Correspondence
Aldosterone Revisited
N Engl J Med 2004; 351:2131-2133November 11, 2004
- Article
To the Editor:
Vasan et al. and Dluhy and Williams (July 1 issue)1,2 revisit the role of aldosterone in hypertension and suggest that the incidence of a positive relationship may be greater than previously thought. However, they do not consider the mechanism of aldosterone-induced hypertension. There are at least three possibilities. One is that an increase in blood volume acts directly to increase the blood pressure. This is not likely, because an intravenous infusion of saline has little immediate effect. The blood pressure will increase with time, however, which suggests an indirect mechanism, such as the release of a digitalis-like factor that constricts blood vessels and increases cardiac contractility.3 A third possibility is that an increase in potassium excretion reduces extracellular potassium concentration, thereby, like the digitalis-like factor, reducing the sodium–potassium pump activity and increasing blood-vessel and heart contractility. The mechanism of aldosterone pressor activity may require more detailed examination.
3 ReferencesFrancis J. Haddy, M.D., Ph.D.
211 Second St. NW, Rochester, MN 55901
tbhaddy@aol.com 1
Vasan RS ,Evans JC ,Larson MG , et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med 2004;351:33-41
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Dluhy RG ,Williams GH . Aldosterone -- villain or bystander? N Engl J Med 2004;351:8-10
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Haddy FJ . Endogenous digitalis-like factor or factors. N Engl J Med 1987;316:621-623
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To the Editor:
Aldosterone is gaining publicity beyond its well-known and doubtless beneficial role in fluid and salt homeostasis. Elevated aldosterone levels are implicated as the cause of detrimental effects on human health in general, and the kidney in particular.1
Patients with Gitelman's syndrome or Bartter's syndrome have substantially elevated aldosterone levels owing to distinct monogenetic defects of salt reabsorption along the nephron.2 During their lifetime, these patients show none of the devastating sequelae depicted in the recent Perspective article by Dluhy and Williams. Has research on aldosterone been sufficient to draw such conclusions?
Blocking aldosterone might be good for the economy, but it can have life-threatening consequences, such as hyperkalemia.3 More and better independent data are needed before consideration is accorded to “antialdosterone” treatment.
3 ReferencesRobert Kleta, M.D., Ph.D.
Kevin O'Brien, M.S.N., C.R.N.P.
National Institutes of Health, Bethesda, MD 20892
kletar@mail.nih. gov 1
Hollenberg NK . Aldosterone in the development and progression of renal injury. Kidney Int 2004;66:1-9
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Kleta R ,Basoglu C ,Kuwertz-Broking E . New treatment options for Bartter's syndrome. N Engl J Med 2000;343:661-662
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Davis KL ,Nappi JM . The cardiovascular effects of eplerenone, a selective aldosterone-receptor antagonist. Clin Ther 2003;25:2647-2668
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To the Editor:
Vasan et al. report that increased aldosterone levels within the physiologic range predisposed normotensive people to the development of hypertension. We agree with their suggestion that “an adaptive response essential to survival in a low-sodium environment could turn maladaptive in contemporary society.” This adds another dimension to the “thrifty genotype” hypothesis1 — genes that promote energy conservation confer a survival advantage in times of famine but lead to obesity in times of plenty. Although originally proposed as an explanation for the epidemic of type 2 diabetes in former hunter-gatherer societies that have undergone a rapid transition to a modern lifestyle, it could equally encompass other survival mechanisms. Thus, persons who carry a thrifty genotype for salt conservation would be predisposed to hypertension in the presence of high dietary intake of sodium. This will no doubt increase the debate on the primacy of genetic versus environmental factors. Whereas little can be done about genetic factors, modifying environmental influences, such as dietary salt and calorie intake, should prove beneficial, as already shown in various studies in animals and humans.
1 ReferencesAkheel A. Syed, M.R.C.P.
Christopher P.F. Redfern, Ph.D.
Jolanta U. Weaver, F.R.C.P., Ph.D.
