- Email: [email protected]
Optimal heart failure therapy and successful cardioversion in heart failure patients with atrial fibrillation
Optimal heart failure therapy and successful cardioversion in heart failure patients with atrial fibrillation Leif-Hendrik Boldt, MD, a ,c Sascha Rolf, MD, a,c Martin Huemer, MD, a Abdul Shokor Parwani, MD, a Friedrich C. Luft, MD, PhD, b Rainer Dietz, MD, PhD, a and Wilhelm Haverkamp, MD, PhD a Berlin, Germany
Background Effectiveness, safety, and other factors associated with success of cardioversion (CV) of atrial fibrillation (AF) have not yet been evaluated in patients with reduced left ventricular ejection fraction. We studied 148 consecutive patients with left ventricular dysfunction (ejection fraction ≤45%), who underwent electrical CV for AF in our department. The patients had New York Heart Association heart failure ranging from class II to IV. The overall CV success rate was 71%. We relied on univariate and multivariate regression and sought variables influencing success rate. Conversion success did not correlate with New York Heart Association class. Instead, we found that the greatest predictor was the degree of heart failure treatment. Patients receiving β-blockers, angiotensin-converting enzyme inhibitors or angiotension receptor blockers, plus mineralocorticoid receptor blockers had the greatest chance for conversion success. Success was more likely in patients with coronary artery disease (91%) than in patients with nonischemic cardiomyopathy. Conclusions Cardioversion is a safe and effective method for the restoration of sinus rhythm in patients with AF and reduced left ventricular ejection fraction. Our findings underscore the value of aggressive heart failure treatment before CV in patients with AF. (Am Heart J 2008;155:890-5.)
Atrial fibrillation (AF) is the most common sustained arrhythmia in man. The prevalence increases with age and concomitant structural heart disease. The lifetime risk of developing AF is approximately 25% for men and women N40 years old.1 Left ventricular systolic dysfunction is an independent risk factor for AF,2 and the prevalence is inversely correlated with left ventricular function.3 Thus, patients with mild heart failure with a class I New York Heart Association (NYHA) functional class have an AF prevalence of 5%; those with class IV NYHA heart failure have an AF prevalence N50%. Numerous illnesses independently predispose to AF, including hypertension, diabetes mellitus, coronary artery disease, hyperthyroidism, and valvular heart disease. Whether AF is associated with an adverse outcome in patients with reduced left ventricular function is controversial.4-6 However, restoration of sinus rhythm improves left ventricular function, exercise tolerance, and quality of life, more than does adequate AF From the aDepartment of Cardiology, Charité–Campus Virchow Clinic, Berlin, Germany, and bExperimental and Clinical Research Center, MDC, Berlin, Germany. c
Drs Boldt and Rolf contributed equally to this work. Submitted May 10, 2007; accepted December 15, 2007. Reprint requests: Leif-Hendrik Boldt, MD, Department of Cardiology, Charité – Campus Virchow Clinic, Augustenburger Platz 1, 13553 Berlin, Germany. E-mail: [email protected] 0002-8703/$ - see front matter © 2008, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2007.12.015
rate control.7,8,12 Atrial fibrillation can lead to clinical and hemodynamic deterioration, particularly in patients with marginal left ventricular function. In these patients, as well as in patients with symptomatic AF, electrical cardioversion (CV) is the treatment of choice to restore normal sinus rhythm. However, successful CV is not always possible. The aim of our study was to identify factors associated with success, as well as to evaluate their safety and effectiveness.
Methods Subjects We studied 148 consecutive patients with left ventricular dysfunction (ejection fraction ≤45%), who underwent electrical CV for AF in our department. The patients were specifically referred for CVof symptomatic AF. Only patients with N24 hours AF were included in the analysis. Patients with atrial flutter or arrhythmias other than AF were excluded. We interpreted the 12-lead electrocardiogram to establish the cardiac rhythm. We focused on the medications, clinical findings, echocardiographic parameters, and laboratory data at the time of direct current shock. Duration of the index AF episode was determined as precisely as possible by a review of either electrocardiogram recordings, Holter recordings or by patient history. For AF episodes lasting b1 month, only the exact date of conversion to AF was accepted for analysis. For episodes lasting between 1 and 6 months, an accuracy of ±1 week was accepted. For episodes lasting longer than 6 months, an accuracy of ±1 month was accepted.
American Heart Journal Volume 155, Number 5
Boldt et al 891
Table I. Patient characteristics and medication are given (univariate analysis)
Clinical characteristics Age (y) Sex (% male/female) (n) NYHA functional class Body mass index Duration of Current AF episode (m) Acute decompensation (% [n]) Arterial hypertension (% [n]) Left ventricular hypertrophy (% [n]) Ischemic cardiomyopathy (% [n]) History of myocardial infarction (% [n]) Nonischemic cardiomyopathy (% [n]) Renal failure (% [n]) Hyperthreosis (% [n]) Hypothyreosis (% [n]) Diabetes mellitus (% [n]) Dyslipidemia (% [n]) Medication β-Blocker (% [n]) ACE inhibitor (% [n]) Aldosterone-antagonist (% [n]) Diuretic (% [n]) ARB (% [n]) Digitalis (% [n]) Calcium-channel blocker (% [n]) Amiodarone (% [n])
Total group (n = 148)
Successful cardioversion (n = 105)
Unsuccessful attempt (n = 43)
67 ± 12 (30-89) 70/30 (104/44) I, 20%; II, 30%; III, 34%; IV, 16% 27.8 ± 5.2 (16.5-46.9) 2.0 ± 6.0 (0.02-36)
68 ± 12 (30-89) 68/32 (71/34) I, 14%; II, 37%; III, 40%; IV, 9% 27.3 ± 5.0 (16.5-46.9) 1.3 ± 4.2 (0.03-36)
65 ± 12 (33-84) 77/23 (33/10) I, 21%; II, 28%; III, 35%; IV, 16% 29.0 ± 5.8 (22.5-44.3) 4.1 ± 8.9 (0.02-36)
34 (51) 81 (120) 43 (63) 59 (87) 28 (41)
33 85 44 81 29
41 (61)
(35) (89) (46) (70) (30)
37 72 40 19 26
P
.127 .270 .335 .099 .016
(16) (31) (17) (17) (11)
.652 .074 .633 .002 .712
33 (35)
61 (26)
.026
44 (65) 6 (9) 9 (14) 31 (46) 45 (66)
48 8 9 35 49
(50) (8) (9) (37) (51)
35 (15) 2 (1) 12 (5) 21 (9) 35 (15)
.156 .221 .564 .088 .128
77 (114) 64 (94) 27 (40) 63 (93) 9 (14) 16 (23) 9 (13) 18 (27)
86 72 33 67 9 18 9 18
(90) (76) (35) (70) (9) (19) (9) (19)
56 (24) 42 (18) 12 (5) 54 (23) 12 (5) 9 (4) 9 (4) 19 (8)
.0001 .0001 .007 .132 .564 .180 .887 .942
P values b.05 are printed in bold.
