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CLINICAL REVIEWEditor: Stephen C. Hammill, M.D.

Pathophysiology and Disease Progression of Atrial Fibrillation:Importance of Achieving and Maintaining Sinus Rhythm

MARC COHEN, M.D., F.A.C.C.∗ and GERALD V. NACCARELLI, M.D.†From the ∗Newark Beth Israel Medical Center, Newark, New Jersey, USA; and †Penn State Heart & Vascular Institute,

Hershey, Pennsylvania, USA

Role of Rhythm Control in Atrial Fibrillation. Atrial fibrillation (AF) is a progressive diseasein which arrhythmia-induced remodeling facilitates evolution from paroxysmal AF to persistent and per-manent AF. Changes in electrical, structural, and contractile properties of cardiac tissue that are thoughtto underlie AF maintenance and progression are reviewed. Also examined is the negative impact of AF onclinical outcomes, as well as the potential benefits of restoration and maintenance of sinus rhythm. Becauseof the limited efficacy and adverse effects of current antiarrhythmics, new antiarrhythmic drugs need to bedeveloped that provide safer and more effective rhythm control in AF. (J Cardiovasc Electrophysiol, Vol. 19,pp. 885-890, August 2008)

atrial fibrillation, pathophysiology, antiarrhythmia agents, rhythm control, ion channels, disease progression

Introduction

Atrial fibrillation (AF) is a supraventricular tachyarrhyth-mia characterized by uncoordinated atrial activation. It af-fects approximately 2.3 million North Americans and 4.5 mil-lion Europeans, particularly the elderly. In the United States,about 75% of individuals with AF are 65 years of age orolder.1,2 If not managed appropriately, AF can have seriousconsequences including hemodynamic impairment (reducedcardiac output), reduced quality of life (discomfort due to AFsymptoms, reduced exercise tolerance, and chronic fatigue),stroke, cardiomyopathy/heart failure, and death.2

Atrial fibrillation is progressive. It has been estimated that14–24% of patients with paroxysmal AF (recurrent AF thatis self-terminating with episode durations of <7 days) even-tually progress to persistent AF (recurrent AF that is notself-terminating with episode durations of >7 days).2,3 Ina 30-year follow-up study, Jahangir et al. reported that 22of 71 patients (31%) with paroxysmal or persistent AF pro-gressed to permanent AF, with most doing so within the first

Funding for editorial support was provided by sanofi-aventis US.

Dr. Cohen is a coinvestigator in the CRESCENDO trial and serves on themedical advisory board of sanofi-aventis.

Dr. Naccarelli is an investigator on research grants from sanofi-aventis, Car-diome, ARYX, Wyeth-Ayerst, Boehringer-Ingleheim, and Reliant. He serveson the medical advisory boards of Xantion, Wyeth-Ayerst, Astellas, Car-diome, sanofi-aventis, Reliant, and CV Therapeutics.

Address for correspondence: Marc Cohen, M.D., F.A.C.C., Director, Di-vision of Cardiology, Newark Beth Israel Medical Center, 201 Lyons Av-enue at Osborne Terrace, Newark, NJ 07112. Fax: 973-282-0839; E-mail:marcohen@sbhcs.com

Manuscript received 17 December 2007; Accepted for publication 24December 2007.

doi: 10.1111/j.1540-8167.2008.01134.x

15 years after diagnosis.4 Moreover, conversion of AF to si-nus rhythm becomes increasingly difficult as the duration ofAF increases.3 Such self-perpetuation has been attributed toAF-related changes in atrial structure and function that facil-itate progression of the disease.

The purpose of this article is to briefly review the patho-physiology of AF progression and the impact of rhythm con-trol on disease course. In addition, potential treatment goalsare described in light of the limitations of existing antiar-rhythmic drugs.

Pathophysiology and Disease Progression

AF is commonly triggered by one or more ectopic fociin the atria and is perpetuated via micro reentrant circuits.5,6

Whether AF is triggered by mother waves, fixed or mov-ing rotors, and/or perpetuated by mechanisms other than mi-cro reentry remains controversial. Electrical, contractile, andstructural remodeling maintain AF and may be responsiblefor the progression of incidental and paroxysmal AF to persis-tent and permanent AF (recurrent AF of >1 year in durationfor which cardioversion was unsuccessful).

Electrical remodeling is characterized by changes in atrialrefractoriness, atrial conduction, and sinus node function.It occurs rapidly and is likely reversible. Reductions in theatrial effective refractory period (ERP) and ERP adaption torate likely reflect long-term reduction of the L-type calcium(Ca2+) current (ICa,L) and result in reduced action poten-tial duration and wavelength.7-9 Under normal conditions,Ca2+ moves into the cell during each action potential andcontributes to cellular repolarization. In AF, the increasednumber of action potentials associated with rapid atrial fir-ing results in increased Ca2+ influx. Short- and long-termcompensatory mechanisms are then triggered to minimizethe potential for Ca2+ overload. These include inactivationof ICa (short term) and downregulation of ICa expression(long term). These actions result in shorter duration of theaction potential plateau and atrial ERP, as well as reduced

