transforming-growth-factor-beta and Atrial-Fibrillation

Heart failure (HF) and atrial fibrillation (AF) are two growing epidemics associated with significant morbidity and mortality. They often coexist due to common risk factors and shared pathophysiological mechanisms. Patients presenting with both HF and AF have a worse prognosis and present a particular therapeutic challenge to clinicians. This review aims to appraise the common pathophysiological background, as well as the prognostic and therapeutic implications of coexistent HF and AF.

Topics: Anticoagulants; Atrial Fibrillation; Calcium; Extracellular Matrix; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Heart Failure; Hemodynamics; Humans; Obesity; Renin-Angiotensin System; Transforming Growth Factor beta

Atrial fibrillation is the most common sustained arrhythmia, but its mechanisms are poorly understood. In particular, little is known about the factors that contribute to the establishment of persistent or permanent atrial fibrillation. This review addresses possible common signaling pathways that might promote both structural and electrical remodeling of the atria, thus contributing to atrial fibrillation perpetuation.. Sustained atrial fibrillation may trigger an inflammatory response leading to activation of myofibroblasts and to the release of cytokines such as transforming growth factor-β and platelet-derived growth factor, as well as profibrotic proteins such as galectin-3. Activation of signaling cascades involving such proteins is critical for the development of fibrosis and may also lead to ion channel dysfunction, which, along with myocyte apoptosis and extracellular matrix generation and turnover, likely contributes to both electrical and structural remodeling and predisposes to atrial fibrillation.. Identifying upstream strategies targeting molecular pathways that are common to fibrosis and electrical remodeling leading to atrial fibrillation perpetuation is highly desirable. This would facilitate finding new target genes with pleiotropic effects on the expression of ion channel proteins in myocytes and profibrotic molecules in nonmyocyte cells that are important for pathologic remodeling, which could become an important goal in persistent atrial fibrillation therapy.

Topics: Apoptosis; Atrial Fibrillation; Atrial Remodeling; Extracellular Matrix; Fibrosis; Galectin 3; Heart Atria; Heart Conduction System; Humans; Inflammation; Myocytes, Cardiac; Myofibroblasts; Platelet-Derived Growth Factor; Signal Transduction; Transforming Growth Factor beta

Topics: Animals; Atrial Fibrillation; Atrioventricular Node; Cardiac Pacing, Artificial; Cell Transplantation; Fibroblasts; Humans; Transforming Growth Factor beta; Transforming Growth Factor beta1

While much has been learned about atrial fibrillation from large animal models, many of these studies are correlative. Genetically-altered mouse models have provided much information about such genetic diseases as the long QT syndrome, but have to date not been utilized much to study atrial fibrillation. The ability to study the importance of a single gene product in pathophysiology make this a potentially powerful tool to understand the causal relationship of several proteins and the substrate for atrial fibrillation. In this manuscript we review the techniques available to study atrial electrophysiology and some of the genetically-altered mouse models that have implications for atrial fibrillation.

Topics: Action Potentials; Animals; Atrial Fibrillation; Connexins; Disease Models, Animal; Electrocardiography; Mice; Mice, Knockout; Mice, Transgenic; Transforming Growth Factor beta

Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with chronic kidney disease (CKD). In this study, we examined the association between inflammation and AF in 3,762 adults with CKD, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. AF was determined at baseline by self-report and electrocardiogram (ECG). Plasma concentrations of interleukin(IL)-1, IL-1 Receptor antagonist, IL-6, tumor necrosis factor (TNF)-α, transforming growth factor-β, high sensitivity C-Reactive protein, and fibrinogen, measured at baseline. At baseline, 642 subjects had history of AF, but only 44 had AF in ECG recording. During a mean follow-up of 3.7 years, 108 subjects developed new-onset AF. There was no significant association between inflammatory biomarkers and past history of AF. After adjustment for demographic characteristics, comorbid conditions, laboratory values, echocardiographic variables, and medication use, plasma IL-6 level was significantly associated with presence of AF at baseline (Odds ratio [OR], 1.61; 95% confidence interval [CI], 1.21 to 2.14; P = 0.001) and new-onset AF (OR, 1.25; 95% CI, 1.02 to 1.53; P = 0.03). To summarize, plasma IL-6 level is an independent and consistent predictor of AF in patients with CKD.

Topics: Adult; Aged; Atrial Fibrillation; C-Reactive Protein; Electrocardiography; Female; Follow-Up Studies; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Male; Middle Aged; Renal Insufficiency, Chronic; Risk Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To construct an animal model of atrial fibrillation and observe the effect of acute atrial fibrillation on renal water and sodium metabolism in mice. A total of 20 C57 mice were randomly assigned to 2 groups (n = 10/group): control group (CON) and atrial fibrillation group (AF). The mice model of atrial fibrillation was induced by chlorhexidine gluconate (CG) in combination with transesophageal atrial spacing. The urine of the two groups of mice was collected, and then we calculate the urine volume and urine sodium content. The expression of TGF-β and type III collagen in the atrial myocardium of the two groups was detected by immunohistochemistry and Western Blot. The levels of CRP and IL-6 in blood were observed by ELISA, and the NF-κB, TGF-β, collagen type III, AQP2, AQP3, AQP4, ENaC-β, ENaC-γ, SGK1 and NKCC proteins in the kidneys of the two groups of mice was observed by Western Blot. Compared with CON, the expression of TGF-β and type III collagen in the atrial myocardium of the mice in AF were increased, the levels of CRP and IL-6 in the blood in AF were increased, and the renal NF-κB, TGF-β, type III collagen AQP2, AQP3, ENaC-β, ENaC-γ, SGK1 and NKCC protein expression in AF were up-regulated. The level of urine volume and urine sodium content in AF were significantly reduced. In the acute attack of atrial fibrillation, the formation of renal inflammatory response and fibrosis is activated, and the renal water and sodium metabolism is hindered, which is related to the up-regulated of the expressions of renal NKCC, ENaC and AQPs.

Topics: Animals; Aquaporin 2; Atrial Fibrillation; Collagen Type III; Disease Models, Animal; Fibrosis; Interleukin-6; Kidney; Mice; NF-kappa B; Sodium; Transforming Growth Factor beta; Transforming Growth Factor beta1

Cartilage oligomeric matrix protein (COMP) regulates transforming growth factor-β (TGF-β) signaling pathway, which has been proved to be associated with skin fibrosis and pulmonary fibrosis. Atrial fibrosis is a major factor of atrial fibrillation (AF). Nevertheless, the interaction between COMP and TGF-β as well as their role in AF remains undefined. The purpose of this study is to clarify the role of COMP in AF and explore its potential mechanism. The hub gene of AF was identified from two datasets using bioinformatics. Furthermore, it was verified by the downregulation of COMP in angiotensin-II (Ang-II)-induced AF in mice. Moreover, the effect on AF was examined using CCK8 assay, ELISA, and western blot. The involvement of TGF-β pathway was further discussed. The expression of COMP was the most significant among all these hub genes. Our experimental results revealed that the protein levels of TGF-β1, phosphorylated Smad2 (P-Smad2), and phosphorylated Smad3 (P-Smad3) were decreased after silencing COMP, which indicated that COMP knockdown could inhibit the activation of TGF-β pathway in AF cells. However, the phenomenon was reversed when the activator SRI was added. COMP acts as a major factor and can improve Ang-II-induced AF via TGF-β signaling pathway. Thus, our research enriches the understanding of the interaction between COMP and TGF-β in AF, and provides reference for the pathogenesis and diagnosis of AF.

