Tachycardia Remodeling Research Articles

Prednisone prevents atrial fibrillation promotion by atrial tachycardia remodeling in dogs

There is evidence suggesting involvement of oxidative stress, inflammation, and calcineurin/nuclear factor of activated T cell pathways in atrial fibrillation. This study evaluated the efficacy of anti-inflammatory and calcineurin-inhibitory drugs on promotion of atrial fibrillation by atrial tachycardia-induced remodeling in dogs. Dogs were subjected to atrial tachypacing at 400 bpm in the absence and presence of treatment with prednisone (15 or 50 mg/day) or ibuprofen (anti-inflammatory) or cyclosporine-A (calcineurin inhibitor). Serial closed-chest electrophysiological studies were performed in each dog at baseline and 2, 4, and 7 days after tachypacing onset. A final open-chest study was performed on day 8. Serum C-reactive protein was measured by ELISA and nitric oxide synthase by Western blotting. The mean duration of induced atrial fibrillation was markedly increased by tachypacing alone, from 26+/-8 to 962+/-317 s (p<0.01), and the atrial effective refractory period was decreased from 117+/-4 to 73+/-7 ms (p<0.001; cycle-length 300 ms). Tachypacing-induced effective refractory period shortening and atrial fibrillation promotion were unaffected by ibuprofen or cyclosporine-A; however, both doses of prednisone suppressed tachypacing-remodeling effects (atrial fibrillation duration to 96+/-60 s and 28+/-11 s at higher and lower doses, respectively; effective refractory period to 101+/-6 ms for higher-dose and 105+/-3 ms for lower-dose group). In addition, prednisone (but not ibuprofen or cyclosporine) significantly decreased C-reactive protein concentrations and attenuated the increase in endothelial nitric oxide synthase expression caused by atrial tachypacing. Prednisone prevents the electrophysiological and atrial fibrillation-promoting effects of atrial tachycardia-remodeling, possibly by an anti-inflammatory action, whereas the less potent anti-inflammatory ibuprofen and the calcineurin inhibitor cyclosporine-A are without effect.

Atrial Tachycardia Remodeling of Pulmonary Vein Cardiomyocytes

The pulmonary veins (PVs) are important in the pathophysiology of atrial fibrillation (AF), as is atrial tachycardia (AT) remodeling. The relative importance of AT remodeling in PVs versus other atrial sites is unknown. The present study assessed AT-induced cellular changes in PVs versus left atrium (LA) and their relationship to arrhythmogenesis. We studied ionic currents (single-cell patch clamp) and action potentials (APs; coronary-perfused multicellular preparations) in the PVs and LA free wall of dogs after 7-day AT pacing (400 bpm), as well as in nonpaced control dogs. In controls, rapid (I(Kr)) and slow (I(Ks)) delayed-rectifier currents were larger in PVs; transient-outward (I(to)), inward-rectifier (I(K1)), and L-type Ca2+ (I(Ca)) currents and AP duration were smaller. AT remodeling reduced I(Ca) and I(to), left I(Kr) and I(Ks) unchanged, and increased I(K1) in both LA and PV. AT reduced action potential duration in both LA and PV. LA-PV AP differences became smaller in AT than in control dogs. Premature extrastimuli induced atrial tachyarrhythmias at 4.5+/-2.8% (mean+/-SEM) sites in 6 control multicellular preparations compared with 64.2+/-7.3% sites in 9 AT-remodeled preparations (P<0.001). Resection of all PVs failed to alter atrial tachyarrhythmia inducibility in AT-remodeled preparations (67.5+/-13.1%). PV resection did not significantly change tachyarrhythmia duration (mean 3.9 seconds per heart, range 0.7 to 15.7 seconds before resection; mean 7.0 seconds per heart, range 0.9 to 36.0 seconds after resection) or cycle length (120+/-6 ms before resection, 115+/-8 ms after resection). AT produces qualitatively similar ionic remodeling in LA and PVs but reduces PV-LA AP differences. PVs are not essential for AT-induced atrial tachyarrhythmia promotion in this model, which may relate to the failure of PV isolation to prevent AF in some patient populations.