886 Journal of Cardiovascular Electrophysiology Vol. 19, No. 8, August 2008

TABLE 1

AF-Associated Structural Changes in the Atria

Model Structural Changes

Preclinical3,8,71 Atrial enlargementIncreased cell sizeGlycogen accumulation around the nucleusMyolysisReduced connexin 40 expressionAltered mitochondrial shape and sizeFragmentation of the sarcoplasmic reticulumHomogenous distribution of nuclear chromatinLocalization of cellular proteins

Patients with AF Atrial enlargement (increased atrial diameter)3

Myocarditis14

Noninflammatory cardiomyopathy14

Patchy fibrosis14

Interstitial fibrosis around the pulmonary vein ostia16

Apoptotic death with myolysis15

Severe cellular degeneration13

Increased expression of collagen I17,19and III17

Upregulation of MMP-219

Downregulation of TIMP-219

Increased expression of the active form of MMP-9and monocyte chemoattractant protein-118

AF = atrial fibrillation; MMP = matrix metalloproteinase; TIMP = tissueinhibitor of metalloproteinase.

ERP adaption to rate. Downregulation of the fast sodium(Na+) current (INa) also may slow atrial conduction and re-duce wavelength.5 In the goat model, maximal shortening ofthe atrial ERP occurred rapidly (within 2 days of AF onset).10

Other ion-channel abnormalities have been described,including decreases in outward potassium (K+) currents(Ito, IKsus, and IKur), increases in the inward rectifier (IK1),decreases in the ATP-dependent K+ current (IKATP), and in-creases/decreases in the acetylcholine-activated K+ current(IKACh).7,11,12 Changes in the expression of these channelswould be expected to alter resting membrane potential andaction potential repolarization, possibly in an effort to coun-teract atrial ERP shortening; however, the consequences ofthese changes are not fully understood.

Loss of contractility owing to contractile remodeling oc-curs rapidly as well.6 Reduced release of systolic Ca2+(due to downregulation of ICa,L) may contribute to thischange, as may myolysis (loss of sarcomeres).9 Conse-quences of contractile remodeling include thrombus forma-tion and atrial dilation. Contractile remodeling also maycontribute to the progression of AF by permitting the coexis-tence of multiple wavelets. Recovery of contractility gen-erally takes longer than reversal of electrical remodeling,likely because of the time it takes for the atria to replace lostsarcomeres.

Sustained AF is associated with structural changes withinthe atria, many of which probably are irreversible.6 Data fromanimal models suggest that such changes occur more slowly(over periods of weeks to months) than electrical changesand primarily reflect dedifferentiation.8 Observed structuralchanges are summarized in Table 1. The most characteristicchanges in animal models are increased cell size, myoly-sis, and the accumulation of glycogen around the nucleus.Human data, although limited, indicate that degenerativechanges also occur.13-15 In patients with AF who undergo mi-tral valve surgery, fibrotic changes were frequently observedin the peripulmonary vein tissue,16 a region often associated

with ectopic impulse formation in AF. Changes in collagenand matrix metalloproteinase expression may contribute toobserved structural changes,17-19 as may atrial stretch andelevated concentrations of catecholamines and angiotensinII triggered by loss of atrial systole and suboptimal ventricu-lar filling.2,3,8,20 The exact mechanism(s) by which structuralchanges in the atria facilitate the progression of AF remainunknown; however, they may do so by altering refractorinessand conduction.8,11

Clinical Implications

Benefits of Rhythm-control Therapy

Because it appears that ongoing AF facilitates disease pro-gression via the mechanisms described earlier, it would seemprudent to strive for rhythm control whenever possible. Con-flicting data on the morbidity and mortality outcomes asso-ciated with rhythm control versus rate control have impededthe widespread use of a rhythm-control approach early inthe course of the disease. In a large trial (N = 4060), theAtrial Fibrillation Follow-up Investigation of Rhythm Man-agement (AFFIRM) study, rhythm control did not prove morebeneficial than rate control with respect to mortality amongthe total population; 69% of patients had recurrent persistentAF.21,22 Subsequent subset analyses showed that younger pa-tients (<65 years of age) and those with a history of conges-tive heart failure (CHF) responded more favorably to rhythmcontrol than did older patients and those without CHF.23 Ithas been suggested that the absence of a greater benefit onsurvival with rhythm control (relative to rate control) in theprimary analysis of AFFIRM reflects the incomplete suppres-sion of AF and/or the negative impact of cardiac and non-cardiac side effects of current antiarrhythmic therapies.24,25

It has also been theorized that drug-related side effects con-tribute to the differences detected between age groups; for in-stance, older patients may have been more vulnerable to drugtoxicities than younger patients. In a post hoc analysis of rela-tionships between sinus rhythm, treatment, and survival in theAFFIRM study, the risk of death decreased dramatically forpatients who remained in sinus rhythm (hazard ratio = 0.53;95% confidence interval [CI] 0.39, 0.72; P < 0.0001).24 Thebenefits of sinus rhythm also are apparent from a separateanalysis of stroke events in which the presence of AF wasassociated with a 60% increase in stroke risk.26 Moreover,in the AFFIRM Functional Status Substudy, the presence ofAF was associated with poorer New York Heart Association(NYHA) functional capacity (P < 0.0001) and rhythm con-trol was associated with modest improvement in 6-minutewalk distance relative to rate control (average increase of8.5% [100 feet]; P = 0.06).27

