Tachycardia-induced Remodeling Research Articles

A Computational Study of the Effects of Tachycardia-Induced Remodeling on Calcium Wave Propagation in Rabbit Atrial Myocytes.

In atrial cardiomyocytes without a well-developed T-tubule system, calcium diffuses from the periphery toward the center creating a centripetal wave pattern. During atrial fibrillation, rapid activation of atrial myocytes induces complex remodeling in diffusion properties that result in failure of calcium to propagate in a fully regenerative manner toward the center; a phenomenon termed “calcium silencing.” This has been observed in rabbit atrial myocytes after exposure to prolonged rapid pacing. Although experimental studies have pointed to possible mechanisms underlying calcium silencing, their individual effects and relative importance remain largely unknown. In this study we used computational modeling of the rabbit atrial cardiomyocyte to query the individual and combined effects of the proposed mechanisms leading to calcium silencing and abnormal calcium wave propagation. We employed a population of models obtained from a newly developed model of the rabbit atrial myocyte with spatial representation of intracellular calcium handling. We selected parameters in the model that represent experimentally observed cellular remodeling which have been implicated in calcium silencing, and scaled their values in the population to match experimental observations. In particular, we changed the maximum conductances of ICaL, INCX, and INaK, RyR open probability, RyR density, Serca2a density, and calcium buffering strength. We incorporated remodeling in a population of 16 models by independently varying parameters that reproduce experimentally observed cellular remodeling, and quantified the resulting alterations in calcium dynamics and wave propagation patterns. The results show a strong effect of ICaL in driving calcium silencing, with INCX, INaK, and RyR density also resulting in calcium silencing in some models. Calcium alternans was observed in some models where INCX and Serca2a density had been changed. Simultaneously incorporating changes in all remodeled parameters resulted in calcium silencing in all models, indicating the predominant role of decreasing ICaL in the population phenotype.

First-in-children epicardial mapping of the heart: unravelling arrhythmogenesis in congenital heart disease.

Patients with congenital heart disease (CHD) are prone to develop atrial and ventricular arrhythmias. Multiple factors throughout life contribute to arrhythmogenicity substrate such as (i) (longstanding) volume and/or pressure overload, (ii) scar tissue, (iii) ageing-related structural remodelling, (iv) cardiovascular risk factors and (v) tachycardia-induced remodelling. At present, it is unknown whether, and to what extent, paediatric patients with CHD have atrial or ventricular conduction disorders early in life and whether there is a correlation between duration of volume/pressure overload and extensiveness of conduction disorders. To investigate this, we initiated high-resolution intraoperative epicardial mapping in paediatric patients with CHD undergoing primary open-heart surgery.

Altered Nuclear Calcium Signaling in Tachycardia-Induced Remodeling in Rabbit Atria: A Mechanism of Altered Excitation-Transcription Coupling in Atrial Fibrillation?

Nuclear calcium (Ca2+) signalling play a major role in cardiac excitation-transcription coupling. The origin of nuclear Ca2+ transient is still controversial. It has been suggested that Ca2+ diffusion from the cytosol through the nuclear pores or perinuclear and intranuclear Ca2+ release mechanisms, mostly via the inositol-3-phosphate receptors (IP3R), participate to nuclear Ca2+ transient. In rabbits subjected to rapid atrial pacing (RAP, 600bp, 5 days), a model for atrial fibrillation (AF), we recently observed that central-cellular, but not subsarcolemmal Ca2+ transient, was largely reduced.

Atorvastatin treatment affects atrial ion currents and their tachycardia-induced remodeling in rabbits

Aims Atrial fibrillation (AF) leads to electrical atrial remodeling including alterations of various ion channels early after arrhythmia onset. The beneficial effects of statins in AF treatment due to their influence on oxidative stress and inflammation are discussed. Our hypothesis was that statins might also alter atrial ion currents and their early tachycardia-induced remodeling. Main methods Effects of an atorvastatin treatment (7 days) on atrial ion currents and their tachycardia-induced alterations were studied in a rabbit model of tachycardia-induced electrical remodeling (rapid atrial pacing (600 min) for 24 and 120 h). Ion currents (L-type calcium channel [I Ca,L], transient outward current [I to]) were measured using whole cell patch clamp method and were compared with previous experiments in untreated but also tachypaced animals. Key findings Atorvastatin treatment alone decreased I Ca,L similar to rapid atrial pacing alone, currents were also further reduced by additional atrial tachypacing. I to and its pacing-induced down-regulation after 24 h were not influenced by atorvastatin treatment. However, I to was still reduced after 120 h in atorvastatin-treated animals and did not return to control values as expected. Significance The present study establishes that an atorvastatin treatment can affect atrial ion currents and their tachycardia-induced remodeling in a rabbit model. These results show that—amongst other positive effects on oxidative stress and inflammation—the impact of statins on ion currents and their tachycardia-induced alterations might also play a role in “upstream” treatment of AF with HMG-CoA reductase inhibitors.

