Atrial fibrillation and inhibition of the Renin Angiotensin System 

Atrial fibrillation (AF) is the most common arrhythmia with an estimated 5.6 million people affected in the US by 2050. AF is associated with a 2-5 times increased risk of thromboembolic stroke and increased mortality. Various therapeutic options using antiarrhythmic drugs or interventional procedures such as ablation of the pulmonary veins are accepted indications for patient with AF. However, novel approaches and therapeutic alternatives are urgently needed to further improve therapeutic strategies in patients with AF.

I - The Renin Angiotensin system

Experimental evidence of a role of the renin angiotensin system in atrial fibrillation
Experimental animal models of AF suggest that the renin angiotensin system (RAS) has a role in the pathogenesis of AF. Inhibition of the RAS with ACE-inhibitiors (ACE-I) or angiotensin II type 1 receptor antagonists (ARB) have become an important tool in the treatment of hypertension and its cardiovascular complications such as stroke, myocardial infarction and heart failure. Several experimental studies on the pathophysiology of cardiovascular diseases (CVD) have revealed that inhibition of the RAS produce beneficial effects beyond the benefits of blood pressure reduction alone. These include several hemodynamic actions of angiotensin II, a very potent vasoconstrictive agent on the systemic circulation along with many non-hemodynamic actions including cell growth promoting actions on fibroblasts, vascular smooth muscle cells, and cardiac myocytes, pro-inflammatory, and pro-fibrotic potential of angiotensin II and its ability to induce oxidative stress and endothelial dysfunction (1;2).

• Structural and electrophysiological changes in atrial tissue

Both structural and electrophysiological changes in atrial tissue constitute an arrhythmogenic substrate for the induction and maintenance of AF. Atrial fibrosis is thought to fundamentally contribute to the development and maintenance of AF. Experimental models demonstrate that rapid pacing or AF induction induces electrophysiological changes, e.g. shortening of atrial effective refractory period (AERP). These changes allow the easier establishment of multiple re-entry circuits and persistent AF. Inhibition of the RAS with ACE-I or ARB has been shown to prevent electric remodelling in animal models subjected to rapid atrial pacing (3). In addition, treatment with candesartan decreases atrial fibrosis and was able to decrease the duration of episodes of AF (4). Further evidence for the role of RAS comes from observations that increase in tissue angiotensin II concentration could be prevented by enalapril treatment (5). In this study, significant apoptosis developed 24h after ventricular tachypacing (VTP) onset and persisted for 1 week. Interestingly, apoptosis was preceded by increases in tissue angiotensin II concentration and was followed by interstitial fibrosis at 5 weeks. On the other hand, ACE inhibition prevented increases in tissue angiotensin II concentration, phosphorylated ERK expression, and cellular apoptosis, and reduced tissue fibrosis (5).

II - Clinical evidence for a role of the renin angiotensin system in atrial fibrillation

A number of clinical studies have evaluated the role of RAS inhibition in AF. In most of the studies, post hoc analyses of randomised clinical trials were performed and only a few studies have directly investigated the role of RAS inhibition in AF.

The TRACE Study

The post hoc analysis of 1577 patients with sinus rhythm of the trandolapril cardiac evaluation (TRACE) study, a randomized double-blind placebo controlled study in patients with acute myocardial infarction and left ventricular dysfunction, demonstrated that ACE inhibition was associated with a significantly lower risk of developing AF compared to placebo (2.8% vs 5.3%, relative risk (RR) 0.45; 95% confidence interval (CI) 0.26–0.76) (6). Similar results were obtained in the SOLVD study. Enalapril treatment was associated with a 19% reduction in the risk of new-onset AF (RR 0.22; 95% CI 0.11–0.44) compared to placebo (mean follow-up 2.9 years) (7) and associated with a significantly decreased risk of hospitalization with tachyarrhythmias or death (RR 0.87; 95% CI 0.79–0.96; mean follow-up 34 months) (8). Comparable results concerning new-onset of AF were obtained in a retrospective analysis of the Val-HeFT trial in patients with heart failure (5.1% vs 7.9%; RR 0.63, 95% CI 0.49–0.81) 9.Interestingly, it appeared that the observed effects are predominantly seen in ACE-I and ARBs and not other drugs besides statins which have been shown to influence AF incidence via their pleiotropic effects (for review see Adam et al.10).

