AbstractAtrial fibrillation (AF) is an irregular heart rhythm, characterised by chaotic atrial activation, which is promoted by remodelling. Once initiated, AF can also propagate the progression of itself in the so-called ‘‘AF begets AF’’. Several lines of investigation have shown that signalling molecules, including reactive oxygen species, angiotensin II, and phosphoinositide 3-kinases (PI3Ks), in presence or absence of cardiovascular disease risk factors, stabilise and promote AF maintenance. In particular, reduced cardiac-specific PI3K activity that is not associated with oncology is cardiotoxic and increases susceptibility to AF. Atrial-specific PI3K(p110α) transgene can cause pathological atrial enlargement. Highlighting the crucial importance of the p110α protein in a clinical problem that currently challenges the professional health care practice, in over forty (40) transgenic mouse models of AF (Table1), currently existing, of which some of the models are models of human genetic disorders, including PI3K(p110α) transgenic mouse model, over 70% of them reporting atrial size showed enlarged, greater atrial size. Individuals with minimal to severely dilated atria develop AF more likely. Left atrial diameter and volume stratification are an assessment for follow-up surveillance to detect AF. Gene therapy to reduce atrial size will be associated with a reduction in AF burden. In this overview, PI3K(p110α), a master regulator of organ size, was investigated in atrial enlargement and in physiological determinants that promote AF.Table 1Transgenic and Knockout Mouse Models of AFGene AlterationAtrial enlargementFibrosisThrombusVentricular dysfunction based on echo and/or catheterConduction abnormalities by ECGAPD AlterationAF pattern/other major cellular and molecular mechanismsReferencesRho GDIα TGCardiac-specific overexpression of Rho GDP dissociation inhibitor (GDI)α with α-myosin heavy chain (α-MHC) promoterAtrial weight 0.6-fold increase vs NTg at 4 months but no changes at 4 weeks✔ no significant increase in atrial and ventricleNot reported ↔ Sinus bradycardia, varying degrees of AV block, prolongation of P-wave duration, and PR interval at 7 monthsNot reportedSpontaneousOther mechanismsoreduced Connexin 40 expressionoincreased expression of RhoA, Rac1, and Cdc42[58]RhoACardiac-specific overexpression of RhoA with α-MHC promoterAtrial weight threefold increase vs NTg✔ inventricleNot reported✔Bradycardia and AV blockNot reportedSpontaneousOther mechanismsoincreased expression of hypertrophic genesoInflammation[59]Junction TGCardiac-specific overexpression of junctin protein with α-MHC promoterAtrial weight, more than tenfold increase vs WT for right atrium✔ in atrial and ventricle✔ in left and right atria✔BradycardiaAtrial and ventricle APD70,phase 3 ↑SpontaneousOther mechanismsoreduced triadin, RYR2, diastolic Ca2+, and Ca2+ transient amplitude[60]Junctate 1 TGCardiac-specific SR-located Ca2+-binding proteinjunctate 1 overexpression with α-MHC promoterAtrial weight, fourfold increase for left atrium and about fivefold increase for right atrium vs WT↑ in atria and ventricle✔ Intra-atrial thrombi✔Ventricular bigeminy, sinus pause, and bradycardiaAPD90, phase 4 ↑SpontaneousOther mechanismsoreduced phospholamban phosphorylation, troponin I phosphorylation, Calreticulin, and RyR2 channeloreduced SR Ca2+ content, Ca2+ transient amplitudeoincreased ICa,L[61]AMPK TGN488ICardiac-specific PRKAG2 (AMPK γ2 subunit) overexpression with missense mutationNot reportedNot reportedNot reported✔Reduced PR interval,persistent sinus bradycardia without AV blockNot reportedSpontaneous and paroxysmalOther mechanismsocardiac glycogen accumulation[62]A1AR TGCardiac-specific overexpression of A1 adenosine receptor (A1AR) with α-MHCNo differenceNo fibrosisNot reported✔Slow AV conductionAPD90, phase 4 ↔ APD50,phase 2 ↔ APD70,phase 2 ↔ Spontaneous[63]A3tg TGCardiac-specific overexpression of A3 adenosine receptor (A3AR) with α-MHC promoterAtrial size onefold and twofold increase at 12 weeks and 21 weeks, respectively, vs