Materiały źródłowe

• #1 Atrial fibrillation: classification, pathophysiology, mechanisms and drug treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1767799/

  The pathogenesis of AF is now thought to involve an interaction between initiating triggers, often in the form of rapidly firing ectopic foci located inside one or more pulmonary veins, and an abnormal atrial tissue substrate capable of maintaining the arrhythmia. Although structural heart disease underlies many cases of AF, the pathogenesis of AF in apparently normal hearts is less well understood. Although there is considerable overlap, pulmonary vein triggers may play a dominant role in younger patients with relatively normal hearts and short paroxysms of AF, whereas an abnormal atrial tissue substrate may play a more important role in patients with structural heart disease and persistent or permanent AF. […] It is now known that foci of rapid ectopic activity, often located in muscular sleeves that extend from the left atrium into the proximal parts of pulmonary veins, play a pivotal role in the initiation of AF in humans. Less frequently, focal initiation of AF may be result from ectopic activity that arises from muscular sleeves in the proximal superior vena cava, from the ligament of Marshall, or other parts of the right and left atria. Initiation of AF by rapid focal activity has been demonstrated not only in patients with structurally normal hearts and paroxysmal AF, but also during the process of reinitiation of persistent AF after electrical cardioversion, both in the presence and absence of associated structural heart disease.

• #2 Atrial Fibrillation

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/atrial-fibrillation/

  Atrial fibrillation may be acutely associated with physiologic stressors such as surgical procedures, pulmonary embolism, chronic lung diseases, hyperthyroidism, and alcohol ingestion. Disease states commonly associated with AF include hypertension, valvular heart disease, CHF, coronary artery disease, Wolff-Parkinson-White syndrome, pericarditis, obstructive sleep apnea, and cardiomyopathy. Considerable research has been devoted to the mechanisms and pathogenesis of AF. Genetic studies have identified specific associations, particularly in the cases of familial AF. Achieving a complete understanding of AF is limited by the complexity of this disorder and the heterogeneous patient population it affects. […] The pathogenesis of AF can be broadly divided into the categories of triggers, substrate, and sustaining mechanisms. Since the late 1990s, it has been recognized that the initiation of AF can occur because of premature atrial contractions triggered by beats that arise from the pulmonary veins (PVs), usually from muscular tissue sleeves near the junction with the left atrium. These triggers may also fire repetitively and contribute to the maintenance of AF, essentially becoming drivers of AF. Focal triggers outside the PV including posterior left atrial, ligament of Marshall, coronary sinus, venae cavae, septum, and left atrial appendage contribute to the disease process. Focal triggers, especially the PVs, are felt to be very important early in the disease process and, in particular, among patients with paroxysmal AF. Over time, myocardial fibrosis develops within the atrial tissue in association with AF to support its maintenance by shortening affected tissue refractory periods. Myocardial fibrosis of the atrium seems to be the common feature of the progression of AF disease state. This has led to the adage that AF begets AF. Once AF is initiated by focal triggers, several theories have been postulated to explain the maintenance of AF. They include the multiple wavelet model, AF rotors and the role of the autonomic nervous system. The multiple wavelet model has suggested that AF is sustained by multiple simultaneous wavelets meandering throughout the atria. Atrial tissue with abnormal electrical propagation recorded by mapping catheters has been referred to as complex fractionated electrograms. Expression of specific connecting protein channels at the cellular level are also felt to be important contributors to the disease substrate and sustaining mechanisms. Contemporary understanding of the AF substrate and sustaining mechanisms now also includes the role of the autonomic nervous system and, more recently, the discovery and evaluation of the concept of AF rotors.

• #3 Mechanisms of Atrial Fibrillation: How Our Knowledge Affects Clinical Practice

  https://www.mdpi.com/2075-1729/13/6/1260

  Atrial fibrillation (AF) is a very common arrhythmia that mainly affects older individuals. The mechanism of atrial fibrillation is complex and is related to the pathogenesis of trigger activation and the perpetuation of arrhythmia. The pulmonary veins in the left atrium are the most common triggers due to their distinct anatomical and electrophysiological properties. As a result, their electrical isolation by ablation is the cornerstone of invasive AF treatment. […] The basic pathophysiological pathways leading to AF’s onset and perpetuation involve triggers, abnormal atrial substrates, neurohormonal hyperactivation and, finally, a genetic predisposition. […] The main AF comorbidities, such as hypertension, ischemic cardiomyopathy, diabetes mellitus, congestive heart failure, and advanced age alter left ventricular elastic properties and subsequently increase left atrial pressure. The most common last step in this pathophysiologic cascade is the development of tissue stretch, which can also induce afterdepolarization and, thus, ectopic activity.

