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The Molecular Pathophysiology of Atrial Fibrillation

January 2018

January 2018

DOI:10.1016/B978-0-323-44733-1.00042-0

In book: Cardiac Electrophysiology: From Cell to Bedside (pp.396-408)

Authors:

Stanley Nattel

Montreal Heart Institute

Jordi Heijman

Medical University of Graz

Niels Voigt

Georg-August University Göttingen, Germany

Xander Wehrens

Baylor College of Medicine

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The Molecular Pathophysiology of Atrial Fibrillation

Stanley Nattel,1, 2,4 Jordi Heijman,3 Niels Voigt,4 Xander H.T. Wehrens5

and Dobromir Dobrev4

1Research Center, Department of Medicine, Montreal Heart Institute and Université de Montréal,

Montreal, Quebec, Canada; 2Department of Pharmacology and Therapeutics, McGill University;

3Department of Cardiology, Maastricht University, Maastricht, The Netherlands; 4Institute of

Pharmacology, West-German Heart and Vascular Center, Faculty of Medicine, University

Duisburg-Essen, Essen, Germany; 5Cardiovascular Research Institute; Departments of Molecular

Physiology and Biophysics, Medicine (Cardiology), Pediatrics, Baylor College of Medicine,

Houston, USA

Correspondence to Stanley Nattel, 5000 Belanger St E, Montreal, Quebec, H1T 1C8, Canada;

Tel.: (514)-376-3330 ext. 3990. Fax: (514)-376-1355. E-mail: stanley.nattel@icm-mhi.org.

Atrial fibrillation (AF) is a highly prevalent and clinically relevant arrhythmia, for which all

current therapeutic approaches have important limitations. An improved understanding of the

mechanistic basis of AF has evolved over the past decades, particularly with respect to molecular

aspects. Mechanistic insights have contributed greatly to the contemporary management of AF

and are expected to further improve arrhythmia therapy in the future (1). The purpose of this

chapter is to review recent findings in the molecular pathophysiology of AF, and to discuss their

potential value for improving management.

We will begin with an overview of the etiological determinants of AF, then discuss briefly

the principal mechanisms contributing to AF, and finally review the molecular basis of specific

arrhythmia determinants.

Etiological Determinants

Heart Disease

The majority of AF-cases have associated cardiac disease (Figure 1). Cardiac senescence

is a major predisposing factor, largely mediated by structural remodeling which causes fibrotic

alterations and microconduction slowing, as well as atrial enlargement (2). Heart failure (HF),

hypertensive heart disease, valvular disease and ischemic heart disease are major contributors to

AF-occurrence. Less common conditions leading to AF include pericarditis, myocarditis, and

various cardiomyopathies. Cardiac surgery is followed by post-operative AF, with a typical

presentation and therapeutic response, in about 30% of cases.

Genetic Determinants

There has been a rapid increase in knowledge of genetic determinants of AF over the past

10 years (3-6). A wide range of disease-causing mutations has been established (Table 1) and

additional AF susceptibility gene-loci have been identified with genome-wide association studies

(GWASs; Table 2). Rare variants linked to monogenic forms of AF have high penetrance and

provide important insights into AF-mechanisms, whereas common genetic variants identified

using GWAS provide new insights into genetic-based population determinants of AF, while

raising challenging pathophysiological issues (6).

Extracardiac Contributors

A variety of extracardiac conditions can affect AF-occurrence. Heavy alcohol

consumption promotes AF (7), and hyperthyroidism is a well-recognized factor (8). Obesity is

increasingly recognized as an AF risk-factor (9), with obstructive sleep apnea, often associated

with obesity, also being an important contributor. Autonomic tone may set the conditions for AF

initiation and maintenance. The AF-promoting properties of vagal activation are well-known,

and there is increasing evidence for an important role of combined sympathovagal discharge (10).

General Mechanisms and AF Forms

Focal ectopic firing and reentrant activity are the primary AF arrhythmia mechanisms

(Figure 2A). Focal activity can be transient, producing isolated atrial extrasystoles or self-

limited tachycardias, and can contribute to AF-generation by acting as a trigger to initiate reentry

in a vulnerable substrate. In addition, sustained focal ectopic activity can produce rapid “driver”

activity that is conducted heterogeneously to generate fibrillatory conduction maintaining the

irregular activity typical of AF (11, 12). Clinical AF can be paroxysmal (self-terminating) or

persistent (terminating only with medical intervention). With increasing duration, persistent AF

becomes increasingly resistant to therapy and “long-standing persistent AF”, lasting >1 year, and

often becomes permanent when attempts to restore sinus rhythm fail or are abandoned.

Repetitively-firing focal ectopic drivers are believed to produce paroxysmal forms. Reentrant

activity generates more persistent AF, tending to become more fixed, therapy-resistant and

irreversible as the substrate evolves (13, 14). Besides progression of AF-associated

comorbidities, the evolution of the substrate is promoted by AF-induced remodeling related to the

rapid atrial rate, cardiac dysfunction, neurohumoral effects and consequences of atrial metabolic

disturbances (Figure 2B). The remodeling induced by long-standing AF involves both functional

and structural components that promote a transition towards complex reentrant mechanisms, as

quantified in recent noninvasive mapping studies (15, 16). These analyses have shown

pronounced temporal and inter-patient variability in AF activity, suggesting dynamic and

complex interactions between AF mechanisms.

Focal Ectopic Activity

Several mechanisms produce abnormal impulse formation and can cause focal ectopic

activity. Spontaneous automatic activity depends on the balance between inward and outward

currents during phase 4 of the action potential (AP). Increased phase 4 inward currents carried by

Na+ or Ca2+, particularly time-dependent activating currents like the “funny current” If, and/or

decreased phase 4 outward currents, produce spontaneous phase-4 depolarization that can reach

threshold and cause ectopic firing.

Focal ectopic activity may also result from afterdepolarizations, which are subdivided into

early afterdepolarizations (EADs; arising before the end of phase 3) or delayed

afterdepolarizations (DADs) occurring after full repolarization. Normal cardiomyocyte Ca2+

handling is crucial for cardiac contractility (Figure 3A). DADs (Figure 3B) are thought to be the

predominant cause of focal atrial ectopic firing. DADs are caused by a diastolic Ca2+ leak from

the sarcoplasmic reticulum (SR) via SR Ca2+-release channels or “ryanodine receptors” (RyRs,

RyR2 being the cardiac isoform). Systolic Ca2+-release through RyR2s mediates cardiac

excitation-contraction coupling. Relaxation is mediated by diastolic Ca2+ removal from the

cytosol into the SR by a Ca2+-uptake pump, the SR Ca2+-ATPase (SERCA2a). RyR2s are

sensitive to both cytosolic and intraluminal SR Ca2+ concentrations and diastolic releases result

from SR Ca2+-overload or when oversensitive RyR2s have an abnormally low Ca2+-threshold for

Ca2+-release. Excess cytosolic Ca2+ is handled by the sarcolemmal Na+, Ca2+-exchanger (NCX),

which moves three Na+ ions (charge +3) into the cell for each Ca2+ ion (charge +2) extruded into

the extracellular space, generating net inward current (called “transient inward current”, “Iti”) that

depolarizes the cell, producing a DAD. When DADs reach threshold they induce premature AP

firing (dashed line in Figure 3B), which promotes its own perpetuation by synchronizing release

events and allowing more Ca2+ to enter the cell (17). Repeated DAD-triggered APs can generate

focal atrial tachycardias. RyR2-function is regulated by channel-phosphorylation:

hyperphosphorylation enhances RyR2 Ca2+-sensitivity and promotes DAD-formation.

Calsequestrin (CSQ) is the principal Ca2+-storage buffer of the SR. Inadequate CSQ

function/expression increases free SR Ca2+-concentration and promotes diastolic RyR2 Ca2+-

release (18).

EADs generally occur when AP-duration (APD) is excessively prolonged. With very long

APs, L-type Ca2+-currents may have enough time to recover from inactivation carrying inward

Ca2+-current to generate an EAD and stimulate a spontaneous extrasystole.

