- Email: [email protected]
Pathophysiology of atrial fibrillation: Insights into the renin–angiotensin system
Archives of Cardiovascular Disease (2008) 101, 787—791
CLINICAL RESEARCH
Pathophysiology of atrial fibrillation: Insights into the renin—angiotensin system Physiopathologie de la fibrillation atriale : implications du système rénine—angiotensine Jean-Yves Le Heuzey ∗, Éloi Marijon, Karim Chachoua, Xavier Waintraub , Antoine Lepillier , Akli Otmani , Thomas Lavergne , Maurice Pornin Service de cardiologie A et rythmologie, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France Received 9 July 2008; received in revised form 19 September 2008; accepted 21 September 2008 Available online 20 November 2008
KEYWORDS Renin—angiotensin system; Atrial fibrillation
MOTS CLÉS Fibrillation atriale ;
∗
Summary Introduction. — Atrial fibrillation is, to date, a major problem of public health with an important cost in the health care system. Discussion. — The therapeutic strategies for atrial fibrillation are complex and their outcomes have been disappointing globally. New ablative techniques have brought important advances but the patient’s profile has to be taken into account in the choice of the therapeutic strategies. The renin-angiotensin system plays a major role in the phenomena of remodelling following the onset of atrial fibrillation. Conclusion. — Drugs blocking the renin-angiotensin system can have a real place in the treatment of atrial fibrillation, not only to maintain sinus rhythm but primarily to prevent cardiovascular accidents in these patients with atrial fibrillation and in some cases to prevent the occurrence of atrial fibrillation, for example in hypertensive patients. © 2008 Elsevier Masson SAS. All rights reserved.
Résumé Introduction. — La fibrillation atriale est, actuellement, un problème majeur de santé publique et représente un coût important dans le système de santé.
Corresponding author. Fax: +33 1 56 09 30 47. E-mail address: [email protected] (J.-Y. Le Heuzey).
1875-2136/$ — see front matter © 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.acvd.2008.09.015
788
Système rénine angiotensine ; Hypertension artérielle ; Inhibiteurs de l’enzyme de conversion ; Antagonistes de l’angiotensine II
J.-Y. Le Heuzey et al. Discussion. — Le traitement de la fibrillation atriale reste complexe et pour certains patients relativement décevant. Les nouvelles techniques ablatives ont apporté des avancées notables, mais le profil pathologique du patient reste un élément majeur dans le choix des stratégies thérapeutiques. Le système rénine angiotensine joue un rôle de premier plan dans les phénomènes de remodelage qui suivent l’installation de la fibrillation atriale. Conclusion. — Les médicaments qui bloquent le système rénine angiotensine peuvent avoir une place réelle dans le traitement de la fibrillation atriale, non tant pour maintenir le rythme sinusal que principalement pour prévenir les accidents cardiovasculaires chez ces patients ayant ou ayant eu de la fibrillation atriale et dans certains cas pour la prévenir, par exemple chez l’hypertendu. © 2008 Elsevier Masson SAS. All rights reserved.
The rate of mortality is higher in patients with atrial fibrillation than in people of the same age who do not have atrial fibrillation [1]. The cost of care for atrial fibrillation can be estimated at greater than D 3000 per year [2], which places a major burden on healthcare systems: D 2.5 billion in France and approximately D 25 billion in Europe. The main cost drivers are hospitalizations (52%), followed by drugs (23%). Most patients with atrial fibrillation have many comorbidities, such as hypertension, coronary artery disease, heart failure, obesity, sleep apnoea syndrome, dyslipidaemia and atheroma. Atrial fibrillation accounts for approximately one third of hospitalizations for cardiac rhythm disturbances. Over the past 10—20 years, there has been an increase of greater than 60% in hospital admissions for atrial fibrillation in Western countries [3]. In recent large studies such as AFFIRM [4], the proportion of hypertensive patients was very high (71%), and 38% of patients had coronary artery disease, 23% had heart failure and 20% had diabetes. In the ALFA study [5], the most frequent comorbidity observed was hypertension followed by coronary artery disease, valvular heart disease and dilated cardiomyopathy. In the Euro Heart Survey [6], the proportion of hypertensive patients was greater than 60%. Nowadays, hypertension plays a major role in the history of most patients with atrial fibrillation. Consequently, the renin—angiotensin system has to be taken into account in the pathophysiology of atrial fibrillation and in its pharmacological treatment. Hypertension can be considered to be a comorbidity but also, in many cases, an aetiology of atrial fibrillation, given its effect on diastolic ventricular function, which leads to atrial enlargement and, ultimately, to increased atrial vulnerability.
