Trends in Molecular Medicine
ReviewInflammatory pathways underlying atrial fibrillation
Section snippets
Atrial fibrillation at the macroscopic and microscopic levels
Atrial fibrillation (AF; see Glossary) is characterized by unorganized and chaotic depolarization of atrial myocytes, which results in undirected wavefronts in the atria. This leads to functionally inadequate atrial contractions, which slows the blood flow velocity in the atria, thus increasing atrial blood load and preventing optimal ventricular filling. First described in the 18th century, AF remains the most prevalent rhythm disorder in men. In Western industrialized countries, the
AF promotes inflammation
Proof of the concept that AF promotes inflammatory processes arises from studies of animal models for rapid atrial pacing (RAP). These studies revealed an increase in 3-nitrotyrosine deposition in atrial tissue [27] that arises from enhanced production of peroxynitrite or other oxidation products of nitric oxide (NO), and an increase in the generation of hydroxyl radicals originating from reaction of hydrogen peroxide with the superoxide radical [28]. It has also been found that reactive
Subcellular mechanisms
An emerging body of evidence now suggests that inflammatory pathways are directly linked to cellular and subcellular signaling cascades known to provoke AF (Figure 1). Among these, ion channel dysfunction remains one of the crucial factors in AF initiation.
The plateau phase of the cardiac action potential depends on an increase in [Ca2+]i, which is preceded by an influx from the extracellular compartment via L-type Ca2+ channels (ICa,L) and sodium–calcium exchangers, as well as from the
Connexin integrity
Dysregulation of intercellular ion flux has also been linked to the genesis of AF. In fact, atrial conduction depends on the integrity of connexins, a group of transmembrane proteins that build up the gap junctions. Because gap junctions allow for intercellular ion exchange, they influence electrical conduction and disturbances of their integrity are potentially proarrhythmic [30]. The most abundant myocardial connexins are connexin 40 and 43, with connexin 40 being exclusively expressed in
Concluding remarks
Accumulating evidence indicates that inflammatory pathways previously identified in vascular and ventricular disease are of significance in AF. Whereas various surrogate markers of inflammation correlate with AF risk, inflammatory mediators have recently been linked to the pathogenesis of AF. In particular, leukocyte activation predisposes an individual to electrical and structural atrial remodeling. The armamentarium of a leukocyte, which is capable of site-specifically generating various
Glossary
- Atrial appendage
- muscular pouch attached to the atrium.
- Atrial myocytes
- muscle cells of the atrium.
- Atrial reentry circuits
- AF-initiating abnormal electrical circles within the atrial myocardium.
- Autocrine
- self-stimulating.
- Dyspnea
- shortness of breath.
- Effective refractory period
- time period of a cardiac action potential when a new depolarization cannot be initiated.
- Fibrillation
- uncoordinated electrical activation of myocytes with consequent deterioration of mechanical function.
- Fibrosis
- abnormal increase in
References (85)
The prevalence of atrial fibrillation in incident stroke cases and matched population controls in Rochester, Minnesota: changes over three decades
J. Am. Coll. Cardiol.
(2003)- et al.
Effects of C-reactive protein and the third and fourth components of complement (C3 and C4) on incidence of atrial fibrillation
Am. J. Cardiol.
(2006) Inflammation in lone atrial fibrillation: new insights by coronary sinus thermography
Int. J. Cardiol.
(2009)Assessment of conventional cardiovascular risk factors and multiple biomarkers for the prediction of incident heart failure and atrial fibrillation
J. Am. Coll. Cardiol.
(2010)Prognostic implications of the high-sensitive C-reactive protein in the catheter ablation of atrial fibrillation
Am. J. Cardiol.
(2010)The effects of steroids on the occurrence of postoperative atrial fibrillation after coronary artery bypass grafting surgery: a prospective randomized trial
J. Thorac. Cardiovasc. Surg.
(2005)The predictive value of inflammatory and oxidative markers following the successful cardioversion of persistent lone atrial fibrillation
Int. J. Cardiol.
(2009)Intracardiac and extracardiac markers of inflammation during atrial fibrillation
Heart Rhythm
(2010)Prognostic significance of raised plasma levels of interleukin-6 and C-reactive protein in atrial fibrillation
Am. Heart J.