Only those medications were included in the analysis that had been ingested for at least 2 weeks. Our institutional review board approved the study, and all patients gave their written informed consent for data acquisition, analysis, and publication. We evaluated all patients with transesophageal echocardiography before CV to rule out an atrial thrombus. We used a standard CV protocol that included adhesive pads with anterior-posterior electrode position and a biphasic shock waveform with up to 3 CV attempts at 100, 200, and 300 J. Patients were sedated with a combination of midazolam and etomidate. A Medtronic LIFEPAK 12 (Medtronic Emergency Response Systems, Redmont, WA) was used as cardioverting device. Successful CV was defined as maintenance of sinus rhythm for at least 24 hours after energy application. After CV, we continued oral anticoagulation with coumarin derivates.
forward model to adjust for potential confounders. Results are given as odds ratios (OR) with 95% CI. Values N1 are in favor of successful CV. We analyzed the effects of heart failure therapy on the chances for successful CV by classifying the patients numerically as follows: (1) “no treatment” for those patients who received no β-blocker (BBL), no angiotensin-converting enzyme (ACE) inhibitor, no angiotensin AT1 receptor blocker (ARB), and no mineralocorticoid receptor (MR) antagonist; (2) “monotherapy” for those patients receiving a BBL, an ACE inhibitor, or an ARB; (3) “dual therapy” for those patients receiving a BBL with an ACE inhibitor or an ARB; and (4) “triple therapy” for those patients receiving a BBL with either an ACE inhibitor or an ARB plus an MR antagonist. For this analysis, we used a 1-way analysis of variance with Bonferroni test. A P value of b.05 was considered statistically significant. Statistical analysis was performed with SPSS for Windows Version 14.0 (SPSS, Chicago, IL).
Statistical analysis We report continuous variables as mean ± SD and range (minimum-maximum) when distributed normally or as median with quintiles and range when the distribution was skewed. Categorical variables are presented as percentages. We compared quantitative variables between groups with a 2-tailed t test after appropriate adjustment. We used χ2 test or Fisher exact test, as appropriate, for qualitative variables, either categorical or ordered. We relied on a univariate analysis or further analyses with stepwise, multivariate binary logistic regression, using a
Results Patient characteristics The patients were aged 67 ± 12 years with a mean left ventricular ejection fraction of 32% (range 15-45%). A third were women. The median AF duration was 2 months. Almost 12% of the patients had received no heart failure treatment. A BBL was prescribed for 77% of the patients, 73% received an ACE inhibitor or ARB,
American Heart Journal May 2008
892 Boldt et al
Table II. Echocardiographic and laboratory parameters are given (univariate analysis)
Echocardiographic parameters Left ventricular ejection fraction (%) Left atrial diameter (mm) Left ventricular end diastolic diameter (mm) Thickness of interventricular septum (mm) Laboratory parameters Serum potassium (mmol/L) Serum sodium (mmol/L) Serum creatinine (mg/dL) Serum troponin (μg/L) CRP (mg/dL) Creatine kinase (U/L) TSH (mU/L)
Total group
Successful cardioversion (n = 105)
Unsuccessful attempt (n = 43)
P
32 ± 9 (15-45) 48 ± 5 (33-61) 56 ± 8 (35-82) 12 ± 3 (7-18)
31 ± 9 (15-45) 48 ± 5 (33-58) 57 ± 8 (40-82) 12 ± 3 (7-18)
34 ± 8 (20-45) 47 ± 6 (36-61) 55 ± 8 (35-70) 12 ± 2 (8-16)
.028 .440 .128 .536
4.2 ± 0.7 (3.0-6.0) 138 ± 3 (129-145) 1.2 ± 0.4 (0.78-2.59) 0.4 ± 0.9 (0.01-3.72) 2.4 ± 3.8 (0.13-17.54) 217 ± 586 (14-3832) 2.4 ± 2.5 (0.22-12.52)
.291 .207 .304 .304 .324 .251 .367
4.3 ± 0.7 (2.5-8.1) 138 ± 4 (126-146) 1.28 ± 0.61 (0.64-6.20) 0.18 ± 0.52 (0.01-3.72) 1.98 ± 3.09 (0.04-17.54) 120 ± 329 (13-3832) 2.16 ± 2.21 (0.01-12.92)
4.3 ± 0.7 (2.5-8.1) 137 ± 4 (126-146) 1.3 ± 0.7 (0.64-6.20) 0.1 ± 0.2 (0.01-1.3) 1.8 ± 2.8 (0.04-13.49) 80 ± 79 (13-531) 2.1 ± 2.1 (0.01-12.92)
CRP, C-reactive protein; TSH, thyroid-stimulating hormone. P values b.05 are printed in bold.
and 27% received a MR antagonist. Almost 12% received the BBL as their sole treatment form, 10% received only an ACE inhibitor or ARB, 41% received dual therapy, and 19% were given triple therapy. Almost two thirds of the patients had NYHA class II to III heart failure, whereas 16% had class IV heart failure. Urgent CV referral was the case for 34% of patients. In those patients, the AF was considered responsible for their acute heart failure deterioration. The conversion success for these patients was no worse than for patients referred electively. Cardiac ischemia was responsible for 59% of heart failure, whereas 41% were considered of nonischemic origin. The latter group included 16% with dilative cardiomyopathy, 15% with hypertensive heart disease, and 5% with valvular heart disease. In 4% of patients, the heart failure was believed to have resulted from chronic tachycardia. Demographic and medication data are supplied in Table I. Echocardiographic and pertinent laboratory values are given in Table II.