Reentry

The two principal competing conceptual frameworks for understanding functional reentry (19)

are shown in Figure 4 (top). The leading-circle model (Figure 4A) posits reentry around a central

zone that is continuously activated by centripetal waves emanating from a reentering activation

wavefront. In this model, reentry establishes itself in a circuit with dimension equal to the

distance travelled during one refractory period (“wavelength”, refractory period times conduction

velocity; CV). When the wavelength is small because of slow conduction or brief refractoriness,

multiple circuits can be accommodated in the atria and spontaneous self-termination is unlikely.

In the spiral-wave model (Figure 4B), reentry is maintained by rotors established by tissue

excitability properties (depending on both conduction and refractoriness), which determine rotor

period, stability and size (greater excitability generates smaller, more stable, and faster rotors).

Anatomical obstacles or complexities favor reentry by anchoring reentry circuits. Figure 4C

illustrates the effect of structural remodeling. Progressive atrial dilation creates longer

conduction pathways for reentry. Tissue fibrosis slows conduction, makes it more heterogeneous

and creates conduction-barriers that favor the development of stable rotors and/or multiple

simultaneous irregular reentry circuits that can sustain AF. In addition, fibroblast proliferation

can promote arrhythmogenesis via cardiomyocyte-fibroblast interactions that alter AP-properties

and slow conduction.

Molecular control mechanisms

Molecular control of gene-expression in AF

There is extensive evidence for an important role of altered gene-control in AF

pathogenesis. Figure 5 presents a simplified schematic of dysregulated molecular gene-

expression control mechanisms that are implicated in AF. These are recognized to occur in at

least 4 different contexts: 1) AF-inducing mutations in transcription factors (TFs); 2) gene-

variants identified by GWAS that are in or related to TFs, which are the presumptive immediate

mediators of AF-substrate control; 3) AF-induced signaling changes that are involved in AF-

induced atrial remodeling; 4) changes in gene-expression that mediate the AF-promoting effects

of predisposing diseases and risk factors. Many of these are discussed in detail below, but we will

provide a general overview here. The tissue-specific cellular phenotype is controlled primarily by

selective expression of genes in the genome. Transcription-patterns from DNA to messenger-

RNA (mRNA) are tissue and disease specific, largely under the regulation of TFs that bind to

specific DNA-sequences and enhance or suppress transcription of associated sequences.

Mutations in the TFs GATA, NKX2-5 and TBX5 cause various forms of congenital heart disease

and predispose to AF (20). In addition, GWASs have identified a number of single-nucleotide

polymorphisms (SNPs) believed to control AF-risk via TFs, like the 4q25 variants for which

PITX2 is the closest gene, the 16q22 SNPs in an intron (non-coding segment) of ZFHX3 and the

1q24 variants in PRRX1 (Table 2). AF itself causes reprogramming of gene-expression, in

particular by increasing cellular Ca2+-loading and thereby activating a variety of signaling

systems (21). Prominent among these is the Nuclear Factor of Activated T-Lymphocytes

(NFAT)/calcineurin system, which regulates the expression of a range of important ion-channels

(21). AF-inducing conditions (in many cases along with AF itself) act through a number of cell-

membrane receptors controlling signaling pathways like the renin-angiotensin-aldosterone and

transforming growth-factor-β systems, which induce atrial remodeling through a range of

downstream TFs. Reactive oxygen species, particularly those derived from NADPH-oxidase, also

play a key role. Nuclear-delimited signaling likely also occurs, although we are just beginning to

understand these pathways and their role in disease states (22). Finally, a range of small non-

coding RNA-sequences called microRNAs, which control gene-expression principally by

blocking translation of target mRNAs, have been implicated in AF-inducing remodeling. Long

non-coding RNA (lncRNA) might also contribute (23), but this research is just in its infancy in

the atria.

Molecular control of cell Ca2+-handling and DAD generation

Normal cell Ca2+-handling is crucial for cellular contraction and relaxation (Figure 3A;

see also Chapter 16 of this book). Abnormal SR Ca2+-handling is seen in both paroxysmal and

chronic AF (pAF, cAF) patients (24-29), promoting spontaneous RyR2-mediated diastolic SR-

Ca2+ releases. Moreover, patients with rare inherited variants in RyR2 linked to

catecholaminergic polymorphic ventricular tachycardia (CPVT) also commonly exhibit AF as a

result of abnormal SR Ca2+ release (30).

Figure 6 summarizes the detailed molecular pathobiology of DAD-inducing diastolic

RyR2 Ca2+-release in non-genetic forms of AF. Protein-kinase A (PKA)-phosphorylation of

RyR2 at Ser2808 (26) and Ca2+-calmodulin dependent kinase-II (CaMKII) phosphorylation at

Ser2814 are increased in dogs and goats with pacing-induced AF and in AF-patients (24, 29-32).

CaMKII-activity is normally autoinhibited. Ca2+-calmodulin binding removes autoinhibition,

activating CaMKII and causing autophosphorylation that activates CaMKII and makes it Ca2+-

independent. Similar activation may result from CaMKII-oxidation. Changes in RyR2

phosphorylation-state at PKA and CaMKII sites may result not only from changed kinase-

activity, but also from alterations in dephosphorylating enzymes, phosphatases (31). Proteomic

studies revealed that the serine/threonine protein phosphatase type-1 (PP1), a major phosphatase

in the heart, is also dysregulated in pAF (33). In particular, extensive changes in PP1 regulatory

subunits were observed, which may underlie heterogeneous changes in the phosphorylation status

of Ca2+-handling proteins in AF patients.

These post-translational alterations increase RyR2 Ca2+-sensitivity, enhancing channel

open-probability (24, 26). Mice deficient in RyR2-inhibitory FK-505 binding protein 12.6, mice

with gain-of-function mutations in RyR2, and mice with constitutively phosphorylated RyR2

channels at S2814 (S2814D mice), all exhibit increased susceptibility to pacing-induced AF in

association with increased atrial-cell SR Ca2+-leak and triggered activity (24, 30, 34, 35).

Angiotensin-effects to promote AF may in part be due to oxidative stress acting via CaMKII-

oxidation on diastolic RyR2 Ca2+-release (36). RyR2-dysfunction can be induced by Ca2+-

overload resulting from phospholamban hyperphosphorylation, which removes phospholamban-

inhibition of SERCA and enhances SR Ca2+-uptake (31), as has been reported for pAF (29).

Phospholamban-hyperphosphorylation can be produced by enhanced PKA or CaMKII-activity,

or by decreased phosphatase-function. Reduced phosphatase-function can be a consequence of

increased activity of an inhibitory protein, I-1, typically caused by I-1 hyperphosphorylation (31).

Increases in NCX expression and/or function are also commonly noted in persistent AF

(24, 28, 31, 37), causing Iti resulting from any specific amount of diastolic SR Ca2+ leak to be

larger in AF, likely contributing to the increased risk of DADs and triggered ectopic activity (24,

38). Cardiac IP3-receptors (IP3R2) act as Ca2+-transporting pathways and can facilitate SR Ca2+-

leak to promote arrhythmogenesis. IP3R2 expression is increased by ATR and is greater in atria

than ventricles (39). IP3R2-coupled amplification of atrial SR Ca2+-release events and related

arrhythmogenesis may thus contribute to AF-related ectopic activity.

Congestive heart failure (CHF) is a very important cause of AF. Focal drivers and

triggered activity play a role in CHF-related AF (40). In experimental dilated cardiomyopathy,

CHF increases SR Ca2+-load and reduces calsequestrin expression, thereby promoting

spontaneous SR Ca2+-release (41). Increased SR Ca2+-load also contributes to arrhythmogenic SR

Ca2+-releases in pAF patients (29). Altered RyR2 activity due to an inherited mutation in the

structural protein junctophilin-2 was shown to cause AF in patients with hypertrophic

cardiomyopathy, and a relative lack of junctophilin-2 due to increased RyR2 protein expression

may contribute to RyR2 dysfunction in pAF (42). The increased RyR2 protein expression in pAF

is at least in part due to a reduction in the inhibitory miRNA-106b-25 complex (43). Coronary

artery disease (CAD) is also an important risk factor for AF. Atrial ischemia promotes AF-

maintenance (44). In a dog model of chronic occlusive coronary-artery disease affecting the

atrium, frequent spontaneous atrial ectopy is associated with an increased incidence of atrial-

cardiomyocyte triggered activity (44). Triggered activity is likely due to spontaneous SR Ca2+-

release events and increased NCX-function in cardiomyocytes from the ischemic border-zone

(44).