Topics: Angiotensin II; Animals; Atrial Fibrillation; Cartilage Oligomeric Matrix Protein; Fibrosis; Mice; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1

Artial fibrosis has been recognized as a typical pathological change in atrial fibrillation. Although present evidence suggests that microRNA-499-5p (miR-499-5p) plays an important role in the development of atrial fibrosis, the specific mechanism is not fully understood. Therefore, this study attempted to assess the influence of miR-499-5p on atrial fibroblasts and explore the potential molecular mechanism.. Atrial fibroblasts from sprague dawley rat were respectively transfected with miR-499-5p mimic, miR-499-5p negative control and miR-499-5p inhibitor, atrial fibroblasts without any treatment were also established. Cell counting kit-8 assay and transwell assay were used to detect the proliferation and migration of atrial fibroblasts in each group. Expressions of miR-499-5p, TGF-β1, smad2, α-SMA, collagen-I and TGFβ-R1 in mRNA and protein level were subsequently detected via quantitative real-time polymerase chain reaction and western blot. Furthermore, the prediction of the binding sites of miR-499-5p and TGFβ-R1 was performed via the bioinformatics online software TargetScan and verified by dual luciferase reporter.. By utilizing miR-499-5p-transfected atrial fibroblasts model, expression of miR-499-5p in the miR-499-5p mimic group was upregulated, while it was downregulated in the miR-499-5p inhibitors group. Upregulated miR-499-5p expression led to to a significant decrease in the proliferative and migratory ability of cultured atrial fibroblasts, while downregulated miR-499-5p expression led to a significant increase in the proliferative and migratory ability of cultured atrial fibroblasts. Additionally, upregulated miR-499-5p expression made a significant rise in TGF-β1-induced mRNA and protein expression of TGF-β1, TGFβ-R1, smad2, α-SMA and collagen-I in atrial fibroblasts. Furthermore, results from the dual luciferase reporter conformed that miR-499-5p may repress TGFβ-R1 by binding the 3'UTR of TGFβ-R1 directly.. miR-499-5p is able to inhibit the activation of transforming growth factor β-induced Smad2 signaling and eventually suppressed the proliferation, migration and invasion of atrial fibroblasts and collagen synthesis by targeting TGFβ-R1.

Topics: Animals; Atrial Fibrillation; Cell Proliferation; Collagen Type I; Fibroblasts; Fibrosis; Luciferases; MicroRNAs; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1

Angiotensin II (Ang II)-induced atrial fibrosis plays a vital role in the development of atrial fibrillation (AF). Lysyl oxidase-like 2 (LOXL2) plays an essential role in matrix remodeling and fibrogenesis, indicating it may involve fibrosis-associated diseases. This study aims to elucidate the role of LOXL2 in AF, and its specific inhibitor can suppress Ang II-induced inflammatory atrial fibrosis and attenuate the enhanced vulnerability to AF.. Male mice C57BL/6 were subcutaneously infused with either saline or Ang II (2 mg/kg/day) for 4 weeks. DMSO or LOXL2 inhibitor LOXL2-IN-1 hydrochloride (LOXL2-IN-1) at a dose of 100 μg/kg/day were intraperitoneally injected once daily for 4 weeks. Morphological, histological, and biochemical analyses were performed. AF was induced by transesophageal burst pacing in vivo.. Expression of LOXL2 was increased in serum of AF patients and Ang II-treated mice. LOXL2-IN-1 significantly attenuated Ang II-induced AF vulnerability, cardiac hypertrophy, atrial inflammation, and fibrosis. LOXL2-IN-1 suppressed Ang II-induced expression of transforming growth factor beta-1 (TGF-β1) and collagen I and phosphorylation of Smad2/3 in atrial tissue.. LOXL2 is a target of AF, and its inhibitor prevents atrial fibrosis and attenuated enhanced vulnerability to AF potentially through the TGF-β/Smad pathway.

Topics: Amino Acid Oxidoreductases; Angiotensin II; Animals; Atrial Fibrillation; Fibrosis; Humans; Male; Mice; Mice, Inbred C57BL; Smad2 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta1

Atherosclerosis is associated with a haemostatic imbalance characterized by excessive activation of pro-inflammatory and pro-coagulant pathways. Non-vitamin K antagonists oral anticoagulant (NOACs) may reduce the incidence of cardiovascular events, cerebral ischemia, thromboembolic events and atherosclerosis. Chronic inflammation, vascular proliferation and the development of atherosclerosis is also influenced by 25-hydroxycholesterol (25-OHC). The aim of the study was to assess the effect of rivaroxaban and dabigatran on the messenger RNA (mRNA) expression of anti-inflammatory cytokines transforming growth factor β (TGF-β), interleukin (IL)-37, IL-35 as well as of pro-inflammatory cytokines IL-18 and IL-23, in endothelial cells damaged by 25-OHC. Human umbilical vascular endothelial cells (HUVECs) were treated with 25-OHC (10 μg/mL), rivaroxaban (100, 500 ng/mL), dabigatran (100, 500 ng/mL), 25-OHC + rivaroxaban, and 25-OHC + dabigatran. The mRNA expression of TGF-β, IL-37, IL-35 subunits EBI3 and p35, IL-18, and IL-23 was analysed using real-time polymerase chain reaction (PCR). The results showed that 25-OHC decreased TGF-β and IL-37 mRNA expression and increased EBI3, p35, IL-18, IL-23 mRNA expression in endothelial cell as compared to an untreated control (P < .05). Messenger RNA expression of TGF-β and IL-37 significantly increased following stimulation with rivaroxaban and dabigatran as compared to an untreated control (P < .01). In HUVECs pre-treated with oxysterol, rivaroxaban and dabigatran increased mRNA expression of TGF-β, IL-37 and decreased mRNA expression of EBI3, p35, IL-23 and IL-18 as compared to 25-OHC (P < .01). Our finding suggests that both rivaroxaban and dabigatran inhibit the inflammatory activation caused by oxysterol in vitro.

Topics: Administration, Oral; Anticoagulants; Atherosclerosis; Atrial Fibrillation; Cytokines; Dabigatran; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Hydroxycholesterols; Interleukin-18; Interleukin-23; Oxysterols; Rivaroxaban; RNA, Messenger; Transforming Growth Factor beta

Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition (EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β-treated human AEECs, cardiac-specific TGF-β-transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-β-treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR-181b antagomir or recombinant Sema3A to TGF-β-transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-β via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention.