• #3 Mechanisms of Atrial Fibrillation: How Our Knowledge Affects Clinical Practice

  https://www.mdpi.com/2075-1729/13/6/1260

  Electrical remodeling consists of (a) the suppression of the Ca2+ current, which shortens the refractory period, (b) the enhancement of outward K+ currents, leading to the accelerated repolarization and hyperpolarization of atrial cells, and (c) the modified expression and localization of connexins, resulting in conduction abnormalities. […] It is apparent that all the above-mentioned pathways affect AF perpetuation and lead to the established perception that AF begets AF. […] The mechanisms of atrial fibrillation are complex and multifactorial. All the comorbidities and predisposing factors that are known to be related in our clinical practice seem to drive different pathways, which have two main targets. The first is the activation of triggers in vulnerable regions, such as the pulmonary veins, in most cases. The second is the formation of a favorable substrate that accounts for atrial fibrillation sustainability.

• #4 Atrial fibrillation – Wikipedia

  https://en.wikipedia.org/wiki/Atrial_fibrillation

  Atrial fibrillation frequently results from bursts of tachycardia that originate in muscle bundles extending from the atrium to the pulmonary veins. […] The ganglionated plexi (autonomic ganglia of the heart atrium and ventricles) can also be a source of atrial fibrillation, and are sometimes also ablated for that reason. […] Not only the pulmonary vein, but the left atrial appendage and ligament of Marshall can be a source of atrial fibrillation and are also ablated for that reason. […] As atrial fibrillation becomes more persistent, the junction between the pulmonary veins and the left atrium becomes less of an initiator and the left atrium becomes an independent source of arrhythmias. […] Cortisol and other stress biomarkers, as well as emotional stress, may play a role in the pathogenesis of atrial fibrillation.

• #4 Atrial fibrillation – Wikipedia

  https://en.wikipedia.org/wiki/Atrial_fibrillation

  The primary pathologic change seen in atrial fibrillation is the progressive fibrosis of the atria. […] This fibrosis is due primarily to atrial dilation; however, genetic causes and inflammation may be factors in some individuals. […] Once dilation of the atria has occurred, this begins a chain of events that leads to the activation of the reninangiotensinaldosterone system (RAAS) and subsequent increase in the matrix metalloproteinases and disintegrin, which leads to atrial remodeling and fibrosis, with loss of atrial muscle mass. […] Along with fibrosis, alterations in the atria that predispose to atrial fibrillation affect their electrical properties, as well as their responsiveness to the autonomic nervous system. […] The atrial remodeling that includes the pathologic changes described above has been referred to as atrial myopathy.

• #5 Atrial fibrillation – Wikipedia

  https://en.wikipedia.org/wiki/Atrial_fibrillation

  An important theory is that the regular impulses produced by the sinus node for a normal heartbeat are overwhelmed by rapid electrical discharges produced in the atria and adjacent parts of the pulmonary veins. […] Non-pulmonary vein sources of triggers for atrial fibrillation have been identified in 10% to 33% of patients. […] These triggers include the coronary sinus, the posterior wall of the left atrium, the ligament of Marshall, and the left atrial appendage. […] In a heart with AF, the increased calcium release from the sarcoplasmic reticulum and increased calcium sensitivity can lead to an accumulation of intracellular calcium and causes downregulation of L-type calcium channels. […] The abnormal distribution of gap junction proteins such as GJA1 (also known as connexin 43), and GJA5 (connexin 40) causes non-uniformity of electrical conduction, thus causing the arrhythmia.

• #6 Atrial Fibrillation: Mechanisms, Therapeutics, and Future Directions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5240842/

  The autonomic nervous system exerts significant control of cardiac electrophysiology, and defects in autonomic function have been associated with AF. […] There is extensive evidence of autonomic dysfunction reflected as increased sympathetic activity in AF observed in various types of large animal AF models. […] The role of sympathetic innervation is further supported by the observation that simultaneous sympathovagal discharge commonly precedes AF. […] Based on these studies, autonomic innervation appears to function as an exacerbating factor in AF as ablation improves AF severity and delays onset; however, it is unable to prevent or reverse AF, suggesting that the targeted forms of autonomic remodeling are not required for AF.

• #6 Atrial Fibrillation: Mechanisms, Therapeutics, and Future Directions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5240842/

  AF occurrence is dependent upon complex electrical defects in the atria which include a rapidly firing focus, complex multiple reentrant circuit, or rotors. […] Alterations in after-depolarization, both early and late, can contribute to ectopic atrial foci. […] Reentrant waves can occur due to reduced refractoriness, slow conduction, and conduction barriers. […] Rotors, or localized electrical spiral waves, are a result of complex substrate changes leading to a stable disease wave. […] These electrical defects are dependent upon remodeling mechanisms, which can be grouped into electrical, structural, and autonomic remodeling that allow for initiation and maintenance of AF. […] One of the most characterized mechanisms driving AF is the electrical remodeling occurring in atrial cardiomyocytes.

