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Prof. Daniel Duprez,
Aldosterone plays a key role in cardiovascular damage in heart failure and hypertension. The addition of aldosterone antagonists to the regimens of patients with left ventricular systolic dysfunction and ongoing symptoms of heart failure despite optimal treatment with ACE inhibition and beta-blockers can substantially reduce overall mortality and the rate of sudden death in this vulnerable population.
Seldom is there such a renewed interest in the study of a compound isolated more than a half century ago as we see now with aldosterone. The mineralocorticoid hormone aldosterone was thought to be produced uniquely in the adrenal cortex and to act exclusively on epithelia to promote sodium retention and potassium excretion. However, it is now known that aldosterone also acts on nonepithelial tissues, such as the brain, the heart, and blood vessels. In addition, enzymes required for aldosterone biosynthesis are expressed in these same tissues, which may be consistent with the idea that aldosterone produced locally acts in a paracrine fashion. (1,2)
Preclinical and clinical studies indicate that aldosterone, independent of angiotensin II and elevated blood pressure, may play a role in cardiovascular disease. In addition to its role in fluid and electrolyte balance and circulatory homeostasis, more recent studies have identified aldosterone as a critical mediator of vascular damage. Aldosterone significantly mediates tissue injury through its effects on endothelial function as well as through other potential effects including increasing sodium influx into vascular smooth muscle cells, increasing vascular smooth muscle cell hypertrophy, generation of reactive oxygen species, inhibition of norepinephrine uptake, upregulation of angiotensin II receptors, and stimulation of several growth factors. Aldosterone interacts with mineralocorticoid receptors to promote endothelial dysfunction, facilitate thrombosis, reduce vascular compliance and impair the baroreceptor function. It also interacts with mineralocorticoid receptors to cause myocardial and vascular fibrosis and left ventricular hypertrophy. (3,4) Aldosterone causes autonomic dysfunction. It may also affect the incidence of sudden cardiac death in ischemic and nonischemic heart failure. Aldosterone potentiates the sympathetic activity of catecholamines by blocking their tissue uptake, including their uptake in myocardial tissue. (5)
Activation of the renin-angiotensin-aldosterone (RAA) system is associated with unsatisfactory outcomes in patients with hypertension and heart failure. The activation of this RAA system is strongly correlated with both the incidence and extent of end-organ damage. Despite the availability of the angiotensin converting enzyme inhibitors (ACE-I) and the angiotensin receptor blockers (ARB), unblocked aldosterone levels remain an important risk factor for cardiovascular disease progression. Moreover ACE-I and ARB reduce plasma aldosterone levels initially, but aldosterone rebound, or 'escape' may occur over the course of long-term therapy. (6)
In light of these findings, the ability to block the actions of aldosterone has gained increased therapeutic importance. Therefore, aldosterone blockade is required to reduce the risk of progressive target organ damage in patients with hypertension and heart failure. This may be achieved nonselectively with spironolactone or with the use of the selective aldosterone blocker eplerenone. While both agents are effective antihypertensive agents, eplerenone may produce improved target organ protection as witnessed in a variety of clinical settings, without the antiandrogenic and progestational effects commonly observed with spironolactone. The RALES Study has provided important proof of the effectiveness of aldosterone blockade in patients with severe left ventricular dysfunction (7) . The mechanisms responsible for the beneficial effects of aldosterone blockade in these patients are, as yet, incompletely understood. Eplerenone is a selective aldosterone receptor blocker. It has been evaluated in numerous hypertension subgroups, including in patients with low plasma renin activity; diabetes, left ventricular hypertrophy or uncontrolled blood pressure and in black-coloured skin patients. Concomitantly, these subgroups also received monotherapy with angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, calcium channel blockers, or beta-blockers;. Results of these trials indicate that eplerenone lowers blood pressure and reduces end-organ damage. (8) Further proof of the therapeutic importance of mineralocorticoid receptor blockade comes from the eplerenone post acute myocardial infarction survival and efficacy study (EPHESUS). (9) In this large-scale clinical outcome trial, eplerenone was shown to reduce total mortality by 15% as well as the combined endpoint of cardiovascular mortality/cardiovascular hospitalisation by 13% when administered at a mean of 7.3 days post myocardial infarction to patients with evidence of systolic left ventricular dysfunction and symptoms of heart failure. Eplerenone is well tolerated, with an adverse effect profile comparable to placebo. One might therefore postulate that eplerenone due to its relatively shorter half life may have a lower incidence of hyperkalemia than spironolactone. However, without further prospective direct comparative study this hypothesis remains speculative.
The addition of aldosterone antagonists to the regimens of patients with left ventricular systolic dysfunction and ongoing symptoms of heart failure despite optimal treatment with ACE inhibition and beta-blockers can substantially reduce overall mortality and the rate of sudden death in this vulnerable population. The use of aldosterone antagonists may be well worth the expense or extra effort required to monitor the potential adverse effects. Supplementary trials are needed to determine whether this drug class will be efficacious in patients with less severe symptoms, or in those whose heart failure is due primarily to diastolic dysfunction. (10)
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
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6. Duprez DA, De Buyzere ML, Rietzschel ER, et al. Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients. Eur Heart J. 1998;19:1371-1376. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9792263
7. Pitt B, Zannad, F., Remme, W.J. 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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10471456
8. Pitt B, Reichek N, Willenbrock R et al, Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation. 2003;108:1831-1838. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14517164
9. Pitt B, Remme, W., Zannad, 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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12668699
10. Jessup M. Aldosterone blockade and heart failure. N. Engl. J. Med. 2003;348:1380- 1321. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12668698
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