Topics: Actin Depolymerizing Factors; Animals; Antagomirs; Atrial Fibrillation; Endothelial Cells; Epithelial-Mesenchymal Transition; Fibrosis; Heart Atria; Mice; Mice, Transgenic; MicroRNAs; Rabbits; Semaphorin-3A; Transforming Growth Factor beta

This study was aimed at exploring whether silencing of TLR4 could inhibit atrial fibrosis and susceptibility to atrial fibrillation (AF) by regulating NLRP3-TGF-. Spontaneously hypertensive rats (SHRs) were transfected with either a virus containing TLR4-shRNA to downregulate TLR4 or an empty virus (vehicle) at the age of 14 weeks. Fibrosis of left atrium and susceptibility to AF were detected, and expression of NLRP3-TGF-. Silencing of TLR4 reduced left atrial fibrosis and susceptibility to AF in SHRs and downregulated expression of NLRP3, TGF-. Silencing of TLR4 can downregulate NLRP3-TGF-

Topics: Angiotensin II; Animals; Atrial Fibrillation; Collagen Type I; Down-Regulation; Fibrosis; Heart Atria; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Inbred SHR; RNA, Small Interfering; Toll-Like Receptor 4; Transforming Growth Factor beta; Transforming Growth Factor beta1

To investigate the role and mechanism of quercetin in isoprenaline (ISO)-induced atrial fibrillation (AF).. Rat cardiac fibroblasts (RCFs) models and RCFs were used to explore the effect and underlying mechanism of quercetin in isoprenaline (ISO)-induced atrial fibrillation (AF) in vivo and in vitro by a series of experiments.. Differentially expressed microRNAs were screened from human AF tissues using the GEO2R and RT-qPCR. The expressions of TGF-β/Smads pathway molecules (TGFβ1, TGFBR1, Tgfbr1, Tgfbr2, Smad2, Smad3, Smad4) in AF tissues were detected by RT-qPCR and Western blot. The relationships between miR-135b and genes (Tgfbr1, Tgfbr2, Smad2) were analyzed by Pearson correlation, TargetScan and dual-luciferase activity assay. RCFs induced by ISO were treated with quercetin (20 or 50 μM), miR-135b mimic and inhibitor, siTgfbr1 and their corresponding controls, then the cell viability was determined by MTT and the expressions of cyclin D1, α-SMA, collagen-related molecules, TGF-β/Smads pathway molecules, and miR-135b were measured by RT-qPCR and Western blot. ISO-induced rats were treated with quercetin (25 mg/kg/day) via gavage, miR-135b antagomir, agomir and their corresponding controls. The treated rats were used for the detection of miR-135b expression by RT-qPCR, histopathological observation by HE and Masson staining, and the detection of Col1A1 and fibronectin contents by immunohistochemical technique.. The expression of miR-135b was downregulated, and those of TGFBR1, TGFBR2, target genes of miR-135b were upregulated in human AF tissues and negatively regulated by miR-135b in RCFs. Through inhibiting TGF-β/Smads pathway via promoting miR-135b expression, quercetin treatment inhibited proliferation, myofibroblast differentiation and collagen deposition in ISO-treated RCFs, as evidenced by reduced expressions of cyclin D1, α-SMA, collagen-related genes and proteins, and alleviated fibrosis and collagen deposition of atrial tissues in ISO-treated rats.. Quercetin may alleviate AF by inhibiting fibrosis of atrial tissues through inhibiting TGF-β/Smads pathway via promoting miR-135b expression.

Topics: Animals; Atrial Fibrillation; Fibrosis; MicroRNAs; Quercetin; Rats; Transforming Growth Factor beta; Transforming Growth Factor beta1

Fibrosis serves a critical role in driving atrial remodelling-mediated atrial fibrillation (AF). Abnormal levels of the transcription factor PU.1, a key regulator of fibrosis, are associated with cardiac injury and dysfunction following acute viral myocarditis. However, the role of PU.1 in atrial fibrosis and vulnerability to AF remain unclear. Here, an in vivo atrial fibrosis model was developed by the continuous infusion of C57 mice with subcutaneous Ang-II, while the in vitro model comprised atrial fibroblasts that were isolated and cultured. The expression of PU.1 was significantly up-regulated in the Ang-II-induced group compared with the sham/control group in vivo and in vitro. Moreover, protein expression along the TGF-β1/Smads pathway and the proliferation and differentiation of atrial fibroblasts induced by Ang-II were significantly higher in the Ang-II-induced group than in the sham/control group. These effects were attenuated by exposure to DB1976, a PU.1 inhibitor, both in vivo and in vitro. Importantly, in vitro treatment with small interfering RNA against Smad3 (key protein of TGF-β1/Smads signalling pathway) diminished these Ang-II-mediated effects, and the si-Smad3-mediated effects were, in turn, antagonized by the addition of a PU.1-overexpression adenoviral vector. Finally, PU.1 inhibition reduced the atrial fibrosis induced by Ang-II and attenuated vulnerability to AF, at least in part through the TGF-β1/Smads pathway. Overall, the study implicates PU.1 as a potential therapeutic target to inhibit Ang-II-induced atrial fibrosis and vulnerability to AF.

Topics: Angiotensin II; Animals; Atrial Fibrillation; Cardiotonic Agents; Cells, Cultured; Fibrosis; Heterocyclic Compounds; Male; Mice; Mice, Inbred C57BL; Myocardium; Myofibroblasts; Proto-Oncogene Proteins; Signal Transduction; Smad3 Protein; Trans-Activators; Transforming Growth Factor beta

BACKGROUND The structural remodeling of atrial architecture, especially increased amounts of fibrosis, is a critical substrate to atrial fibrillation (AF). Doxycycline (Doxy) has recently been shown to exert protective effects against fibrogenic response. This study investigated whether doxycycline (Doxy) can sufficiently ameliorate the fibrosis-induced changes of atrial conduction and AF vulnerability in a chronic intermittent hypoxia (CIH) rat model. MATERIAL AND METHODS Sixty rats were randomized into 3 groups: Control, CIH, and CIH with Doxy treatment (DOXY) group. CIH rats were exposed to CIH (6 h/d) and Doxy-treated rats were treated with Doxy during processing CIH. After 6 weeks, echocardiographic and hemodynamic parameters were measured. Isolated atrial epicardial activation mapping and heart electrophysiology were performed. The extent of atrial interstitial fibrosis were estimated by Masson's trichrome staining. The expression levels of TGF-ß1 and downstream factors were determined by real-Time PCR, immunohistochemistry, and Western blot analysis. RESULTS Compared to Control rats, the CIH rats showed significant atrial interstitial fibrosis, longer inter-atrial conduction time, and elevated conduction inhomogeneity and AF inducibility, and the expression of TGF-ß1, TGF-ßRI, TGF-ßRII, P-Smad2/3, alpha-SMA, CTGF, and Collagen I were significantly increased, whereas the velocity of atrial conduction and the expression of miR-30c were dramatically decreased. All of these changes were significantly improved by Doxy treatment. CONCLUSIONS The findings suggested that Doxy can profoundly mitigate atrial fibrosis, conduction inhomogeneity as well as high AF inducibility secondary to fibrosis in a CIH rat model through suppressing the TGF-ß1 signaling pathway.