• #6 Atrial Fibrillation: Mechanisms, Therapeutics, and Future Directions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5240842/

  Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, affecting 1% to 2% of the general population. […] Current research on AF support and explore the hypothesis that initiation and maintenance of AF require pathophysiological remodeling of the atria, either specifically as in lone AF or secondary to other heart disease as in heart failure-associated AF. […] Remodeling associated changes in AF can be grouped into three categories that include: (i) electrical remodeling, which includes modulation of L-type Ca2+ current, various K+ currents, and gap junction function; (ii) structural remodeling, which includes changes in tissues properties, size, and ultrastructure; and (iii) autonomic remodeling, including altered sympathovagal activity and hyperinnervation. […] Electrical, structural, and autonomic remodeling all contribute to creating an AF-prone substrate which is able to produce AF-associated electrical phenomena including a rapidly firing focus, complex multiple reentrant circuit, or rotors.

• #6 Atrial Fibrillation: Mechanisms, Therapeutics, and Future Directions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5240842/

  Increased K+ currents are intimately associated with electrical remodeling in AF. […] The inward rectifier K+ currents (IK1, and IK,AcH, basal, and acetylcholine dependent, respectively) are increased in AF which alters resting potential and phase 3 activation, leading to reduced atrial refractoriness and wavelength. […] Gap junction function is also affected in AF. […] Gap junction function is directly related to conduction velocity, which is a known determinant of AF. […] Structural remodeling is perhaps the most obvious change in the atria that occurs in AF. […] These effects are characterized by changes is tissue properties (most notably fibrosis), atrial size, and cellular ultrastructure. […] Various factors contribute to the fibrosis underlying AF, including cell stretch, neurohumoral activity, oxidative stress, and even AF itself can contribute to worsening tissue properties.

• #6 Atrial Fibrillation: Mechanisms, Therapeutics, and Future Directions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5240842/

  Atrial fibrosis is a salient feature of a majority of animal models of AF, including aging, myocardial infarction (MI), volume overload, endurance exercise training, and tachypacing-induced HF. […] Evidence from genetic models of cardiac fibrosis suggest that the atria are particularly sensitive to profibrotic signaling potentially due to increased response of atrial fibroblasts compared to ventricular fibroblasts. […] The mechanism by which fibrotic tissue serves as a substrate for AF has been examined in detail. […] Cardiomyocytes in fibrotic atria are more distantly separated than those in nondiseased atria, with the fibroblasts and ECM essentially forming a physical conduction barrier. […] This reduces electrical coupling between cardiomyocytes and provides susceptibility to reentry.

• #6 Atrial Fibrillation: Mechanisms, Therapeutics, and Future Directions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5240842/

  Various types of ionic currents have been found to change in AF and, through animal models, to contribute to its development. […] The ionic currents include the L-type Ca2+ current and inward rectifier K+ currents. […] Gap junction function, specifically connexins 40 and 43, has also been linked to lone AF, though this may have broader effects on conduction. […] Alterations in Ca2+ handling in the atria can contribute to both development and worsening of AF. […] Numerous studies have shown the connection between altered calcium handling and delayed afterdepolarizations, which contribute to formation of ectopic foci and AF initiation. […] In AF, unwarranted calcium release can be triggered by ryanodine receptor (RyR) hypersensitivity or SR Ca2+ overload. […] This is also reflected in patients harboring activating mutations in RyR that exhibit catecholaminergic polymorphic ventricular tachycardia and AF.

• #7 Atrial Fibrillation

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/atrial-fibrillation/

  Cardiac ganglionic plexuses clustered posteriorly and superiorly to the left atrium are known to play an important role in the initiation and maintenance of AF. Both parasympathetic and sympathetic limbs can provoke atrial arrhythmias. Evidence supportive of this concept includes therapeutic benefit derived from destruction of cardiac ganglionic plexuses and also noncardiac plexuses including the stellate ganglion and perinephric ganglia associated with the renal arteries. In addition, completely vagally denervated hearts as in heart transplantation are known to have a very low incidence of AF. […] Atrial fibrillation rotors represent an emerging concept as a sustaining mechanism for AF involving spiral waves detected by spectral analysis of dominant frequencies recorded by intracardiac mapping catheters. Such spiral waves can be conceptualized as wavelets of consistent electrical activation around a central localized source that could be either structural (ie, scar-related) or purely functional (ie, conduction heterogeneity involving certain cellular sodium and potassium channels). The focal impulse and rotor modulation computational mapping system is used to identify AF rotors.

• #8 Atrial fibrillation: classification, pathophysiology, mechanisms and drug treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1767799/

  Both experimental and human mapping studies have demonstrated that persistent AF is generally characterised by the presence of multiple wavelets of excitation that propagate around the atrial myocardium. However, there is considerable variability in the observed patterns of activation, both between patients and between the two atria of individual patients. Perpetuation of AF is facilitated by the existence or development of an abnormal atrial tissue substrate capable of maintaining the arrhythmia, with the number of meandering wavelets that can be accommodated by the substrate determining the stability of AF. Re-entry within the atrial myocardium is facilitated by conduction slowing and shortening of the refractory period. Both have been demonstrated in animal models and patients with AF, with increased dispersion of refractoriness further contributing to arrhythmogenesis. Shortening of the atrial action potential, reduced expression of L type calcium channels, and microfibrosis of the atrial myocardium have also been demonstrated.