There was no significant improvement in morbidity ormortality with rhythm control in the Rate Control versusElectrical Cardioversion (RACE) study (N = 522).28 Further-more, results of a subsequent subanalysis failed to demon-strate an improved prognosis for patients with persistent AFwho remained in sinus rhythm while on rhythm control andanticoagulation treatment relative to patients with permanentAF from the rate-control arm.29 The lack of benefit of rhythmcontrol was attributed, at least in part, to the impact of under-lying heart disease and treatment-related adverse events.

Conversely, several studies have shown that rhythm con-trol is associated with reduced mortality, including those con-ducted in patients with underlying structural heart disease. In

Cohen and Naccarelli Role of Rhythm Control in Atrial Fibrillation 887

the Danish Investigations of Arrhythmia and Mortality OnDofetilide (DIAMOND) study (N = 506), restoration andmaintenance of sinus rhythm in patients with AF/flutter andleft ventricular dysfunction was associated with a significantreduction in mortality (all patients [dofetilide or placebo]:risk ratio, 0.44; 95% CI, 0.30, 0.64; P < 0.0001).30 This re-duction was apparent whether the sinus rhythm was achievedusing dofetilide (risk ratio, 0.43; 95% CI, 0.27, 0.68; P <0.001) or placebo (risk ratio, 0.38; 95% CI, 0.20, 0.73; P <0.004).

The Strategies of Treatment of Atrial Fibrillation (STAF)study included 200 patients with persistent AF, 56% of whomwere in NYHA functional class II or higher.31 The mortalityrate among the rate-control group (4.9% per year) was nearlydouble that for the rhythm-control group (2.5% per year).In the Control of Rate versus Rhythm in Rheumatic AtrialFibrillation Trial (CRAAFT) (N = 144),32 the relative riskof death was 12.4 times higher for the rate-control group(five deaths vs none for the rhythm-control group [95% CI,5.3, 29]). In the Veterans Affairs Congestive Heart FailureSurvival Trial of Antiarrhythmic Therapy (CHF-STAT),33 AFpatients with CHF who were converted and maintained insinus rhythm using amiodarone (n = 16) had a significantlylower mortality rate than those who did not convert to sinusrhythm while on the drug (n = 35; P = 0.04).

Whereas the true impact of rhythm control on mortal-ity remains to be determined, current data suggest that therestoration and maintenance of sinus rhythm in patients withAF may impart other important clinical benefits, such as im-provements in symptoms, exercise tolerance, the ability toperform activities of daily living, and quality of life.34-36

Reductions in atrial remodeling and improvements in leftventricular function also have been described.36,37 In RACE,patients who experienced restoration and maintenance of nor-mal sinus rhythm had a significant reduction in atrial sizeand a significant increase in left ventricular function (bothP < 0.05) compared with patients who did not attain nor-mal sinus rhythm.37 Similarly, in HOT CAFE, significantreductions in both left (P < 0.02) and right (P < 0.01) atrialsize were observed in the rhythm-control group, as was asignificant increase in left ventricular fractional shortening

Figure 1. Algorithm of antiarrhythmic drug therapy to maintain sinus rhythm in patients with recurrent paroxysmal or persistent atrial fibrillation. Reprintedwith permission of Oxford University Press from Fuster et al.2 LVH = left ventricular hypertrophy.

(P < 0.001).36 These benefits were not observed in the rate-control group of this study. In PAF 2, fewer patients withpharmacologically controlled rhythm progressed from parox-ysmal to permanent AF (relative risk reduction, 57%; P =0.02).38 Taken together, these findings suggest that mainte-nance of normal sinus rhythm may slow or prevent the re-modeling that contributes to disease progression.

Overall, studies comparing rhythm and rate control havefailed to identify any single strategy that is optimal for allpatients with AF. Achieving and maintaining sinus rhythmremains a viable and important treatment goal in appropriatepatients. Patients who achieve and maintain rhythm controlmay experience symptomatic improvement and slowed dis-ease progression. Perhaps future research will help identifythose patients who will derive the greatest benefit from thisapproach, as well as those who would be better suited for ratecontrol or combined therapy with rhythm and rate control.

Limitations of Current Antiarrhythmic Therapies

Current treatment guidelines recommend the considera-tion of antiarrhythmic therapy for the conversion from AF andmaintenance of sinus rhythm in patients with persistent AFor recurrent paroxysmal AF if it is associated with disablingsymptoms.2 It is typically reserved for these populations be-cause currently available antiarrhythmic agents commonlyfail to completely suppress AF and have safety profiles thatare less than ideal. The relative efficacy of the various an-tiarrhythmics for the management of AF remains unknown.Therefore, drug selection is largely driven by drug-safety is-sues, particularly the potential for end-organ toxicity withamiodarone, and proarrhythmia with all membrane-activeagents. It is recommended that drug selection for the main-tenance of sinus rhythm be made with careful considerationof concomitant cardiovascular conditions, especially hyper-tension, coronary artery disease, and heart failure (Fig. 1).