Factors associated with successful CV We successfully converted 105 (71%) of 148 patients to sinus rhythm for at least 24 h. No adverse events, such as thromboembolism, worsened heart failure, or acute respiratory failure, were observed. In the univariate analysis, duration of the index AF episode (P = .016); genesis of left ventricular dysfunction (ischemic vs nonischemic, P = .002); and pretreatment with a BBL (P = .0001), an ACE inhibitor or ARB (P = .0001), and an MR antagonist (P = .007) were associated with better CV rates. Patients treated with a diuretic, digitalis, or amiodarone had no better CV results, compared with patients without such treatment (P = .17, P = .17, and P = .96, respectively). Left ventricular ejection fraction was also associated with successful CV. Patients who were successfully cardio-
verted actually had a slightly lower ejection fraction, compared to patients with an unsuccessful attempt (31% vs 34%, P = .028). Neither NYHA functional class nor left atrial diameter had an effect on a successful CV (P = .335 and P = .44, respectively). In the multivariate analysis, pretreatment with an ACE inhibitor or ARB and a BBL was independently associated with successful CV (OR 3.39, 95% CI 1.23-9.38, P = .02 and OR 5.55, 95% CI 1.99-15.54, P = .001, respectively). Duration of the index AF episode was associated with lower success CV rates (OR 0.92 for each month of duration of the index AF episode, 95% CI 0.84-0.99, P = .037). Patients with ischemic origin of left ventricular dysfunction were more often successfully cardioverted than patients with left ventricular dysfunction of nonischemic origin (81% vs 57%, OR 2.7, 95% CI 1.01-7.13, P = .047). We found no significant differences regarding heart failure medication, left atrial diameter, left ventricular ejection fraction, or duration of current AF episode, respectively, in the patients with nonischemic cardiomyopathy. Results of the multivariate analysis are shown in Figure 1. Patients pretreated with a combination of a BBL and an ACE inhibitor or ARB (dual heart failure therapy) were more often successfully cardioverted than were patients without any heart failure treatment or those solely receiving a BBL (80% vs 29% vs 47%, P = .001 and P = .039, respectively). Patients given triple treatment had the highest CV success rate (93%, P = .001 compared with no heart failure treatment and P = .004 compared with BBL treatment only), as shown in Figure 2.
Discussion We found that patients who were taking a combination therapy with a BBL, an ACE inhibitor or ARB, and an MR antagonist, a combination often called “optimal
American Heart Journal Volume 155, Number 5
Figure 1
Predictors of successful CV (multivariate analysis with adjusted odds ratios) are shown. HF, Heart failure.
pharmacological therapy” in large heart failure trials, had the highest CV success rates. Furthermore, our patients who were taking all 3 drugs were significantly more often successfully cardioverted, compared to patients who were not receiving heart failure medications, or who were only treated with a BBL. The success rate of CV in patients receiving optimal heart failure therapy was 93% in our study. This rate is in the range of success rates reported for patients with structurally normal hearts. The genesis of left ventricular dysfunction was also independently associated with success of CV. Patients with nonischemic cardiomyopathy were significantly less often successfully cardioverted, compared with patients who had heart failure related to coronary artery disease. To the best of our knowledge, no prior study has reported such a relationship, and we can only speculate about the possible explanations. In our patient collective, there was no difference between patients with ischemic and nonischemic heart failure in terms of left ventricular ejection fraction, left atrial size, duration of AF, valvular dysfunction (notably mitral insufficiency), or heart failure treatment. Possibly, the cardiac remodeling process and, therefore, also the atrial remodeling process, is more pronounced in patients with non-ischemic heart failure. This explanation is supported by De Ferrari et al.9 In their study, the prevalence of AF varied significantly between patients with nonischemic and ischemic heart failure. Patients with nonischemic cardiomyopathy had a 28% prevalence of AF, which was more than twice that for coronary artery disease patients (OR 2.34, P b .001). Our finding that successful CV is related to the duration of the index AF episode agrees with data from earlier trials.11,13 We were initially surprised to find that successfully cardioverted patients had a (slightly) lower mean left ventricular ejection fraction compared to those patients who could not be successfully cardioverted. We explain this state of affairs by the fact that
Boldt et al 893
Figure 2
We show the success of cardioversion according to heart failure treatment before cardioversion. P values are given according to Bonferroni test. ACE-I, ACE inhibitor.
these patients were more often already receiving optimal heart failure therapy. Two basic approaches are currently available for the management of AF. One approach accepts AF and focuses on controlling the ventricular response (rate control). Another approach is rhythm control, which attempts to restore and maintain sinus rhythm. Large prospective trials could not demonstrate that one approach is superior to the other.14,20 Restoration of sinus rhythm improves exercise tolerance, quality of life, and left ventricular ejection fraction.7,8,12 However, these advantages are possibly offset by the side-effect risk of drugs used to maintain sinus rhythm.10 Atrial fibrillation can lead to clinical and hemodynamic deterioration particularly in heart failure patients, in some cases, even irrespective of ventricular rate. In these patients, as well as in patients with symptomatic AF, CV is the treatment of choice to restore normal sinus rhythm. Cardioversion has been shown to be a safe and effective procedure for patients with echocardiographically otherwise normal hearts. For patients with heart failure, only limited data are available regarding success rates; safety must be taken into consideration with other factors associated with success. In our study, patients with moderate to severe left ventricular dysfunction were successfully cardioverted in 71% of all cases. This value is only slightly below the range reported for patients with structurally normal hearts.11,13 There are several possible explanations for this finding. First, heart failure increases thoracic impedance, probably by thoracic volume expansion, thereby rendering CV more difficult.25 We did not observe a correlation between NYHA functional class and conversion success. New
American Heart Journal May 2008
894 Boldt et al
