- Email: [email protected]
Role of angiotensin-converting enzyme inhibitors in the prevention of atrial fibrillation
Role of Angiotensin-Converting Enzyme Inhibitors in the Prevention of Atrial Fibrillation Dennis Finkielstein,
MD,
trial fibrillation (AF) is the most frequent sustained arrhythmia found in clinical practice. A According to the Framingham Heart Study, AF has a 1,2
prevalence of 4% in the adult population and as the patient population continues to age, the prevalence of this arrhythmia will increase from ⬍0.05% in patients 25 to 35 years of age, to ⬎5% in patients aged ⬎69 years.1 AF can be classified as paroxysmal, persistent, or chronic. Experimental studies suggest that the longer the episode of paroxysmal AF, the more likely it will become chronic. It is unique in that its existence leads to a perpetuation of duration and recurrence after treatment. Put another way, “AF begets AF.”3 It has been postulated that this phenomenon may be secondary to electrical remodeling of atrial myocardium in patients with AF.3,4 Electrical remodeling of the atrium is accomplished through a reduction in the refractory period of atrial tissue. The management of AF includes antiarrhythmic drugs, pacing, and radio frequency ablation. Some recent experimental and clinical studies suggest a role for angiotensin-converting enzyme (ACE) inhibitors in the management of AF. This is the subject of this editorial. ACE inhibitors are not antiarrhythmic in the traditional sense. It has been proposed that they decrease the rates of arrhythmias in patients with decreased left ventricular function.5 For the most part, however, the decrease in arrhythmias reported was secondary to a decrease in the rate of ventricular arrhythmias.6 Several studies have suggested that treatment with ACE inhibitors and angiotensin receptor blockers also may decrease the rate of AF. Pedersen et al7 first described that treatment with ACE inhibitors decreases the incidence of AF in patients after myocardial infarction. However, these investigators did not elaborate on a mechanism for this effect. Animal studies have shown AF induced by rapid atrial pacing produces decreased atrial effective refractory periods (ERPs) and a reverse physiologic rate adaptation of refractoriness.3,8 This phenomenon of electrical remodeling leads to increased inducibilty and stability of AF. Over the past few years, there have been several trials attempting to verify and elucidate the mechanism of the effect of ACE inhibitors (and angiotensin receptor blockers) on AF. From The Heart Institute, Beth Israel Medical Center, New York, New York. Manuscript received July 25, 2003; revised manuscript received and accepted November 24, 2003. Address for reprints: Paul Schweitzer, MD, Beth Israel Medical Center, 11th Floor, Dazian Building, First Avenue at 16th Street, New York, New York 10003. E-mail: [email protected].
734
©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 March 15, 2004
and Paul Schweitzer,
MD
Before discussing the results of 2 clinical studies dealing with the use of ACE inhibitors in the management of AF, we review 2 studies of the pathophysiology of experimental (pacing-induced) AF and the possible mechanism of the beneficial effect of ACE inhibitors in its management. In 2000, Nakashima et al9 studied the effects of candesartan and captopril on electrical remodeling in AF. Atrial ERPs were measured before, during, and after rapid atrial pacing in 24 dogs. Rapid atrial pacing at 800 beats/min was maintained for 180 minutes. The study had 4 arms; saline, candesartan, captopril, and angiotensin II. The infusion of the study drug was initiated 30 minutes before the onset of rapid atrial pacing and continued for 180 minutes. Atrial ERPs were measured at 3 cycle lengths: 200, 300, and 400 ms for each arm. In the saline arm, atrial ERP shortening began after 30 minutes and continued during pacing. The group also noted the loss of a physiologic rate adaptation because the degree of atrial ERP shortening induced was greater at longer basic cycle lengths than at shorter ones. In both the candesartanand captopril-treated groups, the reduction in atrial ERP during rapid atrial pacing was greatly diminished at all basic cycle lengths.9 The percent change was approximately 4% for the candesartan and captopril groups versus approximately 11% for the saline group.9 In addition, in contrast to the saline group, the candesartan and captopril groups maintained physiologic rate adaptivity, thus preventing most remodeling. There was no significant difference in atrial remodeling in the angiotensin II and saline groups.9 In 2001, Li et al10 studied the effects of ACE inhibition on the development of AF in dogs with ventricular tachycardia