In addition to the rare genetic variants in RyR2, two AF-promoting genetic variants have

been linked to DAD-mechanisms: 1) A mutation of the gene encoding the adapter protein

ankyrin-B (Long-QT Syndrome-4, LQTS4), which causes multiple proteins to be poorly-

addressed to their membrane-targets, altering Ca2+ handling and leading to DADs/triggered

activity (45, 46); and 2) A predicted loss-of-function SNP of the SLN gene encoding the Ca2+-

binding protein sarcolipin, which could increase SR Ca2+-load and thereby affect DAD-

susceptibility (47).

Beta-adrenoceptor activation phosphorylates RyR2, promoting diastolic SR Ca2+-release

events (47). Conditions that directly cause DAD-promoting abnormalities in Ca2+-handling may

require adrenergic stimulation to induce Ca2+-sparks and triggered activity (44). Spontaneous AF

paroxysms occur in dog models of autonomic hyperinnervation (48), with sympathovagal-

discharge preceding AF-paroxysms (49). Vagal activation promotes arrhythmogenesis by

reducing APD, allowing afterdepolarizations induced by adrenergic stimulation to induce ectopic

firing in pulmonary veins (50-52). Finally, although Ca2+-handling abnormalities and DADs

occur in atrial cardiomyocytes from pAF and cAF patients, atrial aftercontractions are less

frequent in multicellular atrial trabeculae from AF patients compared to sinus rhythm controls

(53). Similarly, high atrial rates alone may not produce proarrhythmic Ca2+-handling

abnormalities, but may even cause Ca2+-handling silencing to counteract the potentially cytotoxic

effects of chronically elevated intracellular Ca2+ (54). Thus, much more work is needed to

precisely define the role of abnormal Ca2+-handling in AF pathophysiology.

Molecular control of L-type Ca2+-current changes

AF (55), and indeed all very rapid atrial tachyarrhythmias (56), remodel atrial electrical

properties to promote AF initiation and maintenance (atrial tachycardia remodeling, ATR). A

major AF-promoting component of ATR is refractory-period reduction due to APD-abbreviation

(Figure 4B). Reduced depolarizing L-type Ca2+-current (ICa,L), along with increased repolarizing

inward-rectifier K+-currents, underlie ATR-induced APD-shortening (57-64). The molecular

basis of ICa,L-reduction in persistent AF is illustrated in Figure 7A. Rapid atrial activation

induces Ca2+-loading, activating Ca2+-calmodulin/calcineurin/NFAT signalling that causes down-

regulation of Cav1.2 -subunit mRNA (65-67). Other contributors to ICa,L downregulation may

include decreased expression of accessory 1, 2a, 2b, 3 and 22 subunits (59, 68, 69), Cav1.2

dephosphorylation via PP1 and type-2A (PP2A) protein phosphatases (31, 59, 70), increased

Cav1.2 -subunit s-nitrosylation (71), and metabolic stress (72). MicroRNAs are centrally

involved in cardiac remodeling (73) and recent work implicates increased miRNA-328 and miR-

21 in AF-promotion due to ICa,L-downregulation mediated by inhibition of translation and mRNA

destabilization (74, 75). In 82 patients with Brugada syndrome/Short-QT ECG phenotypes,

loss-of-function mutations of the CACNA1C and CACNB2 genes, encoding ICa,L α- and

β-subunits, were observed along with AF in individual patients (76). Patients with full-blown

Short-QT syndromes of various phenotypes have reduced APDs and are also predisposed to AF

(6).

Molecular control of K+-current and basis of AF-promoting alterations

Inward-rectifier K+-current enhancement promotes AF maintenance, by reducing APD

(favouring reentry) and stabilizing/accelerating arrhythmia-maintaining rotors by removing

voltage-dependent INa-inactivation through membrane-hyperpolarization (11, 77). Upregulation

of other K+-currents like two-pore K+-currents, small-conductance Ca2+-dependent K+-currents

and Kv1.1-mediated K+-currents may further contribute to APD-shortening in persistent AF (78-

80). Figure 7B shows how IK1 and IK,AChc are upregulated in persistent AF. IK1 increases because

of upregulation of the underlying Kir2.1 subunit (60-64, 69, 81-83) caused by reduced Kir2.1-

inhibitory microRNAs, like miR-1, miR-26 and miR-101 (83, 84). Kir2.1-dephosphorylation

(activation) via increased PP1 and PP2A function (31, 59, 70, 85) may also contribute.

Congestive HF upregulates fibroblast Kir2.1 expression and related IK1 currents, thereby causing

membrane hyperpolarization, increasing Ca2+ entry, and enhancing atrial fibroblast proliferation

(86), contributing to structural remodeling (see below). The changes in fibroblast IK1 are likely

mediated by miRNA-26a downregulation, positioning miRNA-26a as a common determinant of

both electrical and structural remodeling.

Agonist-induced muscarinic-receptor mediated IK,ACh activation is reduced in AF (60, 61).

This involves a reduction in Kir3.1 and Kir3.4 channel subunits and is associated with a loss of

physiological Na+-mediated IK,ACh activation (87). However, increased agonist-independent

(constitutive) IK,AChc is enhanced, both in dog models (60, 63, 82, 88) and in AF-patients (62, 64,

81, 89). Increased IK,AChc is due to greater IKACh-channel opening-probability, with no change in

single-channel conductance, kinetics or density (62, 82). A key role is played by altered IK,AChc

protein-kinase C (PKC) phosphorylation, with increased phosphorylation by stimulatory Ca2+-

dependent isoforms and reduced inhibitory classical Ca2+-independent isoform function (88, 89).

IK,AChc inhibition suppresses atrial tachyarrhythmias in ATR-preparations (63), suggesting that

IK,AChc contributes to ATR-induced arrhythmogenic remodeling.

The most common AF-promoting monogenic paradigm is accelerated atrial

repolarization due to gain-of-function K+-channel mutations (Table 1). Vagal enhancement is

known to promote clinical AF, and is central in some cases (90). IK,ACh hyperpolarizes atrial

cardiomyocytes and reduces APD in a spatially-heterogeneous way. Vagal enhancement strongly

favors AF initiation and persistence by facilitating the initiation and subsequent stability of

reentrant rotors (90). Kir3.4 knock-out strongly suppresses IK,ACh and prevents cholinergic AF

(91).

Molecular determinants of atrial conduction disturbances

Conduction abnormalities due to ion-channel dysfunction

Conduction-abnormalities favor reentry. Gap junctions are essential for efficient cell

coupling and conduction. There are discrepant results about AF-related atrial gap-junctional

remodeling in the literature (69, 92, 93). Some of the variability may be due to differences in

AF-duration, underlying heart disease and species-related factors (94). Spatially-heterogeneous

connexin-40 remodeling occurs in the goat model of electrically-maintained AF, consistent with

clinical data indicating that gene-variants that affect connexin-40 promoter function may

predispose to AF (95-97). Connexin-43 dephosphorylation/lateralization occurs in CHF, but

CHF-induced conduction-slowing and AF-promotion are unchanged with CHF-recovery, despite

disappearance of connexin-abnormalities (98). Recent evidence indicates that connexin-43 gene

transfer can improve conduction and suppress AF in porcine models, supporting the importance

of gap-junction protein remodeling in AF (99, 100).

Atrial ischemic disease causes localized conduction slowing, which allows for AF-

sustaining local reentry stabilized around a line of conduction-block (44). With acute ischemia,

gap-junction uncoupling predominates (101).

A number of AF-associated gene-variants affect ion-channels that control cardiac

conduction. GJA5 encodes connexin-40, an atrial-selective gap junction ion-channel. Connexin-

40 knockout causes conduction abnormalities and atrial arrhythmia-susceptibility (102). An AF-

causing GJA5 missense somatic mutation was identified in idiopathic AF-patients (96). GJA5-

promoter variants believed to decrease gene-transcription increase AF-susceptibility (95, 97,

103).

INa provides the energy for conduction and governs CV. INa-density decreases in canine

ATR, with corresponding decreases in SCN5A-subunit mRNA and protein (57). In humans with

AF, SCN5A mRNA expression appears unchanged (69). Atrial cardiomyocytes from AF-patients

showed a slightly reduced INa (104).