York Heart Association functional class is a rough indicator of thoracic volume overload and may reflect an increase in thoracic impedance. Van Gelder et al11 made the observation that NYHA functional class has no effect on the CV success rate earlier. Many mechanisms of AF underlying heart failure have been explored. Heart failure leads to atrial stretch and a complex neurohormonal activation with an increase in sympathetic tone and activation of the renin-angiotensinaldosterone system. Atrial stretch decreases the atrial effective refractory period, increases spatial dispersion of refractoriness, and leads to conduction slowing and, eventually, conduction block. All these factors contribute to the maintenance of AF. Atrial stretch is also associated with an increased arrhythmogenic activity of the pulmonary veins that are implicated in the genesis of AF.26 Sympathetic activation increases spontaneous ectopic activity, thereby favoring initiation of AF by supraventricular ectopic beats. Consequently, Van Noord et al15 found that BBL prevented subacute recurrence of AF after direct current CV. Furthermore, both angiotensin II and aldosterone are known to stimulate collagen production. This event causes not only ventricular but also atrial structural remodeling with alterations in atrial myocyte architecture and changes in atrial extracellular matrix resulting in atrial fibrosis.16 Fibrosis leads to zones of slow conduction and stabilization of reentry.17 The cardiac remodeling process in heart failure can be favorably influenced by BBL and ACE inhibitor/ARB therapy.18,19 As a matter of fact, both drug classes are associated with prevention of AF in large clinical trials.21 Van Noord et al22 as well as Zaman et al23 found that, in a general AF population, pretreatment with ACE inhibitors significantly improved the acute CV success rates. Van den Berg et al24 evaluated the effect of lisinopril in patients with heart failure and chronic AF. In their study, patients treated with lisinopril were more often in sinus rhythm at the end of the follow-up period than were patients treated with placebo. In our study, patients who received a combined BBL and ACE inhibitor/ARB therapy, plus an MR antagonist, had the highest CV success rates. The CV success rate of these optimally treated heart failure patients was 93% in our study. We are aware that our nonrandomized observational study has limitations. The medical treatment was not randomly assigned. Therefore, further evaluation by randomized, prospective trials will be needed to finally answer the question whether or not optimal heart failure treatment does in fact increase CV success rate. We cannot exclude referral bias in our study. Possibly, patients who were particularly sick were not referred for CV. Nonetheless, we believe that our patient population adequately represents a general heart failure population with AF. Conceivably, physicians were afraid of aggressively treating heart failure in these patients because of side effects, hypotensive episodes, or fear of hyperkale-
mia. However, we found no difference between patients with optimized heart failure therapy and those with suboptimal treatment regarding NYHA functional class, left ventricular ejection fraction, duration of the index AF episode, or underlying heart failure causes. Finally, we cannot state for certain how long heart failure therapy must be in place so that CV success chances are optimized. Because the duration of the index AF episode was associated with reduced CV success rates, question of heart failure treatment duration for an optimal result remains unclear.
Conclusion Cardioversion is a generally safe and effective procedure to restore sinus rhythm in patients with AF with moderate to severely reduced left ventricular function. Optimized pharmacologic heart failure treatment in AF patients is associated with higher CV success rates. Whenever possible, patients with heart failure and AF should be receiving an optimal pharmacologic heart failure therapy before CV is attempted, particularly in the face of coronary artery disease.
References 1. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004; 110:1042-6. 2. Kannel WB, Wolf PA, Benjamin EJ, et al. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82:2N-9N. 3. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003;91:2D-8D. 4. Dries DL, Exner DV, Gersh BJ, et al. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD Trials. J Am Coll Cardiol 1998;32:695-703. 5. Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advanced heart failure: a study of 390 patients. Circulation 1991;84:40-8. 6. Crijns HJ, Tjeerdsma G, de Kam PJ, et al. Prognostic value of the presence and development of atrial fibrillation in patients with advanced chronic heart failure. Eur Heart J 2000;21:1238-45. 7. Wozakowska-Kaplon B, Opolski G. Effects of sinus rhythm restoration in patients with persistent atrial fibrillation: a clinical, echocardiographic and hormonal study. Int J Cardiol 2004;96:171-6. 8. Hagens VE, Van Veldhuisen DJ, Kamp O, et al. Effect of rate and rhythm control on left ventricular function and cardiac dimensions in patients with persistent atrial fibrillation: results from the RAte Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study. Heart Rhythm 2005;2:19-24. 9. De Ferrari GM, Klersy C, Ferrero P, et al, for the ALPHA Study Group. Atrial fibrillation in heart failure patients: prevalence in daily practice and effect on the severity of symptoms. Data from the ALPHA study registry. Eur J Heart Fail 2007;9:502-9. 10. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. Relationship between sinus rhythm, treatment,
American Heart Journal Volume 155, Number 5
11.
12.
13.
14.
15.
16.
17.
18.
and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study. Circulation 2004;109: 1509-13. Van Gelder IC, Crijns HJ, Van Gilst WH, et al. Prediction of uneventful cardioversion and maintenance of sinus rhythm from direct-current electrical cardioversion of chronic atrial fibrillation and flutter. Am J Cardiol 1991;68:41-6. Hsu LF, Jais P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med 2004;351: 2373-83. Frick M, Frykman V, Jensen-Urstad M, et al. Factors predicting success rate and recurrence of atrial fibrillation after first electrical cardioversion in patients with persistent atrial fibrillation. Clin Cardiol 2001;24:238-44. Wyse DG, Waldo AL, DiMarco JP, et al. Comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825-33. Van Noord T, Tieleman RG, Bosker HA, et al. beta-Blockers prevent subacute recurrences of persistent atrial fibrillation only in patients with hypertension. Europace 2004;6:343-50. Cardin S, Li D, Thorin-Trescases N, et al. Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways. Cardiovasc Res 2003;60:315-25. Li D, Fareh S, Leung TK, et al. Promotion of atrial fibrillation by heart failure in dogs: atrial remodelling of a different sort. Circulation 1999;100:87-95. Greenberg B, Quinones MA, Koilpillai C, et al. Effects of longterm enalapril therapy on cardiac structure and function in patients with
Boldt et al 895
19.
20.
21.
22.
23.
24.
25.
26.
left ventricular dysfunction: results of the SOLVD echocardiography substudy. Circulation 1995;91:2573-81. Hall SA, Cigarroa CG, Marcoux L, et al. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol 1995;25:1154-61. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834-40. Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. JACC 2005;45:1832-9. Van Noord T, Crijns HJGM, van den Berg MP, et al. Pretreatment with ACE inhibitors improves acute outcome of electrical cardioversion in patients with persistent atrial fibrillation. BMC Cardiovascular Disorders 2005;5:3. Zaman AG, Kearney MT, Schecter C, et al. Angiotensin-converting enzyme inhibitors as adjunctive therapy in patients with persistent atrial fibrillation. Am Heart J 2004;147:823-7. Van Den Berg MP, Crijns HJ, Van Veldhuisen DJ, et al. Effects of lisinopril in patients with heart failure and chronic atrial fibrillation. J Card Fail 1995;1:355-63. Fumagalli S, Boni N, Padeletti M, et al. Determinants of thoracic electrical impedance in external electrical cardioversion of atrial fibrillation. Am J Cradiol 2006;98:82-7. Chang SL, Chen YC, Chen YJ, et al. Mechanoelectrical feedback regulates the arrhythmogenic activity of pulmonary veins. Heart 2007;93:82-8.