Pathophysiological mechanisms of atrial fibrillation Arrhythmias may be caused by cellular and/or tissular mechanisms; they may be abnormalities of influx genesis (abnormal automaticity), triggered activity such as early or delayed after-depolarizations, or abnormalities of excitation spread, such as circus movement re-entry by anatomical or functional obstacles and reflexion re-entry. The possibility of abnormal automaticity and delayed after-depolarizations has been demonstrated in the atrium. In most cases, the
mechanism of atrial fibrillation is related to multiple micro re-entries. Less frequently, the initial mechanism may be an after-depolarization or an abnormal automatism. In 1988, Haissaguerre et al. demonstrated that in some cases atrial fibrillation is due to abnormal automaticity coming from the pulmonary veins, with a secondary desynchronization [7]. Other mechanisms, such as rotors, may also interfere. To date, many proposals have been made about the intrinsic cardiac nervous system also playing a role in the perpetuation of atrial fibrillation. When atrial fibrillation is present, remodelling phenomena occur in the atrium: electrical remodelling, contractile remodelling and, finally, structural remodelling. More than 20 years ago, we showed that in atrial fibrillation, most of the action potentials recorded by the microelectrode technique in the human atrium have a triangular shape and a short cellular refractory period [8]. This shortening of action potential duration is a factor of arrhythmia but may also be a consequence of the arrhythmia itself. Indeed, Wijffels et al. demonstrated clearly that atrial fibrillation begets atrial fibrillation [9]. In other words, the occurrence of atrial fibrillation induces a reduction in action potential duration, a reduction in refractory periods and a loss of the adaptation of these refractory periods to the heart rate. Much of the research into this field of remodelling has shown the occurrence of current modifications in atrial fibrillation. Electrical remodelling leads to a decrease in action potential duration and in wavelength (which is the product of the refractory period and the conduction velocity). These modifications also result in contractile remodelling, with a decrease in cytosolic calcium, contractility, dilatation and, finally, stretch of the atrium. Structural remodelling involving connexins has also been observed, inducing fibrosis, which is responsible for anisotropy, zigzag conduction and, ultimately, multiple micro re-entries (Fig. 1) [10]. Fibroblast activation and collagen accumulation also occur during structural remodelling [11]. Drugs such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and spironolactone are capable of limiting this accumulation, that is, modifying the evolution towards remodelling and fibrosis. This is the rationale for the potential beneficial effect of drugs that block the renin—angiotensin system, in what is currently called ‘upstream’ therapy. The goal of this therapeutic approach is to limit the structural remodelling of the atrium in atrial
Pathophysiology of atrial fibrillation: Insights into the renin—angiotensin system
Figure 1. Electrical, contractile and structural remodelling occurring in atrial fibrillation [10].
fibrillation but also, if possible, to have a preventive effect on the occurrence of atrial fibrillation in at-risk patients, such as those with hypertension, coronary artery disease or heart failure.
