**5. Atrial fibrillation and the renin-angiotensin-aldosterone system (RAAS): Clinical observations**

A possible relationship between the RAAS and the risk of developing AF was brought about by several clinical data, derived from patient series in different settings, that are here summarized.

#### **5.1. Heart failure**

sequently attributed to a reduction of action potential duration (APD) secondary to the progressive downregulation of the transient outward current (Ito) and of the L-typeCa2+ current (ICa*,*L).[66] As to the modulation of the ICa*,*L current, the role of angiotensin II is controversial, with studies reporting increase, decrease, or even no effect.[29,67] In contrast, angiotensin II has been demonstrated to downregulate Ito current,[68,67] inas‐ much as AT1 receptor stimulation leads to internalization of the Kv4.3 (i.e., the poreforming *α*-subunit underlying Ito), regulating its cell-surface expression.[68] As shown by Liu and coworkers, chronic Ang-(1-7) infusion prevented the decrease of Ito, ICa*,*L, and of Kv4.3 mRNA expression induced by chronic atrial pacing, [34] thereby contribu‐ ting to reduce AF vulnerability.[33] Subsequently, Nakashima et al. showed that ACEI or ARB treatment results in complete inhibition of the shortening of AERP, that is nor‐ mally induced by rapid atrial pacing.[69] A further mechanism by which the RAAS may exert a proarrhythmic effect is the modulation of gap junctions, that are low-resistance pathways for the propagation of impulses between cardiomyocytes formed by connexins (Cx).[70] Cx40 gene polymorphisms have been associated with the development of non familial AF,[71] and angiotensin II has been implicated in Cx43 downward remodeling. [72-74] Moreover, angiotensin II directly induces delayed after-depolarizations and accel‐ erates the automatic rhythm of isolated pulmonary vein cardiomyocytes.[75] These cells are considered an important source of ectopic beats and of atrial fibrillation bursts, rep‐ resenting the target of AF treatment with radio-frequency ablation.[76] Therefore these experimental results demonstrate that angiotensin II may play a role in the pathophysi‐ ology of atrial fibrillation also by modulating the pulmonary vein electrical activity via an electrophysiological effect that was shown to be AT1 receptor – mediated, being in‐ hibited by losartan, [75] and that is attenuated by heat-stress responses.[77] Recently, al‐ so the direct renin inhibitor aliskiren was shown to reduce the arrhythmogenic activity of pulmonary vein cardiomyocytes.[36] It has also been demonstrated that aldosterone promotes atrial fibrillation, causing a substrate for atrial arrhythmias characterized by at‐ rial fibrosis, myocyte hypertrophy, and conduction disturbances,[78] and the specific an‐ tagonist spironolactone has been shown to prevent aldosterone-induced increased

The ACE DD (deletion/deletion) genotype of the ACE gene has been shown to be a predis‐ posing factor for persistent AF,[80] and it was recently reported that the same genotype is associated with lowest rates of symptomatic response in patients with lone AF.[81] More‐ over, polymorphisms of the angiotensinogen gene have also been associated with nonfami‐ lial AF,[82] and it has been shown that significant interactions exist between angiotensinogen gene haplotypes and ACE I/D (insertion/deletion) polymorphism resulting in increased susceptibility to AF.[83,84] Also aldosterone synthase (CYP11B2) T-344C poly‐ morphism, which is associated with increased aldosterone activity, was shown to be an in‐ dependent predictor of AF in patients with HF.[85] According to Sun and coworkers, this

duration of atrial fibrillation in a rat model.[79]

