Data from animal experiments and clinical investigations suggest that components of the renin-angiotensin system are markedly affected by sex hormones. However, whether estrogen affects human atrial ...myocardium has not been investigated yet. In this study, we determined the effects of estrogen on key components of atrial renin-angiotensin system: angiotensin-converting enzyme, responsible for generation of angiotensin II and angiotensin-converting enzyme 2, counteracting majority of AngII effects, and different renin-angiotensin system receptors, AT1R, AT2R, and MAS. First, the expression levels of estrogen receptors mRNA were determined in right atrial appendages obtained from patients undergoing heart surgery. The amounts of estrogen receptor α and estrogen receptor β mRNA were similar between women (n = 14) and men (n = 10). Atrial tissue slices (350 µm) were prepared from male donors which were exposed to estrogen (1–100 nM; n = 21) or stimulated at 4 Hz for 24 h in the presence or absence of 100 nM estrogen (n = 16), respectively. The administration of estrogen did not change mRNA levels of estrogen receptors, but activated MAP kinases, Erk1/2. Furthermore, estrogen increased the amounts of angiotensin-converting enzyme 2-mRNA (1.89 ± 0.23; P < 0.05) but reduced that of angiotensin-converting enzyme-mRNA (0.78 ± 0.07, P < 0.05). In addition, the transcript levels of AT2R and MAS were upregulated by estrogen. Pacing of tissue slices significantly increased the angiotensin-converting enzyme/angiotensin-converting enzyme 2 ratio at both the mRNA and protein level. During pacing, administration of estrogen substantially lowered the angiotensin-converting enzyme/angiotensin-converting enzyme 2 ratio at the transcript (0.92 ± 0.21 vs. 2.12 ± 0.27 at 4 Hz) and protein level (0.94 ± 0.20 vs. 2.14 ± 0.3 at 4 Hz). Moreover, estrogen elicited anti-inflammatory and anti-oxidative effects on renin-angiotensin system-associated downstream effectors such as pro-oxidative LOX-1 and pro-inflammatory ICAM-1. An antagonist of estrogen receptor α reversed these anti-inflammatory and anti-oxidative effects of estrogen significantly. Overall, our results demonstrated that estrogen modifies the local renin-angiotensin system homeostasis and achieves protective effects in atrial myocardium from elderly men.
Impact statement
The present study demonstrates that estrogen affects the human atrial myocardium and mediates protective actions through estrogen receptors-(ER) dependent signaling. Estrogen substantially modulates the local RAS via downregulation of ACE and simultaneous upregulation of ACE2, AT2R and MAS expression levels. This is indicative of a shift of the classical RAS/ACE axis to the alternative, protective RAS/ACE2 axis. In support of this view, estrogen attenuated the expression of RAS-associated downstream effectors, LOX-1, and ICAM-1. A specific antagonist of ERα reversed the anti-inflammatory and anti-oxidative effects of estrogen in paced and non-paced atrial tissue slices. In summary, our data demonstrate the existence of protective effects of estrogen in atrial tissue from elderly men which are at least in part, mediated by the regulation of local RAS homeostasis.
Aims
The aim of this study was to describe the characteristics of patients with atrial fibrillation (AF) enrolled in the Central Registry of the German Competence NETwork on Atrial Fibrillation ...(AFNET) and to assess current medical practice in patients treated at various levels of medical care in Germany.
Methods and results
From February 2004 to March 2006, 9582 ambulatory and hospitalized patients with ECG-documented AF were enrolled by 194 participating study centres from all levels of medical care in Germany. Clinical type of AF was reported as paroxysmal in 2893, persistent in 1873, and permanent in 3134 patients or classified as a first episode in 1035 patients. Predisposing conditions were common and present in 87.6% of the patients. Most patients were symptomatic with AF (75.1%). Rhythm control in persistent AF was provided to 53.4% of the symptomatic patients and to 47.8% of the patients without symptoms. Anticoagulation for stroke prevention was given to 71.4% of the patients considered eligible by applicable guidelines and to 48.4% of patients with low risk where guidelines do not recommend anticoagulation.
