There is increasing interest in understanding the role and contribution of aldosterone (ALDO) to the pathophysiology of heart failure (HF). RALES and EPHESUS have shown clear benefits of ALDO-receptor antagonism, especially when added on top of ACE inhibitors or AT1receptor blockers. ALDO, however, has multiple actions that involve genomic effects (take several hours and involve protein synthesis) and nongenomic effects (established within minutes and mediated by intracellular cascades).
Prof. Christian Brilla (G) reminded us that ALDO induces myocardial fibrosis (at high Na+), stimulates collagen synthesis and increases pH very rapidly at subnanomolar concentrations consistent with in vivo stimulation in rat cardiac fibroblasts. These effects (nongenomic) are antagonised by spironolactone, which may participate to the prognostic value of anti-ALDO therapy.
Prof. Jan Danser (NL) showed another nongenomic negative inotropic effect of ALDO in human atrial and ventricular trabeculae (thereby antagonising the positive effect of Angiotensin II). This effect involves PKC (blocked by inhibitor chelerythrine) and ERK1/2, and is independent of mineralocorticoid receptors (MR; insensitive to antagonists spironolactone and eplerenone), which leaves the door open for new therapies.
Prof. Allan Struthers (GB) added to the complexity by pointing out many other benefits of MR antagonism such as, for example, improvement of endothelial dysfunction through NADH/NADPH oxidase-dependent mechanisms. He emphasised that ALDO regulates various signalling pathways involved in structural changes and fibrosis development.
Last, but not least, Dr. Jean-Pierre Bénitah (Fr) showed that modulation of Ca2+ signalling at the cardiomyocyte level by ALDO is another key factor. Ca2+ channel expression was physiologically upregulated (genomic effect) by increased levels of circulating ALDO (in absence of any clinical syndrome) using transgenic mice. However, overstimulation of this system by conditional over expression of the human (h) MR in mice, induced arrhythmias and sudden death (which was prevented by MR antagonism), in relation with increased Ca2+ channel currents, and subsequent Ca2+-dependent down regulation of the repolarising transient outward K+ channel current accounting for cellular action potential (AP) prolongation.
Dr. Bénitah showed that similar ionic remodeling occurs at early stages of HF in the rat (after myocardial infarction or aortic constriction), even before development of cellular hypertrophy. However, this remodelling also was prevented by specific ALDO-receptor antagonism (using RU28318).
Overall, these data provided interesting mechanistic explanations for the same antiarrhythmic benefits of ALDO-receptor antagonism.
Conclusion
ALDO has a broad range of adverse effects generating risks of arrhythmia associated with cardiac hypertrophy and HF. ALDO receptor antagonism seems to decrease these risks by preventing both the electrical remodeling (a key mechanism at the cardiomyocyte level), and the structural remodeling (fibrosis) induced by ALDO overstimulation.
However, mechanisms independent of MR seem also to exist. Profiling these mechanisms might allow a comprehensive approach of the benefits and limits of MR antagonism, which might help for validation of existing – or for development of novel - therapeutic strategies.
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European Society of Cardiology.