**4.4. RAAS gene polymorphisms and AF**

8 Atrial Fibrillation - Mechanisms and Treatment

In heart failure, several observations indicate a possible effect of RAAS inhibition in re‐ ducing the incidence of new onset AF. In a retrospective analysis of the SOLVD trial, Vermes et al. showed that enalapril reduces the risk of AF development in patients with various degrees of heart failure.[87] Similarly, Maggioni et al. demonstrated that use of the ARB valsartan is associated with a reduction in the risk of AF in the Val-HeFT trial population.[88] Since the vast majority of these patients (92.5%) were already receiving an ACEI, a combination effect was hypothesized, and the benefit of combined treatment with both an ARB and an ACEI was also supported by the results of the CHARM trial with candesartan.[89] The latter study was composed by three component trials based on left ventricular ejection fraction (LVEF) and ACEI treatment. CHARM-Alternative tri‐ al enrolled patients with LVEF ≤40% not treated with ACEIs because of prior intoler‐ ance, CHARM-Added recruited patients with LVEF ≤40% already treated with an ACEI, and CHARM-Preserved included patients with LVEF >40%, independent of ACEI treat‐ ment. The incidence of new-onset AF was reduced in candesartan-treated patients, espe‐ cially (but not exclusively) in the CHARM-Alternative trial.[89] These data indicate additional benefits in AF prevention, on the top of the already known effects of ACEI/ARB treatment in patients with heart failure.

#### **5.2. Post-MI**

After an acute myocardial infarction, treatment with the ACEI trandolapril reduced the inci‐ dence AF in patients with impaired left ventricular function, irrespective of the effects on ejection fraction per se.[90] Similar results were reported by Pizzetti et al. with lisinopril in their analysis of the GISSI-3 trial.[91]

#### **5.3. Hypertension**

The issue of the possible role of ACEI/ARB drug treatment in the primary prevention of AF in hypertensive patients derives from several conflicting observations. According to the CAPPP and the STOP-H2 trials, ACEIs were comparable to other antihypertensive regiments in preventing AF.[92,93] In contrast, a retrospective, longitudinal, cohort study by L'Allier et al. reported a benefit of ACEIs over calcium channel blockers in terms of new onset AF and AF-related hospitalizations.[94] Similar results were derived from the LIFE trial, showing that when compared with the *β*-blocker atenolol, patients receiving the ARB losartan had significantly lower incidence of new-onset AF and associated stroke.[95] A recent nested case-control observational study showed that compared with treatment with calcium channel blockers, long-term antihypertensive treatment with ACEIs, ARBs, or *β*-blockers may decrease the risk of new-onset AF.[96]

irbesartan showed a dose-dependent preventive effect.[106] In contrast, Tveit and cow‐ orkers did not find any benefit by treating with the ARB candesartan for 3-6 weeks be‐ fore and 6 months after electrical cardioversion.[108] We contributed to this debate by showing that also in the setting of lone AF,[11] long-term treatment with the ACE-I ram‐ ipril is effective in preventing relapses of AF after successful cardioversion.[109] More‐ over, at the end of a 3-year follow-up, ramipril treatment also prevented left atrium enlargement,[109] which has been demonstrated to occur in the natural history of lone

Atrial Fibrillation and the Renin-Angiotensin-Aldosterone System

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11

In patients undergoing catheter ablation for drug refractory AF, ACEIs or ARBs did not show the same promising results,[111-115] raising the question whether these interventions

Both ACEIs and ARBs have shown some promise in the setting of the prevention of paroxysmal AF recurrences. In two long-term clinical trials on amiodarone-treated pa‐ tients, losartan or perindopril were more effective than amlodipine in the maintenance of sinus rhythm. [117,118] The same held true for telmisartan, that Fogari et al. showed as more effective than ramipril in reducing AF recurrence and severity as well as in im‐ proving P-wave dispersion, suggesting a possible specific effect of telmisartan on atrial electric remodeling.[119] In a retrospective analysis of patients with predominantly par‐ oxysmal AF, Komatsu and coworkers showed that the enalapril added to amiodarone reduced the rate of AF recurrence and prevented the development of atrial structural re‐ modeling.[120] In a post hoc subgroup analysis of the AFFIRM trial, Murray et al. showed that ACEIs and ARBs reduced the risk of AF recurrence in patients with a his‐ tory of CHF or impaired left ventricular function. [121] The GISSI-AF trial did not show any significant effect of valsartan treatment on the rate of AF recurrences in a cohort of 1,442 patients with a history of recent AF.[122] Although it has to be noted that valsar‐ tan-treated patients had a significantly higher prevalence of coronary artery disease and peripheral artery disease, and that more than half of the patients were already taking concomitant ACEI treatment, the GISSI-AF shed some doubt on the whole issue of the preventive role of RAAS inhibition in AF prevention.[122] In the same line, the very re‐ cent ANTIPAF trial concluded that 12-month treatment with the ARB olmesartan did not reduce the number of AF episodes in patients with documented paroxysmal AF without structural heart disease.[123] Similar results were shown by the J-RHYTHM II study comparing the ARB candesartan with the calcium antagonist amlodipine in the treatment of paroxysmal AF associated with hypertension.[124] Both studies used daily transtelephonic monitoring to examine asymptomatic and symptomatic paroxysmal AF

are indeed able to revert atrial remodeling in this clinical setting.[116]

