Atrial fibrillation (AF) is an arrhythmia that can occur as the result of numerous different pathophysiological processes in the atria. Some aspects of the morphological and electrophysiological ...alterations promoting AF have been studied extensively in animal models. Atrial tachycardia or AF itself shortens atrial refractoriness and causes loss of atrial contractility. Aging, neurohumoral activation, and chronic atrial stretch due to structural heart disease activate a variety of signaling pathways leading to histological changes in the atria including myocyte hypertrophy, fibroblast proliferation, and complex alterations of the extracellular matrix including tissue fibrosis. These changes in electrical, contractile, and structural properties of the atria have been called "atrial remodeling." The resulting electrophysiological substrate is characterized by shortening of atrial refractoriness and reentrant wavelength or by local conduction heterogeneities caused by disruption of electrical interconnections between muscle bundles. Under these conditions, ectopic activity originating from the pulmonary veins or other sites is more likely to occur and to trigger longer episodes of AF. Many of these alterations also occur in patients with or at risk for AF, although the direct demonstration of these mechanisms is sometimes challenging. The diversity of etiological factors and electrophysiological mechanisms promoting AF in humans hampers the development of more effective therapy of AF. This review aims to give a translational overview on the biological basis of atrial remodeling and the proarrhythmic mechanisms involved in the fibrillation process. We pay attention to translation of pathophysiological insights gained from in vitro experiments and animal models to patients. Also, suggestions for future research objectives and therapeutical implications are discussed.
For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an increased amount of fibrous tissue. ...However, fibrosis is not a singular entity. Various forms can be distinguished, that differ in distribution: replacement fibrosis, endomysial and perimysial fibrosis, and perivascular, endocardial, and epicardial fibrosis. These different forms typically result from diverging pathophysiological mechanisms and can have different consequences for conduction. The impact of fibrosis on propagation depends on exactly how the patterns of electrical connections between myocytes are altered. We will therefore first consider the normal patterns of electrical connections and their regional diversity as determinants of propagation. Subsequently, we will summarize current knowledge on how different forms of fibrosis lead to a loss of electrical connectivity in order to explain their effects on propagation and mechanisms of arrhythmogenesis, including ectopy, reentry, and alternans. Finally, we will discuss a histological quantification of fibrosis. Because of the different forms of fibrosis and their diverging effects on electrical propagation, the total amount of fibrosis is a poor indicator for the effect on conduction. Ideally, an assessment of cardiac fibrosis should exclude fibrous tissue that does not affect conduction and differentiate between the various types that do; in this article, we highlight practical solutions for histological analysis that meet these requirements.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
During atrial fibrillation (AF) intracellular Ca2+ signaling in atrial myocytes changes substantially. This ‘remodeled’ intracellular Ca2+ homeostasis plays an important role in the development of ...the contractile dysfunction and the changes in atrial electrophysiology (contractile and electrical remodeling) that are characteristic of AF. Recent studies also show that unstable intracellular Ca2+ signaling (i.e. increased Ca2+ sparks and Ca2+ waves) is present in atrial myocytes from AF patients and that it might contribute to cellular arrhythmogenic mechanisms that help maintain the arrhythmia. It is currently not well understood how and when unstable Ca2+ signaling develops during the progression of AF, or if, in cases of structural heart disease, it even precedes the onset of AF. Current work therefore in particular aims to elucidate the molecular and sub-cellular mechanisms underlying the arrhythmogenic intracellular Ca2+ signaling instability in AF.
As treatment of AF remains difficult, the identification of novel targets for counteracting or preventing arrhythmogenic Ca2+ signaling is an important part of AF research. It is therefore important to recognize which phase of AF is addressed in a specific research (and ultimately treatment) approach. Here we review and critique the distinct alterations in intracellular Ca2+ signaling during the progression of AF from initial intracellular Ca2+ overload to the remodeling process. We address Ca2+ signaling after cardioversion of the arrhythmia and its potential role in the recurrence of AF.