Cardiac Na+-channel gene (SCN5A) loss-of-function mutations cause AF, presumably via

reentry-promoting conduction-slowing (Table 1). SCN5A mutations were initially associated

with AF in a family presenting a complex and variable phenotype including dilated

cardiomyopathy, AF, sinus node dysfunction, and conduction defects (105). SCN5A mutations

and SNPs were subsequently found in idiopathic-AF subjects (106, 107). Loss-of-function

SCN5A mutations are the most common cause of Brugada Syndrome (108), which typically

presents as VF/sudden death, but can also cause AF (96). Recently, mutations in SCN10A, as

well as in Na+-channel -subunits like SCN1B, 2B and 3B, have been implicated in AF (109-

112).

Structural remodeling

Atrial fibrosis plays an important role in AF of different etiologies (13, 44, 113, 114).

The underlying signalling pathways and clinical manifestations have recently been reviewed

(115). The development of atrial fibrosis is likely determined by multiple signals acting

simultaneously. Cardiomyocytes and fibroblasts interact extensively through autocrine and

paracrine factors, and possibly electrically as well (13, 116). Fibroblasts produce extracellular-

matrix (ECM) proteins and mediators that affect cardiomyocyte phenotype, whereas

cardiomyocytes generate products like reactive oxygen species (ROS), platelet-derived growth

factor (PDGF), transforming growth-factor-β (TGF-β) and connective tissue growth factor

(CTGF) that modulate fibroblast function.

Angiotensin-II (AT-II) plays an important role in AF (117), likely in large measure via

fibroblast-modulation. AT-II type-1 receptors (AT1Rs) promote fibrosis via enhanced actions of

TGF-β, Smad2/3, Smad4, Arkadia, and activated extracellular signal-regulated (ERK) mitogen-

activated protein-kinase (MAPK) (118). Arkadia promotes ubiquination and removal of Smad7,

thereby increasing TGF-β signaling by removing Smad7-antagonism (119). In addition, AT1Rs

act through Shc/Grb2/SOS to activate Ras, which enhances MAPK-phosphorylation (120), and

through phospholipase-C (PLC). PLC breaks down phosphatidylinositol 4,5-bisphosphate (PIP2),

yielding diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates PKC and

IP3 mobilizes intracellular Ca2+, both actions contributing to remodeling. The JAK/STAT

pathway, also AT1R-sensitive, activates transcription-factors such as AP-1 and NF-κB, which

cause further cardiomyocyte remodeling. AT2R-activation counters AT1R-mediated MAPK-

activation by enhancing dephosphorylation via PP2A and phosphotyrosine phosphatase (PTP)

(120).

TGF-β1 is a key player in cardiac fibrosis. It is secreted by both fibroblasts and

cardiomyocytes (121). Overactivity of cardiac TGF-β1 causes atrial-selective fibrosis,

conduction abnormalities, and AF promotion (122). TGF-β1 mediates AT-II effects in both

paracrine and autocrine fashions (123). TGF-β1 acts through SMADs to activate fibroblasts and

enhance collagen production (13, 116, 119). Rapidly-firing atrial cardiomyocytes produce

Ang-II and ROS, acting via enhanced TGF-β production to differentiate cardiac fibroblasts into

ECM-secreting myofibroblasts (124, 125). Progressive fibrosis likely contributes to conduction

disturbances that make long-lasting AF very difficult to treat (14).

PDGF stimulates fibroblast proliferation and differentiation (13, 116, 122). PDGF-

receptors contain two transmembrane-domains that dimerize upon stimulation and then activate

an internal tyrosine-kinase. Tyrosine-kinase autophosphorylation of PDGF-receptors induces

Ras/MEK1/2, MAPK, JAK/STAT, and PLC signaling. PDGF-overexpression induces cardiac

fibrosis and dysfunction (126). Atrial-selective PDGF expression and action may contribute to

the greater fibrotic responses typically seen for atria versus ventricles (121).

Connective-tissue growth factor (CTGF) lies downstream to TGF-β1 and AT-II in

profibrotic-signaling pathways. CTGF activates fibroblasts through Src-kinase and MAPKs

(127). CTGF has emerged as a potentially-central player in atrial structural remodeling (128-

130).

MicroRNAs appear to contribute importantly to atrial structural remodeling. MiR-29

inhibits collagen-gene expression (131) and its downregulation likely contributes to atrial fibrosis

in CHF (132). MiR-30 and miR-133 are also downregulated in CHF, suppress CTGF-translation

(133), and may participate in atrial fibrosis (134). In contrast to miR-29, miR-20 and miR-133,

atrial miR-21 expression increases in CHF (134). MiR-21 targets the Sprouty-1 (Spry-1) gene,

which promotes fibroblast MAPK-phosphorylation and enhances fibroblast survival (135)

Although the significance of this finding for ventricular remodeling has been disputed (136),

more recent work strongly suggests an important role of miR-21 upregulation in CHF-associated

atrial fibrosis and AF-promotion (137).

SNPs in genes determining atrial structural integrity, inflammation and neurohumoral

control, have been associated with AF by conventional approaches. Examples include genes

encoding angiotensin-converting-enzyme (ACE) (138, 139), matrix metalloproteinase-2

(MMP2), and interleukin-10 (140). However, these have not been replicated in hypothesis-free

large-scale population studies. GWASs have implicated SNPs on chromosome 4q25, with

PITX2c being the closest potential target gene, and an SNP in chromosome 16q22 near the zinc

finger homeobox 3 transcription factor gene (ZFHX3) (50, 51, 141). PITX2c is involved in

cardiac development, particularly sidedness and pulmonary-vein aspects (142, 143) implicating

possible structural abnormalities as the way in which it may be involved in AF. ZFHX3 is a

tumor-suppressor (144, 145), which induces expression of PDGF-receptors and protects against

oxidant stress (146), also suggesting structural-remodeling as a potential mechanism of AF-

promotion.

Atrial Ca2+-handling abnormalities may also contribute to reentry-promoting structural

remodeling. Increased fibroblast Ca2+-entry through TRP-channels promotes fibroblast

proliferation and structural remodeling (147). Genetic inhibition of RyR2-hyperphosphorylation

prevents excessive SR Ca2+-leak, suppresses atrial dilatation, and reduces atrial conduction

abnormalities in mice with cardiac-restricted overexpression of a repressor form of the cAMP-

response element modulator (148).

Future directions

The largest and most important challenge related to the molecular basis of AF is translating our

increased knowledge into practical clinical applications. It is widely hoped that targeting the

molecular mechanisms of AF will permit the development of novel, safer and more specific

treatment-approaches. Recent advances suggest that biological therapies capable of specifically

modifying the AF-substrate may be in sight(149). The challenges in moving from scientific

discovery to practical therapeutic innovation in this area are substantial, but the history of this

field suggests that conceptual advances do ultimately result in tangible improvements in patient

management options (1).

Acknowledgements

The authors thank Jennifer Bacchi for excellent secretarial help.

Funding

Supported by the Canadian Institutes of Health Research (MGP6957 and MOP44365), the

Quebec Heart and Stroke Foundation, the Foundation Leducq (European-North American Atrial

Fibrillation Research Alliance, ENAFRA, grant 07CVD03), the German Federal Ministry of

Education and Research through Atrial Fibrillation Competence Network (grant 01Gi0204) and

DZHK (German Centre for Cardiovascular Research), the Deutsche Forschungsgemeinschaft (Do

769/1-3), the European Union (European Network for Translational Research in Atrial

Fibrillation, EUTRAF, grant 261057). NIH-NHLBI grants (R01-HL089598, R01-HL091947,

R01-HL117641, R41-HL129570), and the American Heart Association (13EIA14560061).

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Figure legends:

Figure 1: Etiological contributors to atrial fibrillation.

Figure 2: Mechanistic basis of atrial fibrillation and associated clinical forms. A, Focal

firing usually results from local ectopic activity. Organized discrete reentrant

activity and focal firing can maintain AF by producing regularly-firing drivers that

are conducted irregularly (fibrillatory conduction) in the heterogeneous atrial

substrate. B, AF can progress from paroxysmal (self-terminating) forms, believed to

result primarily from focal drivers, to persistent and longstanding persistent (>1

year) forms due to AF-related remodeling and/or disease progression, resulting in

development of an increasingly vulnerable substrate. Substrate vulnerability, AF-

related remodeling and disease progression are further modulated by genetic

predisposition. . There is overlap between mechanisms and pronounced patient-to-

patient heterogeneity.