Therapeutic implications The treatment of atrial fibrillation remains complex and is sometimes disappointing. There are many goals when treating atrial fibrillation: • to suppress symptomatology; • decrease symptoms; • make symptoms more acceptable; • improve quality of life; • decrease professional absenteeism; • improve exercise performance; • decrease the burden of atrial fibrillation; • increase time to first recurrence; • avoid thromboembolic accidents; • avoid progressive cognitive cerebral deterioration; • avoid progression towards chronicity; • maintain physiological rhythm; • preserve the haemodynamic role of the atrial systole; • prevent the occurrence of heart failure and increase life expectancy. It is not possible to achieve all these goals with only one drug. In fact, four major objectives have to be achieved: • an improvement in symptoms and quality of life; • the avoidance of heart failure; • the avoidance of thromboembolic accidents and; • an increase in life expectancy. In most cases, restoration and maintenance of sinus rhythm is not the only objective that is worth achieving in the treatment of atrial fibrillation. As atrial fibrillation is often considered to be not only an indicator of poor prognosis but also a marker of poor cardiovascular condition, its treatment also aims to decrease cardiovascular events. Hence, drugs that block the renin—angiotensin system may have an important role to play in the therapeutic approach to atrial fibrillation.
789
In 1999, Pedersen et al. published a posthoc analysis of the TRACE trial [12], which evaluated trandolapril versus placebo in postmyocardial infarction patients with low ejection fraction (mean 33%); the authors reported a reduced risk of atrial fibrillation in the group treated with trandolapril. The LIFE trial was published in 2002, comparing atenolol and losartan in hypertensive patients [13]; a posthoc analysis by Wachtell et al. showed that cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation were lower in the group who received losartan [14]. Similarly, Watchell et al. also demonstrated that angiotensin II receptor blockade reduced new onset atrial fibrillation and subsequent strokes compared with atenolol [15]. A favourable effect of angiotensin-converting enzyme inhibitors was also reported in a publication by Vermes et al. in 2003, in which the results of the different SOLVD trials were analysed; the authors concluded that enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction [16]. It is difficult to believe that drugs that block the renin—angiotensin system can have a direct antiarrhythmic effect. However, in a small group of patients (n = 154), Madrid et al. showed that sinus rhythm maintenance after conversion from persistent atrial fibrillation was superior in patients who received amiodarone plus irbesartan than in patients who received amiodarone alone [17]. In the Val-HeFt study, published in 2005, Maggioni et al. showed that valsartan was able to reduce the incidence of atrial fibrillation in patients with heart failure [18]. Comparable results have been obtained in the CHARM trials: alternative, added and preserved [19,20]. More recently, Fogari et al. demonstrated the usefulness of losartan in the prevention of atrial fibrillation recurrence in hypertensive patients [21]. This approach to atrial fibrillation prevention is very interesting and is considered nowadays to be a beneficial strategy. Concerning the maintenance of sinus rhythm, Ueng et al. have shown that enalapril can facilitate sinus rhythm maintenance after external cardioversion of long-standing, persistent atrial fibrillation [22]. All these data are concordant, although a trial designed specifically to demonstrate this theory has yet to be been published. The ACTIVE trial [23] will perhaps give the answer definitively. ACTIVE is a complex study testing different antithrombotic regimens for atrial fibrillation: clopidogrel plus aspirin versus a vitamin K antagonist and clopidogrel plus aspirin versus aspirin alone. Some of the patients included in these arms have also been included in a trial testing irbesartan versus placebo, according to a factorial design. The goal is not to demonstrate better maintenance of sinus rhythm but to analyse the occurrence of cardiovascular events such as stroke, myocardial infarction and vascular death. All these small trials or posthoc analyses of large trials were studied in a meta-analysis published by Healey et al. (Fig. 2) [24], which demonstrated that regardless of the reason for inclusion in the different studies (heart failure, hypertension, postmyocardial infarction or atrial fibrillation itself), the patients treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers had less frequent episodes of atrial fibrillation. Many explanations can be proposed for this favourable outcome: an effect on atrial pressure, on kaliemia, on left ventricular hypertrophy
790
Figure 2. [24].
J.-Y. Le Heuzey et al.
Meta-analysis of atrial fibrillation prevention with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers
and left atrial size and pressure, on atherothrombosis and coagulation, and, of course, on atrial remodelling as described previously. Drugs blocking the renin—angiotensin system are especially interesting to use in atrial fibrillation patients with hypertension and heart failure [25].