• #8 Atrial fibrillation: classification, pathophysiology, mechanisms and drug treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1767799/

  AF in itself can cause progressive changes in atrial electrophysiology such as substantial refractory period shortening, which further facilitate perpetuation of the arrhythmia. In animal studies, changes in ion channel function and shortening of refractory periods start within minutes of AF onset and, by 24 hours, sufficient atrial remodelling has occurred to increase the likelihood of AF persisting. However, restoration of sinus rhythm in this animal model, even after two weeks of persistent AF, results in a rapid reversal of the electrophysiological remodelling. […] AF is initiated by rapid electrical activity, often arising from arrhythmogenic foci located in the muscular sleeves of pulmonary veins. The arrhythmia is maintained by multiple re-entrant wavelets. Reduced refractoriness and conduction slowing facilitate re-entry. After a period of continuous AF, electrical remodelling occurs, further facilitating AF maintenance (AF begets AF). These changes are initially reversible if sinus rhythm is restored, but may become permanent and be associated with structural changes if fibrillation is allowed to continue.

• #8 Atrial fibrillation: classification, pathophysiology, mechanisms and drug treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1767799/

  Electrical remodelling and its reversal also appear to occur in humans. Clinical observations, as well as a number of studies, have suggested that patients with recurrent AF may develop increasing problems with time and a significant proportion may progress to permanent AF. In patients undergoing electrical cardioversion of persistent AF, the duration of the antecedent episode is a potent predictor of maintenance of sinus rhythm. Moreover, patients with AF are at particularly high risk of recurrence of the arrhythmia in the first few days after cardioversion. Indeed, it has been demonstrated that shortened right atrial refractory periods observed immediately after cardioversion of persistent AF lengthen again within four weeks. Although reverse remodelling after restoration of sinus rhythm does occur in humans with established AF, this may no longer be possible after very prolonged periods of AF and thus restoration and maintenance of sinus rhythm in these patients is often difficult.

• #8 Atrial fibrillation: classification, pathophysiology, mechanisms and drug treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1767799/

  Hypertensive, valvar, ischaemic, and other types of structural heart disease underlie most cases of persistent and permanent AF, whereas lone AF accounts for approximately 15% of AF cases. Familial AF is well described, although at present considered rare. A region on chromosome 10 (10q22-q24) was originally identified as containing the gene responsible for AF in families in which the arrhythmia segregated as an autosomal dominant trait. However, familial AF appears to be a heterogeneous disease. A family with a mutation in the gene encoding the pore forming subunit of the cardiac IKs channel on chromosome 11 that results in increased function of this channel, with affected members developing persistent AF probably caused by a reduction in refractoriness, has more recently been described.

• #9 Mechanisms of Atrial Fibrillation – Reentry, Rotors and Reality | AER Journal

  https://www.aerjournal.com/articles/mechanisms-atrial-fibrillation-reentry-rotors-and-reality?language_content_entity=en

  The observations that AF may have different mechanisms in different patients, and that paroxysmal, persistent and permanent forms of AF may differ in how they are initiated and sustained, only serves to reinforce our lack of understanding of this ubiquitous arrhythmia. […] More recently it has become accepted that separate mechanisms may be responsible for triggering and sustaining AF. […] However, AF maintenance probably involves some form of reentrant activity, with the observed irregular fibrillatory activity caused by wavebreak of the main reentrant wavefront into multiple chaotic daughter wavelets as a consequence of inhomogeneity in atrial structure, refractoriness and conduction velocity. […] This concept has been supported by multiple studies which have demonstrated more frequent reentrant drivers of AF in patients with longstanding arrhythmia.

• #10 Mechanisms of Atrial Fibrillation – Reentry, Rotors and Reality | AER Journal

  https://www.aerjournal.com/articles/mechanisms-atrial-fibrillation-reentry-rotors-and-reality?language_content_entity=en

  Recent computational and experimental data have suggested that special types of functional reentry may be of critical importance in sustaining AF. […] The rotor model of AF maintains that although AF appears to be a chaotic and disorganised rhythm, it is actually being continually driven by the highly organised activity of a limited number of high frequency reentrant circuits. […] Mapping studies have demonstrated the existence of localised, organised and high frequency drivers in AF, some of which are thought to represent rotor-like activity. […] The strongest clinical evidence for high-frequency rotors and focal drivers and their critical role in maintaining human AF comes from work by Narayan et al. […] The totality of data suggests that there is highly organised reentrant activity underlying the seemingly chaotic and random atrial activity in AF.