Figure 3: Cellular Ca2+ handling and DADs. A, During the plateau phase of the action

potential (AP) Ca2+ enters the cell via L-type Ca2+ channels. This Ca2+ binds to

ryanodine-receptors (RyR2), triggering a much larger Ca2+ release from the

sarcoplasmic reticulum (SR), which initiates cellular contraction. SR Ca2+ stores are

maintained by pumping Ca2+ into the SR by the SR Ca2+-ATPase, SERCA. B,

Diastolic Ca2+-handling abnormalities underlie DADs. Spontaneous SR Ca2+-

releases through RyR2 elevate cytosolic Ca2+, which is exchanged for extracellular

Na+ by the Na+/Ca2+ exchanger (NCX), producing depolarizing transient inward-

current (Iti). Inappropriate diastolic RyR2 Ca2+-release is promoted by

RyR2-hyperphosphorylation, excess SR Ca2+, or decreased SR Ca2+-binding to

calsequestrin (CSQ; red arrows). Repolarizing conductances oppose Iti and suppress

diastolic depolarization, so reduced diastolic K+ current or increased NCX current

can favor DADs (orange arrows).

Figure 4: Determinants of reentry. Top, Basic concepts of reentry. The leading circle model

(A) posits reentry around a central zone that is continuously activated by centripetal

waves emanating from the reentering activation wavefront. The spiral wave model

(B) describes reentry as a “rotor” established by tissue excitability properties. C,

Structural remodeling (atrial enlargement and fibrosis, most typically affecting the

left atrium, LA) produces relatively-fixed reentry substrates that reverse poorly if at

all.

Figure 5: A schematic representation of gene-regulatory pathway dysregulation in AF.

Abbreviations: AT-II, angiotensin-II; ATR, angiotensin receptor; NFAT, nuclear

factor of activated T-cells; NOX, NADPH-oxidase; P, phosphate; ROS, reactive

oxygen species; TF, transcription factor; TGFβ, transforming growth factor-β;

TGFβR, TGFβ-receptor;.

Figure 6: Molecular basis of DAD-inducing diastolic Ca2+-releases. RyR-dysfunction is

caused by RyR-hyperphosphorylation or excess Ca2+-loads. Phospholamban (PLB)

inhibits SERCA. PLB-hyperphosphorylation removes this inhibitory effect,

enhances SERCA function and can lead to Ca2+-overload. High atrial rate during AF

enhances cellular Ca2+-entry. Increased cell-Ca2+ promotes Ca2+/calmodulin (CaM)

binding to Ca2+/calmodulin-dependent protein kinase-II (CaMKII), disinhibiting the

catalytic subunit. After CaMKII catalytic-subunit activation, oxidation at

Met281/282 or phosphorylation at Thr286 cause persistent CaMKII activity.

Inhibitor-1 (I-1) suppresses protein-phosphatase-1 (PP1) function in the SR and

contributes to PLN and RyR phosphorylation. These factors have been associated

with AF in samples from pAF patients (blue arrows), cAF patients (red arrows), or

animal models (yellow arrows).

Figure 7: Mechanisms of ionic-current remodeling in AF. A, L-type Ca2+-current (ICa,L)

downregulation. High atrial rates in AF enhance intracellular Ca2+-load, activating

calcineurin via the Ca2+/calmodulin (CaM) binding. Calcineurin dephosphorylates

Nuclear Factor of Activated T-Lymphocytes (NFAT), allowing it to translocate into

the nucleus and reduce mRNA-levels of the ICa,L alpha-subunit, Cav1.2. Breakdown

of Cav1.2 protein by calpains might also contribute to reduced Cav1.2 protein

expression. The protein Zinc transporter-1 (ZnT-1) impairs Cav1.2 membrane-

trafficking and is upregulated in AF. Increased protein-phosphatase-1/2a (PP1/PP2a)

activity dephosphorylates Cav1.2-phosphorylation and may also decrease ICa,L. B,

Inward-rectifier K+-current upregulation. Increased Kir2.1 subunit expression is

caused by decreases in inhibitory microRNAs like miR-101, miR-26, miR-1, at least

in part due to NFAT-mediated inhibition of miR-26/miR-1 expression.

Acetylcholine-regulated K+-current (IK,AChc) is increased because of increased

membrane-abundance of the stimulatory protein-kinase C (PKC) isoform PKC and

decreased cellular expression of the inhibitory isoform PKC due to enhanced

calpain-mediated breakdown.

Gene

(Presumed) Functional

target(s)

(Presumed) Arrhythmogenic mechanism

AAC variants affecting K+-currents

ABCC9

IKATP

LOF: Impaired APD adaptation during stress

KCNA5

IKur

GOF: ↓ ERP; LOF: ↑ APD, EADs, TA

KCND3

Ito

GOF: ↓ ERP

KCNE1

IKs

GOF: ↓ ERP; LOF: ↑ APD, EADs

KCNE2

KCNQ1/KCNE2 K+-current

GOF: ↓ ERP

KCNE3

Ito / I Kr

GOF: ↓ ERP

KCNE4

IKs (?)

KCNE5

IKs

GOF: ↓ ERP

KCNH2

GOF: ↓ ERP; LOF: ?

KCNK3

IK2P

LOF: ↑ APD, SAN dysfunction

KCNJ2

IK1

GOF: ↓ ERP, ↓ RMP

KCNJ4

KCNJ5

IK,ACh

KCNJ8

IKATP

GOF: ↓ ERP

KCNJ12

KCNQ1

IKs

GOF: ↓ ERP; LOF: ?

NPPA

IKs

GOF: ↓ ERP, ?

AAC variants affecting Na+ and related currents

HCN4

LOF: SAN dysfunction

SCN5A

INa

GOF: ↑ excitability / TA; LOF: ↓ CV

SCN10A

INa

GOF: ↑ excitability / TA; LOF: ↓ CV

SCN1B

LOF: ↓ CV

SCN1Bb

INa/I to

Mixed: ↓ INa , ↑ Ito , ↓ ERP

SCN2B

INa

LOF: ↓ CV

SCN3B

INa

LOF: ↓ CV

SCN4B

AAC variants affecting Ca2+-handling and current

CACNA1C

ICa,L

CACNA2D2

Ca,L

CASQ2

Ca2+-buffering

JPH2

RyR2-channel

GOF: ↑ SCaEs, TA

RYR2

RyR2-channel

GOF: ↑ SCaEs, TA, ↓ CV

AAC variants not directly affecting sarcolemmal ion currents

GATA4, GATA5, GATA6

LOF: ?

GJA1

Connexin43

LOF: ↓ CV

GJA5

Connexin40

LOF: ↓ CV

GREM2

BMP antagonist

GOF: Abnormal cardiac development, ↓ CV

LMNA

Lamin A/C

Structural remodeling, ↓ CV

MYH6

Contractile proteins

NKX2-5, NKX2-6

LOF: ?

NUP155

Nuclear pore complex

LOF: Impaired nuclear permeability, remodeling,↓ APD

PITX2c

LOF: ?

ZFHX3

Table 1. amino-acid coding (AAC) missense variants associated with atrial fibrillation. APD: action potential duration; ↓

CV: slow/heterogeneous conduction; ↓ ERP: reduced effective refractory period; GOF: Gain of function variants; LOF: Loss

of function variants; ↓ RMP: resting membrane potential hyperpolarization; ↑ SCaEs: spontaneous diastolic Ca2+-release

events; TA: triggered activity; TF: transcription factor; ?: unknown mechanism. Based on [3,4,4a,4b].