NTgNot present in atria and ventricleNot reported✔Absence of normal sinus rhythm, bradycardia, and intermittentlycompleteNot reportedSpontaneousOther mechanismsoreduced SERCA mRNA levels[64]RTEF1 TGCardiac-specific overexpression of Transcription enhancer factor-1-related factor(RTEF1) with α-MHC promoterAtrial weight4–sixfold increase vs controlNot present in atria and ventricle✔ OrganisedNot reportedSlow conduction in working myocardium, prolonged PR interval, and QRS durationNot reportedSpontaneousMechanismsoincreased PP1β phosphataseochronic dephosphorylation of cardiac connexin[65]ACE 8/8 TGCardiac-restricted angiotensin-converting enzyme (ACE)Overexpression with α-MHC Ang II concentration was 4.3-fold higher in ACE mice compared to WTAtrial weight, about threefold increase vs WT✔ in atria but not in ventricleNot reported✔AV blockNot reportedSpontaneous[66]Kir2.1 TGKir2.1 IK1 channel subunit cardiac-specific overexpression with α-MHC promoterAtrial weight, left and right atrial to body weight 65% and 141% increase, respectively, vs controlNot reportedNot reported✔Absence of T wave and reduced QT intervalAPD90, phase 4 ↓APD50,phase 2 ↔ APD75,phase 3 ↔ MAP90Phase 4 ↓MAP75phase 3 ↓MAP50,phase 2 ↔ Spontaneous[67]Kcne1−/−K+-channel KCNE1 subunit global protein deletion in mouseNormal atrial sizeNot present in atria and ventricleNot reported ↔ AV blockAPD50, phase 2 ↓APD90, phase 4 ↓Spontaneous[68]hKCNE1-hKCNQ1 TGHuman (h)KCNE1-hKCNQ1 Cardiac-specific overexpression with α-MHC promoter in mouseNot reportedNot reportedNot reportedNot reportedComplex atrial and irregular ventricular excitationβ-AR mediatedAPD50,phase 2 ↑APD90, phase 4 ↓SpontaneousOther mechanismsoIncreased IKs density[69]Des−/−Desmin global knockoutNot reportedNot reportedNot reportedNot reportedSupraventricular premature beats, spontaneous ventricular premature beats, and Wenckebach periodicityNot reportedSpontaneousOther mechanismsoHypokalemia,oReduced refractory period[70]CREM-IbΔC-XHuman cAMP-response element modulator (CREM) heart-directedoverexpression with α-MHC promoterAtrial weight, about 5–sevenfold increase vs NTg at 12–16 weeksNot present in left atrium and ventricle✔ Organised thrombi in left and right atria✔Not reportedNot reportedSpontaneousOther mechanismsoReduced phosphorylation of CREB and of PLBoIncreased phosphorylation of SERCA2, PP1, and mRNA levels of ANP[71]CREM-IbΔC-XHuman cAMP-CREM heart-directedOverexpression with α-MHC promoterLeft atrial size, twofold increase vs WT at 13–17 weeks↑ in atriaNot reportedNot reportedEctopic beatsAPD25,phase 1 ↑APD50,phase 2 ↑APD90phase 4 ↑Spontaneous and persistentOther mechanismsoLeaky SR Ca2+ storesoDownregulation of connexin 40[72]CREM-IbΔC-XHuman cAMP- CREM and reduced RyR2-S2814A phosphorylation heart-directedoverexpression with germline transmission and Meox2-Cre crossingAtrial weight, sixfold increase vs WT at 3 months↑ in atria and ventricleNot reported ↔ Spontaneous atrial ectopyAPD80, phase 4 ↑Spontaneous at 3-month paroxysmal and persistent at 4–5 monthsOther mechanismsoincreased SR Ca2+ leak and CaMKII activityoreduced connexin 40[73]JDP TGHeart-restricted c-Jun dimerization protein 2 overexpression with α-MHC promoterAtrial cell diameter 1.4-fold increase vs WTNot present in the atrial and ventricleNot reported ↔ Increased PR interval, AV block andWenckebach periodicityNot reportedSpontaneousOther mechanismsoreduced expression of connexin 40 and 43oAng II signalling[74]RacETHeart-restricted constitutively active Rac1 RhoGTPase overexpression with α-MHC promoterAtrial weight, fourfold increase vs WT↑ in atria and ventricleNot reported✔No observable conduction defects except AFNot reportedSpontaneous and persistentOther mechanismsoincreased NADPH oxidase activity[75]Anxa7−/−Annexin global knockoutNot reportedNot reportedNot reported ↔ at basalAV block, ventricular tachyarrhythmia, shorter P-wave and QRS duration, and abnormal conduction velocityNot reportedSpontaneousOther mechanismsoreduced protein expression of SERCA2aoincrease expression of NCX proteinoβ1-adrenergic