Cardiac adrenergic control and atrial fibrillation

“The majority of atrial premature beats that trigger (initiate) AF originate from focal (focussed) ectopic (away from the sinoatrial (SA) node) electrical activity in or near the PVs.”

“Furthermore, α-stimulation may increase inositol (1,4,5)-trisphosphate (InsP 3 ), and InsP 3 can cause Ca 2+ i release, particularly in atrium, in which InsP 3 receptors are prevalent (Bers 2002).”

“However, the plateau elevation has the potential to promote afterdepolarisations, either by increasing APD in the voltage range at which ICaL can reactivate and thus cause EADs (Bers 2008), or by its association with increased Cai loading and DADs.”

“1995), as reported in atria of other species (Mackenzie et al. 2004; Danson et al. 2005; Coutu et al. 2006).”

“β-Blockers reduced the incidence of AF following cardiac surgery (Mathew et al. 2004; Workman et al. 2006), and postsurgery β-blocker withdrawal increased it (Mathew et al.”

“depolarising, current and its agonism and blockade elevate and lower the plateau, respectively, as shown using Bay K 8644 (Yue et al. 1997) or nifedipine (Workman et al.”

“However, an absence of change in atrial wavelength in dogs (Rensma et al. 1988), or an increase due to ERP-prolongation in rabbits (Smeets et al. 1986) also were reported.”

“Moreover, AF substantially increases the risk of stroke, heart failure (HF), and death (Fuster et al. 2006).”

“HF is a major cause of AF, and both systolic and diastolic ventricular dysfunction were independently associated with increased risk of AF (Tsang et al. 2002).”

“For example, in patients with CHF, β 1 -blockade substantially reduced the incidence of AF (Van Veldhuisen et al. 2006).”

“Electrical stimulation of pulmonary vein (PV) autonomic nerves produced rapid PV arrhythmic activation, abolished by the β1-antagonist (β1-blocker) atenolol (Patterson et al. 2005).”

“…AF in patients was associated with a decreased atrial ERP and RA conduction velocity, increased ERP dispersion (Kojodjojo et al. 2007) and decreased atrial isolated tissue or cellular ERP (Workman et al. 2001) or APD 90 (Bosch et al. 1999; Workman et al. 2001; Wettwer et al. 2004; Pau et al. 2007).”

“In ventricle, β 3 -stimulation moderately affected APD (Gauthier et al. 1996; Bosch et al. 2002), probably via I KS (Bosch et al. 2002) which may have limited involvement in human atrium.”

“CHF also increased atrial diastolic [Ca 2+ ] i , the Ca 2+ i transient, and Ca 2+ SR content, associated with " spontaneous Ca 2+ transient events " (Yeh et al. 2008).”

“That might moderately increase wavelength, although acute propranolol did not affect wavelength in canine atrium (Rensma et al. 1988), or ERP in AFremodelled goat atrium (Wijffels et al. 1997).”

“In undiseased human ventricular tissues, adrenaline had no effect on repolarisation already prolonged by dofetilide (Jost et al. 2005), but effects of adrenergic stimulation alone were not studied.”

“This was associated with various ion current changes including decreased I TO , I CaL and I KS and increased I Na/Ca , whilst I K1 , I Kr and I Kur were unaffected (Li et al. 2000).”

“Cai sparks, which reflect Ca release from single clusters of RyRs, were either increased (Hove-Madsen et al. 2004) or unchanged”

“ventricle (Priori and Corr 1990), but whether it would in human atrium is unknown.”

“Ca 2+ i sparks, which reflect Ca 2+ release from single clusters of RyRs, were either increased (Hove-Madsen et al. 2004) or unchanged (Liang et al. 2008) in frequency, and increased (Liang et al. 2008) or unchanged (Hove-Madsen et al. 2004) in duration.”

“ISO also sustained reentrant circuits in PVs, but without changing conduction velocity (Arora et al. 2003).”