(Presumed/nearest) Gene

Variant

(Presumed) Function

Relative risk

C9orf3

rs10821415

1.13 (1.08-1.18)

CAND2

rs4642101

Modulating atrial APD

1.10 (1.06-1.14)

CAV1

rs3807989

Cellular structure and signaling

0.88 (0.84-0.91)

GJA1 rs13216675

Electrical coupling controlling conduction

velocity

1.10 (1.06-1.14)

HCN4

rs7164883

Regulation of If and automaticity

1.16 (1.10-1.22)

KCNN3

rs6666258

Regulation of I

, modulating APD

1.18 (1.13-1.23)

NEURL

rs12415501

Modulating atrial APD

1.18 (1.13-1.23)

PITX2 rs6817105

Left/right division and pulmonary vein sleeve

development

1.64 (1.54-2.21)

PRRX1

rs3903239

Development of great vessels

1.14 (1.10-1.18)

SYNE2

rs1152591

Sarcomere structural protein

1.13 (1.09-1.18)

SYNPO2L / MYOZ1

rs10824026

Regulating actin and cardiomyocyte structure

0.85 (0.81-0.9)

TBX5 rs10507248

Transcription factor controlling conduction

system development

1.12 (1.08-1.16)

ZFHX3

rs2106261

1.24 (1.17-1.30)

Table 2. Genetic variants associated with atrial fibrillation in genome-wide association and large-scale genotyping studies

in patients from European descent. Based on [3,4,4a,4b].

Causes of Atrial Fibrillation

Extrinsic factors

Heart disease

Genetic factors

ATRIAL FIBRILLATION

Abnormalities in cardiac

structure or function

Altered ion channel

function

Calcium-handling

abnormalities

Thyroid dysfunction

Sleep apnea

Autonomic toneAlcohol, drugs

Inflammation

Non-CV disease

Diabetes

Obesity

COPDHypertensive heart diseaseCoronary artery disease

Valvular heart disease Cardiomyopathies

Pericarditis /Myocarditis

Aging heart

Heart failure

Rare disease-

causing mutations

Common variants

with small effect size

Variants of unknown significance

Cigarette smoking

Reentry

Driver

Focal firing Trigger

Fibrillatory

conduction

Substrate+

Atrial Fibrillation –Triggers and Substrates

Single

circuit

reentry

sustained

transient

remodeling

BAtrial Fibrillation –Forms and Progression

Figure 2

Multiple

circuit

reentry

ATRIAL FIBRILLATION

remodeling

AF AF AFAF

0 4 8

days

Vulnerability

triggers trigger triggertriggers

trigger

60 80

Age (years)

Paroxysmal

AF Persistent

AF Longstanding

persistent AF

AF-related remodeling Disease-related remodeling

Genetic predisposition

AF-related

remodeling

Disease-

remodeling

Genetics

Paroxysmal AF Persistent AF Longstanding perAF

progression progression

Figure 3

ICa,L

NCX

Cytosol

3Na+

RyR2

Diastole

[Ca2+]

Ca2+

B. Diastolic Ca2+-handling

abnormalities and DAD generation

Iti

DADs

200 ms

NCX

Ca2+

CSQ

Extracellular

space Repolarizing

conductances

ICa,L

NCX

Cytosol

3Na+

RyR2

Systole

[Ca2+]

Ca2+

A. Systolic Ca2+-handling

producing cell contraction

200 ms

NCX

Ca2+

CSQ

Extracellular

space

SERCA SERCA

SLN

PLB

SLN

PLB

Structural Remodeling

Figure 4

LA enlargement

AF maintaining

substrate

Functional Determinants

Mechanisms of Reentry

Leading circle

Determined by wavelength = effective

refractory period ×conduction velocity

core

Spiral wave

Determined by excitability

and wave curvature

A B

refractory

RA LA

LA fibrosis

Cytosol

Nucleus

DNA

GATA-4

GATA-5

GATA-6 NKX2-5 TBX5

PITX2

ZFHX2

PRRX1

ATR AT-II

TGFβR

TGFβ

SMAD 2/3

STAT

JAK

Ca2+

ICa,L

CaM

NFATc3/c4

Calcineurin NFATc3/c4 P

ROS ROS

SMAD 4

NF-κB

c-fos

NOX

AF-promoting conditions

miRNAs

mRNA

protein

Figure 5

AF-inducing mutations in transcription factors (TFs)

TF-related gene variants implicated in AF

Figure 6

RyR2

[Ca2+]

CSQ

Ser2814

Ser2808

Ser16

Thr17

I-1

PP1

Atrial

rate

Thr35

Ca2+ Leak

Ox CaM

CaM Ca2+

Ca2+

(autoinhibited)

(autophosphorylated)(Ca2+/CaM-dependent)

(oxidized)

CaMKII activity

Factors promoting AF by inducing diastolic

Ca2+ leak through RyR2

Ang-II

Thr286

NADPHox

Cytosol

Extracellular space

SERCA

PLB

SLN PThr5

Met281/282

Associated with AF in:

pAF patients

cAF patients

Animal models

Spin-1

JPH2

DNAmRNA

Cav1.2

Ca2+

PP1/PP2A

ICa,L

GSH

CaM

NFATc3/c4

NFATc3/c4 P

Calcineurin

Oxidative

Stress

Atrial

rate

APD

L-type Ca2+ current

remodeling

Trafficking

Transcription

Degradation

Calpains

Nucleus

Cytosol

ZnT-1

miR-328

mRNA

Kir2.1

IK1

Translation

miR-26

miR-101

miR-1

IK,AChc Basal IR current

APD

Hyperpolarization

PPKCε

Inward rectifier K+current

remodeling

Figure 7

PKCα

mRNA

Transcription miR-101

miR-26

Calpains

Ca2+

Cav1.2

Kir2.1

Classification of intracavitary electrograms in atrial fibrillation using information and complexity measures

Article

Dec 2019
BIOMED SIGNAL PROCES

Abstract Background Classification of complex fractionated atrial electrograms is crucial for the study of atrial fibrillation and the development of treatment strategies, because these electrophysiological phenomena represent a common substrate for radiofrequency ablation in treatment of this arrythmia. Objective The objective of this work is the characterization of short term atrial electrograms using nonlinear dynamics measures, helping in the automatic classification of electrograms. Methods The dataset consists of 113 atrial electrograms recordings from left-atrial endocardial mapping. These signals were classified by three expert electrophysiologists into four classes, from C0 (non fractionated) to C3 (high degree of fractionation). The calculated features were Approximate entropy, Dispersion entropy, Fuzzy entropy, Permutation entropy, Tsallis entropy, Shannon entropy, Renyi entropy, and Lempel-Ziv complexity. Features were selected for classification using Neighborhood Component Analysis. Different classifiers were tested using selected features, and the one with maximum sensitivity and specificity in each task was reported. Results We obtained a classification performance that overcome previous works on this database and are comparable to the results of studies performed over bigger datasets. Separation between C3 signals from (C0, C1, C2) signals was performed with 99.98% sensitivity and 96.61% specificity. Non-fractionated signals (C0 + C1) were separated from fractionated signals (C2 + C3) with 96.72% sensitivity and 94.51% specificity. Moreover, the estimation times of the selected features are low enough to consider the online application of this scheme. Conclusions and significance Classification performance obtained using information and complexity measures shown better results than previous works over this dataset, encouraging the application of these features to characterize atrial electrograms.

Vectorial theory surpasses the local theory in explaining the origin of P-wave dispersion

Article

May 2021
J ELECTROCARDIOL

Background Local theory and the vectorial theory are used to explain the origin of P-wave dispersion (PWD). There are no previous studies that analyze both at the same time. Objectives We set out to determine the implication of local and vectorial theories in the origin of PWD. Methods Cross-sectional study in 153 randomly selected patients aged 18–70 years, undergoing electrophysiological study. Inhomogeneous atrial conduction was evaluated by atrial electrogram dispersion in terms of duration (EGMdurdis) and morphology (EGMmorph dis). P-distal coronary sinus interval (P-DCS) was also measured. P-wave was measured twice, firstly at a calibration of 20 mm/mV and a sweep speed of 50 mm/s, enhancement 10× (basic measurement [BM]), and second time at sweep speed of 150 mm/s, enhancement 80-160× (high precision measurement [HPM]). Results PWD with BM was 48 ms [36–54 ms] while with HPM it was 4 ms [0–10 ms], p < 0.001. With BM, maximum and minimum P- wave duration presented a moderate correlation (r = 0.342; p < 0.001), using HPM it becomes strong (r = 0.750; p < 0.001). In cases with P-DCS < 80 ms (r = 0.965; p < 0.001), but not with P-DCS ≥ 80 ms (r = 0.649; p < 0.001), the previous correlation became almost perfect with HPM. EGMdurdis and EGMmorphdis were weak but significantly correlated with PWD. This correlation became moderate in patients with P-DCS ≥ 80 ms and disappeared in those with P-DCS, using BM and HPM. Conclusion Vectorial theory explains almost entirely the PWD phenomenon. Inhomogeneous conduction could be an additional mechanism to explain PWD, but its contribution is small.