Background Effectiveness, safety, and other factors associated with success of cardioversion (CV) of atrial fibrillation (AF) have not yet been evaluated in patients with reduced left ventricular ejection fraction. We studied 148 consecutive patients with left ventricular dysfunction (ejection fraction ≤45%), who underwent electrical CV for AF in our department. The patients had New York Heart Association heart failure ranging from class II to IV. The overall CV success rate was 71%. We relied on univariate and multivariate regression and sought variables influencing success rate. Conversion success did not correlate with New York Heart Association class. Instead, we found that the greatest predictor was the degree of heart failure treatment. Patients receiving β-blockers, angiotensin-converting enzyme inhibitors or angiotension receptor blockers, plus mineralocorticoid receptor blockers had the greatest chance for conversion success. Success was more likely in patients with coronary artery disease (91%) than in patients with nonischemic cardiomyopathy. Conclusions Cardioversion is a safe and effective method for the restoration of sinus rhythm in patients with AF and reduced left ventricular ejection fraction. Our findings underscore the value of aggressive heart failure treatment before CV in patients with AF. (Am Heart J 2008;155:890-5.)
Atrial fibrillation (AF) is the most common sustained arrhythmia in man. The prevalence increases with age and concomitant structural heart disease. The lifetime risk of developing AF is approximately 25% for men and women N40 years old.1 Left ventricular systolic dysfunction is an independent risk factor for AF,2 and the prevalence is inversely correlated with left ventricular function.3 Thus, patients with mild heart failure with a class I New York Heart Association (NYHA) functional class have an AF prevalence of 5%; those with class IV NYHA heart failure have an AF prevalence N50%. Numerous illnesses independently predispose to AF, including hypertension, diabetes mellitus, coronary artery disease, hyperthyroidism, and valvular heart disease. Whether AF is associated with an adverse outcome in patients with reduced left ventricular function is controversial.4-6 However, restoration of sinus rhythm improves left ventricular function, exercise tolerance, and quality of life, more than does adequate AF From the aDepartment of Cardiology, Charité–Campus Virchow Clinic, Berlin, Germany, and bExperimental and Clinical Research Center, MDC, Berlin, Germany. c
Drs Boldt and Rolf contributed equally to this work. Submitted May 10, 2007; accepted December 15, 2007. Reprint requests: Leif-Hendrik Boldt, MD, Department of Cardiology, Charité – Campus Virchow Clinic, Augustenburger Platz 1, 13553 Berlin, Germany. E-mail: [email protected] 0002-8703/$ - see front matter © 2008, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2007.12.015
rate control.7,8,12 Atrial fibrillation can lead to clinical and hemodynamic deterioration, particularly in patients with marginal left ventricular function. In these patients, as well as in patients with symptomatic AF, electrical cardioversion (CV) is the treatment of choice to restore normal sinus rhythm. However, successful CV is not always possible. The aim of our study was to identify factors associated with success, as well as to evaluate their safety and effectiveness.
Methods Subjects We studied 148 consecutive patients with left ventricular dysfunction (ejection fraction ≤45%), who underwent electrical CV for AF in our department. The patients were specifically referred for CVof symptomatic AF. Only patients with N24 hours AF were included in the analysis. Patients with atrial flutter or arrhythmias other than AF were excluded. We interpreted the 12-lead electrocardiogram to establish the cardiac rhythm. We focused on the medications, clinical findings, echocardiographic parameters, and laboratory data at the time of direct current shock. Duration of the index AF episode was determined as precisely as possible by a review of either electrocardiogram recordings, Holter recordings or by patient history. For AF episodes lasting b1 month, only the exact date of conversion to AF was accepted for analysis. For episodes lasting between 1 and 6 months, an accuracy of ±1 week was accepted. For episodes lasting longer than 6 months, an accuracy of ±1 month was accepted.
American Heart Journal Volume 155, Number 5
Boldt et al 891
Table I. Patient characteristics and medication are given (univariate analysis)
Clinical characteristics Age (y) Sex (% male/female) (n) NYHA functional class Body mass index Duration of Current AF episode (m) Acute decompensation (% [n]) Arterial hypertension (% [n]) Left ventricular hypertrophy (% [n]) Ischemic cardiomyopathy (% [n]) History of myocardial infarction (% [n]) Nonischemic cardiomyopathy (% [n]) Renal failure (% [n]) Hyperthreosis (% [n]) Hypothyreosis (% [n]) Diabetes mellitus (% [n]) Dyslipidemia (% [n]) Medication β-Blocker (% [n]) ACE inhibitor (% [n]) Aldosterone-antagonist (% [n]) Diuretic (% [n]) ARB (% [n]) Digitalis (% [n]) Calcium-channel blocker (% [n]) Amiodarone (% [n])
Total group (n = 148)
Successful cardioversion (n = 105)
Unsuccessful attempt (n = 43)
67 ± 12 (30-89) 70/30 (104/44) I, 20%; II, 30%; III, 34%; IV, 16% 27.8 ± 5.2 (16.5-46.9) 2.0 ± 6.0 (0.02-36)
68 ± 12 (30-89) 68/32 (71/34) I, 14%; II, 37%; III, 40%; IV, 9% 27.3 ± 5.0 (16.5-46.9) 1.3 ± 4.2 (0.03-36)
65 ± 12 (33-84) 77/23 (33/10) I, 21%; II, 28%; III, 35%; IV, 16% 29.0 ± 5.8 (22.5-44.3) 4.1 ± 8.9 (0.02-36)
34 (51) 81 (120) 43 (63) 59 (87) 28 (41)
33 85 44 81 29
41 (61)
(35) (89) (46) (70) (30)
37 72 40 19 26
P
.127 .270 .335 .099 .016
(16) (31) (17) (17) (11)
.652 .074 .633 .002 .712
33 (35)
61 (26)
.026
44 (65) 6 (9) 9 (14) 31 (46) 45 (66)
48 8 9 35 49
(50) (8) (9) (37) (51)
35 (15) 2 (1) 12 (5) 21 (9) 35 (15)
.156 .221 .564 .088 .128
77 (114) 64 (94) 27 (40) 63 (93) 9 (14) 16 (23) 9 (13) 18 (27)
86 72 33 67 9 18 9 18
(90) (76) (35) (70) (9) (19) (9) (19)
56 (24) 42 (18) 12 (5) 54 (23) 12 (5) 9 (4) 9 (4) 19 (8)
.0001 .0001 .007 .132 .564 .180 .887 .942
P values b.05 are printed in bold.
