endothelin-1 and Atrial-Fibrillation

Since its identification in 1988 and the recognition of its primary role as a potent vasoconstrictor, endothelin has been extensively studied and is now considered as a ubiquitous protein, involved in important aspects of human homeostasis as well as in several pathophysiological pathways, mostly associated with cardiovascular disease. From an evolutionary point of view, endothelin consists a primitive molecule with the rare characteristic of being exactly the same in all mammals, thus permitting scientists to perform experiments in animals and doing predictions for humans. The understanding of its contribution to the genesis, evolution and maintenance of disease through activation of special receptor subtypes has led to the development of both selective and unselective receptor antagonists. Despite the disappointing results of these antagonists in the field of heart failure, almost from the initial animal trials of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension, it has been demonstrated that the drug leads at least to hemodynamic and clinical improvement of the patients, thus receiving official approval for the management of this rare but eventually lethal disease. Resistant hypertension is another area where endothelin receptor blockers might potentially play a role, while the pathophysiological role of endothelin in atherosclerotic coronary artery disease is well-established and the relative research goes on. The main goal of this review is to describe the endothelin system and mostly to enlighten its role in pathophysiologic pathways, as well to state the relative research in the various fields of cardiovascular disease and also highlight its prognostic significance wherever there exists one.

Topics: Animals; Atherosclerosis; Atrial Fibrillation; Bosentan; Cardiovascular Diseases; Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Hypertension, Pulmonary; Phenylpropionates; Predictive Value of Tests; Pyridazines; Receptors, Endothelin; Sulfonamides

Atrial fibrillation (AF) recurrence after ablation is difficult to predict. The development of AF is associated with inflammation, and inflammatory markers such as big endothelin-1 (big ET-1) reflect inflammatory status. It is unknown, however, whether big ET-1 can be used as a predictor for AF recurrence. The aim of this study was to investigate the relationship between plasma levels of big ET-1 and AF recurrence.. A total of 158 patients who had undergone primary ablation for symptomatic and/or drug-refractory AF, including 103 with paroxysmal and 55 with persistent AF, were included in this study. Left atrial diameter was measured with echocardiography and plasma big ET-1 levels with ELISA. All patients were followed up for at least 12 months and AF recurrence defined as an episode of AF lasting ≥ 30 s, with or without atrial flutter or atrial tachycardia.. The AF recurrence rate was 44.9% (71/158) during the median follow-up period of 22 (13, 40) months. Plasma levels of big ET-1 in the recurrence group were higher than those in the non-recurrence group in all patients [0.80 (0.54, 1.30) vs. 0.57 (0.48, 0.72) fmol·L(-) (1), p  = 0.001], in patients with paroxysmal AF [0.81 (0.46, 1.30) vs. 0.57 (0.48, 0.70) fmol·L(-) (1), p  = 0.009] as well as in patients with persistent AF [0.77 (0.57, 1.28) vs. 0.57 (0.49, 0.89) fmol·L(-) (1), p = 0.034]. Multiple logistic regression analyses showed that plasma levels of big ET-1 were associated with AF recurrence in patients with paroxysmal AF (p  = 0.037). Kaplan-Meier analysis demonstrated that the sinus rhythm maintenance rate was lower in patients with higher big ET-1 levels than those with lower levels (p  < 0.05).. Baseline plasma big ET-1 levels are associated with AF recurrence after primary ablation procedure in patients with paroxysmal AF, and may be used in the prediction of AF recurrence in these patients.

Topics: Atrial Fibrillation; Biomarkers; China; Endothelin-1; Female; Humans; Incidence; Male; Middle Aged; Recurrence; Reproducibility of Results; Risk Factors; Sensitivity and Specificity

The purpose of this study was to assess the effect of preoperative dexamethasone (DEX) on the occurrence of postoperative atrial fibrillation (AF).. Prospective, randomized, double-blind, placebo-controlled clinical trial.. Tertiary referral center.. Seventy-eight adult patients undergoing combined valve and coronary artery bypass graft (CABG) surgery were randomized to receive either DEX or placebo.. The DEX group received dexamethasone, 0.6 mg/kg, after induction of anesthesia, and the placebo group received an equal volume of normal saline. Interleukin (IL)-6, -8, and -10; tumor necrosis factor alpha; and endothelin (ET)-1 were measured preoperatively and on postoperative days (POD) 1, 2, and 3. Complement (C-4) and C-reactive protein (CRP) were measured preoperatively and on POD 2. Exhaled nitric oxide (NO) was measured preoperatively, 15 minutes after aortic unclamping, and 1 hour after intensive care unit admission.. No significant difference in the incidence of AF was found between the placebo (41%) and DEX groups (30%) (95% confidence interval [-11%, 34%); p = 0.31). DEX significantly reduced at least 1 postoperative level of IL-6, IL-8, IL-10, CRP, and exhaled NO. DEX did not affect ET-1 or C-4 levels. IL-10 on POD 3 was positively correlated with postoperative hospital length of stay (r = 0.30, p = 0.01). Increased levels of IL-8 and IL-10 on POD 1 were positively correlated with the intubation time (r = 0.31, p = 0.01; r = 0.30, p = 0.01, respectively). Conversely, C-4 on POD 2 was negatively correlated with the intubation time and intensive care unit length of stay (r = -0.32, p = 0.006; r = -0.30, p = 0.01, respectively).. DEX did not affect the incidence of AF in patients undergoing combined CABG and valve surgery. However, it did modulate the release of several inflammatory and acute-phase response mediators that are associated with adverse outcomes.