Conclusion
This registry provides insight into current medical care of patients with AF in Germany. The use of oral anticoagulation in eligible patients was among the highest reported, whereas decisions on rate and rhythm control often do not follow current recommendations.
In spontaneously hypertensive rats (SHR) atrial remodeling has been shown to involve increase in endothelin (ET) signaling. Furthermore, inflammatory processes may further contribute to tissue ...remodeling. The aimed of this study was to investigate whether an endothelin receptor antagonist, macitentan, could reduce left atrial (LA) remodeling in arterial hypertension.
Molecular characterization of atria was performed in SHR at the age of 8 months and their age-matched normotensive control rats (WKY). SHR were treated with macitentan and, for comparison with a blood pressure reducing drug, with doxazosin. After two months of treatment, molecules involved in endocardial inflammation and atrial calcium handling were assessed. The molecular changes provoked by rapid-pacing (RAP) were analyzed in atrial tissue slices.
Doxazosin reduced the systolic blood pressure compared with the untreated SHR (159 ± 26 vs. 176 ± 17; P < 0.05) or macitentan (vs. 189 ± 21; P < 0.05). Macitentan lowered the increased levels of atrial ET-1 and abrogated the pacing-induced upregulation of preproET-1-mRNA in atrial slices from SHR. Macitentan reduced the elevated levels of atrial 8-isoprostanes, the increased expression of pro-inflammatory ICAM-1 and IL-8, the phosphorylation of MAP kinases, ERK and p38, the phosphorylation of NF-κB and the expression of VCAM-mRNA. Major Ca2+-regulating proteins and markers of hypertrophy and fibrosis, however, were not affected. Doxazosin elicited similar changes, except for the alterations in ET-1 levels, NF-κB phosphorylation and VCAM-mRNA.
Macitentan reversed pro-inflammatory remodeling in hypertensive atria in a blood pressure-independent manner, which might prevent endocardial dysfunction and thereby, thrombogenesis in arterial hypertension.
Atrial fibrillation (AF) is the most common arrhythmia in clinical practise and its prevalence is increasing. Over the last 25 years, flecainide has been used extensively worldwide, and its capacity ...to reduce AF symptoms and provide long-term restoration of sinus rhythm (SR) has been well documented. The increased mortality seen in patients treated with flecainide in the Cardiac Arrhythmia Suppression Trial (CAST) study, published in 1991, still deters many clinicians from using flecainide, denying many new AF patients a valuable treatment option. There is now a body of evidence that clearly demonstrates that flecainide has a favourable safety profile in AF patients without significant left ventricular disease or coronary heart disease. As a result of this evidence, flecainide is now recommended as one of the first-line treatment options for restoring and maintaining SR in patients with AF under current treatment guidelines. The objective of this article is to review the literature pertaining to the pharmacological characteristics, safety and efficacy of flecainide, and to place this drug in the context of current therapeutic management strategies for AF.
Atrial fibrillation (AF), the most common atrial arrhythmia, has a complex aetiology and causes relevant morbidity and mortality due to different mechanisms, including but not limited to stroke, ...heart failure, and tachy- or bradyarrhythmia. Current therapeutic options (rate control, rhythm control, antithrombotic therapy, 'upstream therapy') only prevent a part of this burden of disease. Several new treatment modalities are therefore under evaluation in controlled trials. Given the multifold clinical consequences of AF, trials in AF patients should assess the effect of therapy in each of the main outcome domains. This paper describes an expert consensus of required outcome parameters in seven relevant outcome domains, namely death, stroke, symptoms and quality of life, rhythm, left ventricular function, cost, and emerging outcome parameters. In addition to these 'requirements' for outcome assessment in AF trials, further, more detailed outcome parameters are described. In addition to a careful selection of a relevant primary outcome parameter, coverage of outcomes in all major domains of AF-related morbidity and mortality is desirable for any clinical trial in AF.
