Phase 3, Prospective, Randomized, Double-blinded, Placebo-controlled Study to Evaluate Efficacy of add-on Therapy With Spironolactone to Reduce Diffuse Myocardial Fibrosis Thus Preventing Recurrent Episodes of Atrial Fibrillation in Patients With Paroxysmal or Persistent Atrial Fibrillation and Preserved Ejection Fraction Compared to Usual Care.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia present in 1% of population under 60 years of age and reaching up to 15 % at 80 years. Due to demographic changes in the Danish population, the incidence and prevalence of AF is expected to double within the next 30 years. Furthermore a number of diseases which are associated with a higher prevalence of AF such as ischemic heart disease, valvular heart disease, diabetes mellitus and hypertension are also expected to increase in prevalence due to the aging population which will contribute to an increased incidence of AF. AF increases mortality and causes important morbidity, mainly due to thromboembolic complications and increases health economic costs. Additionally, AF is associated with reduced quality of life.

The onset and maintenance of AF is highly complex and the most frequent pathoanatomic changes in AF are atrial fibrosis. In recent years, experimental and clinical studies have demonstrated that atrial remodelling and dilation in AF depending on cellular hypertrophy, fibroblast proliferation and tissue fibrosis. Atrial fibrosis leads to disruption of the electrical side-to-side junctions between muscle bundles and has potentially arrhythmogenic mechanisms. The association of atrial fibrosis and AF has been the subject of intense recent investigation, and it is now widely accepted that interstitial fibrosis creates a substrate for arrhythmia. It is believed that when atrial myocardial fibre bundles are separated by connective tissue, the conduction properties are altered because of the effects on axial resistance, leading to arrhythmia. Myocardial fibrosis is preceded by a growing activity of extracellular matrix (ECM), pro-inflammatory cytokines and at the same time more pronounced collagen (type I and III) expression. Histological studies in patients with both AF and sick sinus syndrome have shown extensive fibrosis of the atrial muscle in the sinus node and internodal tracts. These results suggest that myocardial interstitial fibrosis plays a crucial role in AF .

Recent research suggests that many of the structural and electrophysiological changes that lead to AF can be attenuated or reversed through treatment with Upstream Therapy targeting the rennin-angiotensin II-aldosterone system (RAAS). Upstream therapy such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) and spironolactone possess antifibrotic properties, in addition, to their more well-known mechanisms of action. Most clinical trial data suggest RAAS inhibition with ACEI or ARB are associated with a lower risk of incident AF in patients with heart failure, but data from hypertension trials have been inconsistent.

Increased activation of RAAS may have a key role in the development and maintenance in AF. Especially angiotensin II and aldosterone draw attention. Aldosterone has hypertensive action, induces hypertrophy and fibrosis of cardiomyocytes and endothelium, modulating ion currents and refractoriness in the heart cycle. Arrhythmogenic aldosterone mechanisms include inhibition of noradrenalin reuptake, attenuation of baroreceptor activity, increase their sensitivity to catecholamines and reduce sinus rhythm variability. The expression of both the aldosterone receptor and angiotensin II receptors (AT1 and AT2) is increased in the atria of AF patients. For example, Boldt et al. reported a 100 % increase in AT1 receptor density in the left atrium in patients with chronic and paroxysmal AF compared to sinus rhythm . This reflects increased tissue activation of angiotensin II in fibrillating atria. Moreover, multiple studies have demonstrated a vicious cycle of RAAS in which aldosterone enhances the effects of angiotensin II, in part via an increased transcription of the AT1 receptor, whereas angiotensin II increases systemic and tissue levels of aldosterone. These findings are consistent with findings of elevated plasma levels of both angiotensin II and aldosterone during AF in a study by Goette et al. By blocking mineralocorticoid receptors with MRAs, RAAS over-activation can be diminished. Available data suggest that there are direct effects of spironolactone on the structural and electrical properties of the atria, preventing occurrence and maintenance of AF through its antifibrotic properties, as well as the indirect influence of improved control of heart failure and hypertension, both of which are known risk factors for AF.

Dabrowski et al. documented a significant reduction (p<0.0001) in the recurrence of symptomatic AF episodes in patients with symptomatic paroxysmal AF treated with spironolactone 25 mg/day compared to patients treated with enalapril or a beta-blocker. In addition, the effect of spironolactone was more prominent than that of enalapril already after 9-12 months treatment, where the effect of enalapril was less pronounced. Moreover, the addition of enalapril to spironolactone did not influence the frequency of AF recurrences.