Aldosterone-receptor antagonism as a potential therapeutic option for atrial fibrillation

Abstract

Recent research provided important insights into the development of atrial fibrillation (AF)-maintaining substrate and suggested targeting of the underlying molecular mechanisms, ‘upstream’ of the electrical aspects of AF, as a novel strategy for AF treatment (‘upstream’ therapy). Upstream therapies for AF include drugs targeting the renin-angiotensin II-aldosterone system (angiotensin converting enzyme inhibitors and AT₁ receptor antagonists and aldosterone antagonists), statins, steroids and ω-3 fatty acids (fish oil). Aldosterone causes volume retention, cardiac hypertrophy and fibrosis, and systemic inflammation and coagulation that promote AF development and its complications and blockade of aldosterone receptors with spironolactone or eplerenone suppresses inducible AF. Although the clinical impact of spironolactone treatment requires validation in randomized clinical trials in AF patients, further understanding of the molecular mechanisms by which aldosterone causes atrial remodelling is likely to lead to development of novel therapeutic approaches to AF.

This article is a commentary on Zhao et al., pp. 1584–1594 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2009.00551.x

Recent research provided important insights into the development of atrial fibrillation (AF)-maintaining substrate and suggested targeting of the underlying molecular mechanisms, ‘upstream’ of the electrical aspects of AF, as a novel strategy for AF treatment (‘upstream’ therapy). Upstream therapies for AF include drugs targeting the renin-angiotensin II-aldosterone system (RAAS), which include angiotensin converting enzyme (ACE) inhibitors and angiotensin AT₁ receptor antagonists and aldosterone antagonists, along with statins, steroids and ω-3 fatty acids (as in fish oil).

AF is associated with substantial structural changes in atrial tissue that, to a large extent, depend on increased activity of the RAAS. AF can activate the RAAS both in blood and in cardiac tissue, with increased expression/activity of ACE and elevated levels of angiotensin II (Ang II) being major promoters of functional and structural changes during AF. AF also profoundly modulates atrial and ventricular expression levels of both Ang II receptors (AT₁ and AT₂), but AF-related expression patterns differ between short-term (paroxysmal) and persistent AF (Goette et al., 2000a, 2000b).

Aldosterone causes atrial fibrosis independent of changes in wall stress or hypertension and the aldosterone-receptor antagonist spironolactone prevents fibrosis (Sun et al., 1997). Selective aldosterone-receptor blockade with eplerenone suppresses inducible AF in experimental heart failure (Shroff et al., 2006). Plasma aldosterone levels are raised in AF patients (Goette et al., 2001) and aldosterone-receptor expression is higher in atria of AF patients (Pei et al., 2007). In addition, patients with primary aldosteronism have a 12-fold higher risk of developing AF when compared to blood pressure-matched controls further supporting a critical role of aldosterone in the atrial remodelling leading to AF (Milliez et al., 2005).

In various experimental and clinical settings, Ang II and aldosterone synergize to produce deleterious cardiac effects (Milliez et al., 2005; Min et al., 2007; Lemariéet al., 2009). Both Ang II and aldosterone increase volume retention, cardiac hypertrophy and fibrosis, and systemic inflammation and coagulation. However, the relative contribution of aldosterone to AF-dependent atrial fibrosis, hypertrophy, apoptosis, degradation of myofilaments, mitochondrial swelling and dysfunction has not been assessed previously. In this issue of the BJP, Zhao et al. (2010) show that spironolactone largely prevents AF-related changes in atrial structure and function in an in vivo canine model of persistent AF. Spironolactone reduced apoptotic cell death, myolysis, pro-fibrotic pathways and activity, and mitochondrial swelling, and maintained functional parameters such as left atrial ejection fraction. These findings strongly suggested that aldosterone-receptor blockade represents a powerful therapeutic option that, when combined with ACE inhibition or Ang II receptor blockade, may help to maintain atrial integrity and function during AF. Precise molecular mechanisms of how spironolactone prevents structural remodelling were not elucidated in the present study.

Recent evidence indicates that aldosterone has both rapid, non-genomic and slow, genomic effects (Lemariéet al., 2009). Rapid signalling via classical mineralocorticoid receptors (MRs) potentiates the AT₁ receptor-mediated action of Ang II (Min et al., 2007; Lemariéet al., 2009), and non-canonical MRs, probably located on the plasmalemma, have also been implicated in Ang II/AT₁ receptor signalling. Aldosterone enhances the effects of Ang II in part, via increased transcription of AT₁ receptor and ACE, whereas Ang II may increase systemic and tissue levels of aldosterone, consistent with elevated plasma levels of both Ang II and aldosterone during AF (Goette et al., 2001).

Aldosterone and Ang II activate ERK1/2, JNK and NF-κB-signalling pathways in a synergistic manner and these signal pathways are associated with hypertrophic, pro-fibrotic and oxidative stress-responses during AF (Goette et al., 2000a, 2000b; Min et al., 2007). Recent work directly demonstrated that the effects of aldosterone depend on the presence of AT₁ receptors. Aldosterone can also transactivate Ang II type 1a receptors, increasing phosphorylation of ERK1/2, JNK and NF-κB. Interestingly, Ang II stimulates nuclear localization of MRs, and spironolactone inhibits Ang II-mediated MR-dependent gene expression in VSMCs. Ang II-mediated MR activation is also inhibited by losartan, demonstrating a link between AT₁ receptor activation and MR transcriptional activation (Lemariéet al., (2009); Min et al. (2007); Sun et al. 1997). Although aldosterone is produced in the failing human heart (Milliez et al., 2005), it is unclear, whether AF per se induces cardiac synthesis of aldosterone. However, it is tempting to speculate that the increased atrial expression and activation of the Ang II system may enhance cardiac aldosterone synthesis, which could contribute to increased plasma aldosterone levels during AF (Goette et al., 2001). Besides its profibrotic effects, aldosterone enhances potassium and magnesium excretion, decreases myocardial reuptake of catecholamines, and induces baroreceptor dysfunction. Aldosterone increases L-type calcium currents and prolongs action potential duration which may result in early afterdepolarizations. Diastolic calcium leak from the cardiac sarcoplasmic reticulum (SR) leads to delayed afterdepolarizations and AF and chronic stimulation of MRs reduces binding of ryanodine receptor-inhibitory FK506-binding protein, enhancing SR calcium leak (Gómez et al., 2009). Thus, inhibition of aldosterone actions may produce beneficial effects during AF through a variety of mechanisms and further work is needed to dissect the specific pathways of aldosterone-induced atrial remodelling.

In conclusion, although spironolactone appears effective in reducing circulating levels of pro-collagen type III N-terminal amino peptide (a marker of collagen turnover), influencing heart rate variability and molecular atrial biology (Zhao et al., 2010) the clinical impact of spironolactone treatment has not been elucidated in AF patients. In experimental studies, treatments can be administered before AF develops, but clinical AF has to be treated after its onset. There is presently no information about whether targeting MR receptors is effective after AF has become established. Nevertheless, further understanding of the molecular mechanisms by which aldosterone causes atrial remodelling may lead to development of novel therapeutic approaches to AF.

Glossary

Abbreviations:

AF

atrial fibrillation

RAAS

renin-angiotensin-aldosterone system

Conflicts of interest

No conflict of interest to disclose.