Editorial: aldosterone, normotension, and diastolic dysfunction.

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 specificityconferring enzyme 11 hydroxysteroid dehydrogenase (11 HSD2). Cardiomyocytes, in contrast, express MR but not 11 HSD2, 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, 11 HSD2 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 (11 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, Abbreviations: FH-1, Familial hyperaldosteronism type I; 11 HSD, 11 hydroxysteroid dehydrogenase; MR, mineralocorticoid receptor.