Only those medications were included in the analysis that had been ingested for at least 2 weeks. Our institutional review board approved the study, and all patients gave their written informed consent for data acquisition, analysis, and publication. We evaluated all patients with transesophageal echocardiography before CV to rule out an atrial thrombus. We used a standard CV protocol that included adhesive pads with anterior-posterior electrode position and a biphasic shock waveform with up to 3 CV attempts at 100, 200, and 300 J. Patients were sedated with a combination of midazolam and etomidate. A Medtronic LIFEPAK 12 (Medtronic Emergency Response Systems, Redmont, WA) was used as cardioverting device. Successful CV was defined as maintenance of sinus rhythm for at least 24 hours after energy application. After CV, we continued oral anticoagulation with coumarin derivates.
forward model to adjust for potential confounders. Results are given as odds ratios (OR) with 95% CI. Values N1 are in favor of successful CV. We analyzed the effects of heart failure therapy on the chances for successful CV by classifying the patients numerically as follows: (1) “no treatment” for those patients who received no β-blocker (BBL), no angiotensin-converting enzyme (ACE) inhibitor, no angiotensin AT1 receptor blocker (ARB), and no mineralocorticoid receptor (MR) antagonist; (2) “monotherapy” for those patients receiving a BBL, an ACE inhibitor, or an ARB; (3) “dual therapy” for those patients receiving a BBL with an ACE inhibitor or an ARB; and (4) “triple therapy” for those patients receiving a BBL with either an ACE inhibitor or an ARB plus an MR antagonist. For this analysis, we used a 1-way analysis of variance with Bonferroni test. A P value of b.05 was considered statistically significant. Statistical analysis was performed with SPSS for Windows Version 14.0 (SPSS, Chicago, IL).
Statistical analysis We report continuous variables as mean ± SD and range (minimum-maximum) when distributed normally or as median with quintiles and range when the distribution was skewed. Categorical variables are presented as percentages. We compared quantitative variables between groups with a 2-tailed t test after appropriate adjustment. We used χ2 test or Fisher exact test, as appropriate, for qualitative variables, either categorical or ordered. We relied on a univariate analysis or further analyses with stepwise, multivariate binary logistic regression, using a
Results Patient characteristics The patients were aged 67 ± 12 years with a mean left ventricular ejection fraction of 32% (range 15-45%). A third were women. The median AF duration was 2 months. Almost 12% of the patients had received no heart failure treatment. A BBL was prescribed for 77% of the patients, 73% received an ACE inhibitor or ARB,
American Heart Journal May 2008
892 Boldt et al
Table II. Echocardiographic and laboratory parameters are given (univariate analysis)
Echocardiographic parameters Left ventricular ejection fraction (%) Left atrial diameter (mm) Left ventricular end diastolic diameter (mm) Thickness of interventricular septum (mm) Laboratory parameters Serum potassium (mmol/L) Serum sodium (mmol/L) Serum creatinine (mg/dL) Serum troponin (μg/L) CRP (mg/dL) Creatine kinase (U/L) TSH (mU/L)
Total group
Successful cardioversion (n = 105)
Unsuccessful attempt (n = 43)
P
32 ± 9 (15-45) 48 ± 5 (33-61) 56 ± 8 (35-82) 12 ± 3 (7-18)
31 ± 9 (15-45) 48 ± 5 (33-58) 57 ± 8 (40-82) 12 ± 3 (7-18)
34 ± 8 (20-45) 47 ± 6 (36-61) 55 ± 8 (35-70) 12 ± 2 (8-16)
.028 .440 .128 .536
4.2 ± 0.7 (3.0-6.0) 138 ± 3 (129-145) 1.2 ± 0.4 (0.78-2.59) 0.4 ± 0.9 (0.01-3.72) 2.4 ± 3.8 (0.13-17.54) 217 ± 586 (14-3832) 2.4 ± 2.5 (0.22-12.52)
.291 .207 .304 .304 .324 .251 .367
4.3 ± 0.7 (2.5-8.1) 138 ± 4 (126-146) 1.28 ± 0.61 (0.64-6.20) 0.18 ± 0.52 (0.01-3.72) 1.98 ± 3.09 (0.04-17.54) 120 ± 329 (13-3832) 2.16 ± 2.21 (0.01-12.92)
4.3 ± 0.7 (2.5-8.1) 137 ± 4 (126-146) 1.3 ± 0.7 (0.64-6.20) 0.1 ± 0.2 (0.01-1.3) 1.8 ± 2.8 (0.04-13.49) 80 ± 79 (13-531) 2.1 ± 2.1 (0.01-12.92)
CRP, C-reactive protein; TSH, thyroid-stimulating hormone. P values b.05 are printed in bold.
and 27% received a MR antagonist. Almost 12% received the BBL as their sole treatment form, 10% received only an ACE inhibitor or ARB, 41% received dual therapy, and 19% were given triple therapy. Almost two thirds of the patients had NYHA class II to III heart failure, whereas 16% had class IV heart failure. Urgent CV referral was the case for 34% of patients. In those patients, the AF was considered responsible for their acute heart failure deterioration. The conversion success for these patients was no worse than for patients referred electively. Cardiac ischemia was responsible for 59% of heart failure, whereas 41% were considered of nonischemic origin. The latter group included 16% with dilative cardiomyopathy, 15% with hypertensive heart disease, and 5% with valvular heart disease. In 4% of patients, the heart failure was believed to have resulted from chronic tachycardia. Demographic and medication data are supplied in Table I. Echocardiographic and pertinent laboratory values are given in Table II.