Topics: Aged; Atrial Fibrillation; C-Reactive Protein; Cardiac Surgical Procedures; Complement C4; Coronary Artery Bypass; Dexamethasone; Double-Blind Method; Endothelin-1; Female; Glucocorticoids; Heart Valves; Humans; Interleukins; Male; Middle Aged; Nitric Oxide; Placebos; Postoperative Complications; Prospective Studies; Sodium Chloride; Time Factors; Tumor Necrosis Factor-alpha

To investigate the changes in serum levels of endothelin-1 (ET-1) and connective tissue growth factor (CTGF) in patients with atrial fibrillation (AF) and their value for predicting recurrence of AF after radiofrequency ablation (RFCA).. Sixty-six patients with paroxysmal AF (PaAF) and 72 with persistent AF (PaAF) admitted in our hospital were recruited as AF group and 80 patients with sinus rhythm as the control group, and in all the participants, serum levels of ET-1 and CTGF were measured using ELISA and Western blotting. From 6 patients with AF and 6 with sinus rhythm undergoing cardiac surgery in our hospital, tissue samples of the right atrial appendage were taken intraoperatively for observation of structural changes of the cardiomyocytes, myocardial fibrosis and expression of ET-1 and CTGF protein. In AF group, the patients receiving RFCA were followed up for 6 months following the procedure for assessment of the outcomes.. Compared with the control patients, the patients with AF showed obvious damages of the cardiomyocyte structure and myocardial fibrosis. Serum levels of ET-1 and CTGF levels were significantly higher in PaAF and PeAF groups than in the control group, and were higher in PeAF group than in PaAF group. In the patients with AF, serum ET-1 and CTGF levels were positively correlated with left atrial diameter (LAD) (. Serum levels of ET-1 and CTGF are significantly elevated in AF patients in positive correlation with AF duration. ET-1 and CTGF levels are higher in AF patients with postoperative recurrence, and they both have predictive value for recurrence of PeAF following RFCA.

Topics: Atrial Appendage; Atrial Fibrillation; Chronic Disease; Connective Tissue Growth Factor; Endothelin-1; Fibrosis; Humans

Atrial fibrillation (AF) is the most common arrhythmia in patients with hypertrophic cardiomyopathy (HCM). Data regarding the correlations of biomarkers and AF in HCM patients are rather limited. We sought to explore the associations between the presence of AF and circulating biomarkers reflecting cardiovascular function (N-terminal pro-brain natriuretic peptide, NT-pro BNP), endothelial function (big endothelin-1, big ET-1), inflammation (high-sensitivity C-reactive protein), and myocardial damage (cardiac troponin I, cTnI) in HCM patients with and without left ventricular outflow tract obstruction (LVOTO).In all, 375 consecutive HCM in-hospital patients were divided into an AF group (n = 90) and a sinus rhythm (SR) group (n = 285) according to their medical history and electrocardiogram results.In comparison with the SR group, peripheral concentrations of big ET-1, NT-pro BNP, and cTnI were significantly higher in patients with AF. Only the biomarker of big ET-1, together with palpitation and left atrial diameter (LAD), was independently associated with AF in HCM patients. Ln big ET-1 was positively related to Ln NT-pro BNP, LAD, and heart rate, but negatively related to left ventricular ejection fraction. Combined measurements of big ET-1 ≥ 0.285 pmol/L and LAD ≥ 44.5 mm indicated good predictive values in the presence of AF, with a specificity of 94% and a sensitivity of 85% in HCM patients.Big ET-1 has been identified as an independent determinant of AF, regardless of LVOTO, and is significantly related to parameters representing cardiac function and remodeling in HCM. Big ET-1 might be a valuable index to evaluate the clinical status of AF in HCM patients.

Topics: Atrial Fibrillation; Biomarkers; C-Reactive Protein; Cardiomyopathy, Hypertrophic; China; Correlation of Data; Echocardiography; Electrocardiography; Endothelin-1; Female; Heart Atria; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Retrospective Studies; Stroke Volume; Troponin I; Ventricular Outflow Obstruction; Ventricular Remodeling

Our recent study demonstrated that the nonselective cation current mediated by the transient receptor potential canonical 1 (TRPC1) channel is activated by endothelin-1 (ET-1) in human atrial myocytes; however, the related signal molecules involved are unknown.. The purpose of this study was to investigate how the TRPC1 channel is regulated by ET-1 and whether it is upregulated in human atria from patients with atrial fibrillation (AF).. Whole-cell patch technique and molecular biology techniques were used in the study.. The ET-1-evoked TRPC1 current was inhibited by the ET-1 type A (ET. These results demonstrate for the first time that TRPC1 activation by ET-1 is mediated by protein kinase C through the distinct phospholipids pathways phosphoinositide-3-kinase and phospholipase C and that the TRPC1 channel and ET

Topics: Atrial Fibrillation; Blotting, Western; Cells, Cultured; Endothelin-1; Heart Atria; Humans; Myocytes, Cardiac; Protein Kinase C; Real-Time Polymerase Chain Reaction; Reference Values; Sensitivity and Specificity; Signal Transduction; TRPC Cation Channels; Up-Regulation