AF.[110]

**5.7. Paroxysmal AF prevention**

episodes. [123,124]

#### **5.4. Increased cardiovascular risk**

In patients with increased cardiovascular risk, the rate of new onset AF was not reduced by ramipril in a subanalysis of the HOPE clinical trial by Salehian and coworkers,[97] although in a population with a rather low incidence of AF (2.1%). Also in the ACTIVE I trial, there was no benefit of irbesartan treatment in preventing hospitalization for atrial fibrillation or atrial fibrillation recorded by 12-lead electrocardiography, nor was there a benefit in a sub‐ group of patients who underwent transtelephonic monitoring.[98] In contrast, according to Schmieder et al. the VALUE trial showed that valsartan-based antihypertensive treatment reduced the development of new-onset AF compared to amlodipine,[99] in subjects at high‐ er risk of this arrhythmia due to an almost 25% prevalence of electrocardiographically-de‐ fined left ventricular hypertrophy. These conflicting data may indicate that a possible benefit of ACEI or ARB treatment can at best be observed in patients with the highest proba‐ bility of increased RAAS activation.

#### **5.5. Postoperative AF**

A reduced incidence of new-onset AF was observed in patients undergoing coronary artery bypass graft surgery who were treated with ACEIs,[100] in a large multicenter prospective trial recruiting 4,657 subjects. These results were confirmed with the use of ACEIs alone or associated with candesartan,[101] whereas the reduced risk of developing postoperative AF did not reach the statistical significance in the *post hoc* evaluation of patients enrolled in the AFIST II and III trials.[102]

#### **5.6. Secondary prevention after cardioversion and after catheter ablation**

In the setting of secondary prevention, patients undergoing AF cardioversion represent a group in which the potential role of RAAS inhibition has been first investigated by van den Berg et al.[103], iwho studied 30 CHF patients treated with lisinopril or placebo be‐ fore and after the procedure. Although the reduced incidence of recurrent AF in ACE-I treated patients did not reach the statistical significance, this study was followed by many others. Dagres et al. [104] demonstrated that treatment with the ARB irbesartan is associated with attenuated left atrial stunning after cardioversion. Subsequent studies showed that the association of an ACEI or an ARB with amiodarone prevents AF recur‐ rences after cardioversion when compared with amiodarone alone.[105-107] Interestingly, irbesartan showed a dose-dependent preventive effect.[106] In contrast, Tveit and cow‐ orkers did not find any benefit by treating with the ARB candesartan for 3-6 weeks be‐ fore and 6 months after electrical cardioversion.[108] We contributed to this debate by showing that also in the setting of lone AF,[11] long-term treatment with the ACE-I ram‐ ipril is effective in preventing relapses of AF after successful cardioversion.[109] More‐ over, at the end of a 3-year follow-up, ramipril treatment also prevented left atrium enlargement,[109] which has been demonstrated to occur in the natural history of lone AF.[110]

In patients undergoing catheter ablation for drug refractory AF, ACEIs or ARBs did not show the same promising results,[111-115] raising the question whether these interventions are indeed able to revert atrial remodeling in this clinical setting.[116]

#### **5.7. Paroxysmal AF prevention**

regiments in preventing AF.[92,93] In contrast, a retrospective, longitudinal, cohort study by L'Allier et al. reported a benefit of ACEIs over calcium channel blockers in terms of new onset AF and AF-related hospitalizations.[94] Similar results were derived from the LIFE trial, showing that when compared with the *β*-blocker atenolol, patients receiving the ARB losartan had significantly lower incidence of new-onset AF and associated stroke.[95] A recent nested case-control observational study showed that compared with treatment with calcium channel blockers, long-term antihypertensive treatment with