signalling[76]TNF1.6 TGHeart-directedoverexpression of tumour necrosis factor-α with α-MHC promoterIsolated atrial area 3.6-fold increase from 6 to 9 months in female vs NTg✔ in atria✔ Organised thrombi in atriaNot reportedEpisodes of second degree AV block, premature beats, and Ventricular ectopyAPD75Phase 4 ↔ SpontaneousOther mechanismsoimpaired Ca2+ loadingoreduced intracellular Ca2+ transients[77]MHCsTNF TGCardiac-specific overexpression of tumour necroticfactor with α-MHC promoterNot reportedNot reportedNot reported✔AV junctional rhythm, short PR interval and wide QRS complexNot reportedSpontaneousOther mechanismsoreduced connexion 40 expressionoinflammation[78]MURCTGCardiac-specific overexpression of muscle-related coiled-coil protein with α-MHC promoterEnlarged atrial compared to NTg↑ in atria and ventricleThrombus in the left atrial✔Complete AV block and prolongation of the PR intervalNot reportedSpontaneousOther mechanismsoreduced SERCA2, increased ANP, BNP, βMHC, TGF-β1, TGF-β2, and TGF-β3[79]Nup155±Reducednuclear envelope permeability by nucleoporin (NUP) 155 gene missense mutation on R391HNot reportedNot reportedNot reportedNot reportedIrregular RR intervalsAPD90, phase 4 ↓SpontaneousOther mechanismsoreduced HSP70 nuclear localization[80]a1D−/−L-type Ca2+ channel (Cav1.3) subunit global knockoutNot reportedNot reportedNot reportedNot reportedSA andAV nodes conduction defectsNot reportedSpontaneousOther mechanismsolack of Cav1.3, and reduced ICa,L[81]LTCC (α1D−/−)L-type Ca2+ channel α1D subunit global knockoutSmaller compared with WTNot reportedNot reportedNot reportedSinus bradycardia and AV blockNot reportedSpontaneousOther mechanismsoreduced ICa,L, Ca2+ transient amplitude, and SR Ca2+ content[82]dnPI3K-DCMCardiac-specific dominant negative phosphoinositide 3-kinase p110α (dnPI3K) DCM due to overexpression of mammalian sterile 20-like kinase 1 expression with α-MHC promoterAtrial size 3.45-fold increase vs NTg↑ in atriaand ventricle✔ Chronic thrombi in the left atrium✔Prolonged PR intervals, double peak P-wave, and second and third degreeAV blockNot reportedSpontaneousOther mechanismsoaltered expression of metabolic genes and K+ channelsoreduced HSP70[16]Dct−/−Melanin synthesisenzyme dopachrome tautomerase global knockoutNot reportedNoNot reported ↔ No observable conduction defects except for AFAPD50, phase 2 ↔ APD90, phase 4 ↔ SpontaneousOther mechanismsoplasma membrane caveolae accumulationoenlargement of mitochondria[83]RyR2R176Q/+R176Q mutation in RYR2 gene through germline transmission and Meox2-Cre crossingNormal atrial sizeNo fibrosis in atrial and ventricleNot reportedNot reportedRR interval variability, absence of P-waveAPD50 phase 2 ↔ APD80 phase 4 ↔ SpontaneousOther mechanismsoincreased CaMKII-dependent phosphorylation of RyR2oelevated SR Ca2+ leak[84]Gαq TGOverexpression of activated Gαqcardiac protein with α-MHC promoterLeft atrial size, 2.5-fold increase vs WT↑ in atria but not in ventricle✔ Left atrial, unorganised thrombusNot reportedPremature atrial contraction and irregular RR intervalAPD80, phase 4 ↑Spontaneous[85]NppaCre+Pitx2−/−Atrial and ventricular-restricted loss of function of paired-like homeodomain transcription factor 2 (PITX2)Atrial length about 1.6-fold increase for left atrium and 1.2-fold increase for right atrium vs WT↑ in ventricle but not in atriaNot reportedNot reportedAV blockAPD20 phase 1, ↔ APD50 phase 2, ↔ APD90 phase 4, ↔ SpontaneousOther mechanismsoreduced expression of Pitx2,oreduced expression of Nav1.5oreduced expression of Kir2.1[86]AnkB±Ankyrin-B (ANK2) heterologous null mutationNot reportedNot reportedNot reported✔Spontaneous bradycardia and abnormal ventricular responseAPD90 phase 4, ↓SpontaneousOther mechanismsoreduced ICa,Loreduced Cav1.3 expression,osignalling interaction between ankyrin-B and Cav1.2[87]D1275N-Nav1.5Human sodium channelNav1.5 global missense mutationNot reportedNoNot reported✔prolongation of P-wave and QRS duration PR interval and AV blockAPD50, phase 2 ↑APD90, phase 4 ↑SpontaneousOther mechanismsoreduced peak INaoincreased