“…HF may preferentially downregulate β 1 , in atrium, depending on the cause of HF (Steinfath et al. 1992), and that could result from chronic adrenergic stimulation (Brown et al. 1992). β 3 density was not studied in atrium, although this was increased in ventricle (Moniotte et al. 2001).”

“…involves an anti-adrenergic effect on I CaL , which is the main inward current in AV node (Workman et al. 1999). βblockers can also prevent AF, convert it to sinus rhythm, or maintain sinus rhythm after it is restored, depending on β-blocker type and cardiac pathology (Lopez-Sendon et al. 2004).”

“2007), and decreased atrial isolated tissue or cellular ERP (Workman et al. 2001) or”

“2004) produced AF, and ISO facilitated acetylcholine-induced AF (Sharifov et al. 2004).”

“Altered plateau voltages resulting from changes in I Kur also may affect terminal repolarisation via I Kr and I KS (Wettwer et al. 2004), and adrenergic stimulation increased I Kur in human atrium (Li et al. 1996; Su et al. 1994).”

“In dogs, chronic rapid atrial rate also decreased APD90 in isolated PVs (Chen et al. 2000; Cha et al. 2005), and either enhanced (Chen et al.”

“CHF also increased atrial diastolic [Ca 2+ ] i , the Ca 2+ i transient, and Ca 2+ SR content, associated with " spontaneous Ca 2+ transient events " (Yeh et al. 2008).”

“2005), and might enhance a diastolic CaSR leak, as shown in rabbit ventricle (Curran et al. 2007).”

“In patients with LVSD following MI, carvedilol, a β1-, β2-, and α1antagonist, also substantially reduced the incidence of AF/ atrial flutter (McMurray et al. 2005).”

“Adrenergic stimulation 9/32 may increase both I Kr (Heath et al. 2000) and I KS (Volders et al. 2003), but human atrial data are lacking.”

“pathways, terminating on cardiac myocytes and vessels of all chambers (Kawashima 2005).”

“I Kr and I KS were relatively small or present in only a minority of cells (Wang et al. 1994; Schaffer et al. 1998), but this might reflect disruption of these currents by the requisite " chunk " method of cell isolation (Yue et al. 1996), and in intact atrial tissue, I Kr blockade may prolong APD…”

“relapse into AF after electrical or pharmacological cardioversion (Kuhlkamp et al. 2000).”

“1998) or cholinergic (parasympathetic; Bettoni and Zimmermann 2002) branches can promote AF.”

“Chronic AT in dogs caused a spatially heterogeneous atrial adrenergic hyperinnervation, an increased atrial tissue noradrenaline concentration, and nerve sprouting (Jayachandran et al. 2000; Chang et al. 2001).”

“1% of those >85 years (Murphy et al. 2007).”

“Chronic AT in dogs caused a spatially heterogeneous atrial adrenergic hyperinnervation, an increased atrial tissue noradrenaline concentration, and nerve sprouting (Jayachandran et al. 2000; Chang et al. 2001).”

“The majority of atrial premature beats that trigger (initiate) AF originate from focal (focussed) ectopic (away from the sinoatrial (SA) node) electrical activity in or near the PVs.”

“In patients, heart rate variability studies indicated an increased level of adrenergic, relative to cholinergic, activity in the minutes preceding the onset of AF (Dimmer et al. 1998; Coccagna et al. 1997).”

“Reports of effects of adrenergic stimulation on other mechanosensitive currents (Stiber et al. 2009) in human atrium could not be found.”

“Acute β-selective blockade has little or no effect on atrial electrophysiology in the absence of catecholamines (Wit et al. 1975), and catecholamine levels were not affected by β-blockade in patients 16/32 (Bolger et al. 2002).”

“This was probably via decreased CICR, due to transcriptional downregulation of I CaL (Qi et al. 2008).”

“The expression of atrial HCN2 and HCN4 (encode If) was increased in human HF (Stillitano et al. 2008), but atrial If was not measured.”

