Aldosterone induces electrical remodeling independent of hypertension
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.
References (61)
- et al.
Electrical and structural remodeling of the failing ventricle
Pharmacol Ther
(2001) - et al.
Role of angiotensin receptor blockers in the prevention and treatment of arrhythmias
Am J Cardiol
(2006) - et al.
Aldosterone-induced inflammation in the rat heart: role of oxidative stress
Am J Pathol
(2002) - et al.
Beneficial impact of spironolactone in diabetic nephropathy
Kidney Int
(2005) - et al.
Dominant-negative suppression of I(K1) in the mouse heart leads to altered cardiac excitability
J Mol Cell Cardiol
(2003) - et al.
The inward rectifier current (IK1) controls cardiac excitability and is involved in arrhythmogenesis
Heart Rhythm
(2005) - et al.
Changes in the calcium current among different transmural regions contributes to action potential heterogeneity in rat heart
Prog Biophys Mol Biol
(2010) - et al.
Electrocardiographic indexes of dispersion of ventricular repolarization: an isolated heart validation study
J Am Coll Cardiol
(1995) - et al.
Effect of spironolactone on ventricular arrhythmias in congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy
Am J Cardiol
(2000) - et al.
Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease
Am J Cardiol
(1995)
Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system
Am J Hypertens
Calcineurin increases cardiac transient outward K + currents via transcriptional up-regulation of Kv4.2 channel subunits
J Biol Chem
Sudden cardiac death in heart failure. The role of abnormal repolarization
Circulation
Arrhythmic and sudden death in chronic ischemic heart disease — a review of epidemiological data
Card Electrophysiol Rev
Two-year time course and significance of neurohumoral activation in the Survival and Ventricular Enlargement (SAVE) Study
Eur Heart J
The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators
N Engl J Med
Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction
N Engl J Med
Electrophysiological changes in heart failure and their relationship to arrhythmogenesis
Cardiovasc Res
The Lambeth Conventions: guidelines for the study of arrhythmias in ischaemia infarction, and reperfusion
Cardiovasc Res
Calcineurin inhibition attenuates mineralocorticoid-induced cardiac hypertrophy
Circulation
Aldosterone directly induces myocyte apoptosis through calcineurin-dependent pathways
Circulation
Biological determinants of aldosterone-induced cardiac fibrosis in rats
Hypertension
Mineralocorticoid excess, dietary sodium, and myocardial fibrosis
J Lab Clin Med
Aldosterone induces a vascular inflammatory phenotype in the rat heart
Am J Physiol Heart Circ Physiol
Excess aldosterone under normal salt diet induces cardiac hypertrophy and infiltration via oxidative stress
Hypertens Res
Effects of spironolactone and eprosartan on cardiac remodeling and angiotensin-converting enzyme isoforms in rats with experimental heart failure
Am J Physiol Heart Circ Physiol
Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure
Circulation
Edema of cardiac origin. Studies of body water and sodium, renal function, hemodynamic indexes, and plasma hormones in untreated congestive cardiac failure
Circulation
Three new epoxy-spirolactone derivatives: characterization in vivo and in vitro
J Pharmacol Exp Ther
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM)
Eur Heart J
Cited by (31)
Interplay of pro-inflammatory cytokines, pro-inflammatory microparticles and oxidative stress and recurrent ventricular arrhythmias in elderly patients after coronary stent implantations
2021, CytokineCitation Excerpt :ALD induced the cardiac oxidative stress and inflammatory response. ALD activated cardiomyocyte-mineralocorticoid receptor and induced cardiac arrhythmia, and particularly promoted the ventricular premature complexes and ventricular tachycardia in humans [47,48]. ALD increased the susceptibility to develop cardiac arrhythmia and played a key role in cardiac arrhythmia.
The novel mineralocorticoid receptor antagonist finerenone in diabetic kidney disease: Progress and challenges
2016, Metabolism: Clinical and ExperimentalCitation Excerpt :Reduction in endothelium-dependent vasodilatation is thought to be caused by an aldosterone-induced decrease in the bioavailability of nitric oxide (NO). Furthermore, MRAs may prevent renal fibrosis, mesangial expansion and glomerulosclerosis via its effects on transforming growth factor-β1 (TGF-β1), plasminogen activator inhibitor-1 (PAI-1), local oxidative stress and endothelial function [21,22] by blocking the affection of aldosterone on glomerular hypertrophy, glomerulosclerosis, proteinuria, and reduced renal blood flow [23]. The other reason that aldosterone should be targeted in the treatment of diabetes before the onset of DKD is lying on its direct association with insulin resistance (IR) [24].
Eplerenone's role in the management of complex cardiovascular disorders
2015, International Journal of CardiologyPrognostic value of aldosterone and cortisol in patients hospitalized for acutely decompensated chronic heart failure with and without mineralocorticoid receptor antagonism
2015, Journal of Cardiac FailureCitation Excerpt :In particular, activation of cardiac MRs is thought to mediate and/or accelerate cardiac hypertrophy, fibrosis, and apoptosis, and subsequently progression of heart failure.5,16–18 MRAs were shown to prevent collagen synthesis and reverse adverse structural and electrical remodeling associated with myocardial infarction or heart failure both in experimental models and affected individuals.19–24 Controversy exists regarding the ligand that activates cardiac MRs.25,26 Besides aldosterone, cortisol, which circulates at systemic concentrations >100 times higher than aldosterone, may bind and activate the MR. In a recent study performed in volunteers without major structural heart disease, intravenous infusion of an MRA led to an increase of tissue-bound cortisol but not of aldosterone in the myocardium, suggesting that cortisol is the main ligand of cardiac MR in vivo.27
Magnetocardiography at rest predicts cardiac death in patients with acute chest pain
2023, Frontiers in Cardiovascular MedicineThe neurobiology of childhood trauma—aldosterone and blood pressure changes in a community sample
2022, World Journal of Biological Psychiatry