pacing-induced congestive heart failure. The study was designed to elucidate the effects of ACE inhibition (with enalapril) on arrythmogenic atrial remodeling and associated mitogenactivated protein kinase changes in a dog model of congestive heart failure. The dogs were subjected to ventricular tachycardia pacing at 220 to 240 beats/ min. By 5 weeks, ventricular tachycardia pacing induced many detectable changes, most notably congestive heart failure, local atrial conduction slowing, interstitial fibrosis, increased concentrations of atrial angiotensin II, and mitogen-activated protein kinase expression. Prolonged atrial burst pacing was used to induce AF. Enalapril was administered in a dose of 2 mg/kg/day. In the enalapril group, there was a significant reduction in the ventricular tachycardia–paced changes, including a decrease in atrial angiotensin II 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.11.073
and mitogen-activated protein kinase activation.10 Enalapril also attenuated the effects of congestive heart failure on atrial conduction as measured by a reduced conduction heterogeneity index (11.9% placebo to 7.5% enalapril p ⬍0.01) and mean AF duration (from 651 to 218 seconds, p ⬍0.05).10 Of note, the study also included an arm with hydralazine and isosorbide mononitrate, and this arm did not alter congestive heart failure–induced fibrosis or AF promotion, despite improvement in hemodynamic parameters such as left ventricular and atrial pressures. The investigators concluded that congestive heart failure– induced changes in angiotensin II content and mitogen-activated protein kinase expression are contributing factors in arrythmogenic structural remodeling. ACE inhibition hinders signal transduction and the creation of an AF substrate and may therefore represent a valuable new tool in AF therapy. The first clinical studies came in 1999, when a Danish group of investigators lead by Pedersen et al7 studied the effects of trandolapril on the incidence of AF after acute myocardial infarction in patients with decreased left ventricular function.7 Patients in this study were from the TRAndolapril Cardiac Evaluation (TRACE) study. All the TRACE patients who were in normal sinus rhythm on their randomization electrocardiogram were included in this study. TRACE was a double-blind, randomized, placebo-controlled trial of patients aged ⬎18 years with left ventricular ejection fractions of ⬍36%. Patients were randomized to treatment with trandolapril versus placebo on days 3 to 7 after myocardial infarction. Patients in the trandolapril arm received doses of 1 mg/day and were eventually titrated up to 4 mg/day. Patients were followed for 2 to 4 years. Of the 1,749 patients in TRACE, 1,577 had sinus rhythm noted on their randomization electrocardiogram. Of these patients, 790 received trandolapril and 787 received placebo. In all, 64 patients developed AF during the follow-up period: 5.3% (n ⫽ 42) in the placebo group versus 2.3% (n ⫽ 22) in the study group (p ⬍0.05).7 This was the first study to demonstrate that treating patients with decreased ejection fractions after myocardial infarction with ACE inhibitors decreases the rate of AF (55% during the 2- to 4-year follow-up). The investigators go on to propose several mechanisms to explain this effect. These include a decrease in wall stress, modulation of refractoriness, alteration of sympathetic tone, decreased atrial stretch, and stabilization of electrolytes (namely potassium). In 2002 Madrid et al11 investigated the use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent AF. The study was designed to test the effects of an angiotensin-receptor blocker (irbesartan) on maintaining sinus rhythm after conversion from AF. Patients had to have persistent AF for ⬎7 days. Patients were then scheduled for synchronized direct-current cardioversion and randomized to 1 of 2 groups. Group I was treated with amiodarone at a dose of 400 mg/day. Group II was treated with irbesartan at a dose of 150 mg/day (which could be increased to 300 mg/day in patients who remained
