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Cardiovascular Research Jun 2022Recent developments in imaging, mapping, and ablation techniques have shown that the epicardial region of the heart is a key player in the occurrence of ventricular... (Review)
Review
Recent developments in imaging, mapping, and ablation techniques have shown that the epicardial region of the heart is a key player in the occurrence of ventricular arrhythmic events in several cardiac diseases, such as Brugada syndrome, arrhythmogenic cardiomyopathy, or dilated cardiomyopathy. At the atrial level as well, the epicardial region has emerged as an important determinant of the substrate of atrial fibrillation, pointing to common underlying pathophysiological mechanisms. Alteration in the gradient of repolarization between myocardial layers favouring the occurrence of re-entry circuits has largely been described. The fibro-fatty infiltration of the subepicardium is another shared substrate between ventricular and atrial arrhythmias. Recent data have emphasized the role of the epicardial reactivation in the formation of this arrhythmogenic substrate. There are new evidences supporting this structural remodelling process to be regulated by the recruitment of epicardial progenitor cells that can differentiate into adipocytes or fibroblasts under various stimuli. In addition, immune-inflammatory processes can also contribute to fibrosis of the subepicardial layer. A better understanding of such 'electrical fragility' of the epicardial area will open perspectives for novel biomarkers and therapeutic strategies. In this review article, a pathophysiological scheme of epicardial-driven arrhythmias will be proposed.
Topics: Atrial Fibrillation; Brugada Syndrome; Catheter Ablation; Heart Atria; Heart Ventricles; Humans; Myocardium
PubMed: 34152392
DOI: 10.1093/cvr/cvab213 -
Journal of the American College of... May 2015The association of atrial fibrillation (AF) with ischemic stroke has long been recognized; yet, the pathogenic mechanisms underlying this relationship are incompletely... (Review)
Review
The association of atrial fibrillation (AF) with ischemic stroke has long been recognized; yet, the pathogenic mechanisms underlying this relationship are incompletely understood. Clinical schemas, such as the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) score, incompletely account for thromboembolic risk, and emerging evidence suggests that stroke can occur in patients with AF even after sinus rhythm is restored. Atrial fibrosis correlates with both the persistence and burden of AF, and gadolinium-enhanced magnetic resonance imaging is gaining utility for detection and quantification of the fibrotic substrate, but methodological challenges limit its use. Factors related to evolution of the thrombogenic fibrotic atrial cardiomyopathy support the view that AF is a marker of stroke risk regardless of whether or not the arrhythmia is sustained. Antithrombotic therapy should be guided by a comprehensive assessment of intrinsic risk rather than the presence or absence of AF at a given time.
Topics: Atrial Fibrillation; Cardiomyopathies; Fibrosis; Forecasting; Heart Atria; Humans; Risk Factors; Signal Transduction; Stroke; Thromboembolism
PubMed: 25998669
DOI: 10.1016/j.jacc.2015.03.557 -
Journal of the Chinese Medical... Feb 2009Atrial flutter (AFL) is a common arrhythmia in clinical practice. Several experimental models, such as tricuspid regurgitation model, tricuspid ring model, sterile... (Review)
Review
Atrial flutter (AFL) is a common arrhythmia in clinical practice. Several experimental models, such as tricuspid regurgitation model, tricuspid ring model, sterile pericarditis model and atrial crush injury model, have provided important information about reentrant circuit and can test the effects of antiarrhythmic drugs. Human AFL has typical and atypical forms. Typical AFL rotates around the tricuspid annulus and uses the crista terminalis and sometimes sinus venosa as the boundary. The tricuspid isthmus is a slow conduction zone and the target of radiofrequency ablation. Atypical AFL may arise from the right or left atrium. Right AFL includes upper loop reentry, free wall reentry and figure-of-8 reentry. Left AFL includes mitral annular AFL, pulmonary vein-related AFL and left septal AFL. Radiofrequency ablation of the isthmus between the boundaries can eliminate these arrhythmias.
Topics: Animals; Atrial Flutter; Disease Models, Animal; Heart Atria; Heart Conduction System; Humans; Pericarditis; Tricuspid Valve Insufficiency
PubMed: 19251532
DOI: 10.1016/S1726-4901(09)70024-3 -
Therapeutic Advances in Cardiovascular... Jun 2008Atrial Fibrillation (AF) is one of the most frequent arrhythmias, especially in elderly patients. Cardiac overload increases the incidence of AF. Clinical presentation... (Review)
Review
Atrial Fibrillation (AF) is one of the most frequent arrhythmias, especially in elderly patients. Cardiac overload increases the incidence of AF. Clinical presentation of atrial fibrillation can occur as nonsustained paroxysms, persistent episodes and in chronic-permanent form. The physio-pathological mechanisms are: *Circuit of multiple and anarchic re-entries *Atrial fibrillatory conduction *Re-entry circuit with fibrillatory conduction.Remodeling (electrical or structural) facilitates the appearance and persistence of AF: Neurovegetative changes and cytosolic Ca overload facilitate AF. Interstitial atrial fibrosis, in which Renin-Angiotensin System (RAS) hyperactivity is a main aspect of remodeling. There is clinical evidence that supports the antiatrial fibrillatory actions of RAS blockade. Potential mechanisms are: (a) direct modulation of ionic channels, (b) hemodynamic improvement, (c) reduction of atrial stretching, (d) antifibrotic effects. There is less clinical evidence with antialdosterone drugs, but theoretically these might also be useful.
Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Heart Atria; Humans; Renin-Angiotensin System
PubMed: 19124423
DOI: 10.1177/1753944708092111 -
Circulation Jul 2015Atrial disease or myopathy forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. Current... (Review)
Review
Atrial disease or myopathy forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. Current diagnostic approaches in patients with AF focus on identifying clinical predictors with the evaluation of left atrial size by echocardiography serving as the sole measure specifically evaluating the atrium. Although the atrial substrate underlying AF is likely developing for years before the onset of AF, there is no current evaluation to identify the preclinical atrial myopathy. Atrial fibrosis is 1 component of the atrial substrate that has garnered recent attention based on newer MRI techniques that have been applied to visualize atrial fibrosis in humans with prognostic implications regarding the success of treatment. Advanced ECG signal processing, echocardiographic techniques, and MRI imaging of fibrosis and flow provide up-to-date approaches to evaluate the atrial myopathy underlying AF. Although thromboembolic risk is currently defined by clinical scores, their predictive value is mediocre. Evaluation of stasis via imaging and biomarkers associated with thrombogenesis may provide enhanced approaches to assess risk for stroke in patients with AF. Better delineation of the atrial myopathy that serves as the substrate for AF and thromboembolic complications might improve treatment outcomes. Furthermore, better delineation of the pathophysiologic mechanisms underlying the development of the atrial substrate for AF, particularly in its earlier stages, could help identify blood and imaging biomarkers that could be useful to assess risk for developing new-onset AF and suggest specific pathways that could be targeted for prevention.
Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Electrocardiography; Heart Atria; Humans; Magnetic Resonance Imaging; Muscular Diseases; Risk Factors; Stroke; Thrombosis
PubMed: 26216085
DOI: 10.1161/CIRCULATIONAHA.115.016795 -
Cardiovascular Research Mar 2015Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is associated with significant morbidity, mostly secondary to heart failure and stroke, and... (Review)
Review
Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is associated with significant morbidity, mostly secondary to heart failure and stroke, and an estimated two-fold increase in premature death. Efforts to increase our understanding of AF and its complications have focused on unravelling the mechanisms of electrical and structural remodelling of the atrial myocardium. Yet, it is increasingly recognized that AF is more than an atrial disease, being associated with systemic inflammation, endothelial dysfunction, and adverse effects on the structure and function of the left ventricular myocardium that may be prognostically important. Here, we review the molecular and in vivo evidence that underpins current knowledge regarding the effects of human or experimental AF on the ventricular myocardium. Potential mechanisms are explored including diffuse ventricular fibrosis, focal myocardial scarring, and impaired myocardial perfusion and perfusion reserve. The complex relationship between AF, systemic inflammation, as well as endothelial/microvascular dysfunction and the effects of AF on ventricular calcium handling and oxidative stress are also addressed. Finally, consideration is given to the clinical implications of these observations and concepts, with particular reference to rate vs. rhythm control.
Topics: Animals; Atrial Fibrillation; Atrial Function; Calcium Signaling; Coronary Circulation; Heart Atria; Heart Rate; Heart Ventricles; Humans; Inflammation Mediators; Oxidative Stress; Ventricular Function, Left; Ventricular Remodeling
PubMed: 25587048
DOI: 10.1093/cvr/cvv001 -
Circulation Research Apr 2014Atrial fibrillation (AF) is a complex disease with multiple inter-relating causes culminating in rapid, seemingly disorganized atrial activation. Therapy targeting AF is... (Review)
Review
Atrial fibrillation (AF) is a complex disease with multiple inter-relating causes culminating in rapid, seemingly disorganized atrial activation. Therapy targeting AF is rapidly changing and improving. The purpose of this review is to summarize current state-of-the-art diagnostic and therapeutic modalities for treatment of AF. The review focuses on reviewing treatment as it relates to the pathophysiological basis of disease and reviews preclinical and clinical evidence for potential new diagnostic and therapeutic modalities, including imaging, biomarkers, pharmacological therapy, and ablative strategies for AF. Current ablation and drug therapy approaches to treating AF are largely based on treating the arrhythmia once the substrate occurs and is more effective in paroxysmal AF rather than persistent or permanent AF. However, there is much research aimed at prevention strategies, targeting AF substrate, so-called upstream therapy. Improved diagnostics, using imaging, genetics, and biomarkers, are needed to better identify subtypes of AF based on underlying substrate/mechanism to allow more directed therapeutic approaches. In addition, novel antiarrhythmics with more atrial specific effects may reduce limiting proarrhythmic side effects. Advances in ablation therapy are aimed at improving technology to reduce procedure time and in mechanism-targeted approaches.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Catheter Ablation; Diffusion of Innovation; Forecasting; Heart Atria; Heart Conduction System; Humans; Treatment Outcome
PubMed: 24763469
DOI: 10.1161/CIRCRESAHA.114.302362 -
Experimental Biology and Medicine... Jun 2023Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) has a well-established role in myocardial infarction, yet its involvement in atrial fibrosis and...
Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) has a well-established role in myocardial infarction, yet its involvement in atrial fibrosis and atrial fibrillation (AF) has not been elucidated. As cardiac arrhythmias caused by AF are a major global health concern, we investigated whether SHP-1 modulates AF development. The degree of atrial fibrosis was examined using Masson's trichrome staining, and SHP-1 expression in the human atrium was assessed using quantitative polymerase chain reaction (qPCR), immunohistochemistry (IHC), and western blotting (WB). We also examined SHP-1 expression in cardiac tissue from an AF mouse model, as well as in angiotensin II (Ang II)-treated mouse atrial myocytes and fibroblasts. We found that SHP-1 expression was reduced with the aggravation of atrial fibrosis in clinical samples of patients with AF. SHP-1 was also downregulated in the heart tissue of AF mice and Ang II-treated myocytes and fibroblasts, compared with that in the control groups. Next, we demonstrated that SHP-1 overexpression alleviated AF severity in mice by injecting a lentiviral vector into the pericardial space. In Ang II-treated myocytes and fibroblasts, we observed excessive extracellular matrix (ECM) deposition, reactive oxygen species (ROS) generation, and transforming growth factor beta 1 (TGF-β1)/mothers against decapentaplegic homolog 2 (SMAD2) pathway activation, all of which were counteracted by the overexpression of SHP-1. Our WB data showed that STAT3 activation was inversely correlated with SHP-1 expression in samples from patients with AF, AF mice, and Ang II-treated cells. Furthermore, administration of colivelin, a STAT3 agonist, in SHP-1-overexpressing, Ang II-treated myocytes and fibroblasts resulted in higher levels of ECM deposition, ROS generation, and TGF-β1/SMAD2 activation. These findings indicate that SHP-1 regulates AF fibrosis progression by modulating STAT3 activation and is thus a potential treatment target for atrial fibrosis and AF.
Topics: Humans; Mice; Animals; Atrial Fibrillation; Transforming Growth Factor beta1; Reactive Oxygen Species; Heart Atria; Fibrosis; Angiotensin II; STAT3 Transcription Factor
PubMed: 37226737
DOI: 10.1177/15353702231165717 -
International Journal of Cardiology Jul 2019Atrial fibrillation (AF), the most prevalent arrhythmia, is often associated with enhanced inflammatory response. Emerging evidence points to a causal role of... (Review)
Review
Atrial fibrillation (AF), the most prevalent arrhythmia, is often associated with enhanced inflammatory response. Emerging evidence points to a causal role of inflammatory signaling pathways in the evolution of atrial electrical, calcium handling and structural remodeling, which create the substrate of AF development. In this review, we discuss the clinical evidence supporting the association between inflammatory indices and AF development, the molecular and cellular mechanisms of AF, which appear to involve multiple canonical inflammatory pathways, and the potential of anti-inflammatory therapeutic approaches in AF prevention/treatment.
Topics: Atrial Fibrillation; Biomarkers; Cytokines; Heart Atria; Heart Rate; Humans; Inflammasomes; Inflammation; Myocytes, Cardiac; Signal Transduction
PubMed: 30316645
DOI: 10.1016/j.ijcard.2018.10.020 -
Progress in Biophysics and Molecular... 2003Atrial fibrillation frequently occurs under conditions associated with atrial dilatation suggesting a role of mechano-electric feedback in atrial arrhythmogenesis.... (Review)
Review
Atrial fibrillation frequently occurs under conditions associated with atrial dilatation suggesting a role of mechano-electric feedback in atrial arrhythmogenesis. Although atrial arrhythmias may be due both to abnormal focal activity and reentrant mechanisms, the majority of sustained atrial arrhythmias have been ascribed to reentrant activity. Atrial stretch may contribute to focal arrhythmias by inducing afterdepolarizations and to reentrant arrhythmias by increasing the atrial surface, by shortening the refractory period and/or slowing the conduction velocity and by increasing their spatial dispersion. Experimental and clinical studies have demonstrated that changes in mechanical loading conditions may modulate the electrophysiological properties of the atria. These studies have, for the most part, involved the effects of acute stretch on atrial refractoriness. While studies in humans and intact animals yield divergent results due to the variety of loading conditions and neurohumoral influences, experimental studies in isolated preparations clearly show that atrial refractory period and action potential duration at early levels of repolarization shorten by acute atrial dilatation. Both experimental and human studies have shown that acute atrial stretch is arrhythmogenic and may induce triggered premature beats and atrial fibrillation.
Topics: Animals; Arrhythmias, Cardiac; Atrial Fibrillation; Calcium; Electrophysiology; Feedback, Physiological; Heart Atria; Humans; Ions; Models, Biological; Pressure; Time Factors; Water
PubMed: 12732274
DOI: 10.1016/s0079-6107(03)00011-7