Postoperative atrial fibrillation (POAF) is a common complication in patients with obstructive hypertrophic cardiomyopathy (HOCM) who undergo surgical myectomy. POAF is associated with poor outcome. The role of plasma big endothelin-1 level in predicting atrial fibrillation after surgical septal myectomy in HOCM patients has not well been studied.. A total of 118 patients with HOCM who underwent surgical septal myectomy were recruited in this study. Plasma big endothelin-1 level was measured. The heart rhythm was continuously monitored during hospital stay. Preoperative, intraoperative, and postoperative variables were collected.. POAF developed among 26 of the 118 patients (22%) in this study. Compared with those without POAF, patients with POAF were significantly older (53.5 ± 10.6 vs. 47.3 ± 13.6 years, P = 0.033), more likely to undergo mitral valve surgery (38.5% vs. 18.5%, P = 0.032), and had higher plasma big endothelin-1 levels (0.41 ± 0.19 vs. 0.27 ± 0.14 pmol/l, P = 0.001), longer hospital stay (9.1 ± 3.7 vs. 7.5 ± 2.8 days, P = 0.022), larger preoperative left atria (48.0 ± 5.2 vs. 44.1 ± 5.9 mm; P = 0.003). In the receiver operating characteristic curve analysis, the area under the curve for big endothelin-1 was 0.734 (95% CI, 0.634 to 0.834, P<0.001). In multivariate logistic regression analysis, preoperative big endothelin-1 level (OR 100.7, 95%CI: 5.0-2020.0, P = 0.003) and left atrial diameter (OR 1.106, 95%CI: 1.015-1.205, P = 0.022) were independent predictors of POAF.. Elevated preoperative plasma big endothelin-1 level is an independent predictor of POAF in HOCM patients undergoing surgical septal myectomy.

Topics: Adult; Aged; Atrial Fibrillation; Biomarkers; Cardiac Surgical Procedures; Cardiomyopathy, Hypertrophic; Endothelin-1; Female; Heart Rate; Humans; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Up-Regulation

This study analysed the association between endothelin-1 (ET-1) and left atrial dimension (LAD) and evaluated whether ET-1 can be a predictor of postoperative atrial fibrillation (POAF) after mitral valve surgery.. This is a prospective study that enrolled 80 patients who underwent isolated mitral valve surgery. Plasma concentrations of ET-1 from peripheral venous blood were tested. POAF was detected using a telemetry strip or 12-lead electrocardiogram until the time of discharge.. Patients undergoing mitral valve surgery with preoperative sinus rhythm (n = 80; average age 63.9 ± 7.9 years) were recruited to this study. POAF was documented in 31 (38.8%) patients. Preoperative plasma ET-1 levels were higher in patients with POAF compared to those without POAF (2.23 ± 0.67 vs 1.68 ± 0.59 pg/ml; P < 0.001). The plasma concentrations of ET-1 were positively correlated with LAD (Pearson's r = 0.421; P < 0.001). Multivariate logistic regression analysis revealed that LAD (odds ratio 1.170, 95% confidence interval 1.039-1.317; P = 0.009) and preoperative plasma ET-1 levels (upper versus lower 50th percentile: odds ratio 3.713, 95% confidence interval 1.085-12.701; P = 0.037) were predictors of POAF after mitral valve surgery.. Plasma levels of ET-1 were positively correlated with LAD in patients with mitral valve disease. An elevated preoperative plasma ET-1 level can be used as a predictor of POAF after mitral valve surgery.

Topics: Aged; Atrial Fibrillation; Dilatation; Electrocardiography; Endothelin-1; Female; Heart Atria; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Humans; Male; Middle Aged; Mitral Valve; Odds Ratio; Postoperative Complications; Prospective Studies; Treatment Outcome

The prognostic role of big endothelin-1 (ET-1) in atrial fibrillation (AF) is unclear. We aimed to assess its predictive value in patients with AF.. A total of 716 AF patients were enrolled and divided into two groups based on the optimal cut-off value of big ET-1 in predicting all-cause mortality. The primary outcomes were all-cause mortality and major adverse events (MAEs). Cox regression analysis and net reclassification improvement (NRI) analysis were performed to assess the predictive value of big ET-1 on outcomes.. With the optimal cut-off value of 0.55 pmol/L, 326 patients were classified into the high big ET-1 levels group. Cardiac dysfunction and left atrial dilation were factors related to high big ET-1 levels. During a median follow-up of 3 years, patients with big ET-1 ≥ 0.55 pmol/L had notably higher risk of all-cause death (44.8% vs. 11.5%, p < 0.001), MAEs (51.8% vs. 17.4%, p < 0.001), cardiovascular death, major bleeding, and tended to have higher thromboembolic risk. After adjusting for confounding factors, high big ET-1 level was an independent predictor of all-cause mortality (hazard ratio (HR) 2.11, 95% confidence interval (CI) 1.46-3.05; p < 0.001), MAEs (HR 2.05, 95% CI 1.50-2.80; p = 0.001), and cardiovascular death (HR 2.44, 95% CI 1.52-3.93; p < 0.001). NRI analysis showed that big ET-1 allowed a significant improvement of 0.32 in the accuracy of predicting the risk of both all-cause mortality and MAEs.. Elevated big ET-1 levels is an independent predictor of long-term all-cause mortality, MAEs, and cardiovascular death in patients with AF.