“1998), but this might reflect disruption of these currents by the requisite “chunk” method of cell isolation (Yue et al. 1996), and in intact atrial tissue, IKr blockade may prolong APD90 (Wettwer et al.”

“Acute β-selective blockade has little or no effect on atrial electrophysiology in the absence of catecholamines (Wit et al. 1975), and catecholamine levels were not affected by β-blockade in patients 16/32 (Bolger et al. 2002).”

“The Cai transient was also smaller in atrium, and CaSR content substantially larger (Walden et al. 2009).”

“ISO to increase ICaL or HFIUR was attenuated (Ouadid et al. 1995; Piot et al. 1996), unchanged (Workman et al.”

“Adrenergic stimulation has consistently been shown to increase human atrial I CaL , often more than 2-fold, e.g. (Ouadid et al. 1995; Pelzmann et al. 1995; Li et al. 1997; Van Wagoner et al. 1999; Christ et al. 2004; Redpath et al. 2006; Greiser et al. 2007) (Figure 2b).”

“Focal ectopic beats that were preceded by rises in [Ca 2+ ]i were produced by perfusing canine atria with ryanodine plus ISO, but ISO alone was not studied (Chou et al. 2005).”

“1995), as reported in atria of other species (Mackenzie et al. 2004; Danson et al. 2005; Coutu et al. 2006).”

“A reduction of ISO-stimulated IKur by propranolol in human atrial cells (Li et al. 1996) is consistent with its acute effect to moderately increase atrial APD90 and ERP in patients (Shimizu et al.”

“Right atrial (RA) pectinate muscles sometimes featured a “single pacemaker”, and adrenaline transiently decreased, then markedly increased, its rate (Trautwein et al. 1962).”

“This may have resulted from injury of atrial nerves passing through the ventricle (Miyauchi et al. 2003).”

“Focal ectopic beats that were preceded by rises in [Ca 2+ ] i were produced by perfusing canine atria with ryanodine plus ISO, but ISO alone was not studied (Chou et al. 2005).”

“differs between atrium and ventricle ( Dobrev and Nattel 2008 ).”

“and activate cell surface adrenoceptors, including the α, β1, β2 and β3 subtypes, all of which are present in human atrium (Mary-Rabine et al. 1978; Hedberg et al. 1985; Chamberlain et al. 1999).”

“Pacemaker activity was found in rabbit PV isolated cells, which was enhanced by ISO (Chen et al. 2002).”

“Nevertheless, CHF-induced atrial arrhythmic activity may involve RyRs, since it was abolished by RyR blockade in dogs (Stambler et al. 2003; Yeh et al. 2008).”

“Comparable changes were associated with chronic AF in humans, including hyperinnervation and increased tissue noradrenaline (Gould et al. 2006).”

“Nevertheless, human atrial βreceptors , perhaps predominantly β 1 , were upregulated by β-blocker therapy (Hedberg et al. 1985; Michel et al. 1988), possibly related to a reduction in adrenergic nerve activity (Raine et al. 1977).”

“However, the action potential plateau, phase 2, was markedly elevated by adrenergic stimulation in several reports, reflected by increased APD50 (Kecskemeti et al. 1985; Li and Nattel 1997; Redpath et al. 2006).”

“In rabbit SA node, β-stimulation increased If, associated with a positive shift in its activation voltage (Barbuti et al. 2007), and accelerated the deactivation of IKr and IKS (Lei et al.”

“In dogs, chronic rapid atrial rate also decreased APD 90 in isolated PVs (Chen et al. 2000; 14/32 Cha et al. 2005), and either enhanced (Chen et al. 2000) or did not enhance (Cha et al. 2005) the ability of PVs to produce arrhythmic activity.”

“β-Stimulation could elevate CaSR content and [Ca ]i sufficiently to cause propagating waves of CICR, which may increase Ca extrusion via INa/Ca sufficiently to produce DADs (Eisner et al. 2009).”