• #11 Atrial Fibrillation: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/151066-overview

  Atrial fibrillation (AF) has strong associations with other cardiovascular diseases, such as heart failure (HF), coronary artery disease (CAD), valvular heart disease, diabetes mellitus (DM), and hypertension. […] The exact mechanisms by which cardiovascular risk factors predispose to AF are not understood fully but are under intense investigation. Catecholamine excess, hemodynamic stress, atrial ischemia, atrial inflammation, metabolic stress, and neurohumoral cascade activation are all purported to promote AF. […] Three forms of atrial remodeling during a progression of AF have been described: electrical, contractile, and structural. […] Electrical remodeling is a consequence of high atrial rates and includes shortening of the refractory period of atrial myocytes and slowing of atrial conduction velocity.

• #12 Inflammation and the pathogenesis of atrial fibrillation | Nature Reviews Cardiology

  https://www.nature.com/articles/nrcardio.2015.2

  Inflammation and its associated immune response are involved in the initiation and maintenance of atrial fibrillation (AF) […] AF can further promote inflammation, which contributes to the clinical phenomenon of 'AF begets AF’ […] Inflammatory pathways contribute to both electrical and structural atrial remodelling and thrombogenesis in patients with AF […] The mechanisms and dynamic changes that underlie the inflammatory responses in different clinical scenarios of AF should be determined to enable the development of specific, individualized anti-inflammatory strategies […] Therapies that target specific inflammatory cascades might be potential therapeutic strategies for the prevention of AF […] The infiltration of immune cells and proteins that mediate the inflammatory response in cardiac tissue and circulatory processes is associated with AF

• #12 Inflammation and the pathogenesis of atrial fibrillation | Nature Reviews Cardiology

  https://www.nature.com/articles/nrcardio.2015.2

  Furthermore, the presence of inflammation in the heart or systemic circulation can predict the onset of AF and recurrence in the general population, as well as in patients after cardiac surgery, cardioversion, and catheter ablation […] Mediators of the inflammatory response can alter atrial electrophysiology and structural substrates, thereby leading to increased vulnerability to AF […] Inflammation also modulates calcium homeostasis and connexins, which are associated with triggers of AF and heterogeneous atrial conduction […] Myolysis, cardiomyocyte apoptosis, and the activation of fibrotic pathways via fibroblasts, transforming growth factor- and matrix metalloproteases are also mediated by inflammatory pathways, which can all contribute to structural remodelling of the atria […] The development of thromboembolism, a detrimental complication of AF, is also associated with inflammatory activity […] Understanding the complex pathophysiological processes and dynamic changes of AF-associated inflammation might help to identify specific anti-inflammatory strategies for the prevention of AF.

• #13 Aging-associated mechanisms of atrial fibrillation progression and their therapeutic potential

  https://www.oaepublish.com/articles/jca.2024.12

  Aging affects the regulation, storage and cycling of Ca2+ by altering the abundance and function of key Ca2+ handling proteins. […] Dysregulated Ca2+ handling contributes to AF initiation and maintenance. […] Oxidative stress (OS), a state in which the production of radical and non-radical reactive oxygen and nitrogen species (RONS) preponderates over the cells endogenous antioxidative defense capacity, has been proposed as one mechanism of age-associated cellular damage. […] The heart, with its significant metabolic demand, is particularly vulnerable to OS and is thus an area of intense research in the field of age-associated AF pathogenesis. […] Reactive oxygen/nitrogen species, through modification of ion channels, Ca2+ handling protein activity, and the potentiation of inflammation, contribute to a permissive electrical and structural substrate and have been linked to AF pathogenesis. […] Cardiac fibrosis, a hallmark of structural remodeling, promotes pathological changes predominantly in the atria in AF, providing a substrate for AF by increasing conduction heterogeneity and stabilizing reentrant circuits.

• #14

  https://journals.lww.com/cmj/fulltext/2023/11200/atrial_fibrillation__mechanism_and_clinical.3.aspx

  AF risk factors contribute to the formation of ROS, resulting in the impairment of myocardial energetic and electrophysiologic properties. […] A growing body of evidence indicates that inflammasome signaling in atrial cardiomyocytes causes inflammation and contributes to AF pathogenesis. […] ANS plays a critical role not only in the regulation of cardiac rhythm but also in the initiation and maintenance of AF. […] The interaction between sympathetic and parasympathetic fibres is pivotal in both triggering and sustaining AF. […] Over the past few decades, researchers have identified more than 160 genes associated with AF. […] The first gene linked to familial AF was KCNQ1 S140G, which increases susceptibility to AF. […] Despite these discoveries, there remains a significant gap in translating these genetic findings into actionable molecular pathways and potential therapeutic targets.