hypertensive) in addition to amiodarone. Patients were administered oral anticoagulation to maintain an international normalized ratio ⬎2.0. When a therapeutic international normalized ratio was achieved, amiodarone therapy was initiated (with or without irbesartan). Cardioversion was then scheduled for 3 weeks after initiation of amiodarone therapy. Of a total of 154 patients, 75 were randomized to group I and 79 to group II. The irbesartan group had fewer patients with recurrent AF at a 2-month follow-up interval (84.79% vs 63.16% p ⫽ 0.008).11 The investigators concluded that patients treated with irbesartan and amiodarone had a lower recurrence rate of AF than those in the amiodarone only group. The most recent clinical evidence verifying the role of ACE inhibitors in preventing the development of AF comes from Vermes et al.12 The investigators performed a retrospective analysis of the patients from the Montreal Heart Institute included in the Studies Of Left Ventricular Dysfunction (SOLVD).12 The investigators reviewed clinical charts and serial electrocardiograms. Patients with AF on a baseline electrocardiogram were excluded. Of the 374 patients, 186 were taking enalapril and 188 were taking placebo. The average length of follow-up was approximately 3 years. Of the 55 patients found to have AF during the follow-up period, 10 (5.4%) were in the enalapril group and 45 (24%) were in the placebo group. This finding was highly statistically significant (p ⬍0.0001). The term atrial electrical remodeling can be applied to changes elicited by long-lasting AF that lead to both the promotion and maintenance of the arrhythmia. The mechanisms by which ACE inhibitors may provide their protective effect against the development of AF are not completely understood. The renin-angiotensisn-aldosterone system has been implicated in many of the changes seen in atrial myocardium of persistent AF. Angiotensin II is a strong promoter of fibrosis and mitogen-activated protein kinase expression, as previously stated. This may explain some of the specificity of ACE inhibitors in the attenuation of changes promoting AF. It has also been proposed that the mechanism of AF reduction with ACE inhibitors is more an effect of decreased atrial filling pressures and ventricular wall stress, which would in turn lead to decreased left atrial dimensions. The same effect could then be postulated for any medication known to have similar effects, such as  blockers or vasodilators. What speaks against this argument is that Li et al10 were able to demonstrate a decrease in atrial fibrosis and AF only in the enalapril group (and not in the hydralazine/isosorbide group). In light of recent studies, it would appear that administering therapies that lead to regression of atrial remodeling could serve as targeted therapy for AF. Both ACE inhibitors and angiotensin-receptor blockers can lead to regression of remodeling, restoration of normal atrial ERPs, and physiologic rate adaptation. However, the predominance of the evidence in support of the use of ACE inhibitors for preventing AF comes from retrospective studies, the exception being the Spanish study,11 which contained a small number of patients (n ⫽ 154). EDITORIALS
735
With this in mind, larger prospective trials are needed before recommending the use of ACE inhibitors to prevent AF. 1. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features
of atrial fibrillation: The Framingham Study. N Engl J Med 1982;306:1018 –1022. 2. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural
history of atrial fibrillation: incidence risk factors, and prognosis in the Manitoba follow-up group. Am J Med 1995;98:476 –484. 3. Wijffels MCEF, Kirchlof CJHJ, Dorland R, Allessie M. AF begets AF: a study in awake chronically instrumented goats. Circulation 1995;92:1954 –1968. 4. Allessie MA. Atrial electrophysiological remodeling. Another viscous cycle? J Cardiovasc Electrophysiol 1998;9:1378 –1393. 5. Campbell RF. ACE inhibitors and arrhythmias. Heart 1996;76:79 –82. 6. Fletcher RD, Cintron RB, Johnson G, Orndorff J, Carson P, Cohn J, for the V-HeFT II VA Cooperative Studies Group. Enalapril decreases the presence of ventricular tachycardia in patients with chronic congestive heart failure. Circulation 1993;87(suppl VI):VI-49 –VI-55.
736 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 93
7. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation 1999;100:376 –380. 8. Tieleman RG, De Langen C, Van Gelder IC, de Kam PJ, Grandjean J, Bel KJ, Wijffels MC, Allessie MA, Crijns HJ. Verapamil reduces tachycardia-induced electrical remodeling of the atria. Circulation 1997;95:1945–1953. 9. Nakashima H, Kumagai K, Urata H, Gondo N, Ideishi M, Arakawa K. Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation. Circulation 2000;101:2612–2617. 10. Li D, Shingawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S. Effects of angiotensin-converting enzyme inhibition on the development of atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation 2001;104:2608 –2616. 11. Madrid AH, Bueno MG, Rebollo JM, Marin I, Pena G, Bernal E, Rodriguez A, Cano L, Cano JM, Cabeza P, Moro C. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002;106:331–336. 12. Vermes E, Tardif JC, Bourassa MG, Racine N, Levesque S, White M, Guerra PG, Ducharme A. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials. Circulation 2003;10:2926 –2931.