Topics: Aged; Atrial Fibrillation; Electrocardiography; Endothelin-1; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Regression Analysis; Retrospective Studies; Thromboembolism; Treatment Outcome

Endothelin-1 (ET-1) is a potent vasoconstrictor, mitogen and inflammatory factor that may contribute to development of atrial fibrillation (AF). Plasma ET-1 levels are increased in hyperthyroid patients, but studies evaluating its relation to AF development in hyperthyroid patients are lacking.. The present study seeks to evaluate the relation of plasma ET-1 to AF development as a function of thyroid status.. Blood samples from euthyroid patients (n = 41), hypothyroid (n = 61), hyperthyroid (n = 41), AF with hyperthyroidism (n = 9), and euthyroid AF (n = 10) patients were collected. Plasma ET-1, CRP, and thyroid hormone levels were measured and compared between groups.. Plasma ET-1 levels were higher in hyperthyroid and euthyroid AF patients> hyperthyroid-non-AF > hypo and euthyroid non-AF patients. Plasma ET-1 levels positively correlated with free T3 and T4 levels, and negatively with TSH levels. By multivariate analysis, plasma ET-1 was positively associated with AF, hyperthyroidism, and age. Plasma CRP did not vary by study group in either univariate or multivariate analyses.. Plasma ET-1 is associated with AF, elevated in hyperthyroid patients and positively correlated with thyroid hormone levels, suggesting that hyperthyroidism may increase ET-1 expression and release. This study may guide development of novel predictors of AF associated with hyperthyroidism, and may help to personalize therapy in hyperthyroid patients.

Topics: Adrenergic beta-Antagonists; Adult; Atrial Fibrillation; C-Reactive Protein; Carbimazole; Endothelin-1; Female; Humans; Hyperthyroidism; Male; Multivariate Analysis

The relation between arrhythmias and stress is known. The aim of our current study was to elucidate whether plasma levels of previously described stress parameters are altered in highly symptomatic patients with atrial fibrillation (AF) per se and in patients undergoing ablation therapy by pulmonary vein isolation (PVI).. 96 patients with AF undergoing PVI were recruited. Plasma levels of Endothelin-1 (ET-1), MCP-1 and Chromogranin-A (CGA) were measured before and three months after ablation completed with clinical follow-up with respect to AF recurrence. Additionally, we examined 40 healthy age- and sex-matched volunteers as a reference.. Symptomatic AF patients showed increased levels of ET-1 compared to healthy controls (2.62pg/ml vs. 1.57pg/ml; p<0.01). Baseline levels of ET-1 were higher in patients presenting with AF after PVI (2.96pg/ml vs. 2.57pg/ml;p = 0.02). The temporal comparison revealed decreased ET-1 levels in patients without (2.57pg/ml vs. 2.33pg/ml; p<0.01) and unchanged ET-1 levels in patients with AF after PVI. Baseline MCP-1 was increased in AF patients vs. controls (268pg/ml vs. 227 pg/ml; p = 0.03). Both groups, with and without AF after PVI, showed an increase of MCP-1 compared to baseline (268pg/ml vs. 349pg/ml;p<0.01; 281pg/ml vs. 355pg/ml;p = 0.03). CGA was lower in AF patients compared to healthy controls (13.8ng/ml vs. 25.6ng/ml;p<0.01). Over time patients without AF after PVI showed an increase of CGA (14.2ng/ml vs. 20.7ng/ml;p<0.01). No change was observed in patients with AF after PVI.. Our study demonstrated dysregulated levels of ET-1, MCP-1 and CGA in symptomatic AF patients. We could demonstrate an association between ET-1 to presence or absence of AF. Furthermore, we could show that a decrease of ET-1 as well as an increase of CGA after PVI, representing a trend towards control cohort levels, were both associated with restoration of sinus rhythm. These results provide new insights into the role of stress-related biomarkers in AF and AF treatment by ablation therapy.

Topics: Aged; Atrial Fibrillation; Biomarkers; Chemokine CCL2; Chromogranin A; Endothelin-1; Humans; Middle Aged; Pulmonary Veins; Stress, Physiological

Atrial fibrillation (AF) is the most common arrhythmia in the general population. There are numerous factors associated with the incidence and relapse of AF. It seems that some of them, such as neurohumoral changes, may affect AF-related atrial structural remodeling and lead to recurrence of AF.. The study aimed to assess the predictive value of plasma brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), aldosterone (ALD), and endothelin 1 (ET-1) concentrations before and after electrical cardioversion (CV).. The study included 60 patients with a dual-chamber pacemaker, persistent AF, and preserved left ventricular function who underwent successful CV. Blood samples were collected before and 24 hours and 7 days after CV. Recurrence of AF was identified by pacemaker logs lasting 30 minutes or longer.. During a 12-month follow-up, only 5 patients (8%) had no recurrence of AF. Before cardioversion, ANP, ALD, and ET-1 levels were the same as those observed in the control group. BNP levels were significantly elevated and the level of 1237 fmol/ml or higher differentiated between patients with and without the recurrence of AF (sensitivity, 68%; specificity, 67%). Sinus rhythm restoration resulted in a significant decrease only in the BNP level. The BNP level of 700 fmol/ml or higher on day 7 after cardioversion was the most predictive for AF recurrence (sensitivity, 78%; specificity, 71%). In a multivariate analysis, only BNP levels of 700 fmol/ml or higher on day 7 after cardioversion (P = 0.04) and lack of amiodarone (P = 0.03) were independent predictors of AF recurrence.. A BNP level of 700 fmol/ml or higher 7 days after cardioversion is an independent predictor of AF recurrence during 12 months after cardioversion. ANP, ALD, and ET-1 levels at baseline or 7 days after cardioversion are not predictive of AF recurrence.