Topics: Animals; Atrial Fibrillation; Atrial Remodeling; China; Disease Models, Animal; Doxycycline; Fibrosis; Heart Atria; Heart Rate; Hypoxia; Male; Rats; Rats, Sprague-Dawley; Signal Transduction; Transforming Growth Factor beta

Long non-coding RNA predicting cardiac remodeling (lnc LIPCAR) was implicated in several human diseases, while its role in atrial fibrillation (AF) remained poorly understood. Our study aimed to discover the role of LICPAR played in AF. Samples of atrial muscle tissues from patients diagnosed with sinus rhythm (SR) and atrial fibrillation (AF) were collected, and human atrial fibroblasts were isolated and identified under immunofluorescence staining. After Angiotensin II (Ang II, as a activator of TGF-β) stimulation with LICPAR overexpression or knockdown, the viability and proliferation of atrial fibroblasts were respectively determined using cell counting kit-8 (CCK-8) assay and clone formation assay. Relative expressions of LICPAR, fibrosis- and transforming growth factor-β (TGF-β)/Smad2/3-pathway related proteins were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot as needed. LICPAR and TGF-β1 were upregulated and were positively correlated in atrial muscle tissues from AF. Atrial fibroblasts were identified as Vimentin positive. Further analysis indicated that Ang II enhanced the levels of LIPCAR, Smad2/3 phosphorylation and α-smooth muscle actin (α-SMA). Also, upregulating LIPCAR further promoted the promotive effects of Ang II on levels of LIPCAR, Collagen I, Collagen II, α-SMA and Smad2/3 phosphorylation, cell viability and proliferation of atrial fibroblasts, whereas silencing LIPCAR resulted in opposite effects. LICPAR regulates atrial fibrosis via modulating TGF-β/Smad pathway, which provided a potential therapeutic method for AF in clinical practice in the future.

Topics: Angiotensin II; Atrial Fibrillation; Biomarkers; Cell Proliferation; Cell Survival; Fibroblasts; Fibrosis; Heart Atria; Humans; Middle Aged; RNA, Long Noncoding; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Up-Regulation

Atrial fibrillation (AF) is the most common type of heart arrhythmia. Currently, the pathogenesis of AF is not fully understood yet. A growing body of evidence highlighted the strong association between inflammation and the pathogenesis of AF. C-reactive protein (CRP) is an inflammation marker with increased expression in AF. Therefore, the aim of this study was to determine if CRP promotes inflammation, which may sequentially mediate the onset of AF and the concurrent atrial fibrosis, through TLR4/NF-κB/TGF-β pathway. HL-1 cells were treated with either 25 or 50 μg/ml recombinant human CRP. TGF-β1 and NF-κB inhibitors were given either solely or together to the 50 μg/ml CRP-treated cells. Cell proliferation, apoptosis, the expression of apoptotic factors and TLR4, IL-6, TGF-β1, Smad2, and the phosphorylation of Smad2 were determined. Data showed that CRP induced dose-dependent inhibition on cell proliferation and promoted cell apoptosis, which was induced through both intrinsic and extrinsic pathways. Such effects were reversed by inhibiting TGF-β1 and/or NF-κB. Inhibition of TGF-β1 and/or NF-κB also reduced the expression of TLR4 and IL-6. Inhibition of NF-κB alone weakened the expression of TGF-β1 and phosphorylation of Smad2. Our study demonstrated that CRP is not only a marker, but also an important mediator in the induction of inflammation and likely the pathogenesis of AF. We for the first time reported CRP-induced activation and cross-talk between TLR4 and NF-κB/TGF-β1 signaling pathway in a cardiomyocyte model. Reducing CRP and targeting TLR4/NF-κB/TGF-β1 pathway may provide new insights in the therapeutic interventions to inflammation-induced AF.

Topics: Atrial Fibrillation; C-Reactive Protein; Cell Line; Gene Expression Regulation; Humans; Inflammation; NF-kappa B; Signal Transduction; Toll-Like Receptor 4; Transforming Growth Factor beta

Atrial fibrillation is the most prevalent sustained arrhythmia associated with arrhythmic ventricular contractions, incident heart failure, increased morbidity and mortality. The relationship between arrhythmic contractions and ventricular remodelling is incompletely understood. The aim of this study was to characterize the influence of irregular contractions on pro-fibrotic signalling in neonatal rat ventricular cardiomyocytes (NRVM).. Neonatal rat ventricular cardiomyocytes were paced via field stimulation at 3 Hz for 24 h. Irregularity was created by pseudorandomized variation of stimulation intervals and compared to regular pacing. Treatment of neonatal cardiac fibroblasts (NCF) with medium of irregularly paced NRVM increased protein expression of collagen I (206 ± 62%, P = 0.0121) and collagen III (51 ± 37%, P = 0.0119). To identify the underlying mechanism, expression of pro-fibrotic connective tissue growth factor (CTGF) and transforming growth factor beta (TGF-β) was assessed. In irregularly paced NRVM, increased protein expression of CTGF (80 ± 22%, P = 0.0035) and TGF-β (122 ± 31%, P = 0.0022) was associated with enhanced excretion of both proteins into the medium. Electron paramagnetic resonance spectroscopy revealed an increased production of reactive oxygen species (46 ± 21%, P = 0.0352) after irregular pacing accompanied by increased 8-hydroxydeoxyguanosine staining (214 ± 53%, P = 0.0011). Irregular pacing was associated with elevated mRNA levels of anti-oxidative superoxide dismutase 1 (25 ± 7%, P = 0.0175), superoxide dismutase 3 (20 ± 7%, P = 0.0309), and catalase (20 ± 7%, P = 0.046).. These data demonstrate that irregular pacing is an important inductor of pro-fibrotic signalling in NRVM involving paracrine effects of CTGF and TGF-β as well as increased oxidative stress. Thus, irregularity of the heart beat might directly be involved in the progression of maladaptive remodelling processes in atrial fibrillation.

Topics: Animals; Atrial Fibrillation; Cells, Cultured; Connective Tissue Growth Factor; Female; Fibrillar Collagens; Fibroblasts; Fibrosis; Heart Ventricles; Male; Myocytes, Cardiac; Oxidative Stress; Paracrine Communication; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Transforming Growth Factor beta

Atrial fibrillation (AF) is the most frequently diagnosed cardiac arrhythmia worldwide. Patients with permanent atrial fibrillation are at an increased risk of developing valvular heart disease. Atrial fibrosis occurs in this pathophysiological setting. LIM kinase 1 (LIMK1) is a serine/threonine kinase that regulates microtubule stability and actin polymerization in fibroblasts. LIMK1 has been implicated in the pathogenesis of atrial fibrillation. Clinical data and biopsies of the right atrial appendage were collected from 50 patients with valvular heart disease who underwent heart valve replacement surgery. Data from patients with permanent atrial fibrillation (AF) and patients with sinus rhythm (SR) were compared. We found that AF patients had upregulated expression of LIMK1 as well as higher fibrosis. Transforming growth factor-β (TGF-β) stimulation induced the differentiation of cardiac fibroblasts into myofibroblasts as well as upregulated expression of LIMK1. Downregulation of LIMK1 by siRNA inhibited TGF-β induced fibroblast-myofibroblast transition, as evidenced by the downregulation of the expression of several differentiation markers, namely alpha-smooth muscle actin and type I and III collagen. Our findings revealed that increased LIMK1 protein levels may contribute to atrial fibrosis, and suggested that LIMK1 might be involved in AF development by promoting fibrogenesis associated with TGF-β.