In patients with increased cardiovascular risk, the rate of new onset AF was not reduced by ramipril in a subanalysis of the HOPE clinical trial by Salehian and coworkers,[97] although in a population with a rather low incidence of AF (2.1%). Also in the ACTIVE I trial, there was no benefit of irbesartan treatment in preventing hospitalization for atrial fibrillation or atrial fibrillation recorded by 12-lead electrocardiography, nor was there a benefit in a sub‐ group of patients who underwent transtelephonic monitoring.[98] In contrast, according to Schmieder et al. the VALUE trial showed that valsartan-based antihypertensive treatment reduced the development of new-onset AF compared to amlodipine,[99] in subjects at high‐ er risk of this arrhythmia due to an almost 25% prevalence of electrocardiographically-de‐ fined left ventricular hypertrophy. These conflicting data may indicate that a possible benefit of ACEI or ARB treatment can at best be observed in patients with the highest proba‐

A reduced incidence of new-onset AF was observed in patients undergoing coronary artery bypass graft surgery who were treated with ACEIs,[100] in a large multicenter prospective trial recruiting 4,657 subjects. These results were confirmed with the use of ACEIs alone or associated with candesartan,[101] whereas the reduced risk of developing postoperative AF did not reach the statistical significance in the *post hoc* evaluation of patients enrolled in the

In the setting of secondary prevention, patients undergoing AF cardioversion represent a group in which the potential role of RAAS inhibition has been first investigated by van den Berg et al.[103], iwho studied 30 CHF patients treated with lisinopril or placebo be‐ fore and after the procedure. Although the reduced incidence of recurrent AF in ACE-I treated patients did not reach the statistical significance, this study was followed by many others. Dagres et al. [104] demonstrated that treatment with the ARB irbesartan is associated with attenuated left atrial stunning after cardioversion. Subsequent studies showed that the association of an ACEI or an ARB with amiodarone prevents AF recur‐ rences after cardioversion when compared with amiodarone alone.[105-107] Interestingly,

**5.6. Secondary prevention after cardioversion and after catheter ablation**

ACEIs, ARBs, or *β*-blockers may decrease the risk of new-onset AF.[96]

**5.4. Increased cardiovascular risk**

10 Atrial Fibrillation - Mechanisms and Treatment

bility of increased RAAS activation.

**5.5. Postoperative AF**

AFIST II and III trials.[102]

Both ACEIs and ARBs have shown some promise in the setting of the prevention of paroxysmal AF recurrences. In two long-term clinical trials on amiodarone-treated pa‐ tients, losartan or perindopril were more effective than amlodipine in the maintenance of sinus rhythm. [117,118] The same held true for telmisartan, that Fogari et al. showed as more effective than ramipril in reducing AF recurrence and severity as well as in im‐ proving P-wave dispersion, suggesting a possible specific effect of telmisartan on atrial electric remodeling.[119] In a retrospective analysis of patients with predominantly par‐ oxysmal AF, Komatsu and coworkers showed that the enalapril added to amiodarone reduced the rate of AF recurrence and prevented the development of atrial structural re‐ modeling.[120] In a post hoc subgroup analysis of the AFFIRM trial, Murray et al. showed that ACEIs and ARBs reduced the risk of AF recurrence in patients with a his‐ tory of CHF or impaired left ventricular function. [121] The GISSI-AF trial did not show any significant effect of valsartan treatment on the rate of AF recurrences in a cohort of 1,442 patients with a history of recent AF.[122] Although it has to be noted that valsar‐ tan-treated patients had a significantly higher prevalence of coronary artery disease and peripheral artery disease, and that more than half of the patients were already taking concomitant ACEI treatment, the GISSI-AF shed some doubt on the whole issue of the preventive role of RAAS inhibition in AF prevention.[122] In the same line, the very re‐ cent ANTIPAF trial concluded that 12-month treatment with the ARB olmesartan did not reduce the number of AF episodes in patients with documented paroxysmal AF without structural heart disease.[123] Similar results were shown by the J-RHYTHM II study comparing the ARB candesartan with the calcium antagonist amlodipine in the treatment of paroxysmal AF associated with hypertension.[124] Both studies used daily transtelephonic monitoring to examine asymptomatic and symptomatic paroxysmal AF episodes. [123,124]