We propose that altered Ca2+ signaling during AF progression consists of three phases 1.) Ca2+ Overload, 2.) Remodeling, and 3.) Steady State. Similarly, after AF termination three distinct phases of ‘recovery’ of intracellular Ca2+ handling occur. 4.) Calcium Unloading, 5.) Reverse Remodeling and 6.) Full Recovery. While there is evidence that unstable Ca2+ signaling is part of phases 1, 3 and 4, phase 2 (remodeling) appears to have a more stabilizing function on Ca2+ signaling (‘Ca2+ silencing’). This has important implications for the timing and type of pharmacological intervention, especially for new compounds aimed at intracellular ‘Ca2+ stabilization’. This article is part of a Special Issue entitled "Calcium Signaling in Heart".
► Summary of alterations in intracellular Ca2+ signaling during AF. ► Novel concept of 6 distinct phases of altered Ca2+ signaling during AF. ► Table with overview of major studies in the field. ► Discussion of Ca2+ dysregulation based pathologic mechanisms in AF. ► Contribution of heart failure to atrial Ca2+ signaling dysregulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Obstructive sleep apnea (OSA) causes negative tracheal pressure (NTP) and is associated with atrial fibrillation (AF).
This study aimed to determine the mechanism of atrial electrophysiological ...changes during tracheal occlusion with or without applied NTP and to evaluate the role of vagal activation, Na(+)/H(+)exchanger (NHE), and ATP-dependent potassium channels (K(ATP)).
Seventeen closed-chest pigs were anesthetized with urethane, and an endotracheal tube was placed to apply NTP (up to -100 mbar), comparable to clinically observed OSA in patients by a negative pressure device for a time period of 2 minutes. Right atrial refractory periods (AERP) and AF inducibility were measured transvenously by a monophasic action potential recording and stimulation catheter.
All tracheal occlusions with and without applied NTP resulted in comparable increases in blood pressure and hypoxemia. NTP shortened AERP (157.0 ± 2.8 to 102.1 ± 6.2 ms; P <.0001) and enhanced AF inducibility during AERP measurements from 0% at baseline to 90% (P <.00001) during NTP. Release of NTP resulted in a prompt restoration of sinus rhythm, and AERP returned to normal. NTP-induced AERP shortening and AF inducibility were prevented by atropine or vagotomy. Neither the NHE blocker cariporide nor the K(ATP) channel blocker glibenclamide abolished NTP-induced AERP shortening. By contrast, tracheal occlusion without applied NTP caused comparable changes in blood gases but did not induce AERP shortening or AF inducibility.
NTP during obstructive events is a strong trigger for AF compared with changes in blood gases alone. NTP caused AERP shortening and increased susceptibility to AF mainly by enhanced vagal activation. AERP shortening was not prevented by K(ATP) channel blockade or NHE blockade.
Atrial fibrillation is the most common sustained arrhythmia and is associated with significant morbidity and mortality. The autonomic nervous system has a significant role in the milieu predisposing ...to the triggers, perpetuators and substrate for atrial fibrillation. It has direct electrophysiological effects and causes alterations in atrial structure. In a significant portion of patients with atrial fibrillation, the autonomic nervous system activity is likely a composite of reflex excitation due to atrial fibrillation itself and contribution of concomitant risk factors such as hypertension, obesity and sleep-disordered breathing.
We review the role of autonomic nervous system activation, with focus on changes in reflex control during atrial fibrillation and the role of combined sympatho-vagal activation for atrial fibrillation initiation, maintenance and progression. Finally, we discuss the potential impact of combined aggressive risk factor management as a strategy to modify the autonomic nervous system in patients with atrial fibrillation and to reverse the arrhythmogenic substrate.
•Combined sympathetic and vagal activation creates an atrial fibrillation substrate.•Autonomic nervous system activity is contributed by common concomitant risk factors.•Transient autonomic activation contributes to a dynamic atrial fibrillation substrate.•Autonomic nervous system and atrial fibrillation: a bidirectional relationship•Combined risk factor management can modify the autonomic nervous system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Aims
It is recommended to perform atrial fibrillation ablation with continuous anticoagulation. Continuous apixaban has not been tested.