Topics: Actins; Animals; Atrial Fibrillation; Biopsy; Collagen Type I; Female; Fibroblasts; Fibrosis; Gene Expression Regulation; Heart Atria; Heart Valve Diseases; Humans; Lim Kinases; Male; Mice; Middle Aged; Myofibroblasts; RNA, Small Interfering; Transforming Growth Factor beta

Fibrotic remodeling of the atria plays a key role in the pathogenesis of atrial fibrillation (AF). As little is known about the contribution of circulating monocytes in atrial remodeling and the pathophysiology of AF, we investigated profibrotic factors in different subsets of circulating monocytes obtained from patients with atrial fibrillation undergoing catheter ablation.. A 3D high density voltage mapping was performed in sinus rhythm to evaluate the extent of low-voltage areas (LVAs) in the atria of 71 patients with persistent AF. Low-voltage was defined as signals of < 0.5mV during sinus rhythm. Prior to ablation, blood was drawn and monocytes were analyzed by FACS. Based on the expression of CD14 and CD16, three subgroups including CD14++ CD16- ('classical'), CD14++ CD16+ ('intermediate'), and CD14+ CD16++ ('non-classical') were analyzed for the expression of TGFb, CD147, and MMP-9, representing pivotal profibrotic pathways in myocardial remodeling.. Expression of TGFb was increased in CD14+ monocytes of patients with extensive LVAs compared to patients with a low extend of LVAs. While CD14++ CD16- monocytes showed no difference, CD14++ CD16+ and CD14+ CD16++ monocytes showed a strong increase of TGFb abundance. Although CD147 and MMP-9 are strongly associated with myocardial fibrosis, we found no difference in expression between the two groups in any monocyte subsets.. TGFb is specifically upregulated on CD14++ CD16+ and CD14+ CD16++ monocytes in patients with extensive LVAs undergoing catheter ablation.

Topics: Aged; Atrial Fibrillation; Basigin; Electrophysiological Phenomena; Female; Fibrosis; Heart Atria; Humans; Lipopolysaccharide Receptors; Male; Matrix Metalloproteinase 9; Middle Aged; Monocytes; Receptors, IgG; Transforming Growth Factor beta; Up-Regulation

Postoperative atrial fibrillation (AF) occurs frequently after cardiac surgery and contributes significantly to mortality. Transforming growth factor-beta (TGF-β) is associated with postoperative AF after coronary artery bypass grafting and valve surgery. We performed a prospective study to evaluate the role of TGF-β as a predictor of AF after myectomy. A total of 109 consecutive obstructive hypertrophic cardiomyopathy patients without previous AF who underwent myectomy were identified. We measured plasma TGF-β levels before surgery, monitored heart rhythm until discharge, and followed patients for a mean of 36 ± 10 months. AF was documented in 19 patients (17%). AF patients were older (50 ± 10 vs 43 ± 15 years, p = 0.037). Patients who developed AF had higher plasma TGF-β levels (1,695 ± 2,011 vs 1,099 ± 2,494 pg/ml, p = 0.011), more major adverse cardiac events (32% vs 7%, p = 0.006), and more strokes (16% vs 0%, p = 0.005) than patients who did not. TGF-β level ≥358 pg/ml predicted AF with sensitivity and specificity of 58% and 77% (p = 0.011), respectively. Higher TGF-β levels were associated with pulmonary hypertension (25% vs 8%, p = 0.033). In multivariable regression analysis, age (odds ratio 1.05, 95% confidence interval 1.00 to 1.11, p = 0.041) and TGF-β levels (odds ratio 2.42, 95% confidence interval 1.30 to 4.50, p = 0.005) predicted AF independently. In conclusion, elevated preoperative TGF-β value is an independent predictor of postoperative AF in hypertrophic cardiomyopathy patients after surgical ventricular septal myectomy.

Topics: Adult; Atrial Fibrillation; Biomarkers; Cardiac Surgical Procedures; Cardiomyopathy, Hypertrophic; China; Female; Follow-Up Studies; Heart Septum; Humans; Incidence; Male; Middle Aged; Odds Ratio; Postoperative Complications; Preoperative Period; Prognosis; Prospective Studies; Risk Factors; Survival Rate; Time Factors; Transforming Growth Factor beta

Atrial fibrillation (AF) is prevalent in aging populations; however not all individuals age at the same rate. Instead, individuals of the same chronological age can vary in health status from fit to frail. Our objective was to determine the impacts of age and frailty on atrial function and arrhythmogenesis in mice using a frailty index (FI). Aged mice were more frail and demonstrated longer lasting AF compared to young mice. Consistent with this, aged mice showed longer P wave duration and PR intervals; however, both parameters showed substantial variability suggesting differences in health status among mice of similar chronological age. In agreement with this, P wave duration and PR interval were highly correlated with FI score. High resolution optical mapping of the atria demonstrated reduced conduction velocity and action potential duration in aged hearts that were also graded by FI score. Furthermore, aged mice had increased interstitial fibrosis along with changes in regulators of extracellular matrix remodelling, which also correlated with frailty. These experiments demonstrate that aging results in changes in atrial structure and function that create a substrate for atrial arrhythmias. Importantly, these changes were heterogeneous due to differences in health status, which could be identified using an FI.

Topics: Action Potentials; Aging; Animals; Atrial Fibrillation; Biomarkers; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type III; Extracellular Matrix; Fibrosis; Frailty; Gene Expression; Heart Atria; Heart Function Tests; Isoenzymes; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Severity of Illness Index; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta; Voltage-Sensitive Dye Imaging

Postoperative atrial fibrillation is a frequent complication in cardiac surgery. The aberrant activation of signal transducer and activator of transcription 3 (STAT3) contributes to the pathogenesis of atrial fibrillation. MicroRNA-21 (miR-21) promotes atrial fibrosis. Recent studies support the existence of reciprocal regulation between STAT3 and miR-21. Here, we test the hypothesis that these 2 molecules might form a feedback loop that contributes to postoperative atrial fibrillation by promoting atrial fibrosis.. A sterile pericarditis model was created using atrial surfaces dusted with sterile talcum powder in rats. The inflammatory cytokines interleukin (IL)-1β, IL-6, transforming growth factor-β, and tumor necrosis factor-α, along with STAT3 and miR-21, were highly upregulated in sterile pericarditis rats. The inhibition of STAT3 by S3I-201 resulted in miR-21 downregulation, which ameliorated atrial fibrosis and decreased the expression of the fibrosis-related genes, α-smooth muscle actin, collagen-1, and collagen-3; reduced the inhomogeneity of atrial conduction; and attenuated atrial fibrillation vulnerability. Meanwhile, treatment with antagomir-21 decreased STAT3 phosphorylation, alleviated atrial remodeling, abrogated sterile pericarditis-induced inhomogeneous conduction, and prevented atrial fibrillation promotion. The culturing of cardiac fibroblasts with IL-6 resulted in progressively augmented STAT3 phosphorylation and miR-21 levels. S3I-201 blocked IL-6 induced the expression of miR-21 and fibrosis-related genes in addition to cardiac fibroblast proliferation. Transfected antagomir-21 decreased the IL-6-induced cardiac fibroblast activation and STAT3 phosphorylation. The overexpression of miR-21 in cardiac fibroblasts caused the upregulation of STAT3 phosphorylation, enhanced fibrosis-related genes, and increased cell numbers.. Our results have uncovered a novel reciprocal loop between STAT3 and miR-21 that is activated after heart surgery and can contribute to atrial fibrillation.