LIFE study

In a retrospective analysis of the LIFE study, patients on losartan without history or ECG evidence for AF had a 33% reduction in the incidence of new-onset AF compared to patients treated with atenolol (6.8 vs 10.1 per 1,000 person-years, RR 0.67, 95% CI 0.55–0.83)11. Convincingly, the difference in new-onset AF was despite a comparable blood pressure reduction in both groups.

Stop-H2 trial

However, not all studies have shown similar results and post-hoc analyses obtained conflicting results. The STOP-H2 trial showed similar incidence of AF in patients treated with ACE-I compared to other antihypertensive drugs (12) with similar results seen in the GISSI-3 trial (lisinopril, nitrates, or their combination with endpoint morbidity and mortality after myocardial infarction)(13).

Meta-analysis

In 2005, a meta-analysis was performed including 56,308 patients from 11 randomized controlled trials evaluating RAS inhibition with ACE-I or ARB in cardiovascular disease (CHF, hypertension, myocardial infarction) and patients undergoing cardioversion of AF. This meta-analysis showed a 28% relative risk reduction (RR 0.72, 95% CI 0.60–0.85) of AF in patients on RAS blockade (14). RAS inhibition was most effective in AF prevention in patients with CHF (RR 0.56, 95% CI 0.37–0.85) and in patients after cardioversion of AF (RR 0.52, 95% CI 0.35–0.79). No clear benefit was shown for patients treated with ACE-I or ARB for hypertension (RR 0.88, 95% CI 0.66–1.19) or after having myocardial infarction (RR 0.73, 95% CI 0.43–1.26).41

The presented results suggest that RAS inhibition is most effective in preventing AF in patients who are at greatest risk for AF. This includes patients with left ventricular hypertrophy, LV dysfunction, and congestive heart failure.

GISSI

In order to study the role of RAS inhibition on AF prospectively in a cohort of patients with high risk characterizations, the GISSI investigators initiated the GISSI-AF study, the first large prospective, multicenter, randomized, double-blind, placebo-controlled trial in 1442 patients which was published in April 2009 in the New England Journal of Medicine (15). Patients were eligible for the study if they had two or more episodes of symptomatic atrial fibrillation in the previous 6 months or successful cardioversion for atrial fibrillation up to 14 days before randomisation. All patients were in sinus rhythm for at least 2 days before randomization. In order to meet the criteria for a high risk cohort, patients had to have at least signs of heart failure or a history of left ventricular dysfunction (ejection fraction of less than 40%), a history of hypertension with or without left ventricular hypertrophy, type 2 diabetes, a history of coronary artery disease, or atrial fibrillation without coexisting cardiovascular conditions but with left atrial dilatation (left atrial diameter of >45 mm). Patients were assigned to valsartan (target dosis 320mg) or matching placebo.
Recurrent atrial fibrillation occurred in 371 of the 722 patients (51.4%) in the valsartan group and 375 of 720 (52.1%) in the placebo group (adjusted HR, 0.97; 96% CI 0.83 to 1.14; P=0.73). More than one episode of atrial fibrillation occurred in 194 of 722 patients (26.9%) in the valsartan group and in 201 of 720 (27.9%) in the placebo group (adjusted OR, 0.89; 99% CI, 0.64 to 1.23; P=0.34).
Interestingly, the results were comparable in all pre-defined subgroups of patients. The authors concluded that treatment with valsartan was not associated with a reduction in the incidence of recurrent atrial fibrillation.

Various factors may have influenced the results:

1. the observational period of only 1 year was very short with approx. 50% of primary endpoints occurring within 2 months after randomization. From various studies and from the ablation trials we know that recurrence of AF is high within the first months when structural changes within the atria have not taken place, yet.
2. A high proportion of patients was already on ACE-I (57%) and 70% were taking class I or III antiarrhythmic drugs for AF prevention.
3. The GISSI-AF trial was a secondary prevention study. One may speculate that RAS inhibition may demonstrate its greatest benefits in primary prevention by preventing the structural changes within the atria.

What is the clinical quintessence of the GISSI-AF trial? Currently, blockade of the RAS is a pivotal instrument in treating patients with hypertension and heart failure. However, RAS blockade for primary or secondary prevention of AF can currently not be recommended. Future studies will hopefully allow us to clarify the role of ACE-I and ARB in AF prevention.