University of Newcastle, Newcastle upon Tyne NE2 4HH, United Kingdom
a.a. syed@ncl. ac. uk 1
Neel JV . Diabetes mellitus: a “thrifty“ genotype rendered detrimental by “progress“? Am J Hum Genet 1962;14:353-362
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Author/Editor Response
Dr. Haddy speculates on the potential cellular mechanisms by which serum aldosterone may increase vascular tone and cause high blood pressure. We agree that the cellular mechanisms underlying the effects of aldosterone on vascular smooth-muscle cells and endothelial cells merit further investigation. Current knowledge about potential mechanisms has been reviewed elsewhere.1,2
Dr. Kleta and Mr. O'Brien point to the existence of patients with elevated aldosterone levels (such as those with Gitelman's syndrome) in whom hypertension may not develop. We had noted in our article that the Yanomamo Indians also have elevated serum aldosterone levels but seem to escape any adverse sequelae.3 These examples suggest that elevated aldosterone levels may not be universally harmful and raise the possibility that the elevation of serum levels relative to dietary sodium intake may be an important determinant of susceptibility to the harmful effects of aldosterone.4 Dr. Syed and colleagues expand on this notion further and speculate that a thrifty genotype for salt conservation may predispose some persons to hypertension in a salt-replete environment. We believe that this hypothesis warrants additional research. We concur that modifications in environmental influences such as dietary sodium, caloric intake, and levels of physical activity are important nonpharmacologic options for preventing hypertension in those who are genetically predisposed to the condition.5
5 ReferencesRamachandran S. Vasan, M.D.
Emelia J. Benjamin, M.D.
Daniel Levy, M.D.
Framingham Heart Study, Framingham, MA 01702-5827
vasan@bu.edu 1
Losel R ,Schultz A ,Boldyreff B ,Wehling M . Rapid effects of aldosterone on vascular cells: clinical implications. Steroids 2004;69:575-578
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Struthers AD ,Macdonald TM . Review of aldosterone- and angiotensin II-induced target organ damage and prevention. Cardiovasc Res 2004;61:663-670
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Oliver WJ ,Cohen EL ,Neel JV . Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a “no-salt“ culture. Circulation 1975;52:146-151
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Sato A ,Saruta T . Aldosterone-induced organ damage: plasma aldosterone level and inappropriate salt status. Hypertens Res 2004;27:303-310
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Chobanian AV ,Bakris GL ,Black HR , et al. The Seventh Report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572[Erratum, JAMA 2003;290:197.]
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Author/Editor Response
We thank Dr. Haddy for his insights about possible mechanisms for the role of aldosterone in hypertension and agree that more research is needed.
We agree with Dr. Kleta and Mr. O'Brien that elevated aldosterone levels are not necessarily detrimental. In fact, in the two mortality trials of mineralocorticoid-receptor blockade (the Randomized Aldactone Evaluation Study1 and the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study2), the aldosterone levels were not elevated. Yet, both trials documented substantial reductions in cardiovascular morbidity and mortality. Both studies also shared three other features: patients had preexisting cardiovascular disease, they had abnormalities in volume homeostasis, and most important, they were not on severely sodium-restricted diets. As we discussed in our Perspective article, high aldosterone levels per se are not sufficient to produce cardiovascular damage. In the rat model of endothelial dysfunction,3 severe cardiovascular damage is prevented by the administration of a mineralocorticoid-receptor antagonist. However, removing salt from the diet is just as effective in preventing cardiovascular damage, even though the aldosterone levels are 10 times as high as those found in animals ingesting normal “rat chow.”
The patients with Bartter's and Gitelman's syndromes are essentially human genetic counterparts of this animal model, and findings in such patients confirm the critical interactions between levels of aldosterone, on the one hand, and salt intake and volume status, on the other. Although patients with such renal tubular conditions have very high aldosterone levels, they are also volume depleted as a result of renal sodium wasting. We agree with Dr. Kleta and Mr. O'Brien that these patients do not have overt cardiovascular damage mediated by activation of the mineralocorticoid receptor, yet they have the wrong phenotype. Unfortunately, long-term, reliable follow-up data are lacking in patients with the Gitelman's and Bartter's syndromes, in large part because the number of such patients is small. Even if such data were available and they documented increased cardiovascular risk in these subjects, the information would not necessarily negate or support the hypothesis stated above, since these persons also have electrolyte and metabolic derangements that could cause cardiovascular damage. The current hypothesis concerning aldosterone-mediated cardiovascular damage does not require very high levels of aldosterone. Rather, it does require activation of the mineralocorticoid receptor in the presence of both adequate salt intake and, probably, some degree of cardiovascular injury.
3 ReferencesRobert G. Dluhy, M.D.
Gordon H. Williams, M.D.
Brigham and Women's Hospital, Boston, MA 021151
Pitt B ,Zannad F ,Remme WJ , et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-717
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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[Erratum, N Engl J Med 2003;348:2271.]
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Martinez DV ,Rocha R ,Matsumura M , et al. Cardiac damage prevention by eplerenone: comparison with low sodium diet or potassium loading. Hypertension 2003;39:614-618
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