| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Editorial |
Prince Henry’s Institute of Medical Research Clayton 3168, Victoria Australia
Address all correspondence and requests for reprints to: Dr. John W. Funder, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton 3168, Victoria, Australia. E-mail: Susan.Smith{at}phimr.monash.edu.au.
Aldosterone was isolated 52 yr ago and characterized by its ability to promote sodium flux across epithelia. Generations of physicians have thus been taught a relatively straightforward physiology of aldosterone. Levels are elevated via the renin-angiotensin system in response to sodium deficiency or lowered circulating volume; it then acts to retain fluid and electrolytes in the kidney and colon, in a classic homeostatic feedback loop. A year or two later, they were taught in the wards that primary aldosteronism was a rare (<1%) cause of essential hypertension, and that it reflected simple disruption of the feedback loop. Autonomous aldosterone secretion promoted fluid and electrolyte retention and an increase in blood volume; the increased blood volume triggered an increase in cardiac output; the increased cardiac output was then reflexly normalized, at the expense of increased peripheral resistance.
Much has changed since we did Physiology 101. It is now increasingly accepted, for example, that primary aldosteronism represents 8–13% of nonselected essential hypertension, across a range of studies in many different countries: given the prevalence of hypertension, this is thus no longer a boutique disorder (1). Secondly, on the basis of abnormal aldosterone to renin ratios, as evidence of autonomous secretion of aldosterone within normal plasma levels, another approximately 25% of unselected so-called essential hypertensives may evolve into primary aldosteronism, with plasma aldosterone levels that are absolutely as well as relatively elevated (1).
What has also changed is the pathophysiology of mineralocorticoid receptors (MR) and the demonstrated benefits of MR blockade in heart failure and hypertension. In progressive New York Heart Association (NYHA) class III heart failure, spironolactone, at an average daily dose of 26 mg in addition to standard of care, produced a 30% improvement in survival, with 35% fewer hospital admissions (2). Eplerenone, the MR-selective antagonist, similarly improved mortality and morbidity when added to standard of care in patients with heart failure after myocardial infarction (3). The combination of eplerenone and the angiotensin-converting enzyme inhibitor Enalapril was shown to be superior, in terms of reversing left ventricular hypertrophy and proteinuria, to maximal doses of either agent alone, with no further effect on blood pressure in essential hypertensive patients (4). Finally, in dose titration studies of eplerenone in essential hypertensives, no correlation was found at any dose between responder/nonresponder status (in terms of attaining goal diastolic blood pressure) and change in serum [K+] (5). One way or another, the classic epithelial action/fluid and electrolyte homeostasis increasingly looks like only a partial underpinning of the pathophysiology of hypertension and heart failure.
Parallel studies on MR blockade in experimental animals have provided further insights into the mechanisms involved. The vessel wall is clearly a physiological target tissue for both rapid and genomic actions of aldosterone, expressing not only MR but also the aldosterone specificity-conferring enzyme 11ß hydroxysteroid dehydrogenase (11ßHSD2). Cardiomyocytes, in contrast, express MR but not 11ßHSD2, and are unlikely to be physiological aldosterone targets, in that cortisol and aldosterone have equivalent affinity for MR, and glucocorticoid levels are approximately 1000 times those of aldosterone. When, however, 11ßHSD2 is expressed (at relatively low levels compared with distal tubule) specifically in cardiomyocytes in transgenic mice, they develop progressive cardiac fibrosis and heart failure (6). Normally glucocorticoids are tonic inhibitory occupants of cardiomyocyte MR, and even a minor degree of aldosterone occupancy appears to have major pathophysiological sequelae.
Enter the Stowasser/Marwick (7) collaboration, published in this issue. Richard Gordon and Michael Stowasser have pioneered the studies that underpin the emerging acceptance of the relatively high prevalence of primary aldosteronism (8). Thomas Marwick and his colleagues have published extensively in the area of the clinical effects of MR blockade, most recently documenting the functional benefits of low dose (25 mg/d) spironolactone as adjuvant therapy in diastolic heart failure (9). In the paper published in this issue (7), they compare a variety of functional cardiovascular parameters, by echocardiography, pulse wave velocity measurements, and standard biochemical assays, in a group of patients with primary aldosteronism and a matched group of controls.