MARCH 15, 2004
MD,
trial fibrillation (AF) is the most frequent sustained arrhythmia found in clinical practice. A According to the Framingham Heart Study, AF has a 1,2
prevalence of 4% in the adult population and as the patient population continues to age, the prevalence of this arrhythmia will increase from ⬍0.05% in patients 25 to 35 years of age, to ⬎5% in patients aged ⬎69 years.1 AF can be classified as paroxysmal, persistent, or chronic. Experimental studies suggest that the longer the episode of paroxysmal AF, the more likely it will become chronic. It is unique in that its existence leads to a perpetuation of duration and recurrence after treatment. Put another way, “AF begets AF.”3 It has been postulated that this phenomenon may be secondary to electrical remodeling of atrial myocardium in patients with AF.3,4 Electrical remodeling of the atrium is accomplished through a reduction in the refractory period of atrial tissue. The management of AF includes antiarrhythmic drugs, pacing, and radio frequency ablation. Some recent experimental and clinical studies suggest a role for angiotensin-converting enzyme (ACE) inhibitors in the management of AF. This is the subject of this editorial. ACE inhibitors are not antiarrhythmic in the traditional sense. It has been proposed that they decrease the rates of arrhythmias in patients with decreased left ventricular function.5 For the most part, however, the decrease in arrhythmias reported was secondary to a decrease in the rate of ventricular arrhythmias.6 Several studies have suggested that treatment with ACE inhibitors and angiotensin receptor blockers also may decrease the rate of AF. Pedersen et al7 first described that treatment with ACE inhibitors decreases the incidence of AF in patients after myocardial infarction. However, these investigators did not elaborate on a mechanism for this effect. Animal studies have shown AF induced by rapid atrial pacing produces decreased atrial effective refractory periods (ERPs) and a reverse physiologic rate adaptation of refractoriness.3,8 This phenomenon of electrical remodeling leads to increased inducibilty and stability of AF. Over the past few years, there have been several trials attempting to verify and elucidate the mechanism of the effect of ACE inhibitors (and angiotensin receptor blockers) on AF. From The Heart Institute, Beth Israel Medical Center, New York, New York. Manuscript received July 25, 2003; revised manuscript received and accepted November 24, 2003. Address for reprints: Paul Schweitzer, MD, Beth Israel Medical Center, 11th Floor, Dazian Building, First Avenue at 16th Street, New York, New York 10003. E-mail: [email protected].
734
©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 March 15, 2004
and Paul Schweitzer,
MD
Before discussing the results of 2 clinical studies dealing with the use of ACE inhibitors in the management of AF, we review 2 studies of the pathophysiology of experimental (pacing-induced) AF and the possible mechanism of the beneficial effect of ACE inhibitors in its management. In 2000, Nakashima et al9 studied the effects of candesartan and captopril on electrical remodeling in AF. Atrial ERPs were measured before, during, and after rapid atrial pacing in 24 dogs. Rapid atrial pacing at 800 beats/min was maintained for 180 minutes. The study had 4 arms; saline, candesartan, captopril, and angiotensin II. The infusion of the study drug was initiated 30 minutes before the onset of rapid atrial pacing and continued for 180 minutes. Atrial ERPs were measured at 3 cycle lengths: 200, 300, and 400 ms for each arm. In the saline arm, atrial ERP shortening began after 30 minutes and continued during pacing. The group also noted the loss of a physiologic rate adaptation because the degree of atrial ERP shortening induced was greater at longer basic cycle lengths than at shorter ones. In both the candesartanand captopril-treated groups, the reduction in atrial ERP during rapid atrial pacing was greatly diminished at all basic cycle lengths.9 The percent change was approximately 4% for the candesartan and captopril groups versus approximately 11% for the saline group.9 In addition, in contrast to the saline group, the candesartan and captopril groups maintained physiologic rate adaptivity, thus preventing most remodeling. There was no significant difference in atrial remodeling in the angiotensin II and saline groups.9 In 2001, Li et al10 studied the effects of ACE inhibition on the development of AF in dogs with ventricular tachycardia pacing-induced congestive heart failure. The study was designed to elucidate the effects of ACE inhibition (with enalapril) on arrythmogenic