[7]
References
[9]
[1] Wolf PA, Mitchell JB, Baker CS, Kannel WB, D’Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med 1998;158:229—34. [2] Le Heuzey JY, Paziaud O, Piot O, et al. Cost of care distribution in atrial fibrillation patients: the COCAF study. Am Heart J 2004;147:121—6. [3] Stewart S, Murphy NF, Walker A, McGuire A, McMurray JJ. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004;90:286—92. [4] Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825—33. [5] Levy S, Maarek M, Coumel P, et al. Characterization of different subsets of atrial fibrillation in general practice in France: the ALFA study. The College of French Cardiologists. Circulation 1999;99:3028—35. [6] Nieuwlaat R, Capucci A, Camm AJ, et al. Atrial fibrillation management: a prospective survey in ESC member countries:
[8]
[10]
[11]
[12]
[13]
[14]
the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2005;26:2422—34. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659—66. Boutjdir M, Le Heuzey JY, Lavergne T, et al. Inhomogeneity of cellular refractoriness in human atrium: factor of arrhythmia? Pacing Clin Electrophysiol 1986;9:1095—100. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995;92:1954—68. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002;54:230—46. Goette A, Lendeckel U, Klein HU. Signal transduction systems and atrial fibrillation. Cardiovasc Res 2002;54: 247—58. 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—80. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995—1003. Wachtell K, Hornestam B, Lehto M, et al. Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: The Losartan Intervention For End Point
Pathophysiology of atrial fibrillation: Insights into the renin—angiotensin system
[15]
[16]
[17]
[18]
[19]
Reduction in Hypertension (LIFE) study. J Am Coll Cardiol 2005;45:705—11. Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol 2005;45:712—9. Vermes E, Tardif JC, Bourassa MG, et al. 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;107: 2926—31. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002;106:331—6. Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J 2005;149:548—57. Ducharme A, Swedberg K, Pfeffer MA, et al. Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Am Heart J 2006;152:86—92.
791
[20] Olsson LG, Swedberg K, Ducharme A, et al. Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J Am Coll Cardiol 2006;47:1997—2004. [21] Fogari R, Mugellini A, Destro M, et al. Losartan and prevention of atrial fibrillation recurrence in hypertensive patients. J Cardiovasc Pharmacol 2006;47:46—50. [22] Ueng KC, Tsai TP, Yu WC, et al. Use of enalapril to facilitate sinus rhythm maintenance after external cardioversion of long-standing persistent atrial fibrillation. Results of a prospective and controlled study. Eur Heart J 2003;24: 2090—8. [23] Connolly S, Yusuf S, Budaj A, et al. Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events. Am Heart J 2006;151:1187—93. [24] Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol 2005;45:1832—9. [25] Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667—77.
CLINICAL RESEARCH
Pathophysiology of atrial fibrillation: Insights into the renin—angiotensin system Physiopathologie de la fibrillation atriale : implications du système rénine—angiotensine Jean-Yves Le Heuzey ∗, Éloi Marijon, Karim Chachoua, Xavier Waintraub , Antoine Lepillier , Akli Otmani , Thomas Lavergne , Maurice Pornin Service de cardiologie A et rythmologie, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France Received 9 July 2008; received in revised form 19 September 2008; accepted 21 September 2008 Available online 20 November 2008
KEYWORDS Renin—angiotensin system; Atrial fibrillation
MOTS CLÉS Fibrillation atriale ;
∗
Summary Introduction. — Atrial fibrillation is, to date, a major problem of public health with an important cost in the health care system. Discussion. — The therapeutic strategies for atrial fibrillation are complex and their outcomes have been disappointing globally. New ablative techniques have brought important advances but the patient’s profile has to be taken into account in the choice of the therapeutic strategies. The renin-angiotensin system plays a major role in the phenomena of remodelling following the onset of atrial fibrillation. Conclusion. — Drugs blocking the renin-angiotensin system can have a real place in the treatment of atrial fibrillation, not only to maintain sinus rhythm but primarily to prevent cardiovascular accidents in these patients with atrial fibrillation and in some cases to prevent the occurrence of atrial fibrillation, for example in hypertensive patients. © 2008 Elsevier Masson SAS. All rights reserved.