Potential Antiarrhythmic Therapies for the Future

The search continues for antiarrhythmics that have greaterefficacy and a lower risk of end-organ damage and/or

888 Journal of Cardiovascular Electrophysiology Vol. 19, No. 8, August 2008

proarrhythmia. Investigational compounds include atrial-selective agents, multiple ion-channel blockers, and gap-junction modifiers. The atrial-selective compounds (e.g., ver-nakalant, AVE0118, AVE1231, and AZD7009) target ion cur-rents predominantly present in the atria (e.g., the ultrarapiddelayed rectifier [IKur], the late Na+ current [INa], the tran-sient outward current [Ito], the rapid delayed rectifier [IKr],and/or the constitutively active form of the acetylcholine-dependent K+ current [IKACh]), thus minimizing or avoidingeffects on ion currents in the ventricle that could potentiallytrigger proarrhythmia.39-49 Blockade of these specific cur-rents typically is associated with prolongation of atrial refrac-toriness and restoration of sinus rhythm, with minimal effectson ventricular repolarization. GsMTx4, a peptide from spi-der venom, blocks currents carried by stretch-activated non-selective cation channels.50 It has been shown to inhibit AFassociated with dilatation in an animal model.

The multiple-channel blockers (e.g., azimilide,dronedarone, and tedisamil) are believed to optimizeantiarrhythmic activity and minimize proarrhythmic effectsvia select inhibition of multiple channels at different stagesof the action potential.51-56 In addition, they prolong atrialrefractoriness. It has been theorized that blockade of bothIKr (a major contributor to repolarization at physiologicalheart rates) and IKs (a major contributor to repolarization atrapid heart rates) by the multiple-channel blockers azimilideand dronedarone may contribute to improved efficacy (byextending effects to periods of rapid pacing) and reducedproarrhythmic potential.51-55 The antiarrhythmic activity ofthe multiple-channel blocker tedisamil has been attributedto inhibition of Ito in both the atria and the ventricles and toinhibition of IK , IKATP, and the protein kinase A–activatedchloride channel in the ventricles, with a greater effecton action potential duration in the atria relative to theventricles.52,56

The gap-junction modifiers (e.g., rotigaptide [ZP123] andAAP10) promote cellular coupling and facilitate proper con-duction via effects on connexins, the proteins that form thesubunits of gap-junction channels.57-63 Both have demon-strated effects on Cx43, which is expressed primarily in hu-man atria. The lack of influence on membrane (ionic) currentsmay translate into reduced risk of proarrhythmia.64

The availability of safer, more effective agents couldgreatly expand the population suitable for pharmacologicrhythm-control therapy and allow more patients to receivetherapies that could potentially slow the progression of theirdisease.

Treatment Goals

Unfortunately, complete restoration of sinus rhythm(100% freedom from recurrence) often is unachievable withcurrent therapies and remains an impractical treatment goal.It has been estimated that the average 1-year recurrence rateassociated with amiodarone approximates 35%, and that forother currently available antiarrhythmic drug therapies iseven higher (approximately 50%).65

However, it is likely that individuals with AF can derivebenefit from even partial restoration of sinus rhythm. In clin-ical studies of catheter ablation, patients with AF recurrenceexperienced varying degrees of improvement in quality oflife and the frequency or severity of symptoms, albeit lessthan those without AF recurrence.66-69 For example, a study

of patients with drug-refractory paroxysmal AF found thatamong 27 patients who experienced AF recurrence after pul-monary vein isolation, 15 (56%) reported that their qualityof life was better after the procedure.69

Similar findings have been described in studies of rate ver-sus rhythm control. In STAF,31 scores for the rhythm-controlgroup on the Short-Form health survey (SF-36) domains ofphysical role function and mental health improved signif-icantly (both P < 0.05) from baseline to follow-up (mean[SD] duration, 19.5 [8.9] months), despite the relatively lowpercentage of patients in sinus rhythm after cardioversion(70%) and at 36 months (23%). Similarly, in the Pharma-cological Intervention in Atrial Fibrillation (PIAF) study,70

scores for SF-36 physical functioning, physical role function,vitality, and social functioning improved significantly frombaseline to Month 12 in the rhythm-control group (all P <0.05), despite the fact that only 56% of patients in this groupremained in sinus rhythm at the 12-month time point.

Improvements in left ventricular function also have beendescribed for patients with AF and CHF who failed to achieve100% absence of recurrence. Hsu and colleagues reportedsignificant (P = 0.03) improvements in left ventricular func-tion in 4 of 12 patients who achieved conversion from perma-nent AF to paroxysmal AF using catheter ablation and sub-sequent pharmacologic therapy.35 Such improvements weredefined as increases in left ventricular ejection fraction of20% or more or to a value of 55% or more.

Collectively, these findings suggest that patients may de-rive benefit from any therapy that restores sinus rhythm forprolonged periods, even if they experience occasional recur-rence.