Topics: Aged; Aged, 80 and over; Aldosterone; Atrial Fibrillation; Atrial Natriuretic Factor; Electric Countershock; Endothelin-1; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Recurrence; Sensitivity and Specificity

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

An irregular ventricular response during atrial fibrillation (AF) has been shown to mediate an increase in sympathetic nerve activity in human subjects. The molecular mechanisms remain unclear. This study aimed to investigate the impact of rate and irregularity on nerve growth factor (NGF) expression in cardiomyocytes, since NGF is known to be the main contributor to cardiac sympathetic innervation density. Cell cultures of neonatal rat ventricular myocytes were electrically stimulated for 48 h with increasing rates (0, 5 and 50 Hz) and irregularity (standard deviation (SD)=5%, 25% and 50% of mean cycle length). Furthermore, we analyzed the calcineurin-NFAT and the endothelin-1 signalling pathways as possible contributors to NGF regulation during arrhythmic stimulation. We found that the increase of NGF expression reached its maximum at the irregularity of 25% SD by 5 Hz (NGF: 5 Hz 0% SD=1 vs. 5Hz 25% SD=1.57, P<0.05). Specific blockade of the ET-A receptor by BQ123 could abolish this NGF increase (NGF: 5 Hz 25% SD+BQ123=0.66, P<0.05). High frequency electrical field stimulation (HFES) with 50 Hz decreased the NGF expression in a significant manner (NGF: 50Hz=0.55, P<0.05). Inhibition of calcineurin-NFAT signalling with cyclosporine-A or 11R-VIVIT abolished the HFES induced NGF down-regulation (NGF: 50 Hz+CsA=1.14, P<0.05). In summary, this study reveals different signalling routes of NGF expression in cardiomyocytes exposed to increasing rates and irregularity. Whether this translates into different degrees of NGF expression and possibly neural sympathetic growth in various forms of ventricular rate control during AF remains to be elucidated in further studies.

Topics: Animals; Atrial Fibrillation; Atrial Natriuretic Factor; Calcineurin; Cell Nucleus; Cells, Cultured; Culture Media, Conditioned; Electric Stimulation; Endothelin A Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Heart Ventricles; Myocytes, Cardiac; Nerve Growth Factor; Neurites; NFATC Transcription Factors; Peptides, Cyclic; Primary Cell Culture; Rats; Signal Transduction; Transcription, Genetic

Pre-treatment with dietary ω3 polyunsaturated fatty acids (ω3-PUFA) has been reported to reduce the incidence of new-onset atrial fibrillation (AF) following cardiac surgery. In a canine cardiac surgery model, we evaluated the impact of dietary ω3-PUFA on atrial electrophysiological properties, inflammatory markers, the atrial endothelin-1 (ET-1) system, and the expression and distribution of connexin 43.. Adult mongrel dogs received either normal chow (NC, n = 11) or chow supplemented with fish oil (FO, 0.6 g ω3-PUFA/kg/day, n = 9) for 3 weeks before surgery. A left thoracotomy was performed, and the left atrial appendage (LAA) was excised. Atrial pacing/recording wires were placed, and the pericardium/chest was closed. The atrial ratio of ω6/ω3 lipids decreased from 15-20 in NC to 2-3 in FO. FO treatment lowered pre-surgical and stabilized post-surgical arachidonate levels. Peak neutrophil to lymphocyte ratio was lower and decayed faster in FO-treated animals. Extensive inflammatory cell infiltration was present in NC atria, but was reduced in FO-treated dogs. FO-treated animals had lower post-surgical atrial expression of inducible nitric oxide synthase (iNOS) and reduced plasma ET-1. Expression of ET-1 and inositol trisphosphate receptor type-2 proteins in the LAA was also reduced. FO treatment prolonged post-operative atrial effective refractory period, slowed heart rate, and enhanced heart rate variability. Importantly, AF (>30 s) was inducible in four of six NC dogs, but no FO dogs.. Dietary FO attenuated AF inducibility following cardiac surgery by modulating autonomic tone and heart rate. FO also reduced atrial inflammation, iNOS, and ET-1 expression.

Topics: Animals; Atrial Fibrillation; C-Reactive Protein; Cardiac Surgical Procedures; Connexin 43; Dogs; Endothelin-1; Fatty Acids, Omega-3; Female; Heart Rate; Inositol 1,4,5-Trisphosphate Receptors; Lipids; Male; Nitric Oxide Synthase Type II; Peroxidase; Phosphorylation; Postoperative Complications; Receptors, Endothelin

Atrial fibrillation (AF) promotes atrial remodeling and can develop secondary to heart failure or mitral valve disease. Cardiac endothelin-1 (ET-1) expression responds to wall stress and can promote myocyte hypertrophy and interstitial fibrosis. We tested the hypothesis that atrial ET-1 is elevated in AF and is associated with AF persistence.. Left atrial appendage tissue was studied from coronary artery bypass graft, valve repair, and/or Maze procedure in patients in sinus rhythm with no history of AF (SR, n=21), with history of AF but in SR at surgery (AF/SR, n=23), and in AF at surgery (AF/AF, n=32). The correlation of LA size with atrial protein and mRNA expression of ET-1 and ET-1 receptors (ETAR and ETBR) was evaluated. LA appendage ET-1 content was higher in AF/AF than in SR, but receptor levels were similar. Immunostaining revealed that ET-1 and its receptors were present both in atrial myocytes and in fibroblasts. ET-1 content was positively correlated with LA size, heart failure, AF persistence, and severity of mitral regurgitation. Multivariate analysis confirmed associations of ET-1 with AF, hypertension, and LA size. LA size was associated with ET-1 and MR severity. ET-1 mRNA levels were correlated with genes involved in cardiac dilatation, hypertrophy, and fibrosis.. Elevated atrial ET-1 content is associated with increased LA size, AF rhythm, hypertension, and heart failure. ET-1 is associated with atrial dilatation, fibrosis, and hypertrophy and probably contributes to AF persistence. Interventions that reduce atrial ET-1 expression and/or block its receptors may slow AF progression.