Résumé Introduction. — La fibrillation atriale est, actuellement, un problème majeur de santé publique et représente un coût important dans le système de santé.
Corresponding author. Fax: +33 1 56 09 30 47. E-mail address: [email protected] (J.-Y. Le Heuzey).
1875-2136/$ — see front matter © 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.acvd.2008.09.015
788
Système rénine angiotensine ; Hypertension artérielle ; Inhibiteurs de l’enzyme de conversion ; Antagonistes de l’angiotensine II
J.-Y. Le Heuzey et al. Discussion. — Le traitement de la fibrillation atriale reste complexe et pour certains patients relativement décevant. Les nouvelles techniques ablatives ont apporté des avancées notables, mais le profil pathologique du patient reste un élément majeur dans le choix des stratégies thérapeutiques. Le système rénine angiotensine joue un rôle de premier plan dans les phénomènes de remodelage qui suivent l’installation de la fibrillation atriale. Conclusion. — Les médicaments qui bloquent le système rénine angiotensine peuvent avoir une place réelle dans le traitement de la fibrillation atriale, non tant pour maintenir le rythme sinusal que principalement pour prévenir les accidents cardiovasculaires chez ces patients ayant ou ayant eu de la fibrillation atriale et dans certains cas pour la prévenir, par exemple chez l’hypertendu. © 2008 Elsevier Masson SAS. All rights reserved.
The rate of mortality is higher in patients with atrial fibrillation than in people of the same age who do not have atrial fibrillation [1]. The cost of care for atrial fibrillation can be estimated at greater than D 3000 per year [2], which places a major burden on healthcare systems: D 2.5 billion in France and approximately D 25 billion in Europe. The main cost drivers are hospitalizations (52%), followed by drugs (23%). Most patients with atrial fibrillation have many comorbidities, such as hypertension, coronary artery disease, heart failure, obesity, sleep apnoea syndrome, dyslipidaemia and atheroma. Atrial fibrillation accounts for approximately one third of hospitalizations for cardiac rhythm disturbances. Over the past 10—20 years, there has been an increase of greater than 60% in hospital admissions for atrial fibrillation in Western countries [3]. In recent large studies such as AFFIRM [4], the proportion of hypertensive patients was very high (71%), and 38% of patients had coronary artery disease, 23% had heart failure and 20% had diabetes. In the ALFA study [5], the most frequent comorbidity observed was hypertension followed by coronary artery disease, valvular heart disease and dilated cardiomyopathy. In the Euro Heart Survey [6], the proportion of hypertensive patients was greater than 60%. Nowadays, hypertension plays a major role in the history of most patients with atrial fibrillation. Consequently, the renin—angiotensin system has to be taken into account in the pathophysiology of atrial fibrillation and in its pharmacological treatment. Hypertension can be considered to be a comorbidity but also, in many cases, an aetiology of atrial fibrillation, given its effect on diastolic ventricular function, which leads to atrial enlargement and, ultimately, to increased atrial vulnerability.