Summary

AF causes electrical and structural remodeling, which con-tributes to the progression of AF from incidental and parox-ysmal to persistent and permanent. Early restoration of sinusrhythm may minimize this remodeling and, subsequently, theprogression of AF. Although it may be impossible to com-pletely eliminate AF recurrences with pharmacologic ther-apy, agents that decrease episode frequency and durationmay still provide beneficial effects, including improvementsin symptoms and reductions in remodeling. Unfortunately,current rhythm-control therapies are not highly effective andtheir use often is limited by side effects. Therefore, the needremains for safer and more effective pharmacologic treatmentoptions. Future drug trials, evaluating new interventions forrhythm control, also should focus on the impact of adequateanticoagulation and the contribution of drug toxicity on theclinical outcomes observed.

References

1. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV,Singer DE: Prevalence of diagnosed atrial fibrillation in adults: Na-tional implications for rhythm management and stroke prevention: TheAnTicoagulation and RIsk factors in Atrial fibrillation (ATRIA) study.JAMA 2001;285:2370-2375.

2. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, EllenbogenKA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prys-towsky EN, Tamargo JL, Wann S: ACC/AHA/ESC 2006 guidelines forthe management of patients with atrial fibrillation-executive summary:A report of the American College of Cardiology/American Heart Asso-ciation Task Force on practice guidelines and the European Society ofCardiology Committee for Practice Guidelines (Writing Committee to

Cohen and Naccarelli Role of Rhythm Control in Atrial Fibrillation 889

Revise the 2001 Guidelines for the Management of Patients with AtrialFibrillation). Eur Heart J 2006;27:1979-2030.

3. Schoonderwoerd BA, Van Gelder IC, Van Veldhuisen DJ, Van den BergMP, Crijns HJ: Electrical and structural remodeling: Role in the genesisand maintenance of atrial fibrillation. Prog Cardiovasc Dis 2005;48:153-168.

4. Jahangir A, Lee V, Friedman PA, Trusty JM, Hodge DO, Kopecky SL,Packer DL, Hammill SC, Shen WK, Gersh BJ: Long-term progressionand outcomes with aging in patients with lone atrial fibrillation: A 30-year follow-up study. Circulation 2007;115:3050-3056.

5. Shiroshita-Takeshita A, Brundel BJ, Nattel S: Atrial fibrillation: Ba-sic mechanisms, remodeling and triggers. J Interv Card Electrophysiol2005;13:181-193.

6. Van Gelder IC, Hemels ME: The progressive nature of atrial fibrilla-tion: A rationale for early restoration and maintenance of sinus rhythm.Europace 2006;8:943-949.

7. Brundel BJ, Van Gelder IC, Henning RH, Tieleman RG, TuinenburgAE, Wietses M, Grandjean JG, Van Gilst WH, Crijns HJ: Ion channelremodeling is related to intraoperative atrial effective refractory periodsin patients with paroxysmal and persistent atrial fibrillation. Circulation2001;103:684-690.

8. Allessie M, Ausma J, Schotten U: Electrical, contractile and structuralremodeling during atrial fibrillation. Cardiovasc Res 2002;54:230-246.

9. Nattel S: New ideas about atrial fibrillation 50 years on. Nature2002;415:219-226.

10. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA: Atrial fibrillationbegets atrial fibrillation. A study in awake chronically instrumentedgoats. Circulation 1995;92:1954-1968.

11. Brundel BJ, Henning RH, Kampinga HH, Van Gelder IC, Crijns HJ:Molecular mechanisms of remodeling in human atrial fibrillation. Car-diovasc Res 2002;54:315-324.

12. Brugada R: Molecular biology of atrial fibrillation. Minerva Cardioan-giol 2004;52:65-72.

13. Thiedemann KU, Ferrans VJ: Left atrial ultrastructure in mitral valvulardisease. Am J Pathol 1977;89:575-604.

14. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, MaseriA: Histological substrate of atrial biopsies in patients with lone atrialfibrillation. Circulation 1997;96:1180-1184.

15. Aime-Sempe C, Folliguet T, Rucker-Martin C, Krajewska M, Krajew-ska S, Heimburger M, Aubier M, Mercadier JJ, Reed JC, Hatem SN:Myocardial cell death in fibrillating and dilated human right atria. J AmColl Cardiol 1999;34:1577-1586.

16. Corradi D, Callegari S, Benussi S, Nascimbene S, Pastori P, Calvi S,Maestri R, Astorri E, Pappone C, Alfieri O: Regional left atrial inter-stitial remodeling in patients with chronic atrial fibrillation undergoingmitral-valve surgery. Virchows Arch 2004;445:498-505.

17. Boldt A, Wetzel U, Lauschke J, Weigl J, Gummert J, Hindricks G,Kottkamp H, Dhein S: Fibrosis in left atrial tissue of patients withatrial fibrillation with and without underlying mitral valve disease. Heart2004;90:400-405.

18. Nakano Y, Niida S, Dote K, Takenaka S, Hirao H, Miura F,Ishida M, Shingu T, Sueda T, Yoshizumi M, Chayama K: Matrixmetalloproteinase-9 contributes to human atrial remodeling during atrialfibrillation. J Am Coll Cardiol 2004;43:818-825.