Influence of chronic volume overload-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria

Article

Full-text available

Jan 2018

Whereas molecular mechanisms of atrial fibrillation (AF) have been widely investigated, there is limited information regarding interrelation between chronic volume overload and parasympathetic nervous system in the pathophysiology of AF. In this study, we investigated the influence of abdominal aorto-venocaval shunt (AVS) -induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria. Interstitial fibrosis, cardiomyocyte hypertrophy and atrial enlargement, known as structural arrhythmogenic substrates for AF, took place after one month of AVS operation. Carbachol at 0.1 and 1 μM shortened the effective refractory period, acting as functional arrhythmogenic substrates, but increased the conduction velocity both in the atria of the sham-operated and AVS rats. The extents of the electrophysiological responses to carbachol in the atria of the AVS rat were greater than those in the sham-operated ones. Also, the higher inducibility and longer duration of carbachol-mediated AF were detected in the AVS atria than those in the sham-operated ones. These results showed that chronic volume overload-induced atrial remodeling promoted electrophysiological responses to cholinergic receptor stimulation in the isolated atria of rats, suggesting possible synergistic actions between structural arrhythmogenic substrate in the remodeled atria and functional arrhythmogenic substrates modulated by parasympathetic nerve activity.

Las ventajas del sistema de ICD con sensado auricular flotante para la detección de arritmias auriculares, no es brindado por ningún otro sistema

Article

Full-text available

Jan 2014

Elibet Chávez González

Pathophysiology and clinical relevance of atrial myopathy

Article

Full-text available

Mar 2024
BASIC RES CARDIOL

Atrial myopathy is a condition that consists of electrical, structural, contractile, and autonomic remodeling of the atria and is the substrate for development of atrial fibrillation, the most common arrhythmia. Pathophysiologic mechanisms driving atrial myopathy are inflammation, oxidative stress, atrial stretch, and neurohormonal signals, e.g., angiotensin-II and aldosterone. These mechanisms initiate the structural and functional remodeling of the atrial myocardium. Novel therapeutic strategies are being developed that target the pathophysiologic mechanisms of atrial myopathy. In this review, we will discuss the pathophysiology of atrial myopathy, as well as diagnostic and therapeutic strategies.

Atrial Fibrillation

Chapter

Jul 2020

J. Anthony Gomes

Atrial fibrillation (AF) is the commonest arrhythmia seen in clinical practice and is responsible for thromboembolic strokes, substantial impairment in life quality, and mortality. This chapter discusses the epidemiology of AF, the different types of AF, and its mechanisms and treatment including stroke prevention and rate and rhythm control with special reference to current and future catheter ablation strategies.

The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: A critical analysis

Article

Full-text available

Dec 2015

Atrial fibrillation (AF) is an extremely common clinical problem associated with increased morbidity and mortality. Current antiarrhythmic options include pharmacological, ablation and surgical therapies, and have significantly improved clinical outcomes. However, their efficacy remains suboptimal and their use is limited by a variety of potentially serious adverse effects. There is a clear need for improved therapeutic options. Several decades of research have substantially expanded our understanding of the basic mechanisms of AF. Ectopic firing and reentrant activity have been identified as the predominant mechanisms for arrhythmia initiation and maintenance. However, it has become clear that the clinical factors predisposing to AF and the cellular and molecular mechanisms involved are extremely complex. Moreover, all AF-promoting and maintaining mechanisms are dynamically regulated and subject to remodeling caused by both AF and cardiovascular disease. Accordingly, the initial presentation and clinical progression of AF patients is enormously heterogeneous. Improved understanding of arrhythmia mechanisms is likely needed to facilitate therapeutic innovation, but this assumption has not to our knowledge been carefully examined. Here, we review recent insights into the basic mechanisms of AF, critically analyze the role of basic-research insights in the development of presently-used anti-AF therapeutic options, and assess the potential value of contemporary experimental discoveries for future therapeutic innovation. Finally, we highlight some of the important challenges to the translation of basic science findings to clinical application.

Long non-coding RNA expression profile in atrial fibrillation

Article

Full-text available

Sep 2015
Int J Clin Exp Pathol

To investigate the expression profiles of long non-coding RNAs (lncRNAs) in atrial fibrillation (AF), atrial tissues from 3 AF patients and 3 non-AF patients that were collected for lncRNA expression microarray analyses to explore the role of lncRNA in the pathogenesis of AF. Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to identify the main functions of the differentially expressed genes and AF-related pathways. A total of 219 lncRNAs was found to be differentially expressed between AFs and controls. Among them, 156 were upregulated and 63 were downregulated. Eight out of 10 dysregulated lncRNAs such as uc001eqh.1 were validated by quantitative real-time PCR. GO categories, pathway analyses, and interaction network showed a consistent result that differentially expressed genes contribute to the pathogenesis of AF. In conclusion, the findings of our study provide a perspective on lncRNA in AF and the foundation for further study of the biological functions of lncRNAs in AF.

Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation

Article

Full-text available

Sep 2015
BASIC RES CARDIOL

Voltage-gated Kv1.1 channels encoded by the Kcna1 gene are traditionally regarded as being neural-specific with no known expression or intrinsic functional role in the heart. However, recent studies in mice reveal low-level Kv1.1 expression in heart and cardiac abnormalities associated with Kv1.1-deficiency suggesting that the channel may have a previously unrecognized cardiac role. Therefore, this study tests the hypothesis that Kv1.1 channels are associated with arrhythmogenesis and contribute to intrinsic cardiac function. In intra-atrial burst pacing experiments, Kcna1-null mice exhibited increased susceptibility to atrial fibrillation (AF). The atria of Kcna1-null mice showed minimal Kv1 family ion channel remodeling and fibrosis as measured by qRT-PCR and Masson's trichrome histology, respectively. Using RT-PCR, immunocytochemistry, and immunoblotting, KCNA1 mRNA and protein were detected in isolated mouse cardiomyocytes and human atria for the first time. Patients with chronic AF (cAF) showed no changes in KCNA1 mRNA levels relative to controls; however, they exhibited increases in atrial Kv1.1 protein levels, not seen in paroxysmal AF patients. Patch-clamp recordings of isolated human atrial myocytes revealed significant dendrotoxin-K (DTX-K)-sensitive outward current components that were significantly increased in cAF patients, reflecting a contribution by Kv1.1 channels. The concomitant increases in Kv1.1 protein and DTX-K-sensitive currents in atria of cAF patients suggest that the channel contributes to the pathological mechanisms of persistent AF. These findings provide evidence of an intrinsic cardiac role of Kv1.1 channels and indicate that they may contribute to atrial repolarization and AF susceptibility.

Biological Therapies for Atrial Fibrillation: Ready for Prime Time

Article

Jan 2016

John Kevin Donahue

Atrial fibrillation is a prominent cause of morbidity and mortality in developed countries. Treatment strategies center on controlling atrial rhythm or ventricular rate. The need for anticoagulation is an independent decision from the rate versus rhythm control debate. This review discusses novel biological strategies that have potential utility in the management of atrial fibrillation. Rate controlling strategies predominately rely on G-protein gene transfer to enhance cholinergic or suppress adrenergic signaling pathways in the atrioventricular node. Calcium channel blocking gene therapy and fibrosis enhancing cell therapy have also been reported. Rhythm controlling strategies focus on disrupting reentry by enhancing conduction or suppressing repolarization. Efforts to suppress inflammation and apoptosis are also under study. Resistance to blood clot formation has been shown with thrombomodulin. These strategies are in various stages of preclinical development.