Topics: Animals; Atrial Fibrillation; Disease Models, Animal; Fibrosis; Interleukin-1beta; Interleukin-6; MicroRNAs; Pericarditis; Phosphorylation; Rats; Signal Transduction; STAT3 Transcription Factor; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Up-Regulation

Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). However, the underlying mechanisms for the increased propensity for AF in the setting of DM and the potential effects of probucol on atrial remodeling remain unclear.. Eighty Japanese rabbits were randomly assigned to normal/control group (Control, n = 20), alloxan-induced diabetic group (DM, n = 20), probucol-treated group (Control-P, n = 20), and probucol-treated diabetic group (DM-P, n = 20). Rabbits in the DPR and CPR groups were orally administered probucol (1,000 mg/day) for 8 weeks. Serum and left atrial tissue malonaldehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), and catalase (CAT) levels were assessed. Isolated Langendorff perfused rabbit hearts were prepared to evaluate atrial refractory effective period (AERP) and its dispersion (AERPD), interatrial conduction time (IACT), and vulnerability to AF. Atrial interstitial fibrosis was also evaluated. The mRNA expression levels of TNF-α and TLR4 were analyzed. The protein expressions of NF-κB, HSP70, TGF-β, and ERK in left atrial tissue were analyzed by Western blot. Probucol administration decreased the inducibility of AF in diabetic rabbits and attenuated atrial interstitial fibrosis. The DM-P rabbits exhibited significant alleviation of oxidative stress, evidenced by reduced serum and tissue MDA, compared with diabetic rabbits. Moreover, NF-κB, TGF-β, and HSP70 protein expression and TNF-α mRNA expression were significantly downregulated by probucol treatment in alloxan-induced diabetic rabbits.. Probucol prevents atrial remodeling and suppresses AF development in alloxan-induced diabetic rabbits. Its inhibitory effects on oxidative stress, NF-κB, TGF-β, and TNF-α overexpression may contribute to its antiremodeling effects.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Atrial Fibrillation; Atrial Remodeling; Biomarkers; Diabetes Mellitus, Experimental; Fibrosis; Gene Expression Regulation; Heart Atria; Inflammation Mediators; NF-kappa B; Oxidative Stress; Probucol; Rabbits; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Atrial Fibrillation; Atrial Remodeling; Diabetes Mellitus, Experimental; Heart Atria; Inflammation Mediators; NF-kappa B; Oxidative Stress; Probucol; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Atrial fibrosis contributes to development and recurrence of atrial fibrillation (AF). TGF-β and periostin have been reported to be involved in fibrogenesis. Here we investigated the role of TGF-β and periostin in atrial fibrosis of AF and in the recurrence of AF after surgery ablation. Western blot, Masson staining, immunohistochemistry and colorimetry were performed to detect the degree of atrial fibrosis and the expression of TGF-β, periostin and collagens in 70 biopsies of right atrial appendage (RAA) obtained in this study. Then the patients who received surgical ablation were followed up for about one year. The results showed an increasing gradient of atrial expression of TGF-β, periostin and collagens paralleled by a higher level of atrial fibrosis in control, SR and AF groups. The expression of TGF-β and periostin was significantly correlated with fibrotic markers. In addition, LAD and the expression of TGF-β were larger or higher in recurrence group than that in nonrecurrence group after surgery ablation. The results suggest that upregulated expression of TGF-β and periostin in RAAs is correlated with the degree of atrial fibrosis in patients with AF.

Topics: Adult; Atrial Appendage; Atrial Fibrillation; Biopsy; Blotting, Western; Catheter Ablation; Cell Adhesion Molecules; Collagen; Female; Fibrosis; Humans; Immunohistochemistry; Male; Middle Aged; Recurrence; Time Factors; Transforming Growth Factor beta; Treatment Outcome; Up-Regulation

The expression of nerve growth factor-β (NGF-β) is related to cardiac nerve sprouting and sympathetic hyper innervation. We investigated the changes of plasma levels of NGF-β and the relationship to follow-up heart rate variability (HRV) after radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF).. This study included 147 patients with AF (117 men, 55.8±11.5 years, 106 paroxysmal AF) who underwent RFCA. The plasma levels of NGF-β were quantified using double sandwich enzyme linked immunosorbent assay method before (NGF-βpre) and 1 hour after RFCA (NGF-βpost-1 hr). HRV at pre-procedure (HRVpre), 3 months (HRVpost-3 mo), and 1 year post-procedure (HRVpost-1 yr) were analyzed and compared with plasma levels of NGF-β.. 1) The plasma levels of NGF-β significantly increased after RFCA (20.05±11.09 pg/mL vs. 29.60±19.43 pg/mL, p<0.001). The patients who did not show increased NGF-βpost-1 hr were older (p=0.023) and had greater left atrial volume index (p=0.028) than those with increased NGF-βpost-1 hr. 2) In patients with NGF-βpre>18 pg/mL, low frequency components (LF)/high-frequency components (HF) (p=0.003) and the number of atrial premature contractions (APCs, p=0.045) in HRVpost-3 mo were significantly higher than those with ≤18 pg/mL. 3) The LF/HF at HRVpost-3 mo was linearly associated with the NGF-βpre (B=4.240, 95% CI 1.114-7.336, p=0.008) and the NGF-βpost-1 hr (B=7.617, 95% CI 2.106-13.127, p=0.007). 4) Both NGF-βpre (OR=1.159, 95% CI 1.045-1.286, p=0.005) and NGF-βpost-1 hr (OR=1.098, 95% CI 1.030-1.170, p=0.004) were independent predictors for the increase of LF/HF at HRVpost-3 mo.. AF catheter ablation increases plasma level of NGF-β, and high plasma levels of NGF-βpre was associated with higher sympathetic nerve activity and higher frequency of APCs in HRVpost-3 mo.

Topics: Aged; Atrial Fibrillation; Catheter Ablation; Female; Heart Rate; Humans; Male; Middle Aged; Nerve Growth Factor; Nerve Growth Factors; Transforming Growth Factor beta; Treatment Outcome

Left atrial (LA) remodeling associated with atrial fibrillation (AF) is known to be related to inflammation and collagen turnover. We investigated the changes in the biomarkers of inflammation and collagen turnover in relation to LA reverse remodeling during the 1st year after AF ablation.. Biomarkers of inflammation [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6)] and collagen turnover [matrix metalloproteinase-2 (MMP-2), tissue inhibitor of MMP-2 (TIMP-2), transforming growth factor beta 1 (TGF-β1)], as well as asymmetric dimethylarginine (ADMA) and adiponectin levels were measured, and echocardiographic measurements were obtained before and 3, 6, and 12 months after ablation in 60 AF patients (49 males; age, 57.6 ± 10.9 years).. During a 12.1 (11.5-12.9)-month follow-up period, AF recurred in 29 patients (48 %). Neither the LA volume (LAV) nor the left ventricular ejection fraction (LVEF) changed significantly during the 1st year in this group, but the LAV decreased significantly, and the LVEF increased significantly in the nonrecurrence group. The hs-CRP and IL-6 decreased after ablation but returned near to baseline levels in both groups by 12 months. The MMP-2 remained increased during the 1st year in both groups, whereas the TIMP-2 increased markedly in the nonrecurrence group but did not change substantially in the recurrence group. The TGF-β1 increased in both groups, but the change was less pronounced in the recurrence group. The ADMA and adiponectin levels did not change substantially in either group.. Despite reverse remodeling, the inflammation and collagen turnover biomarker levels are quite progressive during the 1st year after ablation and may explain the late AF recurrence.