19. Xu J, Cui G, Esmailian F, Plunkett M, Marelli D, Ardehali A, Odim J,Laks H, Sen L: Atrial extracellular matrix remodeling and the mainte-nance of atrial fibrillation. Circulation 2004;109:363-368.

20. Cha YM, Redfield MM, Shen WK, Gersh BJ: Atrial fibrillation andventricular dysfunction: A vicious electromechanical cycle. Circulation2004;109:2839-2843.

21. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, SchronEB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD: Acomparison of rate control and rhythm control in patients with atrialfibrillation. N Engl J Med 2002;347:1825-1833.

22. Wyse DG: Rate control vs rhythm control strategies in atrial fibrillation.Prog Cardiovasc Dis 2005;48:125-138.

23. Curtis AB, Gersh BJ, Corley SD, DiMarco JP, Domanski MJ, GellerN, Greene HL, Kellen JC, Mickel M, Nelson JD, Rosenberg Y, SchronE, Shemanski L, Waldo AL, Wyse DG: Clinical factors that influenceresponse to treatment strategies in atrial fibrillation: The Atrial Fibrilla-tion Follow-up Investigation of Rhythm Management (AFFIRM) study.Am Heart J 2005;149:645-649.

24. Corley SD, Epstein AE, DiMarco JP, Domanski MJ, Geller N, GreeneHL, Josephson RA, Kellen JC, Klein RC, Krahn AD, Mickel M,Mitchell LB, Nelson JD, Rosenberg Y, Schron E, Shemanski L, WaldoAL, Wyse DG: Relationships between sinus rhythm, treatment, and

survival in the Atrial Fibrillation Follow-up Investigation of RhythmManagement (AFFIRM) study. Circulation 2004;109:1509-1513.

25. Steinberg JS, Sadaniantz A, Kron J, Krahn A, Denny DM, Daubert J,Campbell WB, Havranek E, Murray K, Olshansky B, O’Neill G, SamiM, Schmidt S, Storm R, Zabalgoitia M, Miller J, Chandler M, NascoEM, Greene HL: Analysis of cause-specific mortality in the Atrial Fib-rillation Follow-up Investigation of Rhythm Management (AFFIRM)study. Circulation 2004;109:1973-1980.

26. Sherman DG, Kim SG, Boop BS, Corley SD, DiMarco JP, Hart RG,Haywood LJ, Hoyte K, Kaufman ES, Kim MH, Nasco E, Waldo AL:Occurrence and characteristics of stroke events in the Atrial Fibrilla-tion Follow-up Investigation of Sinus Rhythm Management (AFFIRM)study. Arch Intern Med 2005;165:1185-1191.

27. Chung MK, Shemanski L, Sherman DG, Greene HL, Hogan DB, KellenJC, Kim SG, Martin LW, Rosenberg Y, Wyse DG: Functional sta-tus in rate- versus rhythm-control strategies for atrial fibrillation: Re-sults of the Atrial Fibrillation Follow-up Investigation of Rhythm Man-agement (AFFIRM) Functional Status Substudy. J Am Coll Cardiol2005;46:1891-1899.

28. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, KingmaT, Said SA, Darmanata JI, Timmermans AJ, Tijssen JG, Crijns HJ: Acomparison of rate control and rhythm control in patients with recurrentpersistent atrial fibrillation. N Engl J Med 2002;347:1834-1840.

29. Rienstra M, Van Gelder IC, Hagens VE, Veeger NJ, Van Veldhuisen DJ,Crijns HJ: Mending the rhythm does not improve prognosis in patientswith persistent atrial fibrillation: A subanalysis of the RACE study. EurHeart J 2006;27:357-364.

30. Pedersen OD, Bagger H, Keller N, Marchant B, Kober L, Torp-PedersenC: Efficacy of dofetilide in the treatment of atrial fibrillation-flutter inpatients with reduced left ventricular function: A Danish investigationsof arrhythmia and mortality on dofetilide (diamond) substudy. Circula-tion 2001;104:292-296.

31. Carlsson J, Miketic S, Windeler J, Cuneo A, Haun S, Micus S, WalterS, Tebbe U: Randomized trial of rate-control versus rhythm-controlin persistent atrial fibrillation: The Strategies of Treatment of AtrialFibrillation (STAF) study. J Am Coll Cardiol 2003;41:1690-1696.

32. Vora A, Karnad D, Goyal V, Naik A, Gupta A, Lokhandwala Y, Kulka-rni H, Singh BN: Control of heart rate versus rhythm in rheumaticatrial fibrillation: A randomized study. J Cardiovasc Pharmacol Ther2004;9:65-73.

33. Deedwania PC, Singh BN, Ellenbogen K, Fisher S, Fletcher R, SinghSN: Spontaneous conversion and maintenance of sinus rhythm by amio-darone in patients with heart failure and atrial fibrillation: Observationsfrom the veterans affairs congestive heart failure survival trial of antiar-rhythmic therapy (CHF-STAT). The Department of Veterans AffairsCHF-STAT Investigators. Circulation 1998;98:2574-2579.