Effects of selective mineralocorticoid receptor antagonism on atrial ion currents and early ionic tachycardia-induced electrical remodelling in rabbits

Over the past years, the importance of the renin-angiotensin-aldosterone system in atrial fibrillation (AF) pathophysiology has been recognised. Lately, the role of aldosterone in AF pathophysiology and mineralocorticoid receptor (MR) antagonism in "upstream" AF treatment is discussed. Hypothesising that selective MR antagonism might also influence atrial ion currents (L-type calcium current [I (Ca,L)], transient outward potassium current [I (to)], sustained outward potassium current [I (sus)]) and their tachycardia-induced remodelling, the effects of an eplerenone treatment were studied in a rabbit model. Six groups each with four animals were built. Animals of the control group received atrial pacing leads, but in contrast to the pacing groups, no atrial tachypacing (600 per minute for 24 and 120h immediately before heart removal) was applied. Animals of the eplerenone groups were instrumented/paced as the corresponding control/pacing groups, but were additionally treated with eplerenone (7days before heart removal). Atrial tachypacing was associated with a reduction of I (Ca,L). I (to) was decreased after 24h of tachypacing, but returned to control values after 120h. In the absence of rapid atrial pacing, MR antagonism reduced I (Ca,L) to a similar extent as 120h of tachypacing alone. Based on this lower "take-off level", I (Ca,L) was not further decreased by high-rate pacing. I (to) and its expected tachycardia-induced alterations were not influenced by MR antagonism. In our experiments, selective MR antagonism influenced atrial I (Ca,L) and its tachycardia-induced alterations. As changes of I (Ca,L) are closely linked with atrial calcium signalling, the relevance of these alterations in AF pathophysiology and, accordingly, AF treatment is likely and has to be further evaluated.

Influence of Dexamethasone on Atrial Ion Currents and Their Early Ionic Tachycardia-induced Electrical Remodeling in Rabbits

Background: Certain evidence points to a role of inflammation in AF pathophysiology. Thus, antiinflammatory treatment of AF is discussed. Effects of a dexamethasone treatment (7 days) on atrial ion currents (I_Ca,L, I_to, I_sus) and their tachycardia-induced remodeling were studied in a rabbit model. Methods: 6 groups of 4 animals each were built. Rapid atrial pacing (600 min) was performed for 24 and 120 hours with/ without dexamethasone treatment. Ion currents were measured using whole cell patch clamp method. Results: Rapid atrial pacing reduced (I_Ca,L, I_to was decreased after 24 hours but almost returned to control values after 120 hours. When dexamethasone-treated animals also underwent atrial tachypacing, pacing-induced reduction of I_Ca,L was still observed after 24 hours and was even augmented after 120 hours compared to untreated but tachypaced animals. I_to was not influenced by dexamethasone alone. In dexamethasone-treated animals, reduction of I_to was not observed after 24 hours but occurred after 120 hours of atrial tachypacing. I_sus was neither influenced by rapid atrial pacing nor by dexamethasone. Biophysical properties of all currents were affected neither by rapid atrial pacing nor by dexamethasone. Conclusion: Dexamethasone influenced tachycardia-induced alterations of atrial I_to. Our experiments give evidence that - amongst other anti-inflammatory action – impact of dexamethasone on ion currents and their tachycardia-induced alterations might also play a role in treatment/prevention of AF with steroids.

Funny Current Downregulation and Sinus Node Dysfunction Associated With Atrial Tachyarrhythmia