#### **5.8. Emerging role for aldosterone antagonists**

In the recent years, it has been suggested that upstream therapy using aldosterone antago‐ nists, such as spironolactone or eplerenone, may reduce the deleterious effect of excessive aldosterone secretion on atrial tissue, thereby contributing to modify the risk of developing and of maintaining AF.[125] Dabrowski et al. showed that combined spironolactone plus be‐ ta-blocker treatment might be a simple and valuable option in preventing AF episodes in pa‐ tients with normal left ventricular function and history of refractory paroxysmal AF.[126] In patients with AF, spironolactone treatment was associated with a reduction in the AF bur‐ den, as reflected by a combination of hospitalizations for AF and electrical cardioversion. [127] In a recent trial in patients with systolic heart failure and mild symptoms (EMPHASIS-HF), the aldosterone antagonist eplerenone reduced the incidence of new-onset AF or atrial flutter.[128]

**5.10. Atrial remodeling as a therapeutic target: modulation of the renin-angiotensin-**

Since angiotensin II plays a central role in the development of atrial fibrosis, inhibition of atrial angiotensin converting enzyme (ACE) and AT1 angiotensin receptors might be beneficial in AF. In experimental models, AF susceptibility and atrial fibrosis were de‐ creased by candesartan or enalapril, but not by hydralazine or isosorbide mononitrate despite similar hemodynamic effects,[26,63] thus suggesting a key role of targeting reninangiotensin system, rather than of improving the hemodynamics. This concept was fur‐ ther underscored after demonstrating a preventive role of ramipril treatment in patients with lone AF.[109] Also spironolactone was able to prevent AF episodes in patients with normal left ventricular function and a history of refractory paroxysmal AF.[126] With the notable exception of the GISSI-AF,[122] ANTIPAF,[123] and J-RHYTHM II[124] trials, the majority of the available studies showed that modulation of the renin-angiotensin-al‐ dosterone system is able to reduce the incidence of AF, as well as its recurrence after electrical cardioversion.[134] These data are summarized in several meta-analyses, [131,132,140,143] also including the GISSI-AF data.[135] In a broader view, although ACE inhibitors and angiotensin-II receptor blockers (ARBs) are not to be considered an‐ tiarrhythmic drugs, several studies have shown that they are associated with a lower in‐ cidence of ventricular arrhythmias in patients with ischemic heart disease and left ventricular (LV) dysfunction,[90,144,145] possibly because of the adverse effects of angio‐ tensin II on the cardiac remodeling process. Indeed, it must be recognized that in the presence of a cardiac disease causing atrial overload and/or dysfunction, the effective‐ ness of ACE inhibitors and/or ARBs might be attributable either to a direct antiarrhyth‐ mic effect or to an effect on atrial structure and/or function likely able to favorably modify the arrhythmic substrate, such as the increase in left atrial (LA) dimensions that is frequently observed in patients with arterial hypertension and/or LV dysfunction.

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13

In the setting of AF, it has to be remembered that angiotensin II not only has several effects on the *structure* of the atrial myocardium, but also on its *electrical* properties, as it has been elegantly shown in isolated pulmonary vein cardiomyocytes,[75] and in instrumented ani‐ mal studies.[69] Therefore, the protective effect of ACE inhibition or angiotensin II antago‐ nists on the electrical and structural remodeling of the atria is very likely, due to a combination of their actions on atrial distension/stretch, sympathetic tone, local renin-angio‐

The onset of atrial fibrillation results from a complex interaction between triggers, arrhyth‐ mogenic substrate, and modulator factors. Once established, AF itself alters the electrical and structural properties of the atrial myocardium, thereby perpetuating the arrhythmia. Among many other factors, angiotensin II and aldosterone play an important role not only

tensin system, electrolyte concentrations, and cardiac loading conditions.

