To expect the unexpected shows a thoroughly modern intellect.

Oscar Wilde

Renin–angiotensin–aldosterone system inhibitors (RASIs), including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and angiotensin receptor-neprilysin inhibitors (ARNI) are cornerstones in the management of heart failure with reduced ejection fraction.1 Notably, European Society of Cardiology guidelines recommend RASIs for reducing mortality and the risk of hospitalization in patients with heart failure with reduced ejection fraction, with ARNI also being explicitly considered.1 Strong effects of these drugs stem from their hemodynamic impact, primarily characterized by reducing peripheral resistance and natriuresis boosting.2 Additionally, they promote myocardial reverse-remodeling and fibrosis reduction associated with heart failure.3 Atrial fibrillation (AF) is the most frequent tachyarrhythmia worldwide and can be caused by several cardiovascular diseases.4 However, idiopathic AF is not infrequent and may lead to several issues related to antiarrhythmics therapy resistance.4 Ablation of the AF has emerged as an effective therapeutic option, particularly for young patients and those refractory to current available pharmacological treatment.5 Despite several ongoing attempts to improve technical aspect of the ablation procedure, however, a significant number of patients continue to undergo AF recurrence after ablation.6 It is worth noting that recurrent AF, which is resistant both to medical therapy and to ablation, poses crucial clinical and economic challenges, resulting in substantial resource employment because of recurrent hospitalizations.4 Given the clinical relevance of this condition, an emerging line of research in the realm of AF aims to identify new therapeutic targets to prevent AF recurrence, especially in those cases after unsuccessful ablation.7

The role of the renin–angiotensin–aldosterone system inhibition in the prevention of AF has already been deeply investigated but limited if any research is available regarding the use of RASIs or ARNI specifically in the setting of recurrent AF after ablation.8 The recent meta-analysis by Qian Sun et al9 based on 19 studies, including randomized controlled trials and observational studies, has been conducted to address this knowledge gap (Fig. 1). The overall results indicated a lower recurrence rate in subjects receiving RASIs compared with those who did not (relative risk [RR] = 0.85; 95% confidence interval [CI], 0.72–0.99, P = 0.03).9 Subgroup analyses based on follow-up time, population race, and study design revealed that this effect was slightly different in some cases. Notably, in studies with a follow-up time of 1 year or more, the recurrence rate was not statistically significant (RR = 0.88; 95% CI, 0.76–1.03, P = 0.11), whereas a significant reduction was observed in studies with a 6-month follow-up (RR = 0.52; 95% CI, 0.34–0.78, P = 0.002).9 Moreover, in Asian populations, RASIs were associated with a lower AF recurrence rate (RR = 0.63; 95% CI, 0.47–0.85, P = 0.002), but no statistical significance was found in European and American populations. A pooled analysis of 6 randomized controlled trials indicated a strong association between RASIs use and reduced AF recurrence risk (RR = 0.58; 95% CI, 0.38–0.90, P = 0.01).9 However, the pooled analysis of the 13 cohort studies included showed no statistical association (RR = 0.92; 95% CI, 0.79–1.07, P = 0.28).9 In addition, 3 studies compared the effect of ARNI to RASIs on AF recurrence, revealing a significant statistical difference (P < 0.001).

FIGURE 1.:

Unveiling the impact of RAS inhibitors and ARNI on AF recurrence after ablation.

Notwithstanding many positive aspects of the present work, some important drawbacks are worth to be mentioned, firstly the inclusion of patients from observational studies.9 Furthermore, several clinical studies did not specify participants comorbidities, and there was a relatively brief presence of ARNI administration in the studies involved.9 Noteworthy the fact that prevention of AF events was greater at 6 months of follow-up after ablation rather than 12 months, suggesting that these drugs may not provide long-term protection from AF recurrence.9 Despite such limitations, this work may trace the line for a potential application of RASIs and ARNI in this new clinical setting, but further studies will be mandatory to confirm the hypothesis generated before routinely introducing these drugs for AF prevention after ablation.9 In the meantime, it can be stated, from a pathophysiological perspective, that evidence prove an overlapping action of these drugs on certain pathways that may lead to the development of AF.10 Indeed, it is well-known that ARNI and RASIs can act on left atrial remodelling, leading to a reduction in cardiomyocyte disarray and fibrosis, conditions occurring frequently in atria that have undergone ablation, therefore reducing the arrhythmogenic substrate of AF.11 Moreover, there is a close interplay between the pathophysiology of AF and heart failure: repeated episodes of AF can induce a form of heart failure known as tachycardiomyopathy, whereas the increased left ventricular filling pressures in heart failure lead to left atrial dilation and the development of AF.12

This pathophysiological mechanism is particularly relevant in heart failure with preserved ejection fraction, where ARNI and RAS inhibitors are not yet recommended as first-line treatment but are showing promising data.1 For instance, a pooled analysis of the PARADIGM-HF and PARAGON-HF studies demonstrated that sacubitril/valsartan was associated with a reduction in mortality and hospitalizations in patients with reduced ejection fraction, likely because of improvements in left ventricular and atrial filling pressures.13 Within the realm of cardiovascular pathologies, pleiotropic effects of commonly used drugs in clinical practice have been discovered on multiple occasions. Statins are nowadays recognized not only for their cholesterol-lowering properties but also for their impact on inflammation and plaque stabilization. Colchicine, extensively used in pericarditis, has recently found significant utility in secondary prevention among ischemic patients with poorly controlled cardiovascular risk factors.14 SGLT2 inhibitors, pivotal therapy in heart failure, are being tested by ongoing research for their potential application in cardio-oncology.15 Therefore, when robust pathophysiological foundations are provided, the use of cardiovascular drugs in settings beyond the conventional may unveil new potential therapeutic targets: the case of RASIs and ARNI in recurrent AF after ablation serves as an example of this paradigm, appearing promising. Indeed, it is essential for clinical cardiologists to consider the electro-mechanical pathophysiological continuum of the heart:16 there is no electrical impairment without structural disease and vice versa; this holds more true than ever when we face recurrent AF. Keeping this aspect in mind should guide both clinical practice and patient care, as well as clinical research efforts: for all these reasons we gladly welcome the metanalysis by Sun et al.

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