Topics: Aged; Atrial Appendage; Atrial Fibrillation; Atrial Function, Left; Cardiomegaly; Echocardiography; Endothelin-1; Female; Fibrosis; Heart Diseases; Heart Failure; Humans; Hypertension; Linear Models; Male; Middle Aged; Mitral Valve Insufficiency; Receptor, Endothelin A; Receptor, Endothelin B; Risk Assessment; Risk Factors; RNA, Messenger; Up-Regulation

Atrial fibrillation (AF) may result in endocardial endothelium dysfunction. The main objective of the study was to evaluate the plasma concentration of endothelin-1 (ET-1) during persistent AF and after sinus rhythm recovery following direct-current cardioversion and to assess the predictive value of ET-1 in AF patients.. The study group consisted of 43 patients with persistent AF and normal left ventricle systolic function who had undergone successful cardioversion. Blood samples were collected twice: 24 hours before and 24 hours after cardioversion. All patients were also examined in terms of sinus rhythm maintenance on the 30th day after cardioversion.. There were no differences in ET-1 plasma concentration between the persistent AF group and the control group (2.6 ± 2.9 fmol/mL vs 2.3 ± 4.5 fmol/mL, NS). Plasma ET-1 levels did not change within 24 hours after successful cardioversion (2.5 ± 2.8 fmol/mL vs 2.6 ± 2.9 fmol/mL, NS). There was no correlation between the baseline plasma levels of ET-1 in patients with persistent AF and sinus rhythm maintenance 30 days after cardioversion.. Persistent AF does not affect plasma ET-1 concentration in patients with normal left ventricle systolic function and with no symptoms of heart failure. There are no significant changes in plasma ET-1 level during the 24 hours after cardioversion.

Topics: Aged; Atrial Fibrillation; Biomarkers; Echocardiography; Electric Countershock; Electrocardiography; Endothelin-1; Female; Humans; Male; Middle Aged; Predictive Value of Tests; Prognosis; Recurrence; Ventricular Function, Left

A considerable rate of atrial fibrillation (AF) recurrence is one of the major limitations of pulmonary vein isolation (PVI). Although endothelin-1 (ET-1) is involved in atrial remodeling, it is unknown whether plasma ET-1 level before PVI can be used as a predictive factor for AF recurrence.. The goal of this study was to clarify whether the plasma ET-1 level, before PVI, can be used as a predictive factor for AF recurrence after PVI.. Fifty-one patients without structural heart disease who underwent PVI for symptomatic and drug-refractory paroxysmal/persistent AF were included in the study. Neurohumoral factors were measured, and transthoracic echocardiography was performed before and 6 months after each PVI. Mean left atrial (LA) pressure and arterial blood pressure (BP) were evaluated just before PVI. AF recurrence was detected by 12-lead electrocardiogram (ECG), Holter ECG, and event ECG monitor recordings, 3 to 6 months after PVI.. Among plasma levels of ET-1, atrial and brain natriuretic peptides, renin, angiotensin II, and aldosterone before PVI, only ET-1 was significantly higher in the recurrence group compared with the nonrecurrence group (2.15 +/- 0.51 vs. 1.65 +/- 0.35 pg/ml, P < .001). Both mean LA pressure and diastolic BP in the recurrence group were significantly higher than in the nonrecurrence group (mean LA pressure, 10 +/- 3 vs. 8 +/- 3 mm Hg, P < .01; diastolic BP, 82 +/- 11 vs. 71 +/- 12 mm Hg, P < .01). The plasma ET-1 level and mean LA pressure were correlative. Multiple logistic regression analyses showed that higher levels of plasma ET-1 and diastolic BP were significant prognostic predictors of AF recurrence 3 to 6 months after PVI (P < .01 and P < .05, respectively).. Our findings suggest that the plasma ET-1 level before PVI could be a crucial predictor of AF recurrence 3 to 6 months after PVI.

Topics: Aged; Atrial Fibrillation; Biomarkers; Catheter Ablation; Endothelin-1; Female; Humans; Male; Middle Aged; Predictive Value of Tests; Pulmonary Veins; Recurrence; Time Factors

Atrial fibrillation (AF) is a common comorbidity in heart failure (HF) patients and is classically associated with acceleration in the rate of HF progression. The precise mechanism for this interaction is unclear, but comprises "bidirectional" aspects in which AF promotes HF and HF also increases the likelihood of AF. We therefore studied the relationship between AF in an ovine model of pacing-induced congestive HF, in an attempt to identify the mechanisms that underpin the apparent synergistic relationship between AF and HF.. Sixteen adult sheep were paced at 190 beats/min for 21 days (HF). AF was induced in 8 of these animals at 14 days' pacing using programmed extrastimuli (HF + AF). Left ventricular hemodynamics and the pattern of cardiac neurohormonal activation, via coronary sinus (CS) sampling, were determined at rest and during submaximal exercise testing in both groups at 21 days and after AF reversion (by atrial defibrillation) at 21 days. CS norepinephrine (NE), endothelin (ET-1), and brain natriuretic peptide (BNP) levels were significantly increased in HF + AF animals, whereas LV end-diastolic pressure (EDP) and LV dP/dt max were significantly reduced compared with moderate HF alone. Cardioversion significantly reduced CS NE and BNP levels and improved contractility in AF + HF animals. In a further 6 animals, we explored the mechanism by which HF increases susceptibility to AF, with specific emphasis on the influence of functional mitral regurgitation. The elimination of MR in HF animals using a percutaneous mitral annular reduction device significantly decreased the inducibility of AF.. AF induction significantly depresses left ventricular function and causes activation of myocardial neurohormones. In conjunction, the presence of functional MR increases susceptibility to AF and this may be attenuated by MR reduction by percutaneous mitral annular reduction.