Methods and results
We compared continuous apixaban ...(5 mg b.i.d.) to vitamin K antagonists (VKA, international normalized ratio 2–3) in atrial fibrillation patients at risk of stroke a prospective, open, multi-centre study with blinded outcome assessment. Primary outcome was a composite of death, stroke, or bleeding (Bleeding Academic Research Consortium 2–5). A high-resolution brain magnetic resonance imaging (MRI) sub-study quantified acute brain lesions. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) at baseline and at end of follow-up. Overall, 674 patients (median age 64 years, 33% female, 42% non-paroxysmal atrial fibrillation, 49 sites) were randomized; 633 received study drug and underwent ablation; 335 undertook MRI (25 sites, 323 analysable scans). The primary outcome was observed in 22/318 patients randomized to apixaban, and in 23/315 randomized to VKA {difference −0.38% 90% confidence interval (CI) −4.0%, 3.3%, non-inferiority P = 0.0002 at the pre-specified absolute margin of 0.075}, including 2 (0.3%) deaths, 2 (0.3%) strokes, and 24 (3.8%) ISTH major bleeds. Acute small brain lesions were found in a similar number of patients in each arm apixaban 44/162 (27.2%); VKA 40/161 (24.8%); P = 0.64. Cognitive function increased at the end of follow-up (median 1 MoCA unit; P = 0.005) without differences between study groups.
Conclusions
Continuous apixaban is safe and effective in patients undergoing atrial fibrillation ablation at risk of stroke with respect to bleeding, stroke, and cognitive function. Further research is needed to reduce ablation-related acute brain lesions.
The aim of this study was to identify the relative impact of adrenergic and cholinergic activity on atrial fibrillation (AF) inducibility and blood pressure (BP) in a model for obstructive sleep ...apnea. Obstructive sleep apnea is associated with sympathovagal disbalance, AF, and postapneic BP rises. Renal denervation (RDN) reduces renal efferent and possibly also afferent sympathetic activity and BP in resistant hypertension. The effects of RDN compared with β-blockade by atenolol on atrial electrophysiological changes, AF inducibility, and BP during obstructive events and on shortening of atrial effective refractory period (AERP) induced by high-frequency stimulation of ganglionated plexi were investigated in 20 anesthetized pigs. Tracheal occlusion with applied negative tracheal pressure (NTP; at −80 mbar) induced pronounced AERP shortening and increased AF inducibility in all of the pigs. RDN but not atenolol reduced NTP-induced AF-inducibility (20% versus 100% at baseline; P=0.0001) and attenuated NTP-induced AERP shortening more than atenolol (27±5 versus 43±3 ms after atenolol; P=0.0272). Administration of atropine after RDN or atenolol completely inhibited NTP-induced AERP shortening. AERP shortening induced by high-frequency stimulation of ganglionated plexi was not influenced by RDN, suggesting that changes in sensitivity of ganglionated plexi do not play a role in the antiarrhythmic effect of RDN. Postapneic BP rise was inhibited by RDN and not modified by atenolol. We showed that vagally mediated NTP-induced AERP shortening is modulated by RDN or atenolol, which emphasizes the importance of autonomic disbalance in obstructive sleep apnea-associated AF. Renal denervation displays antiarrhythmic effects by reducing NTP-induced AERP shortening and inhibits postapneic BP rises associated with obstructive events.
Abstract
Recent preclinical and observational cohort studies have implicated imbalances in gut microbiota composition as a contributor to atrial fibrillation (AF). The gut microbiota is a complex and ...dynamic ecosystem containing trillions of microorganisms, which produces bioactive metabolites influencing host health and disease development. In addition to host-specific determinants, lifestyle-related factors such as diet and drugs are important determinants of the gut microbiota composition. In this review, we discuss the evidence suggesting a potential bidirectional association between AF and gut microbiota, identifying gut microbiota-derived metabolites as possible regulators of the AF substrate. We summarize the effect of gut microbiota on the development and progression of AF risk factors, including heart failure, hypertension, obesity, and coronary artery disease. We also discuss the potential anti-arrhythmic effects of pharmacological and diet-induced modifications of gut microbiota composition, which may modulate and prevent the progression to AF. Finally, we highlight important gaps in knowledge and areas requiring future investigation. Although data supporting a direct relationship between gut microbiota and AF are very limited at the present time, emerging preclinical and clinical research dealing with mechanistic interactions between gut microbiota and AF is important as it may lead to new insights into AF pathophysiology and the discovery of novel therapeutic targets for AF.