Pathophysiological mechanisms of atrial fibrillation Arrhythmias may be caused by cellular and/or tissular mechanisms; they may be abnormalities of influx genesis (abnormal automaticity), triggered activity such as early or delayed after-depolarizations, or abnormalities of excitation spread, such as circus movement re-entry by anatomical or functional obstacles and reflexion re-entry. The possibility of abnormal automaticity and delayed after-depolarizations has been demonstrated in the atrium. In most cases, the
mechanism of atrial fibrillation is related to multiple micro re-entries. Less frequently, the initial mechanism may be an after-depolarization or an abnormal automatism. In 1988, Haissaguerre et al. demonstrated that in some cases atrial fibrillation is due to abnormal automaticity coming from the pulmonary veins, with a secondary desynchronization [7]. Other mechanisms, such as rotors, may also interfere. To date, many proposals have been made about the intrinsic cardiac nervous system also playing a role in the perpetuation of atrial fibrillation. When atrial fibrillation is present, remodelling phenomena occur in the atrium: electrical remodelling, contractile remodelling and, finally, structural remodelling. More than 20 years ago, we showed that in atrial fibrillation, most of the action potentials recorded by the microelectrode technique in the human atrium have a triangular shape and a short cellular refractory period [8]. This shortening of action potential duration is a factor of arrhythmia but may also be a consequence of the arrhythmia itself. Indeed, Wijffels et al. demonstrated clearly that atrial fibrillation begets atrial fibrillation [9]. In other words, the occurrence of atrial fibrillation induces a reduction in action potential duration, a reduction in refractory periods and a loss of the adaptation of these refractory periods to the heart rate. Much of the research into this field of remodelling has shown the occurrence of current modifications in atrial fibrillation. Electrical remodelling leads to a decrease in action potential duration and in wavelength (which is the product of the refractory period and the conduction velocity). These modifications also result in contractile remodelling, with a decrease in cytosolic calcium, contractility, dilatation and, finally, stretch of the atrium. Structural remodelling involving connexins has also been observed, inducing fibrosis, which is responsible for anisotropy, zigzag conduction and, ultimately, multiple micro re-entries (Fig. 1) [10]. Fibroblast activation and collagen accumulation also occur during structural remodelling [11]. Drugs such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and spironolactone are capable of limiting this accumulation, that is, modifying the evolution towards remodelling and fibrosis. This is the rationale for the potential beneficial effect of drugs that block the renin—angiotensin system, in what is currently called ‘upstream’ therapy. The goal of this therapeutic approach is to limit the structural remodelling of the atrium in atrial
Pathophysiology of atrial fibrillation: Insights into the renin—angiotensin system
Figure 1. Electrical, contractile and structural remodelling occurring in atrial fibrillation [10].
fibrillation but also, if possible, to have a preventive effect on the occurrence of atrial fibrillation in at-risk patients, such as those with hypertension, coronary artery disease or heart failure.
Therapeutic implications The treatment of atrial fibrillation remains complex and is sometimes disappointing. There are many goals when treating atrial fibrillation: • to suppress symptomatology; • decrease symptoms; • make symptoms more acceptable; • improve quality of life; • decrease professional absenteeism; • improve exercise performance; • decrease the burden of atrial fibrillation; • increase time to first recurrence; • avoid thromboembolic accidents; • avoid progressive cognitive cerebral deterioration; • avoid progression towards chronicity; • maintain physiological rhythm; • preserve the haemodynamic role of the atrial systole; • prevent the occurrence of heart failure and increase life expectancy. It is not possible to achieve all these goals with only one drug. In fact, four major objectives have to be achieved: • an improvement in symptoms and quality of life; • the avoidance of heart failure; • the avoidance of thromboembolic accidents and; • an increase in life expectancy. In most cases, restoration and maintenance of sinus rhythm is not the only objective that is worth achieving in the treatment of atrial fibrillation. As atrial fibrillation is often considered to be not only an indicator of poor prognosis but also a marker of poor cardiovascular condition, its treatment also aims to decrease cardiovascular events. Hence, drugs that block the renin—angiotensin system may have an important role to play in the therapeutic approach to atrial fibrillation.