(2004)Relation of elevated C-reactive protein and interleukin-6 levels to left atrial size and duration of episodes in patients with atrial fibrillation
Am. J. Cardiol.
(2005)
Upregulation of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases in rapid atrial pacing-induced atrial fibrillation
J. Mol. Cell. Cardiol.
Current concepts in the pathogenesis of atrial fibrillation
Am. Heart J.
Atrial fibrosis and atrial fibrillation: the role of the TGF-β1 signaling pathway
Int. J. Cardiol.
Redox-mediated reciprocal regulation of SERCA and Na+-Ca2+ exchanger contributes to sarcoplasmic reticulum Ca2+ depletion in cardiac myocytes
Free Radic. Biol. Med.
Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases
Kidney Int.
Regulation of matrix biology by matrix metalloproteinases
Curr. Opin. Cell Biol.
Increased lysyl oxidase expression and collagen cross-linking during atrial fibrillation
J. Mol. Cell. Cardiol.
Hypochlorous acid generated by myeloperoxidase modifies adjacent tryptophan and glycine residues in the catalytic domain of matrix metalloproteinase-7 (matrilysin): an oxidative mechanism for restraining proteolytic activity during inflammation
J. Biol. Chem.
Myeloperoxidase inactivates TIMP-1 by oxidizing its N-terminal cysteine residue: an oxidative mechanism for regulating proteolysis during inflammation
J. Biol. Chem.
Increased inflammatory cell infiltration in the atrial myocardium of patients with atrial fibrillation
Am. J. Cardiol.
Postoperative white blood cell count predicts atrial fibrillation after cardiac surgery
J. Cardiothorac. Vasc. Anesth.
Information learned from animal models of atrial fibrillation
Cardiol. Clin.
The interferon-γ-induced GTPase, mGBP-2, inhibits TNF-α induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-κB and Rac
J. Biol. Chem.
Atrial fibrosis and the mechanisms of atrial fibrillation
Heart Rhythm
Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors
Cell. Signal.
Attenuated cardiovascular hypertrophy and oxidant generation in response to angiotensin II infusion in glutaredoxin-1 knockout mice
Free Radic. Biol. Med.
Oxidative stress is a critical mediator of the angiotensin II signal in human neutrophils: involvement of mitogen-activated protein kinase, calcineurin, and the transcription factor NF-kappaB
Blood
Mice with cardiac-restricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death
Am. J. Pathol.
Myeloperoxidase attracts neutrophils by physical forces
Blood
Epidemiologic features of chronic atrial fibrillation: the Framingham study
N. Engl. J. Med.
A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study
J. Am. Med. Assoc.
Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins
N. Engl. J. Med.
Treatment of paroxysmal atrial fibrillation by pulmonary vein isolation
Circ. J.
Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF): a randomized, multicentre, international trial
Eur. Heart J.
Pathophysiological mechanisms of atrial fibrillation: a translational appraisal
Physiol. Rev.
Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention
Circulation
Atrial fibrillation: hypertension as a causative agent, risk factor for complications, and potential therapeutic target
Am. J. Cardiol.
Arrhythmias during acute pericarditis. A prospective study of 100 consecutive cases
J. Am. Med. Assoc.
Histological substrate of atrial biopsies in patients with lone atrial fibrillation
Circulation
Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation
Circulation
Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia
Circulation
Relations of biomarkers of distinct pathophysiological pathways and atrial fibrillation incidence in the community
Circulation
Cited by (127)
Effects of different exercise methods and intensities on the incidence and prognosis of atrial fibrillation
2024, Trends in Cardiovascular MedicineUse of the CHA<inf>2</inf>DS<inf>2</inf>-VASc score to predict subsequent myocardial infarction in atrial fibrillation
2023, Hellenic Journal of CardiologyGut Microbiota Dysbiosis Induced by a High-Fat Diet Increases Susceptibility to Atrial Fibrillation
2022, Canadian Journal of CardiologyTriggers for new-onset atrial fibrillation in critically ill patients
2021, Intensive and Critical Care Nursing