late INa[88]SLN−/−Sarcolipin global knockoutNo difference↑ in atriabut not in ventricleNot reportedNot reportedSmall oscillatory wavesAPD50, phase 2 ↔ APD90, phase 4 ↑SpontaneousOther mechanismsoSR Ca2+ overloadoDADsoincreased phosphorylation of RyR2[89]FKBP12.6−/−FK506-binding protein deficiency with reduced RYR2 phosphorylation at S2814Not reportedNot reportedNot reportedNot reportedAbsence of P-waves and irregular RR intervalsAPD30, phase 2 ↔ APD50, phase 2 ↔ SpontaneousOther mechanismsoLack of FK506-binding protein 12.6oDADsoSR Ca2+ leakoincreased INCXoCaMKII phosphorylation of RYR2 and PLB[90]MHC-TGFcys33serCardiac-restricted constitutively active TGFβ1 overexpression with αMHC promoterNot reported↑ in atriaNot reportedNot reportedActivation wavefrontAPD80, phase 4 ↓ for both left and right atriaSpontaneousOther mechanismsoincreased Ca2+ transient[91]DN-MSTN TG13 TGHeart-directed overexpression of the N-terminal pro-peptide with α-MHC promoterAtrial weight 3.7-fold increase vs NTg↑ in atriaAppears present ↔ AV block,BradycardiaIncreased P-waves and QRS durationNot reportedSpontaneousOther mechanismsoreduced connexin 40 expression[92]Casq2−/−Calsequestrin 2 global knockoutAtria tissue area, about 1.8–2.0-fold increase vs WTNo differencesNot reported✔Atrial ectopic activity, bradycardiaAPD80, phase 4↑Spontaneous[93]LKB1 knockoutCardiac-specific AMPK-activating liver kinase B1(LKB1) knockout with α-MHC promoterAtria size, about twofold increase for paroxysmal at 4–6 weeks and threefold increase for persistent AF over 6 weeks vs WT↑ in atria✔ Intra-atrialthrombi ↔ Increased PR interval andQRS duration in paroxysmal AFNot reportedParoxysmal and persistentOther mechanismsoreduced expression of AMPKoincreased in connexin 40 and 43 expressionoROS and inflammation[94]F1759A-Nav1.5-dTGHuman sodium channelNav1.5 cardiac-specific expression with α-MHC promoterRight and left atria area increase by 52% and 54%, respectively, vs control↑ in atria and ventricleNot reported✔Premature ventricularcomplexes andnon-sustained polymorphic VTAPD80, phase 4 ↑ for both right and left atriaSpontaneousOther mechanismsoincreased late INaoincreased glycogen accumulationomyofibril disorganisationomitochondria injuryoNCX regulation of Na+ entry[95]LKB1/CTRLKB1/CT atrial-specific knockdownNot reported↑ in atriaNot reported ↔ Irregularly irregular R–R intervalsNot reportedSpontaneousOther mechanismsoAtrial cardiomyocyte produces calcitoninoCalcitonin receptor and its ligand signalling governs fibroblast rolesoParacrine signalling between atrial cardiomyocyte released calcitonin and fibroblast[96]PLK2 deficiencyPLK2 KnockoutGreater left atrial area↑ in atriaNot reported ↔ ventricular tachycardiaAPD ↔ ERP ↔ SpontaneousOther mechanismsoPLK2/ERK/OPN is a dominant structural remodelling axis for AF generation[97]Mouse models that have been used to study the pathophysiology of AF, including atrial enlargement, electrophysiological alterations, apoptosis, functional and molecular underpinnings, and anatomical, transgenic; RYR2, ryanodine receptor 2; SR, sarcoplasmic reticulum; APD, action potential; SERCA mRNA, sarco/endoplasmic reticulum Ca2+-ATPase messenger ribonucleic acid; CTR, calcitonin receptor; KCNE1, potassium voltage-gated channel subfamily E member 1; AV, Atrioventricular block; MAP, monophasic action potential; PLB, phospholamban; ANP, atrial natriuretic peptide; β-AR, beta adrenergic receptor; PPβ1, protein phosphatase type 1β; NADPH, nicotinamide adenine dinucleotide phosphate; CaMKII, Ca2+/calmodulin-dependent protein kinase II; NCX, sodium–calcium exchanger; SERCA2a, Sarco/endoplasmic reticulum calcium (Ca2+) ATPase gene; TGF- β, Transforming growth factor beta; BNP, brain natriuretic peptide; HSP70, heat shock protein 70; DCM, dilated cardiomyopathy; AMPK, 5' adenosine monophosphate-activated protein kinase; PLK2, polo-like kinase 2; OPN, osteopontin; ERK1/2, extracellular signal-regulated kinase ½. ↔ unchanged in that condition; ✔ present in that condition; ↑ increased in that condition; ↓ reduced in that condition
