Aldosterone induces electrical remodeling independent of hypertension

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Abstract

Background

Treatment of heart failure patients with aldosterone antagonists has been shown to reduce the occurrence of sudden cardiac death. Therefore we aimed at determining the consequences of chronic exposure to aldosterone and the aldosterone antagonists eplerenone and spironolactone on the electrophysiological properties of the heart in a rat model.

Methods and results

Male Wistar rats were chronically treated (4 weeks) with aldosterone (ALD) via an osmotic minipump. Spironolactone (SPI) or eplerenone (EPL) was administered with the rat chow. ALD treated animals developed left ventricular hypertrophy, prolonged QT-intervals, a higher rate of ventricular premature beats and non-sustained ventricular tachycardia despite normal blood pressure values. Spironolactone and eplerenone were both able to inhibit the alterations. Left-ventricular mRNA expressions of Kv4.2 and Kv4.3 (Ito), Kv1.5 (IKur), Kir2.1 and Kir2.3 (IK1) and of Cav1.2 (L-type Ca2+ channel) were significantly down-regulated in ALD. Correspondingly, the protein expressions of subunits Kv1.5, Kir2.3 and Cav1.2 were significantly decreased. A diminished calcineurin activity and mRNA expression of the Aß subunit of calcineurin were found in ALD, which was insensitive to aldosterone antagonists.

Conclusions

Chronic aldosterone-overload induces blood pressure independent structural and electrical remodeling of the myocardium resulting in an increased risk for malignant ventricular arrhythmias.

Introduction

Sudden cardiac death (SCD), to a large extent caused by ventricular tachyarrhythmias, remains one of the major challenges for the treatment of patients with compromised cardiac function. Such arrhythmias have been documented in up to 85% of patients with severe congestive heart failure and SCD is accounting for up to 50% of deaths depending on disease severity [1], [2]. It is believed that electrical remodeling as part of overall cardiac remodeling during the course of heart failure development is contributing to the pathophysiological basis for these arrhythmias [3]. The renin-angiotensin-aldosterone system (RAAS) is intimately involved in the development of electrical remodeling [4]. Particularly aldosterone levels have been reported to correlate significantly with the risk of cardiovascular events [5]. The role of aldosterone is further underlined by two major heart failure trials. Both the RALES [6] as well as the EPHESUS [7] trials demonstrated a significant reduction of SCD in a heart failure population after therapy with aldosterone antagonists. The cardiac action potential is generated by the highly orchestrated activity by a number of depolarizing and repolarizing potassium currents. In various studies heart failure was associated with suppression of repolarizing potassium currents (Ito, IK1, Ikur) and proteins accounting for these currents (Kv4.2 and Kv4.3, Kir2.1 and Kir2.3 and Kv1.5)[8]. Suppression of repolarizing potassium currents leading to action potential prolongation provides an explanation for the QT prolongation/dispersion thereby accounting for a major mechanism of arrhythmogenesis. Despite the clinical data demonstrating the protective effect of aldosterone antagonists against SCD in patients with heart failure, little is known about the effects of aldosterone itself on the ionic basis of electrical remodeling in the heart. The effects of unspecific (spironolactone) and specific (eplerenone) blockade of the mineralocorticoid receptor (MR) on the electrical properties of cardiomyocytes are also mostly unknown.

Therefore the aim of this study was to determine the consequences of chronic aldosterone exposure on the electrical characteristics of the rat heart. In detail, we studied the effects of aldosterone on expression and function of the cardiac ion channels (Ito, IK1, Ikur, ICa) as well as alterations in signal transduction pathways involved in aldosterone mediated signaling. Furthermore we investigated the electrophysiologic effects of the MR antagonists spironolactone and eplerenone individually and in aldosterone treated animals.

Section snippets

Animal model and implantation of osmotic minipumps

Male Wistar rats (48 rats, mean body weight 211 g ± 18 g) (Charles River) were treated with aldosterone (Sigma-Aldrich) or solvent (polyethylene glycole 400, PEG 400) (Sigma-Aldrich) over a period of 4 weeks via an implanted osmotic minipump (ALZET, Pump Model 2004). Aldosterone was dissolved in PEG 400 (aldosterone release 1 μg/h). Pumps were implanted subcutaneously under anesthesia using 70 mg/kg ketamine (Ketavet®, Sanofi) and 5 mg/kg xylazine (Rompun®, Bayer). Rats received either spironolactone

Cardiac hypertrophy and hemodynamic parameters

Aldosterone treatment in male Wistar rats resulted in myocardial hypertrophy with a significant increase in relative heart weight (heart weight/tibia length) compared to control (p < 0.05, Table 1). Aldosterone treated animals showed no signs of congestive heart failure like pale or discolored extremities, shallow, rapid breathing, decreased appetite or rapid weight gain. Spironolactone and eplerenone were able to prevent the development of hypertrophy (p < 0.01 vs. ALD). Tibia length was

Discussion

The presented data support the hypothesis that mild aldosterone-overload causes structural remodeling of the myocardium and electrocardiographic alterations despite normal blood pressure levels resulting in QT prolongation, ventricular extrasystoly and non-sustained VTs. The unspecific aldosterone receptor antagonist spironolactone and the specific antagonist eplerenone are able to prevent most but not all aldosterone-induced alterations suggesting that cardiac mineralocorticoid receptors play

Acknowledgement

This work was supported by “Bundesministerium für Bildung und Forschung, Kompetenznetz Herzinsuffizienz Teilprojekt 8 [01GI0205/16],”Köln Fortune“[56/2008]” and an unrestricted grant by Pfizer©. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

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