• #14

  https://journals.lww.com/cmj/fulltext/2023/11200/atrial_fibrillation__mechanism_and_clinical.3.aspx

  Fibrosis disrupts the normal electrical conduction pathways within the atria, leading to slowed or blocked conduction. […] Meanwhile, it creates an environment facilitating the generation of abnormal electrical impulses and promotes the initiation and maintenance of AF. […] EAT, located closely to the heart muscle, has been associated with an increased risk of AF. […] Electroanatomic mapping studies have confirmed larger low-voltage areas adjacent to the increased EAT volume. […] These emerging findings highlight the importance of EAT and fatty infiltration in atrial electro-structural remodeling. […] Sustained inflammation is a central mediator in atrial electrical and structural remodeling in AF, characterized by increased formation of reactive oxygen species (ROS) and upregulation of cytokines.

• #15 Research improves understanding of mechanism of atrial fibrillation

  https://medicalxpress.com/news/2019-10-mechanism-atrial-fibrillation.html

  Atrial fibrillation is the most common heart arrhythmia in humans. This condition increases the risk of heart failure, stroke, dementia and death, and current treatments have suboptimal efficacy and carry side effects. […] The team reports in the Proceedings of the National Academy of Sciences a functional connection between noncoding DNA regions called Pitx2 enhancers, expression of the Pitx2 gene and atrial fibrillation. […] Here we showed that noncoding DNA regions associated with predisposition to atrial fibrillation loop to the Pitx2 gene. Furthermore, deleting the noncoding DNA regions, called Pitx2 enhancers, resulted in decreased Pitx2 gene expression and predisposed mice to atrial fibrillation. […] In summary, noncoding DNA regions linked to atrial fibrillation risk can display long-range regulatory functions directed at Pitx2 gene and in this way predispose to the condition.

• #16 Research improves understanding of mechanism of atrial fibrillation | The Texas Heart Institute®

  https://www.texasheart.org/research-improves-understanding-of-mechanism-of-atrial-fibrillation/

  Atrial fibrillation is the most common heart arrhythmia in humans. This condition increases the risk of heart failure, stroke, dementia, and death, and current treatments have suboptimal efficacy and carry side effects. […] The team reports in the Proceedings of the National Academy of Sciences a functional connection between noncoding DNA regions called Pitx2 enhancers, expression of the Pitx2 gene and atrial fibrillation. […] Here we showed that noncoding DNA regions associated with predisposition to atrial fibrillation loop to the Pitx2 gene. Furthermore, deleting the noncoding DNA regions, called Pitx2 enhancers, resulted in decreased Pitx2 gene expression and predisposes mice to atrial fibrillation. […] In summary, noncoding DNA regions linked to atrial fibrillation risk can display long-range regulatory functions directed at the Pitx2 gene and in this way predispose to the condition.

• #17

  https://link.springer.com/article/10.1007/s00395-020-00827-7

  The molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. […] Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. […] In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF. […] However, calcium (Ca2+) handling abnormalities and oxidative stress are thought to play central roles in the pathophysiology of AF. […] The extent to which mitochondrial Ca2+ uptake shapes the systolic Ca2+ transient remains somewhat controversial; however, the current consensus is that it has little effect on the free cytosolic Ca2+ concentration.

• #17

  https://link.springer.com/article/10.1007/s00395-020-00827-7

  The majority of cellular ATP is produced by oxidative phosphorylation in the mitochondria. […] There is also evidence for pre-operative downregulation of mitochondrial/oxidative phosphorylation gene clusters as well as mitochondrial dysfunction in patients who develop AF after cardiac surgery (post-operative AF). […] The initial phase of AF has been described as a short period of cellular Ca2+ overload on account of increased atrial activation rate, preceding a longer phase involving adaptation and remodelling of electrophysiology and Ca2+ dynamics, coined Ca2+ silencing. […] It is thus plausible that a relative reduction of intracellular Ca2+, after the initial overload period, may contribute to the mismatch of ATP supply to demand in AF, considering the important role of Ca2+ in stimulating mitochondrial ATP production.

• #18 Mitochondria and the Pathophysiological Mechanism of Atrial Fibrillation

  https://eurekaselect.com/public/article/92772

  Atrial fibrillation (AF) is the most common and significant cardiac arrhythmia in clinical practice, however the pathophysiological mechanism of AF has not been fully explained. […] Mitochondria play central roles in the function of cardiac myocytes and many of the pathophysiological processes implicated in AF are relative to mitochondrial function, including formation of reactive oxygen species (ROS), calcium homeostasis, and alterations of oxygen consumption. […] The changes of levels of phosphocreatine, electron transfer chain proteins and differences in mitochondrial distribution further imply that mitochondria play a role in AF. […] There is a close relationship between mitochondrial dysfunction and the occurrence of AF, which cannot be ignored, and further research in this area is needed.

• #19 The Pathophysiology of Atrial Fibrillation in Heart Failure

  https://www.innovationsincrm.com/cardiac-rhythm-management/2012/july/300-the-pathophysiology-of-atrial-fibrillation-in-heart-failure

  Atrial fibrillation (AF) and heart failure are the emerging epidemics of cardiovascular diseases. […] There are complex interactions between AF and heart failure. […] Clinical and experimental data have defined multiple pathophysiological mechanisms to explain how either condition contributes to the new development of the other. […] AF can cause the worsening of heart failure in those already affected by the condition; also, it can cause the new development of heart failure, so-called tachycardia-induced cardiomyopathy. […] Tachycardia is associated with an overall decrease in myocardial collagen content and altered extracellular collagen distribution, both of which contribute to dilation and thinning of the ventricular walls and decreased contractility. […] The presence of heart failure is the strongest risk factor for AF.