Topics: Adiponectin; Arginine; Atrial Fibrillation; Biomarkers; C-Reactive Protein; Catheter Ablation; Diagnostic Imaging; Echocardiography; Electrocardiography; Extracellular Matrix; Female; Humans; Inflammation; Interleukin-6; Male; Matrix Metalloproteinase 2; Middle Aged; Predictive Value of Tests; Recurrence; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta; Treatment Outcome

Atrial fibrosis is considered as the basis in the development of long-standing atrial fibrillation (AF). However, in advanced heart failure (HF), the independent role of fibrosis for AF development is less clear since HF itself leads to atrial scarring. Our study aimed to differentiate patients with AF from patients without AF in a population consisting of patients with advanced HF. Myocardial samples from the right atrial and the left ventricular wall were obtained during heart transplantation from the explanted hearts of 21 male patients with advanced HF. Long-standing AF was present in 10 of them and the remaining 11 patients served as sinus rhythm controls. Echocardiographic and hemodynamic measurements were recorded prior to heart transplantation. Collagen volume fraction (CVF), transforming growth factor-beta (TGF-beta), and connective tissue growth factor (CTGF) expression in myocardial specimens were assessed histologically and immunohistochemically. The groups were well matched according to age (51.9+/-8.8 vs. 51.3+/-9.3 y) and co-morbidities. The AF group had higher blood pressure in the right atrium (13.6+/-7.7 vs. 6.0+/-5.0 mmHg; p=0.02), larger left atrium diameter (56.1+/-7.7 vs. 50+/-5.1 mm; p=0.043), higher left atrium wall stress (18.1+/-2.1 vs. 16.1+/-1.7 kdynes/m(2); p=0.04), and longer duration of HF (5.0+/-2.9 vs. 2.0+/-1.6 y, p=0.008). There were no significant differences in CVF (p=0.12), in CTGF (p=0.60), and in TGF-beta expression (p=0.66) in the atrial myocardium between the two study groups. In conclusions, in advanced HF, atrial fibrosis expressed by CVF is invariably present regardless of occurrence of AF. In addition to atrial wall fibrosis, increased wall stress might contribute to AF development in long-standing AF.

Topics: Aging; Atrial Fibrillation; Blood Pressure; Collagen; Diagnosis, Differential; Endomyocardial Fibrosis; Heart Atria; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Transforming Growth Factor beta

Atrial fibrosis plays a role in the development of a vulnerable substrate for atrial fibrillation (AF). Transforming growth factor (TGF)-β(1) is related to the degree of atrial fibrosis and the recurrence of AF after surgical maze procedures. Whether TGF-β(1) is associated with the outcome after catheter ablation for AF remains unclear.. The purpose of this study was to investigate whether plasma TGF-β(1) was an independent predictor of AF recurrence after catheter ablation.. Two hundred consecutive AF patients (154 with paroxysmal AF and 46 with nonparoxysmal AF) underwent catheter ablation. Their TGF-β(1) levels and clinical and echocardiographic data were collected before ablation.. Thirty patients (65%) with nonparoxysmal AF and 57 (37%) with paroxysmal AF had AF recurrence after catheter ablation. Among patients with nonparoxysmal AF, those experiencing recurrence had higher TGF-β(1) levels than did those who did not experience recurrence (34.63 ± 11.98 ng/mL vs 27.33 ± 9.81 ng/mL; P = .026). In patients with paroxysmal AF, recurrence was not associated with different TGF-β(1) levels. In patients with nonparoxysmal AF, TGF-β(1) levels and left atrial diameter (LAD) were independent predictors of AF recurrence after catheter ablation. Moreover, TGF-β(1) levels had an incremental value over LAD in predicting AF recurrence after catheter ablation (global χ(2) of LAD alone: 6.3; LAD and TGF-β(1) levels: 11.9; increment in global χ(2) = 5.6; P = .013). Patients with small LAD and low TGF-β(1) levels had the lowest AF recurrence rate at 11%.. TGF-β(1) level is an independent predictor of AF recurrence in patients with nonparoxysmal AF and might be useful for identifying those patients likely to have better outcomes after catheter ablation.

Topics: Atrial Fibrillation; Catheter Ablation; Echocardiography; Female; Humans; Logistic Models; Male; Middle Aged; Predictive Value of Tests; Recurrence; ROC Curve; Transforming Growth Factor beta; Treatment Outcome

Obesity is associated with atrial fibrillation (AF); however, the mechanisms by which it induces AF are unknown.. To examine the effect of progressive weight gain on the substrate for AF.. Thirty sheep were studied at baseline, 4 months, and 8 months, following a high-calorie diet. Ten sheep were sampled at each time point for cardiac magnetic resonance imaging and hemodynamic studies. High-density multisite biatrial epicardial mapping was used to quantify effective refractory period, conduction velocity, and conduction heterogeneity index at 4 pacing cycle lengths and AF inducibility. Histology was performed for atrial fibrosis, inflammation, and intramyocardial lipidosis, and molecular analysis was performed for endothelin-A and -B receptors, endothelin-1 peptide, platelet-derived growth factor, transforming growth factor β1, and connective tissue growth factor.. Increasing weight was associated with increasing left atrial volume (P = .01), fibrosis (P = .02), inflammatory infiltrates (P = .01), and lipidosis (P = .02). While there was no change in the effective refractory period (P = .2), there was a decrease in conduction velocity (P<.001), increase in conduction heterogeneity index (P<.001), and increase in inducible (P = .001) and spontaneous (P = .001) AF. There was an increase in atrial cardiomyocyte endothelin-A and -B receptors (P = .001) and endothelin-1 (P = .03) with an increase in adiposity. In association, there was a significant increase in atrial interstitial and cytoplasmic transforming growth factor β1 (P = .02) and platelet-derived growth factor (P = .02) levels.. Obesity is associated with atrial electrostructural remodeling. With progressive obesity, there were changes in atrial size, conduction, histology, and expression of profibrotic mediators. These changes were associated with spontaneous and more persistent AF.

Topics: Analysis of Variance; Animals; Atrial Fibrillation; Biomarkers; Blotting, Western; Connective Tissue Growth Factor; Disease Progression; Endothelin-1; Heart Atria; Heart Conduction System; Hemodynamics; Immunoenzyme Techniques; Magnetic Resonance Imaging; Obesity; Platelet-Derived Growth Factor; Receptor, Endothelin A; Receptor, Endothelin B; Refractory Period, Electrophysiological; Sheep; Statistics, Nonparametric; Transforming Growth Factor beta

The degree of electroanatomical remodeling of the left atrial (LA) affects the clinical outcome after rhythm control of atrial fibrillation (AF). Our hypothesis was that plasma concentrations of transforming growth factor (TGF)-β and tissue inhibitor of metalloproteinase (TIMP)-1 reflect LA voltage and structural remodeling in patients with non-valvular AF.. In the study, 242 patients (male 79.4%, 55.1 ± 11.0 years old) with AF (155 paroxysmal AF, 87 persistent AF) underwent catheter ablation. Pre-ablation plasma concentrations of TGF-β and TIMP-1 and the degree of electroanatomical remodeling quantified by LA voltage map (NavX) and 3D-CT were evaluated. The mean LA voltage and volume were compared in patients with high TGF-β (≥10.0 ng/ml, H-TGF) vs. low TGF-β (<10.0 ng/ml, L-TGF) and high TIMP-1 (≥1.1 ng/ml, H-TIMP) vs. low TIMP-1 (<1.1 ng/ml, L-TIMP). Patients with H-TGF had lower mean LA voltage (P=0.014) and greater LA volume (P=0.022), particularly, posterior venous LA volume (P=0.005) than those with L-TGF. In patients with H-TIMP, the mean LA voltage (P=0.019) was lower than those with L-TIMP. LA volume was significantly higher (P<0.001) in patients with ejection fraction ≤58% than those with >58%.. In patients with non-valvular AF, high plasma concentrations TGF-β and TIMP-1 and low ejection fraction were closely related with electroanatomical remodeling of LA.