Cardiac Fibrosis in Patients With Atrial Fibrillation

Article

Aug 2015

Atrial fibrillation (AF) is associated with structural, electrical, and contractile remodeling of the atria. Development and progression of atrial fibrosis is the hallmark of structural remodeling in AF and is considered the substrate for AF perpetuation. In contrast, experimental and clinical data on the effect of ventricular fibrotic processes in the pathogenesis of AF and its complications are controversial. Ventricular fibrosis seems to contribute to abnormalities in cardiac relaxation and contractility and to the development of heart failure, a common finding in AF. Given that AF and heart failure frequently coexist and that both conditions affect patient prognosis, a better understanding of the mutual effect of fibrosis in AF and heart failure is of particular interest. In this review paper, we provide an overview of the general mechanisms of cardiac fibrosis in AF, differences between fibrotic processes in atria and ventricles, and the clinical and prognostic significance of cardiac fibrosis in AF. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Biological therapies for atrial fibrillation

Article

Jul 2015
J CARDIOVASC PHARM

John Kevin Donahue

Atrial fibrillation is a prominent cause of morbidity and mortality in developed countries. Treatment strategies center on controlling atrial rhythm or ventricular rate. The need for anticoagulation is an independent decision from the rate vs. rhythm control debate. This review discusses novel biological strategies that have potential utility in the management of atrial fibrillation. Rate controlling strategies predominately rely on G-protein gene transfer to enhance cholinergic or suppress adrenergic signaling pathways in the atrioventricular node. Calcium channel blocking gene therapy and fibrosis enhancing cell therapy have also been reported. Rhythm controlling strategies focus on disrupting reentry by enhancing conduction or suppressing repolarization. Efforts to suppress inflammation and apoptosis are also under study. Resistance to blood clot formation has been shown with thrombomodulin. These strategies are in various stages of preclinical development.

Atrial Fibrillation Activates AMP-Dependent Protein Kinase and its Regulation of Cellular Calcium Handling

Article

Jul 2015

Background Atrial fibrillation (AF) is associated with metabolic stress, which activates adenosine monophosphate-regulated protein kinase (AMPK). Objectives This study sought to examine AMPK response to AF and associated metabolic stress, along with consequences for atrial cardiomyocyte Ca2+ handling. Methods Calcium ion (Ca2+) transients (CaTs) and cell shortening (CS) were measured in dog and human atrial cardiomyocytes. AMPK phosphorylation and AMPK association with Ca2+-handling proteins were evaluated by immunoblotting and immunoprecipitation. Results CaT amplitude and CS decreased at 4-min glycolysis inhibition (GI) but returned to baseline at 8 min, suggesting cellular adaptation to metabolic stress, potentially due to AMPK activation. GI increased AMPK-activating phosphorylation, and an AMPK inhibitor, compound C (CompC), abolished the adaptation of CaT and CS to GI. The AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) increased CaT amplitude and CS, restoring CompC-induced CaT and CS decreases. CompC decreased L-type calcium channel current (ICa,L), along with ICa,L-triggered CaT amplitude and sarcoplasmic reticulum (SR) Ca2+ content under voltage clamp conditions in dog cells and suppressed CaT and ICa,L in human cardiomyocytes. Small interfering ribonucleic acid-based AMPK knockdown decreased CaT amplitude in neonatal rat cardiomyocytes. L-type Ca2+ channel α subunits coimmunoprecipitated with AMPKα. Atrial AMPK-activating phosphorylation was enhanced by 1 week of electrically maintained AF in dogs; fractional AMPK phosphorylation was increased in paroxysmal AF and reduced in longstanding persistent AF patients. Conclusions AMPK is activated by metabolic stress and AF, and helps maintain the intactness of atrial ICa,L, Ca2+ handling, and cell contractility. AMPK contributes to the atrial compensatory response to AF-related metabolic stress; AF-related metabolic responses may be an interesting new therapeutic target.

Cholinergic Atrial Fibrillation in a Computer Model of a Two-Dimensional Sheet of Canine Atrial Cells With Realistic Ionic Properties

Article

May 2002

James Kneller

Classical concepts of atrial fibrillation (AF) have been rooted in Moe’s multiple-wavelet hypothesis and simple cellular-automaton computer model. Recent experimental work has raised questions about the multiple-wavelet mechanism, suggesting a discrete “driver region” underlying AF. We reexplored the theoretical basis for AF with a 2-dimensional computer model of a 5×10-cm sheet of atrial cells with realistic ionic and coupling properties. Vagal actions were formulated based on patch-clamp studies of acetylcholine (ACh) effects. In control, a single extrastimulus resulted in a highly meandering unstable spiral wave. Simulated electrograms showed fibrillatory activity, with a dominant frequency (DF, 6.5 Hz) that correlated with the mean rate. Uniform ACh reduced core meander of the spiral wave by ≈70% (as measured by the standard deviation of spiral-wave tip position) and accelerated the DF to 17.0 Hz. Simulated vagally induced refractoriness heterogeneity caused wavefront breakup as accelerated reentrant activity in regions of short refractoriness impinged on regions unable to respond in a 1:1 fashion because of longer refractoriness. In 7 simulations spanning the range of conditions giving sustained AF, 5 were maintained by single dominant spiral waves. On average, 3.0±1.3 wavelets were present (range, 1 to 7). Most wavelets were short-lived and did not contribute to AF maintenance. In contrast to predictions of the multiple-wavelet hypothesis, but in agreement with recent experimental evidence, our model indicates that AF can result from relatively stable primary spiral-wave generators and is significantly organized. Our results suggest that vagal AF may arise from ACh-induced stabilization of the primary spiral-wave generator and disorganization of the heterogeneous tissue response. The full text of this article is available at http://www.circresaha.org.

The Role of Pharmacogenetics in Atrial Fibrillation Therapeutics - Is Personalized Therapy in Sight?

Article

May 2015
J CARDIOVASC PHARM

Dawood Darbar

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide requiring therapy. Despite recent advances in catheter-based and surgical therapy, antiarrhythmic drugs (AAD) remain the mainstay of treatment for symptomatic AF. However, response in individual patients is highly variable with over half the patients treated with rhythm control therapy experiencing recurrence of AF within a year. Contemporary AADs used to suppress AF are incompletely and unpredictably effective and associated with significant risks of proarrhythmia and non-cardiac toxicities. Furthermore, this 'one-size' fits all strategy for selecting antiarrhythmics is based largely on minimizing risk of adverse effects rather than on the likelihood of suppressing AF. The limited success of rhythm-control therapy is in part due to heterogeneity of the underlying substrate, interindividual differences in disease mechanisms, and our inability to predict response to AADs in individual patients. Genetic studies of AF over the last decade have revealed that susceptibility to and response to therapy for AF is modulated by the underlying genetic substrate. However, the bedside application of these new discoveries to the management of AF patients has thus far been disappointing. This may in part be related to our limited understanding about genetic predictors of drug response in general, the challenges associated with determining efficacy of response to AADs and lack of randomized genotype-directed clinical trials. Nonetheless, recent studies have shown that common AF susceptibility risk alleles at the chromosome 4q25 locus modulated response to AADs, electrical cardioversion and ablation therapy. This monograph discusses how genetic approaches to AF have not only provided important insights into underlying mechanisms but also identified AF sub-types that can be better targeted with more mechanism-based 'personalized' therapy.

Upregulation of K(2P)3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

Article

May 2015
CIRCULATION

-Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanism-based approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K2P3.1 (TASK-1) two-pore-domain K(+) (K2P) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic AF patients is unknown. -Right and left atrial tissue was obtained from patients with paroxysmal (p) or chronic (c)AF and from sinus rhythm (SR) controls. Ion channel expression was analyzed by quantitative real-time PCR and Western blot. Membrane currents and action potentials were recorded using voltage- and current-clamp techniques. K2P3.1 subunits exhibited predominant atrial expression, and atrial K2P3.1 transcript levels were highest among functional K2P channels. K2P3.1 mRNA and protein levels were increased in cAF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD90) compared to patients in SR. By contrast, K2P3.1 expression was not significantly affected in pAF subjects. Pharmacological K2P3.1 inhibition prolonged APD90 in atrial myocytes from cAF patients to values observed among SR subjects. -Enhancement of atrial-selective K2P3.1 currents contributes to APD shortening in cAF patients, and K2P3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K2P3.1 as a novel drug target for mechanism-based AF therapy.

The Molecular Pathophysiology of Atrial Fibrillation

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