“proportion with an increasing stimulation rate (Wit and Boyden 2007), as demonstrated in canine atria with”

“Calibrations: 25 mV, 100 ms. Based on data in (Stengl et al. 2006) (i), (Koumi et al. 1995) (ii), (Yeh et al. 1992) (iii), and (Redpath et al. 2006) (iv) with 19/32 permission from Oxford University Press, American Society for Clinical Investigation, S. Karger AG, Basel, and Elsevier, respectively.…”

“INa/Ca was increased by ISO in cat atrium (Zhou and Lipsius 1993), but human atrial data are lacking.”

“It has been suggested (Lehnart et al. 2004) that chronic adrenergic activation in HF may cause hyperphosphorylation of RyRs and a consequent increased diastolic leak of Ca 2+ SR .”

“Nevertheless, chronic AF has consistently been shown to be associated with a potentiated effect of ISO to increase human atrial ICaL (Van Wagoner et al. 1999; Skasa et al. 2001; Christ et al. 2004; Greiser et al. 2007).”

“2007), as demonstrated in canine atria with adrenaline (Johnson et al. 1986).”

“…repolarisation, since in isolated tissues or cells, APD 95 was markedly prolonged by noradrenaline or ISO in three of four available studies (Eckel et al. 1982; Mitchell et al. 1986; Koumi et al. 1995) (Figure 2aii), and by adrenaline in two of three tissues in the other study (Yeh et al.…”

“I CaL did not change, either in amplitude (Workman et al. 2003b; Pau et al. 2003; Redpath et al. 2006; Workman et al. 2006; Pau et al. 2007), activation voltage-dependence (Redpath et al. 2006), single channel gating (Klein et al. 2003) or expression (Grammer et al. 2001).”

“…increased I f , associated with a positive shift in its activation voltage (Barbuti et al. 2007), and accelerated the deactivation of I Kr and I KS (Lei et al. 2000); each potentially accelerating phase 4. β-stimulation also increases SA nodal I CaL and peak [Ca 2+ ] i , potentially enhancing…”

“Infusion of isoprenaline (isoproterenol, ISO), a mixed β-receptor agonist, produced AF in 5% of patients with no history of AF, and in 84% of patients with paroxysmal AF, in a dose-dependent manner (Oral et al. 2008).”

“Nevertheless, chronic AF has consistently been shown to be associated with a potentiated effect of ISO to increase human atrial ICaL (Van Wagoner et al. 1999; Skasa et al. 2001; Christ et al. 2004; Greiser et al. 2007).”

“2009), or potentiated (Dinanian et al. 2008) in patients with”

“A β 1 -blocker also caused a moderate reduction in the incidence of paroxysmal AF (Steeds et al. 1999) or of relapse into AF after electrical or pharmacological cardioversion (Kuhlkamp et al. 2000).”

“For example, a reduction by atenolol of cAMPstimulated I CaL in human atrial cells (Mewes et al. 1993) might suppress arrhythmic activity that involves increased CICR.”

“In human atrium, however, although up to 55% of β-receptors are β 2 (Hedberg et al. 1985), ISO did not affect APD 75 (Redpath et al. 2006). β 2 -stimulation increased human atrial I CaL (Skeberdis et al. 1997) and I f (Lonardo et al. 2005), although the I f increase was greater with β 1 than β 2…”

“Carvedilol was more effective than a β 1 -blocker (Haghjoo et al. 2007), perhaps by decreasing I Kur and I TO (Deng et al. 2007).”

“CHF also increased atrial diastolic [Ca 2+ ] i , the Ca 2+ i transient, and Ca 2+ SR content, associated with " spontaneous Ca 2+ transient events " (Yeh et al. 2008).”

“A similar effect of adrenergic stimulation was observed in other human studies (Mary-Rabine et al. 1980; Levi et al. 1981), as well as in healthy animal atria (Davis 1975; Ono et al. 1995).”

“Based on data in (Stengl et al. 2006) (i), (Koumi et al.”

“outweighed by an opposing increase in Igap (Salameh et al. 2006).”