Factors associated with successful CV We successfully converted 105 (71%) of 148 patients to sinus rhythm for at least 24 h. No adverse events, such as thromboembolism, worsened heart failure, or acute respiratory failure, were observed. In the univariate analysis, duration of the index AF episode (P = .016); genesis of left ventricular dysfunction (ischemic vs nonischemic, P = .002); and pretreatment with a BBL (P = .0001), an ACE inhibitor or ARB (P = .0001), and an MR antagonist (P = .007) were associated with better CV rates. Patients treated with a diuretic, digitalis, or amiodarone had no better CV results, compared with patients without such treatment (P = .17, P = .17, and P = .96, respectively). Left ventricular ejection fraction was also associated with successful CV. Patients who were successfully cardio-
verted actually had a slightly lower ejection fraction, compared to patients with an unsuccessful attempt (31% vs 34%, P = .028). Neither NYHA functional class nor left atrial diameter had an effect on a successful CV (P = .335 and P = .44, respectively). In the multivariate analysis, pretreatment with an ACE inhibitor or ARB and a BBL was independently associated with successful CV (OR 3.39, 95% CI 1.23-9.38, P = .02 and OR 5.55, 95% CI 1.99-15.54, P = .001, respectively). Duration of the index AF episode was associated with lower success CV rates (OR 0.92 for each month of duration of the index AF episode, 95% CI 0.84-0.99, P = .037). Patients with ischemic origin of left ventricular dysfunction were more often successfully cardioverted than patients with left ventricular dysfunction of nonischemic origin (81% vs 57%, OR 2.7, 95% CI 1.01-7.13, P = .047). We found no significant differences regarding heart failure medication, left atrial diameter, left ventricular ejection fraction, or duration of current AF episode, respectively, in the patients with nonischemic cardiomyopathy. Results of the multivariate analysis are shown in Figure 1. Patients pretreated with a combination of a BBL and an ACE inhibitor or ARB (dual heart failure therapy) were more often successfully cardioverted than were patients without any heart failure treatment or those solely receiving a BBL (80% vs 29% vs 47%, P = .001 and P = .039, respectively). Patients given triple treatment had the highest CV success rate (93%, P = .001 compared with no heart failure treatment and P = .004 compared with BBL treatment only), as shown in Figure 2.
Discussion We found that patients who were taking a combination therapy with a BBL, an ACE inhibitor or ARB, and an MR antagonist, a combination often called “optimal
American Heart Journal Volume 155, Number 5
Figure 1
Predictors of successful CV (multivariate analysis with adjusted odds ratios) are shown. HF, Heart failure.
pharmacological therapy” in large heart failure trials, had the highest CV success rates. Furthermore, our patients who were taking all 3 drugs were significantly more often successfully cardioverted, compared to patients who were not receiving heart failure medications, or who were only treated with a BBL. The success rate of CV in patients receiving optimal heart failure therapy was 93% in our study. This rate is in the range of success rates reported for patients with structurally normal hearts. The genesis of left ventricular dysfunction was also independently associated with success of CV. Patients with nonischemic cardiomyopathy were significantly less often successfully cardioverted, compared with patients who had heart failure related to coronary artery disease. To the best of our knowledge, no prior study has reported such a relationship, and we can only speculate about the possible explanations. In our patient collective, there was no difference between patients with ischemic and nonischemic heart failure in terms of left ventricular ejection fraction, left atrial size, duration of AF, valvular dysfunction (notably mitral insufficiency), or heart failure treatment. Possibly, the cardiac remodeling process and, therefore, also the atrial remodeling process, is more pronounced in patients with non-ischemic heart failure. This explanation is supported by De Ferrari et al.9 In their study, the prevalence of AF varied significantly between patients with nonischemic and ischemic heart failure. Patients with nonischemic cardiomyopathy had a 28% prevalence of AF, which was more than twice that for coronary artery disease patients (OR 2.34, P b .001). Our finding that successful CV is related to the duration of the index AF episode agrees with data from earlier trials.11,13 We were initially surprised to find that successfully cardioverted patients had a (slightly) lower mean left ventricular ejection fraction compared to those patients who could not be successfully cardioverted. We explain this state of affairs by the fact that
Boldt et al 893
Figure 2
We show the success of cardioversion according to heart failure treatment before cardioversion. P values are given according to Bonferroni test. ACE-I, ACE inhibitor.
these patients were more often already receiving optimal heart failure therapy. Two basic approaches are currently available for the management of AF. One approach accepts AF and focuses on controlling the ventricular response (rate control). Another approach is rhythm control, which attempts to restore and maintain sinus rhythm. Large prospective trials could not demonstrate that one approach is superior to the other.14,20 Restoration of sinus rhythm improves exercise tolerance, quality of life, and left ventricular ejection fraction.7,8,12 However, these advantages are possibly offset by the side-effect risk of drugs used to maintain sinus rhythm.10 Atrial fibrillation can lead to clinical and hemodynamic deterioration particularly in heart failure patients, in some cases, even irrespective of ventricular rate. In these patients, as well as in patients with symptomatic AF, CV is the treatment of choice to restore normal sinus rhythm. Cardioversion has been shown to be a safe and effective procedure for patients with echocardiographically otherwise normal hearts. For patients with heart failure, only limited data are available regarding success rates; safety must be taken into consideration with other factors associated with success. In our study, patients with moderate to severe left ventricular dysfunction were successfully cardioverted in 71% of all cases. This value is only slightly below the range reported for patients with structurally normal hearts.11,13 There are several possible explanations for this finding. First, heart failure increases thoracic impedance, probably by thoracic volume expansion, thereby rendering CV more difficult.25 We did not observe a correlation between NYHA functional class and conversion success. New
American Heart Journal May 2008
894 Boldt et al
York Heart Association functional class is a rough indicator of thoracic volume overload and may reflect an increase in thoracic impedance. Van Gelder et al11 made the observation that NYHA functional class has no effect on the CV success rate earlier. Many mechanisms of AF underlying heart failure have been explored. Heart failure leads to atrial stretch and a complex neurohormonal activation with an increase in sympathetic tone and activation of the renin-angiotensinaldosterone system. Atrial stretch decreases the atrial effective refractory period, increases spatial dispersion of refractoriness, and leads to conduction slowing and, eventually, conduction block. All these factors contribute to the maintenance of AF. Atrial stretch is also associated with an increased arrhythmogenic activity of the pulmonary veins that are implicated in the genesis of AF.26 Sympathetic activation increases spontaneous ectopic activity, thereby favoring initiation of AF by supraventricular ectopic beats. Consequently, Van Noord et al15 found that BBL prevented subacute recurrence of AF after direct current CV. Furthermore, both angiotensin II and aldosterone are known to stimulate collagen production. This event causes not only ventricular but also atrial structural remodeling with alterations in atrial myocyte architecture and changes in atrial extracellular matrix resulting in atrial fibrosis.16 Fibrosis leads to zones of slow conduction and stabilization of reentry.17 The cardiac remodeling process in heart failure can be favorably influenced by BBL and ACE inhibitor/ARB therapy.18,19 As a matter of fact, both drug classes are associated with prevention of AF in large clinical trials.21 Van Noord et al22 as well as Zaman et al23 found that, in a general AF population, pretreatment with ACE inhibitors significantly improved the acute CV success rates. Van den Berg et al24 evaluated the effect of lisinopril in patients with heart failure and chronic AF. In their study, patients treated with lisinopril were more often in sinus rhythm at the end of the follow-up period than were patients treated with placebo. In our study, patients who received a combined BBL and ACE inhibitor/ARB therapy, plus an MR antagonist, had the highest CV success rates. The CV success rate of these optimally treated heart failure patients was 93% in our study. We are aware that our nonrandomized observational study has limitations. The medical treatment was not randomly assigned. Therefore, further evaluation by randomized, prospective trials will be needed to finally answer the question whether or not optimal heart failure treatment does in fact increase CV success rate. We cannot exclude referral bias in our study. Possibly, patients who were particularly sick were not referred for CV. Nonetheless, we believe that our patient population adequately represents a general heart failure population with AF. Conceivably, physicians were afraid of aggressively treating heart failure in these patients because of side effects, hypotensive episodes, or fear of hyperkale-
mia. However, we found no difference between patients with optimized heart failure therapy and those with suboptimal treatment regarding NYHA functional class, left ventricular ejection fraction, duration of the index AF episode, or underlying heart failure causes. Finally, we cannot state for certain how long heart failure therapy must be in place so that CV success chances are optimized. Because the duration of the index AF episode was associated with reduced CV success rates, question of heart failure treatment duration for an optimal result remains unclear.