34. Bubien RS, Knotts-Dolson SM, Plumb VJ, Kay GN: Effect of radiofre-quency catheter ablation on health-related quality of life and activi-ties of daily living in patients with recurrent arrhythmias. Circulation1996;94:1585-1591.

35. Hsu LF, Jais P, Sanders P, Garrigue S, Hocini M, Sacher F, Takahashi Y,Rotter M, Pasquie JL, Scavee C, Bordachar P, Clementy J, HaissaguerreM: Catheter ablation for atrial fibrillation in congestive heart failure. NEngl J Med 2004;351:2373-2383.

36. Opolski G, Torbicki A, Kosior DA, Szulc M, Wozakowska-Kaplon B,Kolodziej P, Achremczyk P: Rate control vs rhythm control in patientswith nonvalvular persistent atrial fibrillation: The results of the PolishHow to Treat Chronic Atrial Fibrillation (HOT CAFE) study. Chest2004;126:476-486.

37. Hagens VE, Van Veldhuisen DJ, Kamp O, Rienstra M, Bosker HA,Veeger NJ, Tijssen JG, Crijns HJ, Van Gelder IC: Effect of rate andrhythm control on left ventricular function and cardiac dimensions inpatients with persistent atrial fibrillation: Results from the Rate Con-trol versus Electrical Cardioversion for Persistent Atrial Fibrillation(RACE) study. Heart Rhythm 2005;2:19-24.

38. Brignole M, Menozzi C, Gasparini M, Bongiorni MG, Botto GL,Ometto R, Alboni P, Bruna C, Vincenti A, Verlato R: An evaluationof the strategy of maintenance of sinus rhythm by antiarrhythmic drugtherapy after ablation and pacing therapy in patients with paroxysmalatrial fibrillation. Eur Heart J 2002;23:892-900.

39. Knobloch K, Brendel J, Rosenstein B, Bleich M, Busch AE, WirthKJ: Atrial-selective antiarrhythmic actions of novel Ikur vs. Ikr, Iks,and IKAch class Ic drugs and beta blockers in pigs. Med Sci Monit2004;10:BR221-BR228.

40. Bachmann A, Gutcher I, Kopp K, Brendel J, Bosch RF, Busch AE,Gogelein H: Characterization of a novel Kv1.5 channel blocker in

890 Journal of Cardiovascular Electrophysiology Vol. 19, No. 8, August 2008

Xenopus oocytes, CHO cells, human and rat cardiomyocytes. NaunynSchmiedebergs Arch Pharmacol 2001;364:472-478.

41. Wirth KJ, Brendel J, Steinmeyer K, Linz DK, Rutten H, Gogelein H: Invitro and in vivo effects of the atrial selective antiarrhythmic compoundAVE1231. J Cardiovasc Pharmacol 2007;49:197-206.

42. Decher N, Kumar P, Gonzalez T, Pirard B, Sanguinetti MC: Binding siteof a novel Kv1.5 blocker: A “foot in the door” against atrial fibrillation.Mol Pharmacol 2006;70:1204-1211.

43. Gogelein H, Brendel J, Steinmeyer K, Strubing C, Picard N, RampeD, Kopp K, Busch AE, Bleich M: Effects of the atrial antiarrhythmicdrug AVE0118 on cardiac ion channels. Naunyn Schmiedebergs ArchPharmacol 2004;370:183-192.

44. Persson F, Carlsson L, Duker G, Jacobson I: Blocking characteristics ofhKv1.5 and hKv4.3/hKChIP2.2 after administration of the novel antiar-rhythmic compound AZD7009. J Cardiovasc Pharmacol 2005;46:7-17.

45. Persson F, Carlsson L, Duker G, Jacobson I: Blocking characteristicsof hERG, hNav1.5, and hKvLQT1/hminK after administration of thenovel anti-arrhythmic compound AZD7009. J Cardiovasc Electrophys-iol 2005;16:329-341.

46. Persson F, Andersson B, Duker G, Jacobson I, Carlsson L: Functionaleffects of the late sodium current inhibition by AZD7009 and lidocainein rabbit isolated atrial and ventricular tissue and Purkinje fibre. Eur JPharmacol 2007;558:133-143.

47. Fedida D: Vernakalant (RSD1235): A novel, atrial-selective antifibril-latory agent. Expert Opin Investig Drugs 2007;16:519-532.

48. Schotten U, de Haan S, Verheule S, Harks EG, Frechen D, BodewigE, Greiser M, Ram R, Maessen J, Kelm M, Allessie M, Van WagonerDR: Blockade of atrial-specific K+-currents increases atrial but not ven-tricular contractility by enhancing reverse mode Na+/Ca2+-exchange.Cardiovasc Res 2007;73:37-47.

49. Naccarelli GV, Wolbrette DL, Samii S, Banchs JE, Penny-PetersonE, Gonzalez MD: New antiarrhythmic treatment of atrial fibrillation.Expert Rev Cardiovasc Ther 2007;5:707-714.