Sinoatrial node (SAN) dysfunction is frequently associated with atrial tachyarrhythmias (ATs). Abnormalities in SAN pacemaker function after termination of ATs can cause syncope and require pacemaker implantation, but underlying mechanisms remain poorly understood. This study examined the hypothesis that ATs impair SAN function by altering ion channel expression. SAN tissues were obtained from 28 control dogs and 31 dogs with 7-day atrial tachypacing (400 bpm). Ionic currents were measured from single SAN cells with whole-cell patch-clamp techniques. Atrial tachypacing increased SAN recovery time in vivo by approximately 70% (P<0.01), a change which reflects impaired SAN function. In dogs that underwent atrial tachypacing, SAN mRNA expression (real-time reverse-transcription polymerase chain reaction) was reduced for hyperpolarization-activated cyclic nucleotide-gated subunits (HCN2 and HCN4) by >50% (P<0.01) and for the beta-subunit minK by approximately 42% (P<0.05). SAN transcript expression for the rapid delayed-rectifier (I(Kr)) alpha-subunit ERG, the slow delayed-rectifier (I(Ks)) alpha-subunit KvLQT1, the beta-subunit MiRP1, the L-type (I(CaL)) and T-type (I(CaT)) Ca2+-current subunits Cav1.2 and Cav3.1, and the gap-junction subunit connexin 43 (were unaffected by atrial tachypacing. Atrial tachypacing reduced densities of the HCN-related funny current (I(f)) and I(Ks) by approximately 48% (P<0.001) and approximately 34% (P<0.01), respectively, with no change in voltage dependence or kinetics. I(Kr), I(CaL), and I(CaT) were unaffected. SAN cells lacked Ba2+-sensitive inward-rectifier currents, irrespective of AT. SAN action potential simulations that incorporated AT-induced alterations in I(f) accounted for slowing of periodicity, with no additional contribution from changes in I(Ks). AT downregulates SAN HCN2/4 and minK subunit expression, along with the corresponding currents I(f) and I(Ks). Tachycardia-induced remodeling of SAN ion channel expression, particularly for the "pacemaker" subunit I(f), may contribute to the clinically significant association between SAN dysfunction and supraventricular tachyarrhythmias.

Atrial Remodeling and Atrial Fibrillation

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. It can occur at any age but is very rare in children and becomes extremely common in the elderly, with a prevalence approaching 20% in patients >85 years of age.1 AF is associated with a wide range of potential complications and contributes significantly to population morbidity and mortality. Present therapeutic approaches to AF have major limitations, including limited efficacy and significant adverse effect liability. These limitations have inspired substantial efforts to improve our understanding of the mechanisms underlying AF, with the premise that improved mechanistic insights will lead to innovative and improved therapeutic approaches.2 Our understanding of AF pathophysiology has advanced significantly over the past 10 to 15 years through an increased awareness of the role of “atrial remodeling.” Any persistent change in atrial structure or function constitutes atrial remodeling. Many forms of atrial remodeling promote the occurrence or maintenance of AF by acting on the fundamental arrhythmia mechanisms illustrated in Figure 1. Both rapid ectopic firing and reentry can maintain AF. Reentry requires a suitable vulnerable substrate, as well as a trigger that acts on the substrate to initiate reentry. Ectopic firing contributes to reentry by providing triggers for reentry induction. Atrial remodeling has the potential to increase the likelihood of ectopic or reentrant activity through a multitude of potential mechanisms. This article reviews the types of atrial remodeling, their underlying pathophysiology, the molecular basis of their occurrence, and finally, their potential therapeutic significance. Figure 1. General schema representing AF mechanisms and the role of remodeling. The mechanisms underlying AF are portrayed schematically in Figure 2. AF can be maintained by rapid focal firing, which may itself be regular but result in fibrillatory activity because of wave breakup in portions of the atrium that …

Induction of Heat Shock Response Protects the Heart Against Atrial Fibrillation

There is evidence suggesting that heat shock proteins (HSPs) may protect against clinical atrial fibrillation (AF). We evaluated the effect of HSP induction in an in vitro atrial cell line (HL-1) model of tachycardia remodeling and in tachypaced isolated canine atrial cardiomyocytes. We also evaluated the effect of HSP induction on in vivo AF promotion by atrial tachycardia-induced remodeling in dogs. Tachypacing (3 Hz) significantly and progressively reduced Ca(2+) transients and cell shortening of HL-1 myocytes over 4 hours. These reductions were prevented by HSP-inducing pretreatments: mild heat shock, geranylgeranylacetone (GGA), and transfection with human HSP27 or the phosphorylation-mimicking HSP27-DDD. However, treatment with HSP70 or the phosphorylation-deficient mutant HSP27-AAA failed to alter tachycardia-induced Ca(2+) transient and cell-shortening reductions, and downregulation (short interfering RNA) of HSP27 prevented GGA-mediated protection. Tachypacing (3 Hz) for 24 hours in vitro significantly reduced L-type Ca(2+) current and action potential duration in canine atrial cardiomyocytes; these effects were prevented when tachypacing was performed in cells exposed to GGA. In vivo treatment with GGA increased HSP expression and suppressed refractoriness abbreviation and AF promotion in dogs subjected to 1-week atrial tachycardia-induced remodeling. In conclusion, our findings indicate that (1) HSP induction protects against atrial tachycardia-induced remodeling, (2) the protective effect in HL-1 myocytes requires HSP27 induction and phosphorylation, and (3) the orally administered HSP inducer GGA protects against AF in a clinically relevant animal model. These findings advance our understanding of the biochemical determinants of AF and suggest the possibility that HSP induction may be an interesting novel approach to preventing clinical AF.

