A Lifetime of Aldosterone Excess: Long-Term Consequences of Altered Regulation of Aldosterone Production for Cardiovascular Function

Abstract

Up to 15% of patients with essential hypertension have inappropriate regulation of aldosterone; although only a minority have distinct adrenal tumors, recent evidence shows that mineralocorticoid receptor activation contributes to the age-related blood pressure rise and illustrates the importance of aldosterone in determining cardiovascular risk. Aldosterone also has a major role in progression and outcome of ischemic heart disease. These data highlight the need to understand better the regulation of aldosterone synthesis and its action. Aldosterone effects are mediated mainly through classical nuclear receptors that alter gene transcription. In classic epithelial target tissues, signaling mechanisms are relatively well defined. However, aldosterone has major effects in nonepithelial tissues that include increased synthesis of proinflammatory molecules and reactive oxygen species; it remains unclear how these effects are controlled and how receptor specificity is maintained. Variation in aldosterone production reflects interaction of genetic and environmental factors. Although the environmental factors are well understood, the genetic control of aldosterone synthesis is still the subject of debate. Aldosterone synthase (encoded by the CYP11B2 gene) controls conversion of deoxycorticosterone to aldosterone. Polymorphic variation in CYP11B2 is associated with increased risk of hypertension, but the molecular mechanism that accounts for this is not known. Altered 11beta-hydroxylase efficiency (conversion of deoxycortisol to cortisol) as a consequence of variation in the neighboring gene (CYP11B1) may be important in contributing to altered control of aldosterone synthesis, so that the risk of hypertension may reflect a digenic effect, a concept that is discussed further. There is evidence that a long-term increase in aldosterone production from early life is determined by an interaction of genetic and environmental factors, leading to the eventual phenotypes of aldosterone-associated hypertension and cardiovascular damage in middle age and beyond. The importance of aldosterone has generated interest in its therapeutic modulation. Disadvantages associated with spironolactone (altered libido, gynecomastia) have led to a search for alternative mineralocorticoid receptor antagonists. Of these, eplerenone has been shown to reduce cardiovascular risk after myocardial infarction. The benefits and disadvantages of this therapeutic approach are discussed.

The Effects of Vitamin D Deficiency on Atrial Fibrillation

“…[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] Vitamin D ensures blood pressure regulation by inhibiting RAAS and PTH. 32,33 The studies showed that the levels of renin and angiotensin II could be diminished with vitamin D and its analogues. 34 Calcium plays an important role in initiating AF and in electrophysiological remodeling.…”

Feline primary hyperaldosteronism: an emerging endocrine disease

“…Aldosterone increases blood pressure both by the expanding the extracellular fluid, and by increasing peripheral vascular resistance (CONNELL et al, 2008). As demonstrated in humans, long-term excessive mineralocorticoids can trigger microangiopathy, fibrosis and proliferation of endothelium and smooth muscle in tissues such as the heart and kidneys.…”

“…It was previously thought to be produced only in the adrenal glands; recent studies have shown its production by other tissues including heart, brain and blood vessels, in which it presents both autocrine and paracrine action (CONNELL et al, 2008).…”

PROGRESS IN PRIMARY ALDOSTERONISM: Mineralocorticoid antagonist treatment for aldosterone-producing adenoma

“…Retrospective case-control studies found that the cardiovascular and renal consequences of hypertension were more severe in patients with PA than in patients with essential hypertension and similar levels of office BP (19,20). Consequently, treatment objectives include correction for aldosterone hypersecretion or for the excess stimulation of mineralocorticoid receptors (21). In patients with lateralized aldosterone hypersecretion, this goal can be achieved by adrenalectomy and probably by the long-term prescription of MRAs (22), and MRAs provide a specific treatment for PA in patients who are not candidates for surgery.…”