• #19 The Pathophysiology of Atrial Fibrillation in Heart Failure

  https://www.innovationsincrm.com/cardiac-rhythm-management/2012/july/300-the-pathophysiology-of-atrial-fibrillation-in-heart-failure

  Understanding the pathophysiology of AF in heart failure will enhance opportunities for discovering effective AF prevention and treatment strategies. […] Although the pathophysiology of AF remains incompletely understood, the role of the pulmonary veins in AF initiation and the role of atria in AF maintenance are well established. […] Numerous experimental and clinical observations suggest that both the triggers and electrophysiological substrates of AF in patients with heart failure are different from those present in patients without structural heart disease. […] The study from Chens group showed that heart failure enhanced PV arrhythmogenesis in an animal model. […] The DAD-related activity induced by the increase in NCX activity may account for the occurrence of focal atrial tachyarrhythmias in heart failure.

• #19 The Pathophysiology of Atrial Fibrillation in Heart Failure

  https://www.innovationsincrm.com/cardiac-rhythm-management/2012/july/300-the-pathophysiology-of-atrial-fibrillation-in-heart-failure

  Fibrosis is a hallmark of arrhythmogenic structural remodeling in heart failure. […] The atrial electrical and structural remodeling associated with paroxysmal AF may be reversible or preventable if therapy aimed at substrate remodeling is initiated early rather than later in the course of the disease. […] There is complex interplay of AF and heart failure. […] Development of AF in a patient with heart failure often leads to symptomatic deterioration, predisposes to episodes of worsening heart failure, increases the risk of thromboembolic episodes, and worsens long-term outcome.

• #20

  https://ijconline.id/index.php/ijc/article/view/98

  Atrial fibrillation (AF) is the most common cardiac arrhythmia other than sinus tachycardia encountered in hyperthyroidism and representing an independent risk factor for cardiovascular event. […] Hyperthyroidism is associated with an increased supraventricular ectopic activity. Hyperthyroidism increases the rate of systolic depolarization and diastolic repolarization, decreases the duration of the action potential and refraction period of the atrial myocardium, as well as atrioventricular nodal therefore facilitated the occurrence of atrial fibrillation.

• #21 Electrolyte’s imbalance role in atrial fibrillation: Pharmacological management | International Journal of Arrhythmia | Full Text

  https://arrhythmia.biomedcentral.com/articles/10.1186/s42444-022-00065-z

  The contribution of the perpetuation of atrial fibrillation is caused by electrical remodeling in which calcium, sodium and potassium channels could refer to changes in the ion channel protein expression, development of fibrosis, gene transcription and ion channel redistribution. […] Calcium and magnesium could influence the risk of atrial fibrillation which is the leading cause of cardiac death, heart failure and ischemic stroke. […] The elevated serum concentration of calcium had a higher range of in-patients mortality, increased total cost of hospitalization and increased length of hospital stay as compared to those without hypercalcemia in atrial fibrillation patients. […] Moreover, chloride channels could affect homeostasis, atrial myocardial metabolism which may participate in the development of atrial fibrillation.

• #21 Electrolyte’s imbalance role in atrial fibrillation: Pharmacological management | International Journal of Arrhythmia | Full Text

  https://arrhythmia.biomedcentral.com/articles/10.1186/s42444-022-00065-z

  Up to a 50% risk of incidence of AF are higher in which left ventricular hypertrophy, sudden cardiovascular death and overall mortality relate to a low serum magnesium level. […] Additionally, magnesium prevents the occurrence of AF after cardiac surgery, whereas greater levels of serum phosphorus in the large population-based study and the related calciumphosphorus products were linked with a greater incidence of AF. […] Numerous clinical studies had shown the high preoperative risk of AF that is linked with lower serum potassium levels. […] The conventional risk factor of increased risk of new onset of AF events could independently link with high dietary sodium intake which enhances the fibrosis and inflammation in the atrium but the mechanism remains unknown. […] This review concludes that electrolytes imbalance plays a significant role in the pathogenesis of atrial fibrillation.

• #22 Disrupted Calcium Release as a Mechanism for Atrial Alternans Associated with Human Atrial Fibrillation | PLOS Computational Biology

  https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004011

  We therefore sought to determine, using a computer model of human atrial tissue, whether Ca2+ handling abnormalities, or other electrophysiological changes that occur in AF, lead to APD alternans. […] We identified a critical change in the kinetics of the ryanodine receptor (RyR) that was responsible for APD alternans onset at slower pacing rates, and subsequently aimed to elucidate the mechanistic relationship between this disruption in RyR kinetics and alternans onset. […] We established that alternans in the cAFalt model at the onset CL were Ca2+-driven rather than voltage-driven, and that they depended upon SR Ca2+ release. […] Lastly, we demonstrated that the ability to generate alternans at slower pacing rates by modulating kiCa depended upon the negative feedback properties of SR Ca2+ release.