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 fibrillation: the remodelling phenomenon

Atrial fibrillation (AF) is a progressive disease and may be self-sustaining. The processes that lead to the worsening of AF over time include electrical, contractile, neurohormonal, macroanatomical and ultrastructural changes, and these may occur over different periods of time. The term ‘electrical remodelling’ indicates long-term changes in atrial electrophysiological parameters that result from prolonged changes in atrial rate. The mechanism of tachycardia-induced remodelling is associated with altered ion channel function, the most important of which is a reduction in L-type calcium current, which is responsible for a reduction in the duration of the action potential, atrial refractory period and refractory period adaptation to rate. Recovery from atrial electrical remodelling occurs within a few days, even in cases of very long-lasting AF, although clinically the atria remain vulnerable for weeks after cardioversion. A so-called ‘second factor’ may play a role in this prolonged vulnerability to recurrent AF. In animals tachycardia-induced electrophysiological modification is reduced by verapamil and angiotensin II receptor antagonists, but the effect of these drugs in preventing atrial electrical remodelling in humans is disputed. Despite these findings, there is growing clinical evidence that verapamil and angiotensin II receptor antagonists could reduce the recurrence of AF after cardioversion. In this report current knowledge of the mechanisms and clinical consequences of AF-induced electrical remodelling is discussed. © 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved

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.

Remodeling of Ca(2+)-handling by atrial tachycardia: evidence for a role in loss of rate-adaptation.

Loss of rate-dependent action potential (AP) duration (APD) adaptation is a characteristic feature of atrial tachycardia-induced remodeling (ATR). ATR causes sarcolemmal ion-channel remodeling (ICR) and changes in Ca(2+)-handling. The present studies were designed to quantify Ca(2+)-handling changes and then to apply a mathematical AP model to assess the contributions of Ca(2+)-handling abnormalities and ICR to loss of APD rate-adaptation. Indo-1 fluorescence was used to measure intracellular Ca(2)-transients and whole-cell patch-clamp to record APs in atrial myocytes from control dogs and dogs subjected to atrial pacing at 400/min for 6 weeks. A previously developed ionic model of the canine atrial AP was modified to reproduce measured Ca(2+)-transients of control and ATR myocytes. In control, APD to 95% repolarization (APD(95)) decreased by 91 ms experimentally and by 88 ms in the model over the 1-6 Hz range. In ATR myocytes, APD(95) failed to decrease over the 1-6 Hz range. Ca(2+)-handling abnormalities in ATR myocytes included slowed upstroke, decreased amplitude and strong single-beat post-rest potentiation. Unaltered Ca(2+)-handling properties included caffeine-releasable Ca(2+)-stores and Ca(2+)-transient relaxation before and after exposure to the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor cyclopiazonic acid (CPA). Including ICR alone in the model accounted for loss of APD(50) rate-adaptation; however, KR alone reduced APD(95) rate-adaptation by only 19% to 71 ms. When both ICR and Ca(2+)-handling changes were incorporated, APD(95) rate-adaptation decreased to 6 ms, accounting for experimental observations. ICR alone does not fully account for loss of APD rate-adaptation with atrial remodeling: Ca(2+)-handling changes appear to contribute to this clinically significant phenomenon.

Effects of verapamil on atrial fibrillation and its electrophysiological determinants in dogs.