“I CaL did not change, either in amplitude (Workman et al. 2003b; Pau et al. 2003; Redpath et al. 2006; Workman et al. 2006; Pau et al. 2007), activation voltage-dependence (Redpath et al. 2006), single channel gating (Klein et al. 2003) or expression (Grammer et al. 2001).”

“Specialised conducting fibres from human RA were identified by their pacemaker activity after ceasing stimulation, and adrenaline increased phase 4 and automatic rate (Mary-Rabine et al. 1978).”

“dispersion (Kojodjojo et al. 2007), and decreased atrial isolated tissue or cellular ERP (Workman et al.”

“%) decrease (Shimizu et al. 1994a) and of no change (Redpath et al. 2006).”

“Moreover, AF substantially increases the risk of stroke, heart failure (HF) and death (Fuster et al. 2006).”

“I KATP was increased by ISO in cat ventricle, from ATP i depletion rather than a direct effect (Schackow et al. 1994), but atrial data are lacking.”

“That is consistent with a lack of change in APD 50 (Workman et al. 2003b; Redpath et al. 2006).”

“No reports on atrial Ca 2+ i were found, but chronic β1-blockade in mice increased a HF-impaired ventricular Ca 2+ i transient (Bartholomeu et al. 2008).”

“Such " pharmacological remodelling " (Workman et al. 2003b) was originally demonstrated in rabbits (Raine et al. 1981).”

“associated with a reduction in the atrial cellular ERP (Workman et al. 2009).”

“without HF may not change catecholamine levels in patients (Berglund et al. 1990).”

“…β 1 -, β 2 -and α 1 -antagonist, also substantially reduced the incidence of AF/atrial flutter (McMurray et al. 2005). β-blockers reduced the incidence of AF following cardiac surgery (Mathew et al. 2004; Workman et al. 2006), and post-surgery β-blocker withdrawal increased it (Mathew et al. 2004).”

“1995), as reported in atria of other species (Mackenzie et al. 2004; Danson et al. 2005; Coutu et al. 2006).”

“In ventricle, β 3 -stimulation moderately affected APD (Gauthier et al. 1996; Bosch et al. 2002), probably via I KS (Bosch et al. 2002) which may have limited involvement in human atrium.”

“That is consistent with a lack of change in APD 50 (Workman et al. 2003b; Redpath et al. 2006).”

“However, ISO had inconsistent effects on human atrial I Cl , with either an increase (Tsai et al. 2001) or no change (Sakai et al. 1995) in I Cl.cAMP , or no change in I Cl.swell (Sato et al. 1998).”

“However, ISO had inconsistent effects on human atrial I Cl , with either an increase (Tsai et al. 2001) or no change (Sakai et al. 1995) in I Cl.cAMP , or no change in I Cl.swell (Sato et al. 1998).”

“Species differences in effects of adrenergic stimulation on atrial terminal repolarisation should be noted, however, with shortening in dog (Liang et al. 1985; Yeh et al. 2007), and lengthening in guinea pig (Yoshimoto et al.”

“This contrasts with an attenuated effect of 5-hydroxytryptamine (5- HT) on I CaL (Pau et al. 2007), despite both acting via cAMP.”

“In patients, heart rate variability studies indicated an increased level of adrenergic, relative to cholinergic, activity in the minutes preceding the onset of AF (Dimmer et al. 1998; Coccagna et al. 1997).”

“1981), as well as in healthy animal atria (Davis 1975; Ono et al. 1995).”

“In RA isolated cells stimulated at physiological rate, ISO caused action potentials to be interrupted frequently by low amplitude, usually sub-threshold, transient depolarisations, termed " cellular arrhythmic depolarisations " (CADs) (Redpath et al. 2006) (Figure 1b).”

“Species differences in effects of adrenergic stimulation on atrial terminal repolarisation should be noted, however, with shortening in dog (Liang et al. 1985; Yeh et al. 2007), and lengthening in guinea pig (Yoshimoto et al. 1998) and rat (Webb et al. 1956).”

“1988), possibly related to a reduction in adrenergic nerve activity (Raine and Chubb 1977).”

