Historicallv, aldosterone was classified as a steroid hormone synthesized from the
I backbone cholesterol molecule in the
I mitochondria of the adrenal zona glomerulosa. Recent research has shown that it is produced in many extra-adrenal sites, including cardiovascular tissue. Since the adrenals contain only 1 to 2 pg aldosterone but secrete some 70 to 250 |ig daily, yielding plasma levels of 5 to 100 pg/mL, it follows that their function is rapid aldosterone synthesis rather than storage. Over 85% of aldosterone is metabolized on first pass through the liver. Thus, its rate of degradation is dependent on hepatic blood flow and its extraction by parenchymal cells, each of which may be impaired in congestive heart failure (CHF).
The main stimuli to aldosterone synthesis by the zona glomerulosa cells are:
Angiotensin-II, the most potent stimulus, acts via AT-II type 1 (ATj) receptors; it also promotes growth of the zona glomerulosa.
Adrenocorticotrophic hormone (ACTH), a stress hormone: the raised cortisol levels in CHF provide indirect evidence that ACTH, the stimulus to cortisol secretion, undergoes a concomitant increase.
Miscellaneous stimulants, all of whose levels change in CHF: endothelin, prolactin, vasopressin, catecholamines, acetylcholine, prostaglandins, and nitric oxide.
The inhibitors of aldosterone synthesis are:
Atrial natriuretic peptide (ANP), which acts by reducing mitochondrial cholesterol uptake.
Heparin, which binds to the AT, receptors in the zona glomerulosa, thus preventing stimulation by angiotensin II.
Ouabain, a digitalis glycoside that inhibits aldosterone synthesis under basal conditions and in response to hyperkalemia; the exact mechanism is unknown, but probably involves inhibition of membrane-bound sodium-potassium ATPase.
Aldosterone promotes sodium reabsorption, thereby expanding the extracellular volume. In patients with CHF, the resulting volume overload has a negative hemodynamic impact. Cardiac output decreases, thus lowering renal blood flow and setting in motion a vicious circle through continuous stimulation of the renin-angiotensin-aldosterone system. The expansion of interstitial fluid volume can then result in clinical congestion and edema. In promoting salt and water retention, aldosterone enhances urinary potassium and magnesium excretion, thus inducing hypokalemia and hypomagnesemia, and electrical instability.
In vivo studies in rats with experimental chronic hyperaldosteronism have shown an association with structural remodeling of the heart, arteries, and systemic organs. Experimental evidence suggests a relationship between myocardial fibrosis in heart failure and chronic elevation of circulating angiotensin II and aldosterone levels. Collagen protein synthesis by cardiac fibroblasts increases, shown by the accumulation of mRNA for types I and III collagen. This observation has been extended to show that aldosterone induces the formation of collagen mRNA directly, as well as indirectly by increasing the hemodynamic load on the ventricle. Clinically, myocardial fibrosis is a key process in the development of myocardial stiffness, malignant ventricular arrhythmia, and left ventricular dysfunction.
Aldosterone also has harmful effects on the peripheral vasculature. Duprez et al found an inverse relationship between plasma aldosterone and large artery compliance, presumably due to the induction of fibrosis and vascular remodeling, or to other negative effects of aldosterone. Wang showed in the dog that aldosterone depresses baroreceptor function, which is thought to be related to large-artery compliance. Recently Swan et al identified aldosterone levels as a determinant of insulin resistance in CHE Insulin sensitivity probably depends on a vessel’s ability to release nitric oxide in response to insulin, and it is also quite likely that the same ability to release nitric oxide determines an artery’s compliance. Thus, according to this hypothesis aldosterone, by acting on nitric oxide, could be the link between compliance and insulin sensitivity. It is of interest that patients with primary aldosteronism have endothelial dysfunction, evidenced by a decrease in their forearm vascular response to acetylcholine vs normal subjects. Resection of the aldosterone-secreting tumor restores normal endothelial function. Endothelial dysfunction has been suggested as a mechanism for the reduced vasodilation in CHF. Thus in several different ways aldosterone could contribute to the generalized vasoconstriction occurring in heart failure.
The diuretics taken by most patients with CHF compound the potassium and magnesium depletion caused by the aldosterone-induced increase in urinary output. Both hypokalemia and hypomagnesemia predispose patients to recurrent ventricular arrhythmia, digitalis toxicity and possible sudden death. Aldosterone may also precipitate ventricular arrhythmia by increasing norepinephrine uptake and thus potentiating the effects of catecholamines. Other studies, however, have suggested that it modulates sympathetic neurotransmission and blocks norepinephrine uptake into myocardium. Thus it has been shown in CHF patients that spironolactone increases the myocardial uptake of meta-iodobenzylguanidine (MIBG), a norepinephrine analogue; in addition, decreased myocardial fixation of MIBG may be associated with altered left ventricular function and a poor prognosis. The exact mechanism and consequences of this potential interaction with myocardial neurotransmission in CHF warrant further studies, which should provide new insights into the detrimental effects of aldosterone.
Aldosterone also seems to influence the baroreflex response, independently of angiotensin II. Perfusion of the canine carotid sinus with aldosterone decreases baroreceptor discharges. In normal humans, aldosterone decreases the heart rate response to norepinephrine infusion mediated by the baroreflex, whereas the pressor response is not modified. Aldosterone increases sodium transport by increasing Na-K pump activity; whether similar effects occur in nerve endings is not known. As the baroreceptor response in heart failure alters due to baroreceptor desensitization, aldosterone contributes to the sympathetic/parasympathetic imbalance in these patients.
High aldosterone levels may also precipitate recurrent ischemic events in patients with left ventricular dysfunction, acting via endothelial dysfunction, hypomagnesemia (which increases coronary resistance), and/or by promoting atherosclerosis (by lowering HDL cholesterol levels).
In CHF patients treated with diuretics and angiotensin-converting enzyme (ACE) inhibitors, aldosterone may escape ACE-inhibitor suppression and remain elevated, for reasons that are incompletely understood. Alternative pathways of angiotensin II production have been identified and are likely to dominate after prolonged ACE blockade and a resultant increase in renin. Aldosterone may be produced by non-angiotensin II-depend-ent mechanisms involving cortisol, ACTH, and ANP, whose levels all increase in CHF. It is also noteworthy that aldosterone escape occurs during exercise, independently of ACE inhibition, suggesting that CHF patients on ACE-inhibitor therapy also experience aldosterone escape during daily life.