Graphical Abstract
Graphical Abstract
Gut microbiota and possible molecular pathways linked to AF. Dashed lines indicate potential mechanisms in AF pathogenesis. Solid lines indicate evidence-based mechanisms in AF pathogenesis. The BAs part deals with the primary/ secondary BAs ratio. AF, atrial fibrillation; BAs, bile acids; DAD, delayed afterdepolarizations; EAD, early after depolarizations; ERP, effective refractory period; LPS, lipopolysaccharide; SCFA, short-chain fatty acids; TMA, trimethylamine; TMAO, trimethylamine N-oxide.
A trial fibrillation (AF), the most common human cardiac arrhythmia, is associated with abnormal intracellular Ca2+ handling. Diastolic Ca2+ release from the sarcoplasmic reticulum via "leaky" ...ryanodine receptors (RyR2s) is hypothesized to contribute to arrhythmogenesis in AF, but the molecular mechanisms are incompletely understood. Here, we have shown that mice with a genetic gain-of-function defect in Ryr2 (which we termed Ryr2R176Q/+ mice) did not exhibit spontaneous AF but that rapid atrial pacing unmasked an increased vulnerability to AF in these mice compared with wild-type mice. Rapid atrial pacing resulted in increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2, while both pharmacologic and genetic inhibition of CaMKII prevented AF inducibility in Ryr2R176Q/+ mice. This result suggests that AF requires both an arrhythmogenic substrate (e.g., RyR2 mutation) and enhanced CaMKII activity. Increased CaMKII phosphorylation of RyR2 was observed in atrial biopsies from mice with atrial enlargement and spontaneous AF, goats with lone AF, and patients with chronic AF. Genetic inhibition of CaMKII phosphorylation of RyR2 in Ryr2S2814A knockin mice reduced AF inducibility in a vagotonic AF model. Together, these findings suggest that increased RyR2-dependent Ca2+ leakage due to enhanced CaMKII activity is an important downstream effect of CaMKII in individuals susceptible to AF induction.
Fibroblast proliferation and differentiation are central in atrial fibrillation (AF)-promoting remodeling. Here, we investigated fibroblast regulation by Ca(2+)-permeable transient receptor potential ...canonical-3 (TRPC3) channels.
Freshly isolated rat cardiac fibroblasts abundantly expressed TRPC3 and had appreciable nonselective cation currents (I(NSC)) sensitive to a selective TPRC3 channel blocker, pyrazole-3 (3 μmol/L). Pyrazole-3 suppressed angiotensin II-induced Ca(2+) influx, proliferation, and α-smooth muscle actin protein expression in fibroblasts. Ca(2+) removal and TRPC3 blockade suppressed extracellular signal-regulated kinase phosphorylation, and extracellular signal-regulated kinase phosphorylation inhibition reduced fibroblast proliferation. TRPC3 expression was upregulated in atria from AF patients, goats with electrically maintained AF, and dogs with tachypacing-induced heart failure. TRPC3 knockdown (based on short hairpin RNA shRNA) decreased canine atrial fibroblast proliferation. In left atrial fibroblasts freshly isolated from dogs kept in AF for 1 week by atrial tachypacing, TRPC3 protein expression, currents, extracellular signal-regulated kinase phosphorylation, and extracellular matrix gene expression were all significantly increased. In cultured left atrial fibroblasts from AF dogs, proliferation rates, α-smooth muscle actin expression, and extracellular signal-regulated kinase phosphorylation were increased and were suppressed by pyrazole-3. MicroRNA-26 was downregulated in canine AF atria; experimental microRNA-26 knockdown reproduced AF-induced TRPC3 upregulation and fibroblast activation. MicroRNA-26 has NFAT (nuclear factor of activated T cells) binding sites in the 5' promoter region. NFAT activation increased in AF fibroblasts, and NFAT negatively regulated microRNA-26 transcription. In vivo pyrazole-3 administration suppressed AF while decreasing fibroblast proliferation and extracellular matrix gene expression.
TRPC3 channels regulate cardiac fibroblast proliferation and differentiation, likely by controlling the Ca(2+) influx that activates extracellular signal-regulated kinase signaling. AF increases TRPC3 channel expression by causing NFAT-mediated downregulation of microRNA-26 and causes TRPC3-dependent enhancement of fibroblast proliferation and differentiation. In vivo, TRPC3 blockade prevents AF substrate development in a dog model of electrically maintained AF. TRPC3 likely plays an important role in AF by promoting fibroblast pathophysiology and is a novel potential therapeutic target.
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