Conclusion Cardioversion is a generally safe and effective procedure to restore sinus rhythm in patients with AF with moderate to severely reduced left ventricular function. Optimized pharmacologic heart failure treatment in AF patients is associated with higher CV success rates. Whenever possible, patients with heart failure and AF should be receiving an optimal pharmacologic heart failure therapy before CV is attempted, particularly in the face of coronary artery disease.
References 1. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004; 110:1042-6. 2. Kannel WB, Wolf PA, Benjamin EJ, et al. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82:2N-9N. 3. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003;91:2D-8D. 4. Dries DL, Exner DV, Gersh BJ, et al. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD Trials. J Am Coll Cardiol 1998;32:695-703. 5. Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advanced heart failure: a study of 390 patients. Circulation 1991;84:40-8. 6. Crijns HJ, Tjeerdsma G, de Kam PJ, et al. Prognostic value of the presence and development of atrial fibrillation in patients with advanced chronic heart failure. Eur Heart J 2000;21:1238-45. 7. Wozakowska-Kaplon B, Opolski G. Effects of sinus rhythm restoration in patients with persistent atrial fibrillation: a clinical, echocardiographic and hormonal study. Int J Cardiol 2004;96:171-6. 8. Hagens VE, Van Veldhuisen DJ, Kamp O, et al. Effect of rate and rhythm control on left ventricular function and cardiac dimensions in patients with persistent atrial fibrillation: results from the RAte Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study. Heart Rhythm 2005;2:19-24. 9. De Ferrari GM, Klersy C, Ferrero P, et al, for the ALPHA Study Group. Atrial fibrillation in heart failure patients: prevalence in daily practice and effect on the severity of symptoms. Data from the ALPHA study registry. Eur J Heart Fail 2007;9:502-9. 10. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. Relationship between sinus rhythm, treatment,
American Heart Journal Volume 155, Number 5
11.
12.
13.
14.
15.
16.
17.
18.
and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study. Circulation 2004;109: 1509-13. Van Gelder IC, Crijns HJ, Van Gilst WH, et al. Prediction of uneventful cardioversion and maintenance of sinus rhythm from direct-current electrical cardioversion of chronic atrial fibrillation and flutter. Am J Cardiol 1991;68:41-6. Hsu LF, Jais P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med 2004;351: 2373-83. Frick M, Frykman V, Jensen-Urstad M, et al. Factors predicting success rate and recurrence of atrial fibrillation after first electrical cardioversion in patients with persistent atrial fibrillation. Clin Cardiol 2001;24:238-44. Wyse DG, Waldo AL, DiMarco JP, et al. Comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825-33. Van Noord T, Tieleman RG, Bosker HA, et al. beta-Blockers prevent subacute recurrences of persistent atrial fibrillation only in patients with hypertension. Europace 2004;6:343-50. Cardin S, Li D, Thorin-Trescases N, et al. Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways. Cardiovasc Res 2003;60:315-25. Li D, Fareh S, Leung TK, et al. Promotion of atrial fibrillation by heart failure in dogs: atrial remodelling of a different sort. Circulation 1999;100:87-95. Greenberg B, Quinones MA, Koilpillai C, et al. Effects of longterm enalapril therapy on cardiac structure and function in patients with
Boldt et al 895
19.
20.
21.
22.
23.
24.
25.
26.
left ventricular dysfunction: results of the SOLVD echocardiography substudy. Circulation 1995;91:2573-81. Hall SA, Cigarroa CG, Marcoux L, et al. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol 1995;25:1154-61. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834-40. Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. JACC 2005;45:1832-9. Van Noord T, Crijns HJGM, van den Berg MP, et al. Pretreatment with ACE inhibitors improves acute outcome of electrical cardioversion in patients with persistent atrial fibrillation. BMC Cardiovascular Disorders 2005;5:3. Zaman AG, Kearney MT, Schecter C, et al. Angiotensin-converting enzyme inhibitors as adjunctive therapy in patients with persistent atrial fibrillation. Am Heart J 2004;147:823-7. Van Den Berg MP, Crijns HJ, Van Veldhuisen DJ, et al. Effects of lisinopril in patients with heart failure and chronic atrial fibrillation. J Card Fail 1995;1:355-63. Fumagalli S, Boni N, Padeletti M, et al. Determinants of thoracic electrical impedance in external electrical cardioversion of atrial fibrillation. Am J Cradiol 2006;98:82-7. Chang SL, Chen YC, Chen YJ, et al. Mechanoelectrical feedback regulates the arrhythmogenic activity of pulmonary veins. Heart 2007;93:82-8.