Ion Channel Remodeling Is Related to Intraoperative Atrial Effective Refractory Periods in Patients With Paroxysmal and Persistent Atrial Fibrillation

Brundel, Bjjm; Gelder, van Isabelle; Henning, Robert H.; Tieleman, RG; Tuinenburg, AE; Wietses, Mirian; Grandjean, JG; Gilst, van Wiekert; Crijns, Hjgm

doi:10.1161/01.cir.103.5.684

Cited by 222 publications

(135 citation statements)

References 34 publications

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“…Although there is evidence for transcriptional downregulation as a mechanism for ATinduced decreases in ion-current density in animal models 21 and in humans, 3,22 Schotten et al 23 did not find I Ca ␣ 1c -protein to be reduced in atrial samples from AF patients. Therefore, other mechanisms at the regulatory level, such as enhanced phosphatase activity (Christ et al, unpublished observations) and alterations in Ca 2ϩ -calmodulin kinase II, 24 may also be involved.…”

Section: Potential Limitationsmentioning

confidence: 97%

Atrial Ionic Remodeling Induced by Atrial Tachycardia in the Presence of Congestive Heart Failure

et al. 2004

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Background-Atrial fibrillation (AF) and congestive heart failure (CHF) produce discrete forms of atrial ionic remodeling.The in vivo effects of atrial tachycardia (AT) remodeling are altered by CHF. This study evaluated underlying mechanisms at the level of ionic remodeling. Methods and Results-We studied 4 groups of dogs: (1) unpaced controls (CTLs); (2) CHF caused by 2-week ventricular tachypacing (VTP, 240 bpm); (3) AT (400 bpm ϫ7 days); and (4) CHFϩAT (2-week VTP with AT for the last 7 days). CHF and CHFϩAT groups equally increased left atrial pressure. AF duration was increased in all paced groups. Effective refractory period (ERP) was decreased by 42% in AT versus CTL but by only 24% in ATϩCHF versus CHF. CHF reduced L-type Ca 2ϩ (I Ca ), transient-outward (I to ), and the slow delayed-rectifier (I Ks ) currents while increasing the Na ϩ -Ca 2ϩ exchanger (I NCX ) and not affecting the inward-rectifier (I K1 ) current. AT reduced I to and I Ca while increasing I K1 and leaving I Ks unaltered. The addition of AT to CHF failed to alter I to , I Ks , or I NCX beyond the effect of CHF alone, decreased I Ca slightly compared with CHF alone, but had smaller effects on I Ca and I K1 compared with AT alone. Thus, CHFϩAT, as would occur in a CHF patient who develops AF, produced an ionic remodeling pattern different from that of CHF or AT alone and from what would have been predicted from additive effects of CHF and AT. Conclusions-The presence of CHF alters AT-induced ionic remodeling. Thus, the ionic remodeling caused by cardiac arrhythmias in the presence of cardiac pathology is not necessarily predictable from the effects of either alone, with important potential implications for understanding the pathophysiology of arrhythmias in the diseased heart.

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Section: Potential Limitationsmentioning

confidence: 97%

Atrial Ionic Remodeling Induced by Atrial Tachycardia in the Presence of Congestive Heart Failure

et al. 2004

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“…Reductions in L-type Ca 2ϩ current, 16 apparently caused by transcriptional downregulation of the ␣1c pore-forming Ca 2ϩ -channel subunit, Ca v 1.2, [17][18][19] are important in mediating electrophysiological changes caused by atrial tachycardia remodeling. We therefore quantified the expression of Ca v 1.2 protein in the RA and LA appendages in nonpaced dogs and dogs subjected to ATP during treatment with simvastatin, vitamin C, and vitamins C and E. …”

Section: Changes In L-type Ca 2؉ -Channel ␣-Subunit Protein Expressionmentioning

confidence: 99%

Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Promotion by Atrial-Tachycardia Remodeling in Dogs

