**6. Conclusions**

**5.8. Emerging role for aldosterone antagonists**

12 Atrial Fibrillation - Mechanisms and Treatment

required to draw definitive conclusions.[141]

and TRANSCEND trials.[142]

flutter.[128]

**5.9. Meta-analyses**

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

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

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

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 in determining atrial fibrosis, but also in modulating the electrical properties of the atrial myocardium. These aspects may be relevant in explaining the many clinical observations in‐ dicating the role of drugs modulating the renin-angiotensin-aldosterone system in prevent‐ ing atrial fibrillation in different settings.

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