While management of atrial fibrillation (AF) patients is improved by guideline-conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, ...the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF.
Aim
New technologic tools for continuous ECG monitoring have been developed to detect and treat atrial fibrillation (AF) in specific populations with high cardiovascular risk. We evaluated the ...prevalence and the management of AF diagnosed in patients with high cardiovascular risk and non-documented clinical palpitation undergoing systematic 14-day continuous ECG–Holter monitoring.
Methods
Patients were prospectively enrolled from December 2019 to December 2021 in this multicentre study, sponsored by the French National College of Cardiology. Patients met the following criteria: CHA
2
DS
2
VASc score ≥ 2 in males and ≥ 3 in females and clinical palpitations without previously documented arrhythmia. Enrolled patients underwent a continuous 14-day Holter–ECG monitoring for arrhythmia detection.
Results
Among the 336 included patients, 39% were male, 75% were greater than 65 years of age and 46.5% had suffered a prior stroke. AF was detected in 14% of patients, among which 23.4% were detected in the first 24 h of monitoring. Finally, age ≥ 65 years (
p
= 0.037) was significantly associated with AF, as well as male gender (
p
= 0.023) and a lower rate of antiplatelet therapy (
p
= 0.018). Patients with diagnosed AF had a prescription of anticoagulation therapy in 90%. Antiarrhythmic drugs were administered in 90% of AF patients and 13% underwent AF ablation.
Conclusions
The systematic AF screening of patients with palpitations and high cardiovascular risk resulted in a diagnostic yield of AF in 14% of the population with a 14-day continuous ECG–Holter monitor. This strategy resulted in the prescription of anticoagulation and antiarrhythmic therapy in 90% of the AF detected population.
Graphical abstract
Aims Patients with paroxysmal atrial fibrillation (AF) often present with typical angina pectoris and mildly elevated levels of cardiac troponin (non ST-segment elevation myocardial infarction) ...during an arrhythmic event. However, in a large proportion of these patients, significant coronary artery disease is excluded by coronary angiography. Here we explored the potential underlying mechanism of these events. Methods and results A total of 14 pigs were studied using a closed chest, rapid atrial pacing (RAP) model. In five pigs RAP was performed for 7 h (600 b.p.m.; n = 5), in five animals RAP was performed in the presence of angiotensin-II type-1-receptor (AT1-receptor) inhibitor irbesartan (RAP+Irb), and four pigs were instrumented without intervention (Sham). One-factor analysis of variance was performed to assess differences between and within the three groups. Simultaneous measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) before, during, and after RAP demonstrated unchanged FFR (P = 0.327), but decreased CFR during RAP (RAP: 67.7 ± 7.2%, sham: 97.2 ± 2.8%, RAP+Irb: 93.2 ± 3.3; P = 0.0013) indicating abnormal left ventricular (LV) microcirculation. Alterations in microcirculatory blood flow were accompanied by elevated ventricular expression of NADPH oxidase subunit Nox2 (P = 0.039), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1, P = 0.004), and F2-isoprostane levels (P = 0.008) suggesting RAP-related oxidative stress. Plasma concentrations of cardiac troponin-I (cTn-I) increased in RAP (RAP: 613.3 ± 125.8 pmol/L vs. sham: 82.5 ± 12.5 pmol/L; P = 0.013), whereas protein levels of eNOS and LV function remained unchanged. RAP+Irb prevented the increase of Nox2, LOX-1, and F2-isoprostanes, and abolished the impairment of microvascular blood flow. Conclusion Rapid atrial pacing induces AT1-receptor-mediated oxidative stress in LV myocardium that is accompanied by impaired microvascular blood flow and cTn-I release. These findings provide a plausible mechanism for the frequently observed cTn-I elevation accompanied with typical angina pectoris symptoms in patients with paroxysmal AF and normal (non-stenotic) coronary arteries.
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