Rapid stimulation causes electrical remodeling in cultured atrial myocytes

Objective. – Rapid stimulation causes electrical remodeling in the intact atrium, with shortening of action potential duration (APD), down-regulation of L-type Ca 2+ currents ( I Ca,L), and increased vulnerability to atrial fibrillation (AF). The essential elements required for this process are currently unknown. We tested the hypothesis that rapid stimulation of cardiomyocytes in vitro is sufficient to recapitulate the remodeling process, and that atrial cells subjected to rapid pacing in culture would display changes similar to those that occur in vivo. Methods. – Atrial (HL-1) cells were cultured in the presence of rapid field stimulation (300 beats per min) for 24 h. Action potentials and ionic currents were recorded from stimulated cells, as well as control cells cultured in parallel, using whole-cell voltage-clamp techniques. Results. – Rapid stimulation of atrial cells for 24 h significantly shortened APD. HL-1 cells displayed both I Ca,L blocked by nimodipine, and T-type Ca 2+ currents ( I Ca,T) sensitive to mibefradil. Rapid activation in culture caused down-regulation of I Ca,L, while I Ca,T was similarly reduced. Multiple outward currents were present in response to a depolarizing voltage-clamp protocol, and rapid pacing resulted in up-regulation of the rapidly-activating delayed rectifier K + current, I Kr. Conclusions. – Rapid stimulation of atrial cells in culture produces electrical remodeling, recapitulating principal phenotypic features of atrial tachycardia remodeling in vivo. Our results demonstrate that an important component of this process is cell autonomous, given that in vivo conditions are not required for the development of electrical remodeling.

Effects of Antiarrhythmic Drugs on Fibrillation in the Remodeled Atrium

The basis of the unique effectiveness of amiodarone for atrial fibrillation (AF) is poorly understood. The present study tested the hypothesis that amiodarone blocks electrical remodeling induced by atrial tachycardia. Mongrel dogs were subjected to atrial tachycardia (400 bpm for 7 days) in the absence and presence of therapy with amiodarone, the class III cardiac antiarrhythmic drug dofetilide, or the class I agent flecainide begun 3 days before the onset of tachypacing and maintained until a final electrophysiological study. AF vulnerability (percentage of sites with AF induction by single premature extrastimuli), mean AF duration, atrial effective refractory period (ERP), and conduction velocity were compared among these dogs and in unpaced dogs in the absence or presence of treatment with the same agents. Only amiodarone prevented promotion of AF duration and vulnerability by atrial tachycardia. Furthermore, only amiodarone eliminated tachycardia-induced ERP abbreviation and loss of ERP rate adaptation while obviating L-type Ca2+-current alpha1c-subunit downregulation as determined by Western blot. In an additional series of dogs monitored with repeated electrophysiological studies, amiodarone administered after the induction of atrial tachycardia remodeling reversed remodeling within several days, despite continued atrial tachypacing during amiodarone therapy. Amiodarone is uniquely effective against AF promotion by atrial tachycardia remodeling in this experimental model and prevents electrophysiological and biochemical consequences of remodeling. Amiodarone also reversed remodeling established by 4 days of atrial tachycardia. The inhibition of atrial tachycardia remodeling may therefore contribute to the superior efficacy of amiodarone in AF.

Effects of inhibiting Na(+)/H(+)-exchange or angiotensin converting enzyme on atrial tachycardia-induced remodeling.

Inhibitors of the Na(+)/H(+)-exchanger (NHE1) and of angiotensin-converting enzyme (ACE) have been shown to reduce short-term (<6 h) tachycardia-induced atrial electrical remodeling. The role of NHE1 and ACE in longer-term electrical remodeling, as might occur with persistent AF, has not been studied. Dogs were subjected to atrial-tachypacing (400 bpm) for 7 days during treatment with 240 mg/day (standard clinical dose) of the NHE1 inhibitor cariporide (CariL, n=6), 1000 mg/day cariporide (CariH, n=6), 2 mg/kg/day of the ACE inhibitor enalapril (E, n=6), or no-drug controls (n=7). To ensure steady state concentrations at the onset of pacing, treatment began 3 days before the initiation of atrial tachypacing. Results were compared to those of unpaced dogs (n=9). Atrial tachypacing reduced atrial effective refractory period (ERP), e.g. at a basic cycle length of 300 ms from 126+/-4 ms (unpaced, mean+/-S.E.) to 79+/-8 ms (no-drug controls, P<0.001). ERP abbreviation was unchanged by CariL (83+/-8 ms), CariH (80+/-7 ms), or E (76+/-5 ms). Atrial tachypacing increased mean duration of the longest AF episode in each dog (DAF) from 130+/-80 s (unpaced) similarly in all groups: 864+/-364 s, no-drug controls; 609+/-376 s, CariL; 709+/-353 s, CariH; 645+/-365 s, E (P=NS for differences among groups). Sustained AF requiring cardioversion for termination was induced in 0% of unpaced dogs vs. 33% of CariL, 33% of CariH, 33% of E, and 43% of control dogs. AF inducibility by single extrastimuli increased from 4+/-2% in unpaced dogs to 48+/-13% (P<0.01) in no-drug control dogs, an effect not changed by CariL (33+/-14%), CariH (35+/-17%) or E (48+/-16%). In contrast to short-term (several-hour) atrial tachycardia-induced remodeling, remodeling by 7-day tachycardia is not affected by NHE1 or ACE inhibition. These results support the notion that short-term atrial tachycardia remodeling involves different mechanisms from longer-term remodeling, and urges caution in extrapolating results from studies of short-term remodeling to effects in longer-term remodeling as often occurs clinically.