title: [Biology of the substrate of atrial fibrillation].
abstract: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia in clinical practice, is often associated with progressive dilatation and remodeling of the atria which constitute the substrate of the arrhythmia. This atrial remodeling is characterized by complex structural and functional alterations of the atrial myocardium: short action potentials, heterogeneous refractory periods, dystrophic myocytes and interstitial fibrosis which act together to favor local conduction bloc, activation of ectopies and the forma-tion of microreentries of the electrical excitation. However, the underlying mechanisms of the AF substrate are not yet fully understood. The possibility of studying human atrial myocytes has led to the identification of ionic currents that contribute to the shortening of the action potential and refractory periods during AF. The down-regulation of the L-type calcium current plays a central role in this electrical remodeling. It results mainly from the dephosphorylation of calcium channels as the consequence of an excessive stimulation of atrial myocytes by neurohormones such as the atrial natriuretic factor. Abnormal trafficking and targeting of ion channels at the plasma membrane has emerged as mechanisms that can contribute to the abnormal electrical properties of the atria during AF. Fibrosis is the other feature of the AF substrate and it is favored by the atrial hemodynamic overload. Local activation of the renin-angiotensin system is involved in the extracellular matrix remodeling of the atrial myocardium. Thrombin that accumulates in dilated and fibrillating atria could be another important mediator of the myocardial structural alterations during AF. This peptide, by binding on its receptor PAR1, can modulate several signaling pathways regulating growth and survival of myocardial cells. Better understanding of pathogenic factors involved in the formation of the AF substrate is crucial for the identification of novel biomarkers and therapeutic targets that could be used to improve the diagnostic and treatment of AF.
authors.affiliation: ICAN Institute of Cardiometabolism & Nutrition, UMRS-956 (INSERM/UPMC), Faculté de Médecine Pitié-Salpêtrière, 91 boulevard de l'Hôspital, 75634 Paris Cedex 13, France. Stephane.Hatem@chups.jussieu.fr
authors.forename: Stéphane
authors.initials: S
authors.lastname: Hatem
mesh_terms: D000200:Action Potentials; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D001281:Atrial Fibrillation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D000074288:Discs Large Homolog 1 Protein; D006329:Heart Conduction System / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D017136:Ion Transport; D051666:Kv1.5 Potassium Channel / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D021381:Protein Transport; D044463:Receptor, PAR-1 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013917:Thrombin / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020746:Calcium Channels, L-Type; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D008565:Membrane Proteins; D044463:Receptor, PAR-1; D013917:Thrombin; D011188:Potassium; D002118:Calcium