Topics: Animals; Atrial Fibrillation; Biomarkers; Blood Pressure; Comorbidity; Disease Progression; Electric Countershock; Endothelin-1; Heart Failure; Heart Rate; Models, Animal; Natriuretic Peptide, Brain; Norepinephrine; Risk Factors; Sheep; Time Factors

Endothelin-1 (ET-1) is elevated in patients with atrial fibrillation (AF) and heart failure. We investigated effects of ET-1 on human atrial cellular electrophysiological measurements expected to influence the genesis and maintenance of AF. Action potential characteristics and L-type Ca(2+) current (I(CaL)) were recorded by whole cell patch clamp, in atrial isolated myocytes obtained from patients in sinus rhythm. Isoproterenol (ISO) at 0.05 muM prolonged the action potential duration at 50% repolarisation (APD(50): 54 +/- 10 vs. 28 +/- 5 ms; P < 0.05, N = 15 cells, 10 patients), but neither late repolarisation nor cellular effective refractory period (ERP) were affected. ET-1 (10 nM) reversed the effect of ISO on APD(50), and had no basal effect (in the absence of ISO) on repolarisation or ERP. During repetitive stimulation, ISO (0.05 microM) produced arrhythmic depolarisations (P < 0.05). Each was abolished by ET-1 at 10 nM (P < 0.05). ISO (0.05 microM) increased peak I(CaL) from -5.5 +/- 0.4 to -14.6 +/- 0.9 pA/pF (P < 0.05; N = 79 cells, 34 patients). ET-1 (10 nM) reversed this effect by 98 +/- 10% (P < 0.05), with no effect on basal I(CaL). Chronic treatment of patients with a beta-blocker did not significantly alter basal APD(50) or I(CaL), the increase in APD(50) or I(CaL) by 0.05 microM ISO, nor the subsequent reversal of this effect on APD(50) by 10 nM ET-1. The marked anti-adrenergic effects of ET-1 on human atrial cellular action potential plateau, arrhythmic depolarisations and I(CaL), without affecting ERP and independently of beta-blocker treatment, may be expected to contribute a potentially anti-arrhythmic influence in the atria of patients with AF and heart failure.

Topics: Action Potentials; Adrenergic beta-Antagonists; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Calcium Channels; Endothelin-1; Endothelins; Female; Heart Atria; Humans; Isoproterenol; Male; Middle Aged

Endothelin-1 secretion and sympathetic activation may play important role in cardiovascular pathophysiology. In vivo interactions between these systems are not defined. We aimed to study the electrophysiological and haemodynamic effects of simultaneous intracoronary endothelin-1 and intravenous isoproterenol infusions. 18 anaesthetised open chest dogs were studied after AV-ablation. Mean arterial blood pressure, coronary blood flow, left ventricular contractility, standard electrocardiograms, right and left ventricular epi- and endocardial monophasic action potential (MAP) signals were recorded. Intracoronary endothelin-1 (30 pmol/min) was given to Group ET (n=6), intravenous isoproterenol (0.2 microg/kg/min) to Group ISO (n=6), both endothelin-1 and isoproterenol to Group ET+ISO (n=6) for 30 min. MAP duration increased in all studied regions of Group ET, decreased in all studied regions of Group ISO and ET+ISO (control vs. maximal changes of left ventricular epicardial MAP 90% duration, Group ET: 296+/-22 vs 369+/-20 ms, p<0.05, Group ISO: 298+/-18 vs 230+/-27 ms, p<0.01, Group ET+ISO: 302+/-18 vs 231+/-10 ms, p<0.01). In Group ET, early after depolarisations (3/6), polymorphic non-sustained ventricular tachycardias (6/6), and ventricular fibrillation (3/6) could be observed. In Group ISO, monomorphic non-sustained ventricular tachycardias (5/6) and atrial fibrillation (3/6) appeared. In Group ET+ISO, mono- and polymorphic non-sustained ventricular tachycardias occurred (5/6), neither ventricular fibrillation nor atrial fibrillation developed. An additive effect of endothelin-1 and isoproterenol on left ventricular contractility was observed. Isoproterenol treatment showed antagonistic effect against endothelin-1 induced MAP duration prolongation, early after depolarisation and ventricular fibrillation formation, while endothelin-1 showed protective effect against the development of isoproterenol induced atrial fibrillation.