Atrial tachycardia-induced remodeling promotes the occurrence and maintenance of atrial fibrillation (AF) and decreases L-type Ca(2+) current. There is also a clinical suggestion that acute L-type Ca(2) channel blockade can promote AF, consistent with an AF promoting effect of Ca(2+) channel inhibition. To evaluate the potential mechanisms of AF promotion by Ca(2+) channel blockers, we administered verapamil to morphine-chloralose anesthetized dogs. Diltiazem was used as a comparison drug and autonomic blockade with atropine and nadolol was applied in some experiments. Epicardial mapping with 240 epicardial electrodes was used to evaluate activation during AF. Verapamil caused AF promotion in six dogs, increasing mean duration of AF induced by burst pacing, from 8+/-4 s (mean+/-S.E.) to 95+/-39 s (P<0.01 vs. control) at a loading dose of 0.1 mg/kg and 228+/-101 s (P<0.0005 vs. control) at a dose of 0.2 mg/kg. Underlying electrophysiological mechanisms were studied in detail in five additional dogs under control conditions and in the presence of the higher dose of verapamil. In these experiments, verapamil shortened mean effective refractory period (ERP) from 122+/-5 to 114+/-4 ms (P<0.02) at a cycle length of 300 ms, decreased ERP heterogeneity (from 15+/-1 to 10+/-1%, P<0.05), heterogeneously accelerated atrial conduction and decreased the cycle length of AF (94+/-4 to 84+/-3 ms, P<0.005). Diltiazem did not affect ERP, AF cycle length or AF duration, but produced conduction acceleration similar to that caused by verapamil (n=5). In the presence of autonomic blockade, verapamil failed to promote AF and increased, rather than decreasing, refractoriness. Neither verapamil nor diltiazem affected atrial conduction in the presence of autonomic blockade. Epicardial mapping suggested that verapamil promoted AF by increasing the number of simultaneous wavefronts reflected by separate zones of reactivation in each cycle. Verapamil promotes AF in normal dogs by promoting multiple circuit reentry, an effect dependent on intact autonomic tone and not shared by diltiazem.

Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs.

Tachycardia-induced remodeling likely plays an important role in atrial fibrillation (AF) maintenance and recurrence after cardioversion, and Ca(2+) overload may be an important mediator. This study was designed to evaluate the relative efficacies of selective T-type (mibefradil) and L-type (diltiazem) Ca(2+)-channel blockers in preventing tachycardia-induced atrial remodeling. Dogs were given daily doses of mibefradil (100 mg), diltiazem (240 mg) or placebo in a blinded fashion, beginning 4 days before and continuing through a 7-day period of atrial pacing at 400 bpm. An electrophysiological study was then performed to assess changes in refractoriness, refractoriness heterogeneity and AF duration. Mean duration of burst-pacing induced AF was similar in placebo (567+/-203 s) and diltiazem-treated (963+/-280 s, P=NS) animals, but was much less in mibefradil-treated dogs (3.6+/-0.9 s, P<0.002) and non-paced controls (6.6+/-2.7 s). In contrast to mibefradil, diltiazem did not alter tachycardia-induced refractoriness abbreviation or heterogeneity. To exclude inadequate dosing as an explanation for diltiazem's inefficacy, we studied an additional group of dogs treated with 720 mg/day of diltiazem, and again noted no protective effect. Acute intravenous administration of diltiazem to control dogs failed to alter atrial refractoriness or AF duration, excluding a masking of remodeling suppression by offsetting profibrillatory effects of the drug. Whereas the selective T-type Ca(2+)-channel blocker mibefradil protects against atrial remodeling caused by 7-day atrial tachycardia, the selective L-type blocker diltiazem is without effect. These findings are potentially important for understanding the mechanisms and prevention of clinically-relevant atrial-tachycardia-induced remodeling.

Atrial electrophysiological remodeling caused by rapid atrial activation: underlying mechanisms and clinical relevance to atrial fibrillation.

One of the most exciting developments in our understanding of atrial fibrillation (AF) over the last several years has been the recognition that AF itself modifies atrial electrical properties in a way that promotes the occurrence and maintenance of the arrhythmia, a process termed 'atrial remodeling'. The principle stimulus for AF-induced atrial remodeling is the rapid atrial rate that results: rapid regular atrial pacing produces changes similar to those caused by AF in animal models. The mechanisms of atrial tachycardia-induced remodeling have been extensively explored, and involve changes in atrial electrophysiology associated with altered ion channel function. The most important ionic change is a reduction in L-type Ca2+ current, which reduces action potential duration (APD) and APD adaptation to rate. AF-induced changes in ion channel function appear to be due both to rapid voltage- and time-dependent alterations in channel availability caused by tachycardia and to slower downregulation of messenger RNA concentrations encoding alpha-subunits of specific ion channels. Atrial remodeling likely contributes importantly to a wide variety of clinical phenomena of previously unrecognized mechanism, including atrial dysfunction after cardioversion of AF, the increasing resistance to therapy of longer-standing AF, the association of AF with other forms of supraventricular tachyarrhythmia and the tendency of paroxysmal AF to become chronic. The present paper reviews the state of knowledge regarding the mechanisms and clinical consequences for AF of atrial remodeling caused by rapid atrial activation.