50. Bode F, Sachs F, Franz MR: Tarantula peptide inhibits atrial fibrillation.Nature 2001;409:35-36.

51. Singh BN, Sarma JS: Mechanisms of action of antiarrhythmic drugs rel-ative to the origin and perpetuation of cardiac arrhythmias. J CardiovascPharmacol Ther 2001;6:69-87.

52. Castro A, Bianconi L, Santini M: New antiarrhythmic drugs for thetreatment of atrial fibrillation. Pacing Clin Electrophysiol 2002;25:249-259.

53. Khan MH: Oral class III antiarrhythmics: What is new? Curr OpinCardiol 2004;19:47-51.

54. Singh S: Trials of new antiarrhythmic drugs for maintenance of sinusrhythm in patients with atrial fibrillation. J Interv Card Electrophysiol2004;10(Suppl 1):71-76.

55. Kathofer S, Thomas D, Karle CA: The novel antiarrhythmic drugdronedarone: Comparison with amiodarone. Cardiovasc Drug Rev2005;23:217-230.

56. Doggrell SA: Tedisamil: Master switch of nature? Expert Opin InvestigDrugs 2001;10:129-138.

57. Dhein S, Larsen BD, Petersen JS, Mohr FW: Effects of the new an-tiarrhythmic peptide ZP123 on epicardial activation and repolarizationpattern. Cell Commun Adhes 2003;10:371-378.

58. Clarke TC, Thomas D, Petersen JS, Evans WH, Martin PE: The an-tiarrhythmic peptide rotigaptide (ZP123) increases gap junction inter-cellular communication in cardiac myocytes and HeLa cells expressingconnexin43. Br J Pharmacol 2006;147:486-495.

59. Stahlhut M, Petersen JS, Hennan JK, Ramirez MT: The antiarrhyth-mic peptide rotigaptide (ZP123) increases connexin43 protein expres-sion in neonatal rat ventricular cardiomyocytes. Cell Commun Adhes2006;13:21-27.

60. Axelsen LN, Stahlhut M, Mohammed S, Larsen BD, NielsenMS, Holstein-Rathlou NH, Andersen S, Jensen ON, Hennan JK,Kjølbye AL: Identification of ischemia-regulated phosphorylationsites in connexin43: A possible target for the antiarrhythmic pep-tide analogue rotigaptide (ZP123). J Mol Cell Cardiol 2006;40:790-798.

61. Muller A, Gottwald M, Tudyka T, Linke W, Klaus W, Dhein S: In-crease in gap junction conductance by an antiarrhythmic peptide. Eur JPharmacol 1997;327:65-72.

62. Muller A, Schaefer T, Linke W, Tudyka T, Gottwald M, Klaus W,Dhein S: Actions of the antiarrhythmic peptide AAP10 on intercel-lular coupling. Naunyn Schmiedebergs Arch Pharmacol 1997;356:76-82.

63. Weng S, Lauven M, Schaefer T, Polontchouk L, Grover R, DheinS: Pharmacological modification of gap junction coupling by anantiarrhythmic peptide via protein kinase C activation. FASEB J2002;16:1114-1116.

64. Eloff BC, Gilat E, Wan X, Rosenbaum DS: Pharmacological modu-lation of cardiac gap junctions to enhance cardiac conduction: Evi-dence supporting a novel target for antiarrhythmic therapy. Circulation2003;108:3157-3163.

65. Naccarelli GV, Wolbrette DL, Khan M, Bhatta L, Hynes J, Samii S,Luck J: Old and new antiarrhythmic drugs for converting and maintain-ing sinus rhythm in atrial fibrillation: Comparative efficacy and resultsof trials. Am J Cardiol 2003;91:15D-26D.

66. Gerstenfeld EP, Guerra P, Sparks PB, Hattori K, Lesh MD: Clinicaloutcome after radiofrequency catheter ablation of focal atrial fibrillationtriggers. J Cardiovasc Electrophysiol 2001;12:900-908.

67. Berkowitsch A, Neumann T, Kurzidim K, Reiner C, Kuniss M, SiemonG, Sperzel J, Pitschner HF: Comparison of generic health survey SF-36 and arrhythmia related symptom severity check list in relation topost-therapy AF recurrence. Europace 2003;5:351-355.

68. Erdogan A, Carlsson J, Neumann T, Berkowitsch A, Neuzner J, HammCW, Pitschner HF: Quality-of-life in patients with paroxysmal atrial fib-rillation after catheter ablation: Results of long-term follow-up. PacingClin Electrophysiol 2003;26:678-684.

69. Chen J, Hoff PI, Erga KS, Rossvoll O, Ohm OJ: A clinical study of pa-tients with and without recurrence of paroxysmal atrial fibrillation afterpulmonary vein isolation. Pacing Clin Electrophysiol 2005;28(Suppl1):S86-S89.

70. Hohnloser SH, Kuck KH, Lilienthal J: Rhythm or rate control in atrialfibrillation–Pharmacological Intervention in Atrial Fibrillation (PIAF):A randomised trial. Lancet 2000;356:1789-1794.

71. Ausma J, Wijffels M, Thone F, Wouters L, Allessie M, Borgers M:Structural changes of atrial myocardium due to sustained atrial fibrilla-tion in the goat. Circulation 1997;96:3157-3163.