atrial remodeling and associated mitogenactivated protein kinase changes in a dog model of congestive heart failure. The dogs were subjected to ventricular tachycardia pacing at 220 to 240 beats/ min. By 5 weeks, ventricular tachycardia pacing induced many detectable changes, most notably congestive heart failure, local atrial conduction slowing, interstitial fibrosis, increased concentrations of atrial angiotensin II, and mitogen-activated protein kinase expression. Prolonged atrial burst pacing was used to induce AF. Enalapril was administered in a dose of 2 mg/kg/day. In the enalapril group, there was a significant reduction in the ventricular tachycardia–paced changes, including a decrease in atrial angiotensin II 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.11.073
and mitogen-activated protein kinase activation.10 Enalapril also attenuated the effects of congestive heart failure on atrial conduction as measured by a reduced conduction heterogeneity index (11.9% placebo to 7.5% enalapril p ⬍0.01) and mean AF duration (from 651 to 218 seconds, p ⬍0.05).10 Of note, the study also included an arm with hydralazine and isosorbide mononitrate, and this arm did not alter congestive heart failure–induced fibrosis or AF promotion, despite improvement in hemodynamic parameters such as left ventricular and atrial pressures. The investigators concluded that congestive heart failure– induced changes in angiotensin II content and mitogen-activated protein kinase expression are contributing factors in arrythmogenic structural remodeling. ACE inhibition hinders signal transduction and the creation of an AF substrate and may therefore represent a valuable new tool in AF therapy. The first clinical studies came in 1999, when a Danish group of investigators lead by Pedersen et al7 studied the effects of trandolapril on the incidence of AF after acute myocardial infarction in patients with decreased left ventricular function.7 Patients in this study were from the TRAndolapril Cardiac Evaluation (TRACE) study. All the TRACE patients who were in normal sinus rhythm on their randomization electrocardiogram were included in this study. TRACE was a double-blind, randomized, placebo-controlled trial of patients aged ⬎18 years with left ventricular ejection fractions of ⬍36%. Patients were randomized to treatment with trandolapril versus placebo on days 3 to 7 after myocardial infarction. Patients in the trandolapril arm received doses of 1 mg/day and were eventually titrated up to 4 mg/day. Patients were followed for 2 to 4 years. Of the 1,749 patients in TRACE, 1,577 had sinus rhythm noted on their randomization electrocardiogram. Of these patients, 790 received trandolapril and 787 received placebo. In all, 64 patients developed AF during the follow-up period: 5.3% (n ⫽ 42) in the placebo group versus 2.3% (n ⫽ 22) in the study group (p ⬍0.05).7 This was the first study to demonstrate that treating patients with decreased ejection fractions after myocardial infarction with ACE inhibitors decreases the rate of AF (55% during the 2- to 4-year follow-up). The investigators go on to propose several mechanisms to explain this effect. These include a decrease in wall stress, modulation of refractoriness, alteration of sympathetic tone, decreased atrial stretch, and stabilization of electrolytes (namely potassium). In 2002 Madrid et al11 investigated the use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent AF. The study was designed to test the effects of an angiotensin-receptor blocker (irbesartan) on maintaining sinus rhythm after conversion from AF. Patients had to have persistent AF for ⬎7 days. Patients were then scheduled for synchronized direct-current cardioversion and randomized to 1 of 2 groups. Group I was treated with amiodarone at a dose of 400 mg/day. Group II was treated with irbesartan at a dose of 150 mg/day (which could be increased to 300 mg/day in patients who remained
hypertensive) in addition to amiodarone. Patients were administered oral anticoagulation to maintain an international normalized ratio ⬎2.0. When a therapeutic international normalized ratio was achieved, amiodarone therapy was initiated (with or without irbesartan). Cardioversion was then scheduled for 3 weeks after initiation of amiodarone therapy. Of a total of 154 patients, 75 were randomized to group I and 79 to group II. The irbesartan group had fewer patients with recurrent AF at a 2-month follow-up interval (84.79% vs 63.16% p ⫽ 0.008).11 The investigators concluded that patients treated with irbesartan and amiodarone had a lower recurrence rate of AF than those in the amiodarone only group. The most recent clinical evidence