These patients are referred to as the FH-1 group (familial hyperaldosteronism type I), also known as glucocorticoid remediable aldosteronism or glucocorticoid suppressible hypertension. This syndrome was first described almost 30 yr ago (10), and its molecular etiology was documented by Rick Lifton et al. (11) in a landmark paper published in 1992. Underlying the syndrome is the presence of a chimeric gene, with the 5' end of CYP11B1 (11ß hydroxylase) and the 3' end of CYP11B2 (aldosterone synthase). The 5' moiety means that the chimeric gene is expressed throughout the adrenal fasciculata (rather than being confined to the narrow zona glomerulosa); it also means that aldosterone is produced in response to ACTH rather than angiotensin II and [K+]. Although aldosterone secretion is thus not strictly autonomous, in that it can be lowered by dexamethasone administration, it is clearly outside the normal feedback control system, and patients with FH-1, as documented in Ref. 7 , show modestly elevated plasma aldosterone levels.
What the group of eight patients also show, as a selection criterion for inclusion in the study, is normotension: 2-h ambulatory blood pressure values of 120/71, compared with the 24 controls (118/70). The point of the study, then, is clear: to explore the possible negative cardiovascular effects of a modest doubling in ambient aldosterone levels absent any hemodynamic sequelae due to hypertension per se. The results are also clear: the primary aldosterone patients have structural and functional changes characteristic of diastolic dysfunction. Ventricular wall thickness was increased by 15–20%, and mitral early peak velocity decreased to the same extent; peak myocardial early velocity decreased by approximately 20%, and both early and late peak diastolic transmitral flow velocity by approximately 25%. In contrast, indices of systolic function, and of possible cardiac fibrosis, did not differ between the groups, as neither did carotid or femoral pulse wave velocities, as an index of endothelial function.
Animal studies are often illuminating but need to be considered in context. Administration of robust doses (10 times the maximal physiological level) of aldosterone to uninephrectomized rats maintained on 0.9% NaCl drinking solution is followed by spectacular hypertension, cardiac hypertrophy, and florid perivascular and interstitial cardiac fibrosis (12, 13). This is a time-telescoped, brute-forced model of human malignant hypertension, now mercifully a very rare event. The absence of frank fibrosis by myocardial backscatter measurement, the normal pulse wave velocity measurements, and the normal PIIINP (collagen III precursor N terminal peptide, an index of collagen turnover) may thus reflect the youth of the subjects studied (average age, 26 yr) and, as the authors acknowledge, the relatively early stage of their disease. Seven of the eight subjects were members of a single extended family, picked up by screening, and with no blood pressure elevation (including three of eight subjects on oral contraceptives and with substantially elevated plasma renin concentrations). Whether or not other measures of myocardial fibrosis (e.g. endocardial biopsy) or abnormal vascular responses might show differences in the primary aldosterone patients at this stage of their disease remains moot. What also remains to be explored are the cellular and molecular mechanisms responsible for the cardiac hypertrophy and diastolic dysfunction.
Given the demonstrated increases in wall thickness and the indices of diastolic dysfunction, the authors appropriately ask at the end of their paper whether such patients may be better treated with a combination of MR antagonist plus dexamethasone, rather than with dexamethasone alone. In a variety of animal studies in hypertension and heart failure, MR blockade has been shown to be remarkably vasoprotective, even without any alteration in blood pressure (14). Given the premature mortality of patients with FH-1 from stroke, their vasculoprotective effects would also appear to be an additional reason for including an MR antagonist as a prophylactic in the treatment of normotensive patients with FH-1.
Footnotes
Abbreviations: FH-1, Familial hyperaldosteronism type I; 11ßHSD, 11ß hydroxysteroid dehydrogenase; MR, mineralocorticoid receptor.
Received July 19, 2005.
Accepted July 21, 2005.
References
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
