Aldosterone as an endogenous cardiovascular toxin and the options for its therapeutic management

Česká verzia

Authors: K. Horký
Authors place of work: II. interní klinika kardiologie a angiologie 1. lékařské fakulty UK a VFN Praha, přednosta prof. MUDr. Aleš Linhart, DrSc.
Published in the journal: Vnitř Lék 2011; 57(12): 1012-1016
Category: 70th birthday of prof. MUDr. Petr Dítě, DrSc.

Summary

In physiological, as well as pathological situations, aldosterone significantly influences volume, pressure and electrolyte balance. Primary hyperaldosteronism is caused by autonomous over-production, most frequently due to adrenal adenoma. Patients with primary hyperaldosteronism (Conn’s syndrome) have more pronounced left ventricular hypertrophy and higher frequency of cardiovascular events than patients with essential hypertension (EH) with comparable blood pressure values. Consequently, there is an increased interest in the role of aldosterone tissue function in cardiovascular disease. The aim of the present paper is to emphasise the pleiotropic actions of aldosterone on cardiovascular system and the options for their therapeutic management. Apart from the effects of circulating aldosterone on BP and its renal actions on water and electrolyte excretion, extra-renal effects are also been explored; paracrine affects through tissue mineralocorticoid receptors (MR) may impact on endothelial dysfunction, vascular elasticity, inflammatory changes in the myocardium, vessels and kidneys. Initial oxidative stress due to increased aldosterone concentrations may initiate subclinical endothelial changes and subsequent myocardial fibrosis. The effects on all three layers of vascular wall, together with increased blood coagulation and vascular thrombogenicity increases likelihood of microthrombosis and tissue microinfarctions. Slight increase in aldosterone concentrations in cardiac tissue adversely affects myofibrils as well as coronary artery function. Similar to peripheral vessels, it increases collagen content and changes vascular rigidity and the velocity of pulse wave and facilitates development of perivascular fibrosis. Higher salt intake may potentiate these pathophysiological effects of aldosterone, while higher intake of potassium may restrict them. Aldosterone vasculopathy together with perivascular fibrosis occurring at aldosterone concentrations seen with heart failure contributes to manifestation of heart failure. Consequently, aldosterone may rightly be called “cardiovascular toxin”. The adverse effects of aldosterone in patients on long-term ACEI therapy are further facilitated by the aldosterone’s ability to evade inhibitory effects of ACEI and parallel activation of renin-angiotensin system. To manage these situations, receptors of mineralcorticoids or direct renin inhibitor aliskiren are used. The positive effect of MR blockade is based on an increased release of nitric oxide (NO) with further improvement in endothelial functions. Detailed review of pleotropic effects of aldosterone helps to clarify a number of pathophysiological situations in essential hypertension, supports the view of aldosterone as a potential cardiovascular toxin and indicates the use of mineralocorticoid receptor blockers in resistant hypertension and patients with cardiovascular or renal organ damage.

Key words:
aldosterone – endogenous cardiovascular toxin – hyperaldosteronism – extra-renal effects of aldosterone – aliskiren

Zdroje

1. Vonend O, Quack I, Rump LC. Aldosterone und Hypertonie. Wien Klin Wochenshr 2010; 122: 65–74.

2. Gordon RD. Primary aldosteronism – actual epidemics or false alarm? Arq Bras Endocrinol Metab 2004; 48: 666–673.

3. Funder JW, Carey RM, Fardella C et al. Endocrine Society. Case detection, diagnosis and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrin Metab 2008; 9: 3266–3281.

4. Widimský jr. J. Primární hyperaldosteronizmus: epidemie anebo jen častá příčina sekundární hypertenze. Cor Vasa 2008; 50: 366–367.

5. Štrauch B, Zelinka T, Widimský jr. J et al. Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens 2003; 17: 349–352.

6. Miliez P, Girard X, Plouinn PF et al. Evidence for an increased rate of cardiovascular events in patients with primary hyperaldosteronism. J Am J Coll Cardiol 2005; 45: 1243–1248.

7. Stehr CB, Mellado R, Ocaranza MP et al. Increase levels of oxidative stress, subclinical inflammation and myocardial fibrosis markers in primary aldosteronism patients. J Hypertens 2010; 28: 2120–2126.

8. Rossi GP, DiBello V, Ganzaroli C et al. Excess of adosterone is associated with alterations of myocardial textures in primary aldosteronism Hypertension 2002; 40: 523–526.

9. Pitt B, Zanand F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341: 709–717.

10. Pitt B, Remme W, Zanand F et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348: 1309–1321.

11. Struthers AD, MacDonald TM. Review of aldosterone and angiotensin II-induced target organ damage and prevention. Cardiovasc Res 2004; 61: 663–670.

12. Chai W, Danser AH. Why are mineralocorticoid receptor antagonists cardioprotective? Naunyn-Schmiedbergs Arch Parmacol 2006; 374: 153–162.

13. Barbato JC, Rashid S, Mulrow PJ et al. Mechanisms for aldosterone and spirolactone-induced positive inotropic action in the rat heart. Hypertension 2004; 44: 751–757.

14. Funder JW. The nongenomic actions of aldosterone. Endocr Rev 2005; 26: 313–321.

15. Urabe A, Izumi T, Abe Y et al. Effects of eplerenone and salt intake on left ventricular remodeling after myocardial infarction in rats. Hypertens Res 2006; 29: 627–634.

16. Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol 2007; 3: 486–492.

17. Krum H, Gilbert RE. Novel therapies blocking the renin-angiotensin-aldosterone system in the management of hypertension and related disorders. J Hypertens 2007; 25: 25–35.

18. Büssenmaker E, Hillebrand U, Hausberg K et al. Pathogenesis of hypertension: Interactions among sodium, potassium and aldosterone. Am J Kidney Dis 2010; 55: 1111–1123.

19. Tomaschitz A, Maerz W, Pilz S et al. Aldosterone/renin ratio determines peripheral and central blood pessure values over a broad range. J Am Coll Cardiol 2010; 55: 2171–2178.

20. Hillebrand U, Schillers H, Rietthmüller K et al. Dose-dependent endothelial cell growth and stiffening by aldosterone: endothelial protection by eplerenone. J Hypertens 2007; 25: 639–647.

21. Shah NC, Pringle S, Struthers A. Aldosterone blockade over and above ACE--Inhibitors in patients with coronary artery disease but without heart failure. J Renin Angiotensin Aldosterone Syst 2006; 7: 20–30.

22. Wray DW, Supiano MA. Impact of aldosterone receptor blockade compared with thiazide therapy on sympathetic nervous system function in geriatric hypertension. Hypertension 2010; 55: 1217–1223.

23. Anand K, Mooss AN, Mohiuddin SM. Aldosterone inhibition reduces the risk of sudden cardiac death in patients with heart failure. J Renin Angiotensin Aldosterone Syst 2006; 7: 15–19.

24. Ezekowitz JA, McAlister FS. Aldosterone blockade and left ventricular dysfunction: a systemic review of randomized clinical trials. Eur Heart J 2009; 30: 469–477.

25. Struthers AD. The clinical implications of aldosterone escape in congestive heart failure. Eur J Heart Fail 2004; 6: 539–545.

26. Struthers AD. Aldosterone blockade in cardiovascular disease. Heart 2004; 90: 1229–1234.