et al. 2004

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Background-There is evidence for a role of oxidant stress and inflammation in atrial fibrillation (AF). Statins have both antioxidant and antiinflammatory properties. We compared the effects of simvastatin with those of antioxidant vitamins on AF promotion by atrial tachycardia in dogs. Methods and Results-We studied dogs subjected to atrial tachypacing (ATP) at 400 bpm in the absence and presence of treatment with simvastatin, vitamin C, and combined vitamins C and E. Serial closed-chest electrophysiological studies were performed in each dog at baseline and 2, 4, and 7 days after tachypacing onset. Atrioventricular block was performed to control ventricular rate. Mean duration of induced AF was increased from 42Ϯ18 to 1079Ϯ341 seconds at terminal open-chest study after tachypacing alone (PϽ0.01), and atrial effective refractory period (ERP) at a cycle length of 300 ms was decreased from 117Ϯ5 to 76Ϯ6 ms (PϽ0.01). Tachypacing-induced ERP shortening and AF promotion were unaffected by vitamin C or vitamins C and E; however, simvastatin suppressed tachypacing-induced remodeling effects significantly, with AF duration and ERP averaging 41Ϯ15 seconds and 103Ϯ4 ms, respectively, after tachypacing with simvastatin therapy. Tachypacing downregulated L-type Ca 2ϩ -channel ␣-subunit expression (Western blot), an effect that was unaltered by antioxidant vitamins but greatly attenuated by simvastatin. Conclusions-Simvastatin attenuates AF promotion by atrial tachycardia in dogs, an effect not shared by antioxidant vitamins, and constitutes a potentially interesting new pharmacological approach to preventing the consequences of atrial tachycardia remodeling.

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“…It causes electrophysiological and structural alterations that induce progression and self-maintenance of the cardiac disorder (see Reference 1 for review). 1 Among the electrophysiological alterations associated with AF, cell membrane depolarization 2 and downregulation of potassium channels I TO and I Kur , 3,4 L-type Ca 2ϩ current, 5,6 and protein expression 7 have been reported in atrial myocytes from patients with AF. Furthermore, electrically induced AF shortened the atrial effective refractory period, and it could be reversed by administration of the L-type Ca 2ϩ channel agonist BayY5959, which increased atrial contractility and prolonged atrial refractoriness.…”

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confidence: 99%

Atrial Fibrillation Is Associated With Increased Spontaneous Calcium Release From the Sarcoplasmic Reticulum in Human Atrial Myocytes

et al. 2004

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Background— Spontaneous Ca 2+ release from the sarcoplasmic reticulum (SR) can generate afterdepolarizations, and these have the potential to initiate arrhythmias. Therefore, an association may exist between spontaneous SR Ca 2+ release and initiation of atrial fibrillation (AF), but this has not yet been reported. Methods and Results— Spontaneous Ca 2+ release from the SR, manifested as Ca 2+ sparks and Ca 2+ waves, was recorded with confocal microscopy in atrial myocytes isolated from patients with and those without AF. In addition, the spontaneous inward current associated with Ca 2+ waves was measured with the use of the perforated patch-clamp technique. The Ca 2+ spark frequency was higher in 8 patients with AF than in 16 patients without (6.0±1.2 versus 2.8±0.8 sparks/mm per second, P <0.05). Similarly, the spontaneous Ca 2+ wave frequency was greater in patients with AF (2.8±0.5 versus 1.1±0.3 waves/mm per second, P <0.01). The spontaneous inward current frequency was also higher in 10 patients with AF than in 13 patients without this arrhythmia (0.101±0.028 versus 0.031±0.007 per second, P <0.05, at a clamped potential of −80 mV). In contrast, both the Ca 2+ released from the SR and the Na + -Ca 2+ exchange rate induced by a rapid caffeine application were comparable in patients with and without AF. Conclusions— The observed increase in spontaneous Ca 2+ release in patients with AF probably is due to an upregulation of the SR Ca 2+ release channel activity, which may contribute to the development of AF.

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Ion Channel Remodeling Is Related to Intraoperative Atrial Effective Refractory Periods in Patients With Paroxysmal and Persistent Atrial Fibrillation

Abstract: AF is predominantly accompanied by decreased protein contents of the L-type Ca(2+) channel and several potassium channels. Reductions in L-type Ca(2+) channel correlated with AERP and rate adaptation, and they represent a probable explanation for the electrophysiological changes during AF.

Cited by 222 publications

References 34 publications

Atrial Ionic Remodeling Induced by Atrial Tachycardia in the Presence of Congestive Heart Failure

Atrial Ionic Remodeling Induced by Atrial Tachycardia in the Presence of Congestive Heart Failure

Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Promotion by Atrial-Tachycardia Remodeling in Dogs

Atrial Fibrillation Is Associated With Increased Spontaneous Calcium Release From the Sarcoplasmic Reticulum in Human Atrial Myocytes

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