• #23 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20240108/Comprehensive-insights-on-pathophysiology-and-clinical-management-of-atrial-fibrillation.aspx

  Atrial fibrillation (AF) is a major global health concern impacting millions and causing symptoms like palpitations, dyspnea, fatigue, dizziness, and chest discomfort. […] The medical community agrees that epicardial adipose tissue (EAT), chronic inflammation, imbalances in the autonomic nervous system (ANS), stretch-induced fibrosis, and genetic alterations are the main factors that influence AF pathogenesis. […] First, the authors delve into AF’s pathogenic mechanisms, highlighting the impact of stretch-induced fibrosis triggered by pressure or volume overload, leading to profound remodeling of atrial tissue. This remodeling leads to lower conductivity, calcium overload, fibrosis, fibroblast proliferation, and modified collagen degradation. The fibrosis disrupts electrical conduction in atrial tissue and creates an environment conducive to the onset of AF. EAT aggregating around atrial muscle promotes AF. The EAT induces fat infiltration and fibrosis that cause dysfunction in atrial muscle. The damage caused by sustained inflammation mainly results from reactive oxygen species (ROS). These ROS impair the energetic and electrophysiologic properties of myocardial tissue. The sympathetic and parasympathetic components of the ANS can also exacerbate the onset of and sustain AF. Genetic AF traits include common and rare variants spanning more than 160 genes and underscores the complexity of these genetic alterations. […] While AF poses considerable healthcare challenges due to its complex nature, ongoing research will help further understand AF and improve patient outcomes.

• #24 Take a look at the Recent articles

  https://www.oatext.com/New-perspective-on-atrial-fibrillation-A-theoretical–assumption.php

  Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. Many studies have investigated the cause for the development of AF, however, the question remains unanswered. Recently the hypothesis was proposed that atrial fibrillation is a protective physiological mechanism, based on the termination of atrial mechanical systole. This reduces the pressure in the system of the pulmonary veins and alveolar capillaries in pathological situations, and thus reduces the likelihood for development of pulmonary congestion and edema. […] The reasoning of the hypothesis is as follow. The end diastolic pressure(EDP) is the algebraic sum of the left ventricle diastolic pressure(LVdp) and left atrial systolic pressure(atrial kick pressure, AKp). EDP=LVdp+AKP. Normal range of EDP is 8-12 mm Hg, AKp is 2-6 mm Hg. At the end of the diastole when the mitral valve(MV) is still open, EDP immediately transmitted and equalized (according to hydrodynamic law) throughout the communicating system of the LV, LA, pulmonary veins(PV), and alveolar capillaries(AC), as there are no obstacles to the spread of the EDP wave. EDP is thus equal to pulmonary wedge pressure(PWP) with a normal range of 8-12 mm Hg.

• #24 Take a look at the Recent articles

  https://www.oatext.com/New-perspective-on-atrial-fibrillation-A-theoretical–assumption.php

  In the conditions of LV dysfunction(HF varying degrees), EDP increases due to failure of the LV(i.e. LV diastolic pressure component increases). EDP = LVdp + AKp. This increased EDP at the end of diastole wth opened MV transmits to the entire communicating system of the LA-PV-AC and with the increased PWP, but with the threat of exit of fluid through the alveolar-capillary membrane. Pulmonary edema is usually present when PWP increases to 20 mm Hg. […] However, it is possible to reduce the total EDP (and to reduce pressure in the entire system!) by stopping the mechanical systole of left atrium, thus, excluding the LA pressure component from the total EDP. EDP = LVdp + AKp. This is accomplished by AF which stops the mechanical systole of left atrium. […] Many facts confirm that the termination of mechanical systole of both atriums by the development AF in the cases of LV dysfunction/HF creates optimal hydrodynamic conditions in the heart when the pressure in the communicating system of LA-PV-AC increases, and therefore, it appears that the heart NEEDS AF:

• #24 Take a look at the Recent articles

  https://www.oatext.com/New-perspective-on-atrial-fibrillation-A-theoretical–assumption.php

  Thus, the assumption that AF is a physiological protective mechanism in the conditions of LV dysfunction/HF explains well all the facts and phenomena associated with the AF and allows us to build the algorithms of their relationships in various diseases. […] The above proposed hypothesis suggests that AF is a protective physiological mechanism, most likely genetically programmed. The main purpose of AF is eliminate the mechanical systole of the LA to reduce pressure in the LA-PV-AC system, and of the RA with the effect of reducing preload, that creates more optimal hydrodynamic conditions for the heart in the LV dysfunction /HF and thus decreases the threat of pulmonary congestion or edema.

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