verifying the role of ACE inhibitors in preventing the development of AF comes from Vermes et al.12 The investigators performed a retrospective analysis of the patients from the Montreal Heart Institute included in the Studies Of Left Ventricular Dysfunction (SOLVD).12 The investigators reviewed clinical charts and serial electrocardiograms. Patients with AF on a baseline electrocardiogram were excluded. Of the 374 patients, 186 were taking enalapril and 188 were taking placebo. The average length of follow-up was approximately 3 years. Of the 55 patients found to have AF during the follow-up period, 10 (5.4%) were in the enalapril group and 45 (24%) were in the placebo group. This finding was highly statistically significant (p ⬍0.0001). The term atrial electrical remodeling can be applied to changes elicited by long-lasting AF that lead to both the promotion and maintenance of the arrhythmia. The mechanisms by which ACE inhibitors may provide their protective effect against the development of AF are not completely understood. The renin-angiotensisn-aldosterone system has been implicated in many of the changes seen in atrial myocardium of persistent AF. Angiotensin II is a strong promoter of fibrosis and mitogen-activated protein kinase expression, as previously stated. This may explain some of the specificity of ACE inhibitors in the attenuation of changes promoting AF. It has also been proposed that the mechanism of AF reduction with ACE inhibitors is more an effect of decreased atrial filling pressures and ventricular wall stress, which would in turn lead to decreased left atrial dimensions. The same effect could then be postulated for any medication known to have similar effects, such as  blockers or vasodilators. What speaks against this argument is that Li et al10 were able to demonstrate a decrease in atrial fibrosis and AF only in the enalapril group (and not in the hydralazine/isosorbide group). In light of recent studies, it would appear that administering therapies that lead to regression of atrial remodeling could serve as targeted therapy for AF. Both ACE inhibitors and angiotensin-receptor blockers can lead to regression of remodeling, restoration of normal atrial ERPs, and physiologic rate adaptation. However, the predominance of the evidence in support of the use of ACE inhibitors for preventing AF comes from retrospective studies, the exception being the Spanish study,11 which contained a small number of patients (n ⫽ 154). EDITORIALS
735
With this in mind, larger prospective trials are needed before recommending the use of ACE inhibitors to prevent AF. 1. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features
of atrial fibrillation: The Framingham Study. N Engl J Med 1982;306:1018 –1022. 2. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural
history of atrial fibrillation: incidence risk factors, and prognosis in the Manitoba follow-up group. Am J Med 1995;98:476 –484. 3. Wijffels MCEF, Kirchlof CJHJ, Dorland R, Allessie M. AF begets AF: a study in awake chronically instrumented goats. Circulation 1995;92:1954 –1968. 4. Allessie MA. Atrial electrophysiological remodeling. Another viscous cycle? J Cardiovasc Electrophysiol 1998;9:1378 –1393. 5. Campbell RF. ACE inhibitors and arrhythmias. Heart 1996;76:79 –82. 6. Fletcher RD, Cintron RB, Johnson G, Orndorff J, Carson P, Cohn J, for the V-HeFT II VA Cooperative Studies Group. Enalapril decreases the presence of ventricular tachycardia in patients with chronic congestive heart failure. Circulation 1993;87(suppl VI):VI-49 –VI-55.
736 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 93
7. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation 1999;100:376 –380. 8. Tieleman RG, De Langen C, Van Gelder IC, de Kam PJ, Grandjean J, Bel KJ, Wijffels MC, Allessie MA, Crijns HJ. Verapamil reduces tachycardia-induced electrical remodeling of the atria. Circulation 1997;95:1945–1953. 9. Nakashima H, Kumagai K, Urata H, Gondo N, Ideishi M, Arakawa K. Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation. Circulation 2000;101:2612–2617. 10. Li D, Shingawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S. Effects of angiotensin-converting enzyme inhibition on the development of atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation 2001;104:2608 –2616. 11. Madrid AH, Bueno MG, Rebollo JM, Marin I, Pena G, Bernal E, Rodriguez A, Cano L, Cano JM, Cabeza P, Moro C. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002;106:331–336. 12. Vermes E, Tardif JC, Bourassa MG, Racine N, Levesque S, White M, Guerra PG, Ducharme A. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials. Circulation 2003;10:2926 –2931.
MARCH 15, 2004