Topics: Action Potentials; Adrenergic beta-Agonists; Animals; Atrial Fibrillation; Blood Pressure; Coronary Circulation; Coronary Vessels; Dogs; Drug Antagonism; Drug Therapy, Combination; Electrocardiography; Endothelin-1; Heart Ventricles; Hemodynamics; Infusions, Intra-Arterial; Infusions, Intravenous; Isoproterenol; Ventricular Fibrillation; Ventricular Function, Left

Increased plasma endothelin-1 concentrations have been observed in patients with rheumatic mitral stenosis. Endothelin-1 levels have never been investigated in patients with mitral stenosis and history of cerebral thromboembolism.. We measured plasma concentrations of endothelin-1 in the peripheral venous blood samples obtained from 20 patients with moderate to severe rheumatic mitral stenosis (16 with permanent atrial fibrillation and 4 with sinus rhythm). Six patients had history of thromboembolism. The remaining 14 patients did not have history of thromboembolism. Plasma endothelin-1 concentrations were measured using solid phase sandwich enzyme linked-immuno-sorbent assay.. The peripheral venous concentrations of endothelin-1 of the six patients with history of thromboembolism did not differ from the concentrations of the 14 patients without history of thromboembolism (2.40 +/- 1.39 pg/ml vs. 2.49 +/- 0.66 pg/ml, p = 0.9).. Although plasma endothelin-1 concentrations were increased in patients with mitral stenosis, plasma endothelin-1 concentrations were not further elevated in patients with mitral stenosis and history of thromboembolism.

Topics: Adult; Aged; Atrial Fibrillation; Endothelin-1; Female; Humans; Intracranial Embolism and Thrombosis; Male; Middle Aged; Mitral Valve Stenosis; Rheumatic Heart Disease

Activation of the endothelin system is an important compensatory mechanism that is activated during left ventricular dysfunction. Whether this system plays a role at the atrial level during atrial fibrillation (AF) has not been examined in detail. The purpose of this study was to investigate mRNA and protein expression levels of the endothelin system in AF patients with and without concomitant underlying valve disease.. Right atrial appendages of 36 patients with either paroxysmal or persistent AF were compared with 36 controls in sinus rhythm. The mRNA amounts of pro-endothelin-1 (pro-ET-1), endothelin receptor A (ET-A), and endothelin receptor B (ET-B) were studied by semiquantitative polymerase chain reaction. Protein amounts of the receptors were investigated by slot-blot analysis. mRNA amounts of pro-ET-1 were increased (+40%; P = 0.002) only in AF patients with underlying valve disease. ET-A and ET-B receptor protein amounts were significantly reduced in patients with paroxysmal AF (-39% and -47%, respectively) and persistent AF with underlying valve disease (-28% and -30%, respectively) and in persistent AF without valve disease (-20% and -40%, respectively). ET-A mRNA expression was unaltered in paroxysmal and persistent AF, whereas ET-B mRNA was reduced by 30% in persistent AF with (P < 0.001) or without (P = 0.04) valve disease, but unchanged in paroxysmal AF.. Substantial changes in gene expression of the endothelin system were observed in human atria during AF, especially in the presence of underlying valve disease. Alterations in endothelin expression associated with AF could play a role in the pathophysiology of AF and the progression of underlying heart disease.

Topics: Aged; Atrial Fibrillation; Endothelin-1; Endothelins; Female; Glyceraldehyde-3-Phosphate Dehydrogenases; Heart Atria; Humans; Male; Middle Aged; Myocardium; Protein Isoforms; Protein Precursors; Reference Values; RNA, Messenger

The objective was to determine the independent association between atrial fibrillation (A-Fib) and activation of natriuretic peptides.. The association of A-Fib with activation of N-terminal atrial and brain natriuretic peptides (N-ANPs and BNPs, respectively) is uncertain but of great importance for the diagnostic utilization of natriuretic peptides. This uncertainty is related to the lack of appropriate controls, with left ventricular (LV) and atrial overload similar to A-Fib.. We prospectively measured N-terminal atrial and BNPs and endothelin-1 levels in 100 patients and 14 age- and gender-matched control subjects. The 32 patients with A-Fib were compared with 68 patients in sinus rhythm and similar LV and atrial overload (due to mitral regurgitation or LV dysfunction) measured simultaneously with hormonal levels with comprehensive Doppler echocardiography.. Patients with A-Fib compared with those in sinus rhythm had similar symptoms, comorbid conditions, cardioactive medications, pulmonary pressure, left atrial volume, and LV ejection fraction and filling characteristics but demonstrated higher N-ANP levels (2,613 +/- 1,681 vs. 1,654 +/- 1,323 pg/ml, p = 0.007) even after adjustment for the underlying cardiac disease (p < 0.0001). Conversely, BNP levels were similar in both groups (165 +/- 163 vs. 160 +/- 269 pg/ml, p = 0.9). In multivariate analysis, a higher N-ANP level was associated with A-Fib (p = 0.0003), symptom class (p < 0.0001) and endothelin-1 level (p = 0.032) independently of left atrial volume and LV ejection fraction. Conversely, BNP showed no independent association with and was most strongly associated with LV ejection fraction (p < 0.0001).. Atrial fibrillation is an independent determinant of higher N-ANP levels and blurs its association with LV dysfunction. Conversely, the BNP is not independently associated with A-Fib and is strongly determined by LV dysfunction, for which it is an independent marker.

Topics: Aged; Atrial Fibrillation; Atrial Natriuretic Factor; Biomarkers; Case-Control Studies; Chronic Disease; Echocardiography, Doppler; Endothelin-1; Female; Humans; Male; Multivariate Analysis; Natriuretic Peptide, Brain; Prospective Studies; Protein Precursors; Reproducibility of Results; Severity of Illness Index; Stroke Volume; Ventricular Dysfunction, Left