Topics: Adult; Aged; Atrial Fibrillation; Biomarkers; Biomechanical Phenomena; Electrophysiologic Techniques, Cardiac; Electrophysiological Phenomena; Female; Heart Atria; Humans; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies; Stroke Volume; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Topics: Atrial Fibrillation; Biomechanical Phenomena; Heart Atria; Humans; Predictive Value of Tests; Stroke Volume; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. The pathophysiology of AF involves electrical, structural and contractile remodeling, which is associated with changes in cardiac gene expression. Previous studies of gene-expression changes in clinical AF have mostly been limited to a small number of candidate genes and have not all been well controlled for underlying heart disease. The present study assessed AF-related gene-expression changes in valve-disease patients with microarrays representing the cardiac transcriptome. Right atrial appendages from 11 patients with chronic AF and underlying valvular heart disease (AF-VHD) and seven patients in sinus rhythm with VHD (SR-VHD) were individually compared to an age-matched sinus-rhythm control group (SR-CTRL, 11 patients) using cardiac-specific microarray analysis. One-class statistical analysis was used to identify genes differentially expressed between SR-VHD and SR-CTRL patients. Two-class statistical analysis was used to identify genes differentially expressed between AF-VHD and SR-VHD patients. Out of 3863 analyzed genes, 832 genes were differentially expressed between SR-VHD and SR-CTRL patients, and 169 genes were differentially expressed between AF-VHD and SR-VHD patients. Striking AF-related changes included altered expression of nine genes pointing towards the development of fibrosis (e.g. upregulation of transforming growth factor beta1), and changes in eight genes potentially related to an increased risk of thromboembolic events (e.g. upregulation of alpha2 macroglobulin). Microarray results were confirmed by quantitative PCR. Our results suggest that AF produces a characteristic profile of gene-expression changes that may be related to the pathophysiology of the arrhythmia.

Topics: Aged; alpha-Macroglobulins; Atrial Fibrillation; Female; Gene Expression Profiling; Heart Valve Diseases; Humans; Male; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Transforming Growth Factor beta; Transforming Growth Factor beta1

Studies on patients and large animal models suggest the importance of atrial fibrosis in the development of atrial fibrillation (AF). To investigate whether increased fibrosis is sufficient to produce a substrate for AF, we have studied cardiac electrophysiology (EP) and inducibility of atrial arrhythmias in MHC-TGFcys33ser transgenic mice (Tx), which have increased fibrosis in the atrium but not in the ventricles. In anesthetized mice, wild-type (Wt) and Tx did not show significant differences in surface ECG parameters. With transesophageal atrial pacing, no significant differences were observed in EP parameters, except for a significant decrease in corrected sinus node recovery time in Tx mice. Burst pacing induced AF in 14 of 29 Tx mice, whereas AF was not induced in Wt littermates (P<0.01). In Langendorff perfused hearts, atrial conduction was studied using a 16-electrode array. Epicardial conduction velocity was significantly decreased in the Tx RA compared with the Wt RA. In the Tx LA, conduction velocity was not significantly different from Wt, but conduction was more heterogeneous. Action potential characteristics recorded with intracellular microelectrodes did not reveal differences between Wt and Tx mice in either atrium. Thus, in this transgenic mouse model, selective atrial fibrosis is sufficient to increase AF inducibility.

Topics: Action Potentials; Amino Acid Substitution; Animals; Atrial Fibrillation; Cardiac Pacing, Artificial; Electrocardiography; Fibrosis; Genetic Predisposition to Disease; Heart Atria; Heart Conduction System; Mice; Mice, Transgenic; Models, Animal; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Angiotensin II; Animals; Arrhythmias, Cardiac; Atrial Fibrillation; Dogs; Fibrosis; Heart Atria; Heart Failure; Humans; Mice; Mice, Transgenic; Models, Animal; Myocardium; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Remodeling

Atrial fibrillation (AF) is accompanied by intracellular calcium overload. The purpose of this study was to assess the role of calcium-dependent calpains and cytokines during AF. Atrial tissue samples from 32 patients [16 with chronic AF and 16 in sinus rhythm (SR)] undergoing open heart surgery were studied. Atrial expression of calpain I and II, calpastatin, troponin T (TnT), troponin C (TnC), and cytokines [interleukin (IL)-1 beta, IL-2, IL-6, IL-8, IL-10, transforming growth factor (TGF)-beta 1, and tumor necrosis factor-alpha] were determined. Expression of calpain I was increased during AF (461 +/- 201% vs. 100 +/- 34%, P < 0.05). Amounts of calpain II and calpastatin were unchanged. Total calpain enzymatic activity was more than doubled during AF (35.2 +/- 17.7 vs. 12.4 +/- 9.2 units, P < 0.05). In contrast to TnC, TnT levels were reduced in fibrillating atria by 26% (P < 0.05), corresponding to the myofilament disintegration seen by electron microscopy. Small amounts of only IL-2 and TGF-beta 1 mRNA and protein were detected regardless of the underlying cardiac rhythm. In conclusion, atria of patients with permanent AF show evidence of calpain I activation that might contribute to structural remodeling and contractile dysfunction, whereas there is no evidence of activation of tissue cytokines.

Topics: Actin Cytoskeleton; Adult; Aged; Atrial Appendage; Atrial Fibrillation; Blotting, Western; Calcium-Binding Proteins; Calpain; Cytokines; Female; Humans; In Vitro Techniques; Interleukin-2; Male; Middle Aged; Myocardium; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

We have previously reported that pulsatile mechanical stretch in vitro induced rapid secretion of vascular endothelial growth factor (VEGF) by cultured cardiac myocytes and that the stretch-induced secretion of VEGF was mainly mediated by secretion of transforming growth factor (TGF)-beta1 by cardiac myocytes in an autocrine fashion. To investigate whether tachycardia-induced mechanical overload increases serum levels of VEGF and TGF-beta1, we investigated the serum levels of VEGF and TGF-beta1 in patients with atrial fibrillation undergoing defibrillation therapy. The serum VEGF level before defibrillation was significantly increased in 13 out of 20 patients (89.48 +/- 16.09 pg/ml [mean +/- SE]). After defibrillation, the serum VEGF level in these 13 patients significantly (p = 0.019) decreased (65.04 +/- 16.61 pg/ml [mean +/- SE]), although it increased slightly in one patient. The serum TGF-beta1 level before defibrillation therapy (13.01 +/- 1.97 pg/ml [mean +/- SE]) in these 12 patients also decreased after defibrillation therapy (11.47 +/- 2.06 pg/ml [mean +/- SE]). The changes in serum VEGF level significantly correlated with those in the serum TGF-beta1 level in these 12 patients (r = 0.73, p < 0.05, n = 12). Our data suggest that tachyarrhythmia-induced mechanical overload can increase the serum VEGF level, which can be a useful clinical marker for relative myocardial oxygen shortage in such patients.

Topics: Aged; Atrial Fibrillation; Electric Countershock; Endothelial Growth Factors; Female; Humans; Lymphokines; Male; Tachycardia; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Atrial Fibrillation; Endothelial Growth Factors; Humans; Lymphokines; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors