Aldosterone — Villain or Bystander?
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《新英格兰医药杂志》
The two primary regulators of aldosterone secretion are potassium and the renin–angiotensin system. The latter is involved in volume homeostasis, with high salt intake suppressing the renin–angiotensin system and aldosterone levels and low salt intake having the opposite effect. Secondary hyperaldosteronism, a physiologic response to dietary salt restriction, promotes renal sodium conservation. In this setting, hyperaldosteronism is a bystander that has no cardiovascular consequences. Hyperaldosteronism emerges as villain in persons whose dietary salt intake is normal if the production of aldosterone is inappropriate for the level of sodium intake, resulting in excessive renal sodium retention, potassium wasting, hypertension, and cardiovascular damage (see Figure).
Figure. Physiologic and Pathophysiologic Effects of Aldosterone on the Kidney and Heart in Relation to Dietary Salt Levels.
Defects in the regulatory relationship between the renin–angiotensin system and aldosterone production occur by means of two mechanisms: autonomous secretion of aldosterone by the adrenal cortex secondary to a neoplasm or bilateral hyperplasia (primary aldosteronism) or hyperaldosteronism secondary to the activation of the renin–angiotensin system, such as that caused by renal-artery stenosis (secondary aldosteronism). Traditionally, hypertension in the setting of hyperaldosteronism has been thought to be due to the expansion of extracellular volume, resulting from excessive renal resorption of sodium.
During the past decade, a revised hypothesis has evolved, featuring an expanded role of aldosterone in the pathogenesis of cardiovascular disease. First, the oft-quoted low prevalence of primary aldosteronism among persons with essential hypertension (0.5 to 1 percent) has been challenged. Recent studies have reported that 8 to 15 percent of persons with essential hypertension fulfill the biochemical criteria for primary aldosteronism. Most of these persons have mild hyperaldosteronism, usually idiopathic bilateral hyperplasia; most do not have hypokalemia.1 Thus, the presence of a normal potassium level does not rule out primary aldosteronism.
Second, new research has focused on the actions of aldosterone in target organs beyond the kidney. In the 1950s, Selye and others realized that aldosterone had nonepithelial effects such as the induction of inflammatory processes, collagen formation, fibrosis, and necrosis. Recent studies in various animal models have confirmed the occurrence of cardiac and renal damage in nonepithelial target tissues.2 Clinical trials in humans (the Randomized Aldactone Evaluation Study [RALES] and the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study [EPHESUS]) have also demonstrated a beneficial effect of mineralocorticoid-antagonist treatment on survival in patients with heart disease. In animal models, aldosterone-induced injury was not observed with low salt intake, even though the aldosterone levels were frankly elevated. Thus, the level of aldosterone alone may not be useful in determining its potential causative role in cardiovascular disease. Rather, when aldosterone is produced in inappropriate amounts for the level of sodium intake, it becomes villainous.
In light of the pleiotropic cardiovascular toxicity of aldosterone, the benefits of aldosterone inhibition as demonstrated in clinical trials, and the likelihood that primary aldosteronism is the most frequent secondary form of hypertension, there has been renewed interest in this hormone. In this issue of the Journal, Vasan and colleagues (pages 33–41) attempt to extend these observations, hypothesizing that a single morning measurement of aldosterone in a cohort of normotensive subjects from the Framingham Offspring Study would correlate with the risk of blood-pressure–related outcomes (the development of hypertension or an increase in blood pressure by one or more categories as defined by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) approximately four years later. A sodium index, calculated as the number of millimoles of sodium per gram of creatinine in a spot urine sample, was used to assess dietary salt intake.
The results indicated a monotonic modest association between the aldosterone level and the risk of an increase in blood pressure. The risk of an increase by one blood-pressure category or the development of hypertension was significant only in the highest quartile of serum aldosterone and only among participants with a sodium index above the median. The authors conclude that increased aldosterone levels within the physiologic range predispose normotensive persons to the development of elevated blood pressure. Yet the mean level of aldosterone in the highest quartile — 19 ng per deciliter (range, 14 to 72) — should be viewed as clearly elevated in a person with normal salt intake. It would have been helpful if the authors had presented the sodium index in each of the quartiles, as well as that in participants with very high aldosterone levels. It is likely that some participants in the highest quartile had mild primary aldosteronism; the authors acknowledge that this is an alternative explanation, but they dismiss this possibility, since the trend toward an increasing risk of the blood-pressure–related outcomes was observed from the second quartile of aldosterone upward. However, when they tried to adjust for aldosterone levels and the urine sodium index, formal testing showed that the interaction was not statistically significant.
As the authors acknowledge, there are a number of limitations to their study. Diagnosing hyperaldosteronism requires knowledge of the level of salt intake as well as the functional status of the renin–angiotensin system. Since aldosterone production is also positively regulated by potassium balance and momentarily by corticotropin, a random measurement of plasma aldosterone has no value unless it is interpreted in the context of dietary sodium intake as well these regulatory factors. The sodium balance was assessed by means of a spot urine sample rather than a 24-hour collection. Potassium and plasma renin activity levels were not measured; therefore, the ratio of the plasma aldosterone level to the plasma renin activity level could not be calculated, and patients could not be classified as having primary or secondary hyperaldosteronism.
Nevertheless, if we assume that all the participants had an ample sodium intake, the association between the highest aldosterone levels and the increase in blood pressure in this study suggests that the aldosterone levels were inappropriate for the salt intake. If so, one potentially important interpretation of these data is that the risk of the development of hypertension in some persons is related to the presence of underlying mild primary hyperaldosteronism. Thus, in these persons, aldosterone may indeed be a villain rather than a bystander in a society in which dietary sodium intake is high.
Dr. Williams reports having received consulting fees from Pharmacia, Novartis, Biogen, and Eli Lilly, as well as lecture fees from Pfizer.
Source Information
From the Division of Endocrine, Diabetes, and Hypertension, Brigham and Women's Hospital; and Harvard Medical School — both in Boston.
References
Young WF Jr. Minireview: primary aldosteronism -- changing concepts in diagnosis and treatment. Endocrinology 2003;144:2208-2213.
Williams JS, Williams GH. 50th Anniversary of aldosterone. J Clin Endocrinol Metab 2003;88:2364-2372.
Related Letters:
Aldosterone Revisited
Haddy F. J., Kleta R., O'Brien K., Syed A. A., Redfern C. P.F., Weaver J. U., Vasan R. S., Benjamin E. J., Levy D., Dluhy R. G., Williams G. H.(Robert G. Dluhy, M.D., an)
Figure. Physiologic and Pathophysiologic Effects of Aldosterone on the Kidney and Heart in Relation to Dietary Salt Levels.
Defects in the regulatory relationship between the renin–angiotensin system and aldosterone production occur by means of two mechanisms: autonomous secretion of aldosterone by the adrenal cortex secondary to a neoplasm or bilateral hyperplasia (primary aldosteronism) or hyperaldosteronism secondary to the activation of the renin–angiotensin system, such as that caused by renal-artery stenosis (secondary aldosteronism). Traditionally, hypertension in the setting of hyperaldosteronism has been thought to be due to the expansion of extracellular volume, resulting from excessive renal resorption of sodium.
During the past decade, a revised hypothesis has evolved, featuring an expanded role of aldosterone in the pathogenesis of cardiovascular disease. First, the oft-quoted low prevalence of primary aldosteronism among persons with essential hypertension (0.5 to 1 percent) has been challenged. Recent studies have reported that 8 to 15 percent of persons with essential hypertension fulfill the biochemical criteria for primary aldosteronism. Most of these persons have mild hyperaldosteronism, usually idiopathic bilateral hyperplasia; most do not have hypokalemia.1 Thus, the presence of a normal potassium level does not rule out primary aldosteronism.
Second, new research has focused on the actions of aldosterone in target organs beyond the kidney. In the 1950s, Selye and others realized that aldosterone had nonepithelial effects such as the induction of inflammatory processes, collagen formation, fibrosis, and necrosis. Recent studies in various animal models have confirmed the occurrence of cardiac and renal damage in nonepithelial target tissues.2 Clinical trials in humans (the Randomized Aldactone Evaluation Study [RALES] and the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study [EPHESUS]) have also demonstrated a beneficial effect of mineralocorticoid-antagonist treatment on survival in patients with heart disease. In animal models, aldosterone-induced injury was not observed with low salt intake, even though the aldosterone levels were frankly elevated. Thus, the level of aldosterone alone may not be useful in determining its potential causative role in cardiovascular disease. Rather, when aldosterone is produced in inappropriate amounts for the level of sodium intake, it becomes villainous.
In light of the pleiotropic cardiovascular toxicity of aldosterone, the benefits of aldosterone inhibition as demonstrated in clinical trials, and the likelihood that primary aldosteronism is the most frequent secondary form of hypertension, there has been renewed interest in this hormone. In this issue of the Journal, Vasan and colleagues (pages 33–41) attempt to extend these observations, hypothesizing that a single morning measurement of aldosterone in a cohort of normotensive subjects from the Framingham Offspring Study would correlate with the risk of blood-pressure–related outcomes (the development of hypertension or an increase in blood pressure by one or more categories as defined by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) approximately four years later. A sodium index, calculated as the number of millimoles of sodium per gram of creatinine in a spot urine sample, was used to assess dietary salt intake.
The results indicated a monotonic modest association between the aldosterone level and the risk of an increase in blood pressure. The risk of an increase by one blood-pressure category or the development of hypertension was significant only in the highest quartile of serum aldosterone and only among participants with a sodium index above the median. The authors conclude that increased aldosterone levels within the physiologic range predispose normotensive persons to the development of elevated blood pressure. Yet the mean level of aldosterone in the highest quartile — 19 ng per deciliter (range, 14 to 72) — should be viewed as clearly elevated in a person with normal salt intake. It would have been helpful if the authors had presented the sodium index in each of the quartiles, as well as that in participants with very high aldosterone levels. It is likely that some participants in the highest quartile had mild primary aldosteronism; the authors acknowledge that this is an alternative explanation, but they dismiss this possibility, since the trend toward an increasing risk of the blood-pressure–related outcomes was observed from the second quartile of aldosterone upward. However, when they tried to adjust for aldosterone levels and the urine sodium index, formal testing showed that the interaction was not statistically significant.
As the authors acknowledge, there are a number of limitations to their study. Diagnosing hyperaldosteronism requires knowledge of the level of salt intake as well as the functional status of the renin–angiotensin system. Since aldosterone production is also positively regulated by potassium balance and momentarily by corticotropin, a random measurement of plasma aldosterone has no value unless it is interpreted in the context of dietary sodium intake as well these regulatory factors. The sodium balance was assessed by means of a spot urine sample rather than a 24-hour collection. Potassium and plasma renin activity levels were not measured; therefore, the ratio of the plasma aldosterone level to the plasma renin activity level could not be calculated, and patients could not be classified as having primary or secondary hyperaldosteronism.
Nevertheless, if we assume that all the participants had an ample sodium intake, the association between the highest aldosterone levels and the increase in blood pressure in this study suggests that the aldosterone levels were inappropriate for the salt intake. If so, one potentially important interpretation of these data is that the risk of the development of hypertension in some persons is related to the presence of underlying mild primary hyperaldosteronism. Thus, in these persons, aldosterone may indeed be a villain rather than a bystander in a society in which dietary sodium intake is high.
Dr. Williams reports having received consulting fees from Pharmacia, Novartis, Biogen, and Eli Lilly, as well as lecture fees from Pfizer.
Source Information
From the Division of Endocrine, Diabetes, and Hypertension, Brigham and Women's Hospital; and Harvard Medical School — both in Boston.
References
Young WF Jr. Minireview: primary aldosteronism -- changing concepts in diagnosis and treatment. Endocrinology 2003;144:2208-2213.
Williams JS, Williams GH. 50th Anniversary of aldosterone. J Clin Endocrinol Metab 2003;88:2364-2372.
Related Letters:
Aldosterone Revisited
Haddy F. J., Kleta R., O'Brien K., Syed A. A., Redfern C. P.F., Weaver J. U., Vasan R. S., Benjamin E. J., Levy D., Dluhy R. G., Williams G. H.(Robert G. Dluhy, M.D., an)