. However, the amount of alcohol intake per drinking session did not present any clear association with new-onset AF. Regardless of whether weekly alcohol intake exceeded 210 g, the frequency of drinking was significantly associated with the risk of new-onset AF. In contrast, when patients were stratified by weekly alcohol intake (210 g per week), those who drink large amounts of alcohol per drinking session showed a lower risk of new-onset AF. CONCLUSION: Frequent drinking and amount of alcohol consumption per week were significant risk factors for new-onset AF, whereas the amount of alcohol consumed per each drinking session was not an independent risk factor. Avoiding the habit of consuming a low but frequent amount of alcohol might therefore be important to prevent AF.

Atria-selective antiarrhythmic drugs in need of alliance partners.

Atria-selective antiarrhythmic drugs in need of alliance partners. Guideline-based treatment of atrial fibrillation (AF) comprises prevention of thromboembolism and stroke, as well as antiarrhythmic therapy by drugs, electrical rhythm conversion, ablation and surgical procedures. Conventional antiarrhythmic drugs are burdened with unwanted side effects including a propensity of triggering life-threatening ventricular fibrillation. In order to solve this therapeutic dilemma, 'atria-selective' antiarrhythmic drugs have been developed for the treatment of supraventricular arrhythmias. These drugs are designed to aim at atrial targets, taking advantage of differences in atrial and ventricular ion channel expression and function. However it is not clear, whether such drugs are sufficiently antiarrhythmic or whether they are in need of an alliance partner for clinical efficacy. Atria-selective Na+ channel blockers display fast dissociation kinetics and high binding affinity to inactivated channels. Compounds targeting atria-selective K+ channels include blockers of ultra rapid delayed rectifier (Kv1.5) or acetylcholine-activated inward rectifier K+ channels (Kir3.x), inward rectifying K+ channels (Kir2.x), Ca2+-activated K+ channels of small conductance (SK), weakly rectifying two-pore domain K+ channels (K2P), and transient receptor potential channels (TRP). Despite good antiarrhythmic data from in-vitro and animal model experiments, clinical efficacy of atria-selective antiarrhythmic drugs remains to be demonstrated. In the present review we will briefly summarize the novel compounds and their proposed antiarrhythmic action. In addition, we will discuss the evidence for putative improvement of antiarrhythmic efficacy and potency by addressing multiple pathophysiologically relevant targets as possible alliance partners.

Pathophysiological and therapeutic implications in patients with atrial fibrillation and heart failure.

Heart failure and atrial fibrillation are common and responsible for significant mortality of patients. Both share the same risk factors like hypertension, ischemic heart disease, diabetes, obesity, arteriosclerosis, and age. A variety of microscopic and macroscopic changes favor the genesis of atrial fibrillation in patients with preexisting heart failure, altered subcellular Ca2+ homeostasis leading to increased cellular automaticity as well as concomitant fibrosis that are induced by pressure/volume overload and altered neurohumoral states. Atrial fibrillation itself promotes clinical deterioration of patients with preexisting heart failure as atrial contraction significantly contributes to ventricular filling. In addition, atrial fibrillation induced tachycardia can even further compromise ventricular function by inducing tachycardiomyopathy. Even though evidence has been provided that atrial functions significantly and independently of confounding ventricular pathologies, correlate with mortality of heart failure patients, rate and rhythm controls have been shown to be of equal effectiveness in improving mortality. Yet, it also has been shown that cohorts of patients with heart failure benefit from a rhythm control concept regarding symptom control and hospitalization. To date, amiodarone is the most feasible approach to restore sinus rhythm, yet its use is limited by its extensive side-effect profile. In addition, other therapies like catheter-based pulmonary vein isolation are of increasing importance. A wide range of heart failure-specific therapies are available with mixed impact on new onset or perpetuation of atrial fibrillation. This review highlights pathophysiological concepts and possible therapeutic approaches to treat patients with heart failure at risk for or with atrial fibrillation.

Eplerenone Reduces Atrial Fibrillation Burden Without Preventing Atrial Electrical Remodeling.