“This probably involves an anti-adrenergic effect on I CaL , which is the main inward current in AV node (Workman et al. 1999). βblockers can also prevent AF, convert it to sinus rhythm, or maintain sinus rhythm after it is restored, depending on β-blocker type and cardiac pathology (Lopez-Sendon et…”

“For example, in patients with CHF, β 1 -blockade substantially reduced the incidence of AF (Van Veldhuisen et al. 2006).”

“responses to ISO were attenuated (Harding et al. 1990).”

“was associated with chronic AF in patients (Gould et al. 2006).”

“The mechanism is a slowing of atrioventricular (AV) nodal conduction, associated with increased AV nodal ERP and AH interval (Prystowsky 1988).”

“(Liang et al. 2008) in frequency, and increased (Liang et al.”

“thus potentially promoting reentry (Stambler et al. 1996).”

“I CaL did not change, either in amplitude (Workman et al. 2003b; Pau et al. 2003; Redpath et al. 2006; Workman et al. 2006; Pau et al. 2007), activation voltage-dependence (Redpath et al. 2006), single channel gating (Klein et al. 2003) or expression (Grammer et al. 2001).”

“Reports of effects of adrenergic stimulation on other mechanosensitive currents (Stiber et al. 2009) in human atrium could not be found.”

“However, since β3-stimulation can affect IK1 (Scherer et al. 2007), ICaL, and Ca 2+ i (Cheng et al.”

“In human atrial cells, β-stimulation increased the Ca 2+ i transient amplitude (Hatem et al. 1995), as reported in atria of other species (Mackenzie et al. 2004; Danson et al. 2005; Coutu et al. 2006).”

“Altered plateau voltages resulting from changes in I Kur also may affect terminal repolarisation via I Kr and I KS (Wettwer et al. 2004), and adrenergic stimulation increased I Kur in human atrium (Li et al. 1996; Su et al. 1994).”

“An attenuated β-response may involve impaired βreceptor function or signalling, or a reduction in receptor density, as shown in atria of patients with end stage HF (Steinfath et al. 1992) or pigs with CHF (Roth et al. 1993).”

“…however, although up to 55% of β-receptors are β 2 (Hedberg et al. 1985), ISO did not affect APD 75 (Redpath et al. 2006). β 2 -stimulation increased human atrial I CaL (Skeberdis et al. 1997) and I f (Lonardo et al. 2005), although the I f increase was greater with β 1 than β 2 -stimulation.”

“β-Stimulation also increased atrial diastolic [Ca]i (Danson et al. 2005), and might enhance a diastolic CaSR leak, as shown in rabbit ventricle (Curran et al.”

“…repolarisation, since in isolated tissues or cells, APD 95 was markedly prolonged by noradrenaline or ISO in three of four available studies (Eckel et al. 1982; Mitchell et al. 1986; Koumi et al. 1995) (Figure 2aii), and by adrenaline in two of three tissues in the other study (Yeh et al. 1992).”

“…AF in patients was associated with a decreased atrial ERP and RA conduction velocity, increased ERP dispersion (Kojodjojo et al. 2007) and decreased atrial isolated tissue or cellular ERP (Workman et al. 2001) or APD 90 (Bosch et al. 1999; Workman et al. 2001; Wettwer et al. 2004; Pau et al. 2007).”

“I Kr and I KS were relatively small or present in only a minority of cells (Wang et al. 1994; Schaffer et al. 1998), but this might reflect disruption of these currents by the requisite " chunk " method of cell isolation (Yue et al. 1996), and in intact atrial tissue, I Kr blockade may prolong APD…”

“…however, although up to 55% of β-receptors are β 2 (Hedberg et al. 1985), ISO did not affect APD 75 (Redpath et al. 2006). β 2 -stimulation increased human atrial I CaL (Skeberdis et al. 1997) and I f (Lonardo et al. 2005), although the I f increase was greater with β 1 than β 2 -stimulation.”