**aldosterone system**

**6. Conclusions**

#### **5.9. Meta-analyses**

The promise of a protective role of RAAS inhibition is largely based on the analysis of retro‐ spective data, although on several thousands of patients. Another limitation is the fact that in most cases, the detection of AF recurrences is based on annual electrocardiograms, peri‐ odical 24-hour Holter analysis, or patient self-reported symptoms symptoms. In recent years, with the analysis of data from patients with an implanted pacemaker, it is becoming increasingly clear that continuous monitoring is much more reliable in identifying the pres‐ ence of asymptomatic recurrences, with a mean sensitivity in detecting an AF episode last‐ ing >5 minutes that was 44.4%, 50.4%, and 65.1% for 24-hour Holter, 1-week Holter, and 1 month Holter monitoring, respectively.[129] To partially overcome some of these limitations, several meta-analyses of the available trials have been conducted.[130-141] In synthesis, despite the promising preliminary experimental and clinical data, the efficacy of RAAS inhibition in the prevention of atrial fibrillation recurrences is still under debate, lead‐ ing Disertori et al. in a very recent review article to the definition of "an unfulfilled hope". [136] In meta-analysis including 92,817 randomized patients, Khatib and coworkers con‐ cluded that although RAAS inhibition appears to reduce the risk of developing new onset atrial fibrillation in different patient groups, further research with stronger quality trials is required to draw definitive conclusions.[141]

Indeed, ACE-I or ARBs cannot be considered as an alternative to the established antiar‐ rhythmic agents and transcatheter ablation. However, since they are recommended for most concomitant cardiovascular diseases that are associated with an increased risk of AF (i.e., hypertension, heart failure, ischemic heart disease) and since there are several lines of evidence that increased angiotensin II tissue levels are involved in both structur‐ al and electrical remodeling of the atrial tissue, it appears reasonable to use these drugs. In general, no substantial difference was found in the comparison between ACE-I and ARB treatment, a finding that was confirmed also by the results of the the ONTARGET and TRANSCEND trials.[142]

#### **5.10. Atrial remodeling as a therapeutic target: modulation of the renin-angiotensinaldosterone system**

Since angiotensin II plays a central role in the development of atrial fibrosis, inhibition of atrial angiotensin converting enzyme (ACE) and AT1 angiotensin receptors might be beneficial in AF. In experimental models, AF susceptibility and atrial fibrosis were de‐ creased by candesartan or enalapril, but not by hydralazine or isosorbide mononitrate despite similar hemodynamic effects,[26,63] thus suggesting a key role of targeting reninangiotensin system, rather than of improving the hemodynamics. This concept was fur‐ ther underscored after demonstrating a preventive role of ramipril treatment in patients with lone AF.[109] Also spironolactone was able to prevent AF episodes in patients with normal left ventricular function and a history of refractory paroxysmal AF.[126] With the notable exception of the GISSI-AF,[122] ANTIPAF,[123] and J-RHYTHM II[124] trials, the majority of the available studies showed that modulation of the renin-angiotensin-al‐ dosterone system is able to reduce the incidence of AF, as well as its recurrence after electrical cardioversion.[134] These data are summarized in several meta-analyses, [131,132,140,143] also including the GISSI-AF data.[135] In a broader view, although ACE inhibitors and angiotensin-II receptor blockers (ARBs) are not to be considered an‐ tiarrhythmic drugs, several studies have shown that they are associated with a lower in‐ cidence of ventricular arrhythmias in patients with ischemic heart disease and left ventricular (LV) dysfunction,[90,144,145] possibly because of the adverse effects of angio‐ tensin II on the cardiac remodeling process. Indeed, it must be recognized that in the presence of a cardiac disease causing atrial overload and/or dysfunction, the effective‐ ness of ACE inhibitors and/or ARBs might be attributable either to a direct antiarrhyth‐ mic effect or to an effect on atrial structure and/or function likely able to favorably modify the arrhythmic substrate, such as the increase in left atrial (LA) dimensions that is frequently observed in patients with arterial hypertension and/or LV dysfunction.

In the setting of AF, it has to be remembered that angiotensin II not only has several effects on the *structure* of the atrial myocardium, but also on its *electrical* properties, as it has been elegantly shown in isolated pulmonary vein cardiomyocytes,[75] and in instrumented ani‐ mal studies.[69] Therefore, the protective effect of ACE inhibition or angiotensin II antago‐ nists on the electrical and structural remodeling of the atria is very likely, due to a combination of their actions on atrial distension/stretch, sympathetic tone, local renin-angio‐ tensin system, electrolyte concentrations, and cardiac loading conditions.