789
In 1999, Pedersen et al. published a posthoc analysis of the TRACE trial [12], which evaluated trandolapril versus placebo in postmyocardial infarction patients with low ejection fraction (mean 33%); the authors reported a reduced risk of atrial fibrillation in the group treated with trandolapril. The LIFE trial was published in 2002, comparing atenolol and losartan in hypertensive patients [13]; a posthoc analysis by Wachtell et al. showed that cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation were lower in the group who received losartan [14]. Similarly, Watchell et al. also demonstrated that angiotensin II receptor blockade reduced new onset atrial fibrillation and subsequent strokes compared with atenolol [15]. A favourable effect of angiotensin-converting enzyme inhibitors was also reported in a publication by Vermes et al. in 2003, in which the results of the different SOLVD trials were analysed; the authors concluded that enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction [16]. It is difficult to believe that drugs that block the renin—angiotensin system can have a direct antiarrhythmic effect. However, in a small group of patients (n = 154), Madrid et al. showed that sinus rhythm maintenance after conversion from persistent atrial fibrillation was superior in patients who received amiodarone plus irbesartan than in patients who received amiodarone alone [17]. In the Val-HeFt study, published in 2005, Maggioni et al. showed that valsartan was able to reduce the incidence of atrial fibrillation in patients with heart failure [18]. Comparable results have been obtained in the CHARM trials: alternative, added and preserved [19,20]. More recently, Fogari et al. demonstrated the usefulness of losartan in the prevention of atrial fibrillation recurrence in hypertensive patients [21]. This approach to atrial fibrillation prevention is very interesting and is considered nowadays to be a beneficial strategy. Concerning the maintenance of sinus rhythm, Ueng et al. have shown that enalapril can facilitate sinus rhythm maintenance after external cardioversion of long-standing, persistent atrial fibrillation [22]. All these data are concordant, although a trial designed specifically to demonstrate this theory has yet to be been published. The ACTIVE trial [23] will perhaps give the answer definitively. ACTIVE is a complex study testing different antithrombotic regimens for atrial fibrillation: clopidogrel plus aspirin versus a vitamin K antagonist and clopidogrel plus aspirin versus aspirin alone. Some of the patients included in these arms have also been included in a trial testing irbesartan versus placebo, according to a factorial design. The goal is not to demonstrate better maintenance of sinus rhythm but to analyse the occurrence of cardiovascular events such as stroke, myocardial infarction and vascular death. All these small trials or posthoc analyses of large trials were studied in a meta-analysis published by Healey et al. (Fig. 2) [24], which demonstrated that regardless of the reason for inclusion in the different studies (heart failure, hypertension, postmyocardial infarction or atrial fibrillation itself), the patients treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers had less frequent episodes of atrial fibrillation. Many explanations can be proposed for this favourable outcome: an effect on atrial pressure, on kaliemia, on left ventricular hypertrophy
790
Figure 2. [24].
J.-Y. Le Heuzey et al.
Meta-analysis of atrial fibrillation prevention with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers
and left atrial size and pressure, on atherothrombosis and coagulation, and, of course, on atrial remodelling as described previously. Drugs blocking the renin—angiotensin system are especially interesting to use in atrial fibrillation patients with hypertension and heart failure [25].
[7]
References
[9]
[1] Wolf PA, Mitchell JB, Baker CS, Kannel WB, D’Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med 1998;158:229—34. [2] Le Heuzey JY, Paziaud O, Piot O, et al. Cost of care distribution in atrial fibrillation patients: the COCAF study. Am Heart J 2004;147:121—6. [3] Stewart S, Murphy NF, Walker A, McGuire A, McMurray JJ. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004;90:286—92. [4] Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825—33. [5] Levy S, Maarek M, Coumel P, et al. Characterization of different subsets of atrial fibrillation in general practice in France: the ALFA study. The College of French Cardiologists. Circulation 1999;99:3028—35. [6] Nieuwlaat R, Capucci A, Camm AJ, et al. Atrial fibrillation management: a prospective survey in ESC member countries:
[8]
[10]
[11]
[12]
[13]
[14]
the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2005;26:2422—34. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659—66. Boutjdir M, Le Heuzey JY, Lavergne T, et al. Inhomogeneity of cellular refractoriness in human atrium: factor of arrhythmia? Pacing Clin Electrophysiol 1986;9:1095—100. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995;92:1954—68. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002;54:230—46. Goette A, Lendeckel U, Klein HU. Signal transduction systems and atrial fibrillation. Cardiovasc Res 2002;54: 247—58. 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—80. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995—1003. Wachtell K, Hornestam B, Lehto M, et al. Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: The Losartan Intervention For End Point
Pathophysiology of atrial fibrillation: Insights into the renin—angiotensin system
[15]
[16]
[17]
[18]
[19]
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