BACKGROUND: The aldosterone inhibitor eplerenone (EPL) has been shown to reduce the incidence of atrial fibrillation (AF) in patients with systolic heart failure, but the mechanism is unknown. OBJECTIVES: This study hypothesized that by reducing atrial dilation and fibrosis in the absence of heart failure, EPL also reduces AF burden and prevents AF perpetuation. METHODS: The authors conducted a randomized controlled study in 34 sheep that were atrially tachypaced (13 ± 1 week). They compared daily oral EPL (n = 19) versus sugar pill (SP) treatment (n = 15) from the start of tachypacing. The endpoint was a continuous 7-day stretch of persistent AF (n = 29) or completion of 23 weeks tachypacing (n = 5). RESULTS: EPL significantly reduced the rate of left atrial dilation increase during AF progression. Atria from EPL-treated sheep had less smooth muscle actin protein, collagen-III expression, interstitial atrial fibrosis, and cell hypertrophy than SP-treated sheep atria did. However, EPL did not modify the AF-induced increase in the rate of dominant frequency and ion channel densities seen under SP treatment, but rather prolonged the time to persistent AF in 26% of animals. It also reduced the degree of fibrillatory conduction, AF inducibility, and AF burden. CONCLUSIONS: In the sheep model, EPL mitigates fibrosis and atrial dilation, modifies AF inducibility and AF complexity, and prolongs the transition to persistent AF in 26% of animals, but it does not prevent AF-induced electrical remodeling or AF persistence. The results highlight structural remodeling as a central upstream target to reduce AF burden, and the need to prevent electrical remodeling to avert AF perpetuation.

Catheter ablation in patients with persistent atrial fibrillation.

Catheter ablation is increasingly offered to patients who suffer from symptoms due to atrial fibrillation (AF), based on a growing body of evidence illustrating its efficacy compared with antiarrhythmic drug therapy. Approximately one-third of AF ablation procedures are currently performed in patients with persistent or long-standing persistent AF. Here, we review the available information to guide catheter ablation in these more chronic forms of AF. We identify the following principles: Our clinical ability to discriminate paroxysmal and persistent AF is limited. Pulmonary vein isolation is a reasonable and effective first approach for catheter ablation of persistent AF. Other ablation strategies are being developed and need to be properly evaluated in controlled, multicentre trials. Treatment of concomitant conditions promoting recurrent AF by life style interventions and medical therapy should be a routine adjunct to catheter ablation of persistent AF. Early rhythm control therapy has a biological rationale and trials evaluating its value are underway. There is a clear need to generate more evidence for the best approach to ablation of persistent AF beyond pulmonary vein isolation in the form of adequately powered controlled multi-centre trials.

Galectin-3 Regulates Atrial Fibrillation Remodeling and Predicts Catheter Ablation Outcomes.

OBJECTIVES: To determine whether Gal-3 mediates sustained atrial fibrillation (AF)-induced atrial structural and electrical remodeling and contributes to AF perpetuation. BACKGROUND: Galectin-3 (Gal-3) mediates extracellular matrix remodeling in heart failure, but its role in AF progression remains unexplored. METHODS: We examined intracardiac blood samples from patients with AF (N=55) to identify potential biomarkers of AF recurrence. In a sheep model of tachypacing-induced AF (N=20), we tested the effects of Gal-3 inhibition during AF progression. RESULTS: In patients, intracardiac serum Gal-3 levels were greater in persistent than paroxysmal AF and independently predicted atrial tachyarrhythmia recurrences after a single ablation procedure. In the sheep model, both Gal-3 and TGF-ß1 were elevated in the atria of persistent AF animals. The Gal-3 inhibitor GM-CT-01 (GMCT) reduced both Gal-3 and TGF-ß1-induced sheep atrial fibroblast migration and proliferation in vitro. GMCT (12 mg/kg twice/week) prevented the increase in serum procollagen type III N-terminal peptide seen during progression to persistent AF, and also mitigated atrial dilatation, myocyte hypertrophy, fibrosis, and the expected increase in dominant frequency of excitation. Atria of GMCT-treated animals had significantly less TGF-ß1-Smad2/3 signaling pathway activation and expression of α-smooth muscle actin and collagen than saline-treated animals. Ex-vivo hearts from GMCT-treated animals had significantly longer action potential durations and fewer rotors and wavebreaks during AF, and myocytes had lower functional expression of inward rectifier K+ channel (Kir2.3) than saline-treated animals. Importantly, GMCT increased the probability of spontaneous AF termination, decreased AF inducibility and reduced overall AF burden. CONCLUSIONS: Inhibiting Gal-3 during AF progression might be useful as an adjuvant treatment to improve outcomes of catheter ablation for persistent AF. Gal-3 inhibition may be a potential new upstream therapy for prevention of AF progression.