“…HF may preferentially downregulate β 1 , in atrium, depending on the cause of HF (Steinfath et al. 1992), and that could result from chronic adrenergic stimulation (Brown et al. 1992). β 3 density was not studied in atrium, although this was increased in ventricle (Moniotte et al. 2001).”

“However, whether such an increase could lead to atrial arrhythmias from AA is uncertain (Workman and Rankin 1998), because of the rather negative activation voltage of If relative to atrial MDP, and the small current size under physiological [K]o.”

“Carvedilol was more effective than a β 1 -blocker (Haghjoo et al. 2007), perhaps by decreasing I Kur and I TO (Deng et al. 2007).”

“%) decrease (Shimizu et al. 1994a) and of no change (Redpath et al. 2006).”

“However, the hyperpolarisation caused by rewarming of human atrial tissue, considered to be due to I p reactivation, was unaffected by adrenaline (Rasmussen et al. 1985).”

“That was confirmed in plasma and tissue samples (Raine et al. 1980).”

“In dogs, adrenaline (Sharifov et al. 2004) or ISO (Kiss et al. 2004; Sharifov et al. 2004) produced AF, and ISO facilitated acetylcholine-induced AF (Sharifov et al. 2004).”

“Species differences in effects of adrenergic stimulation on atrial terminal repolarisation should be noted, however, with shortening in dog (Liang et al. 1985; Yeh et al. 2007), and lengthening in guinea pig (Yoshimoto et al. 1998) and rat (Webb et al. 1956).”

“induced AA in canine atrial fibres (Davis 1975), or AT in a CHF-remodelled atrium that produced spontaneous depo-”

“Of the six available reports in isolated tissues or cells, five showed no significant effect of adrenaline or ISO on APD 90 (Sleator et al. 1964; Gelband et al. 1977; Kecskemeti et al. 1985; Yeh et al. 1992; Redpath et al. 2006 ).”

“Adrenergic stimulation has consistently been shown to increase human atrial I CaL , often more than 2-fold, e.g. (Ouadid et al. 1995; Pelzmann et al. 1995; Li et al. 1997; Van Wagoner et al. 1999; Christ et al. 2004; Redpath et al. 2006; Greiser et al. 2007) (Figure 2b).”

“However, the APD increase could also involve an increase in the Cai transient (Jahnel et al. 1992), although data are lacking in human atrium.”

“However, ISO had inconsistent effects on human atrial ICl, with either an increase (Tsai et al. 2001) or no change (Sakai et al.”

“The I TO 17/32 reduction, as found also in atrial cells from rabbits treated with carvedilol (Cao et al. 2006), did not involve altered voltage-dependency, kinetics or channel expression (Marshall et al. 2009).”

“Species differences in effects of adrenergic stimulation on atrial terminal repolarisation should be noted, however, with shortening in dog (Liang et al. 1985; Yeh et al. 2007), and lengthening in guinea pig (Yoshimoto et al. 1998) and rat (Webb et al. 1956).”

“…patients in sinus rhythm showed that β 1 -blocker treatment for ≥ 7 days was associated with an increased APD 90 and ERP (Workman et al. 2003b; Redpath et al. 2006; Workman et al. 2006) (Figure 3b), and a decreased I TO (Workman et al. 2003b; Marshall et al. 2009) and I K1 (Marshall et al. 2006).”

“I Na was reduced by ISO in human atrium (Lee et al. 1990).”

“However, radiofrequency ablation of atrial ganglionated plexi, sites rich in adrenergic and cholinergic neurons, may not be as efficacious as other ablation procedures (Katritsis 2008).”

“Indeed, sympathetic stimulation provides an important trigger promoting Ca-handling abnormalities and AF initiation.(30)”

“In several animal and human studies of atrial fibrillation and heart failure, there is an increase in several CaMKII upstream signals such as ROS (27, 132, 133), renin-angiotensin-aldosterone system metabolites (134, 135), and catecholamines (136, 137) in atrial tissue or circulating plasma.”