Published online before print February 7, 2005, doi: 10.1161/01.HYP.0000154364.00763.d5
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(Hypertension. 2005;45:766.)
© 2005 American Heart Association, Inc.
Original Articles |
Hyperaldosteronism and Hypertension
Ethnic Differences
From the Departments of Medicine (C.E.G., S.K., T.A.K.), Physiology (A.W.C., M.L.K., R.R.), and Epidemiology (J.M.K.), Medical College of Wisconsin, Milwaukee; and Centre Hospitalier (P.H., D.G., Z.P., J.T.), University of Montreal, Canada.
Correspondence to Theodore A. Kotchen, MD, Professor of Medicine, Associate Dean for Clinical Research, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail tkotchen{at}mcw.edu
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Abstract |
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The purpose of this study is to evaluate the relationship between aldosterone and blood pressure in a total of 220 normotensive and 293 essential hypertensive subjects in 2 genetically distinct populations—blacks and white French Canadians. The 24-hour blood pressure monitoring was performed under standardized conditions after discontinuing antihypertensive medications. Plasma renin activity and plasma aldosterone were measured in the supine position and after standing for 10 minutes. Plasma atrial natriuretic factor was also measured. Supine and standing plasma renin activities were lower (P
0.01), plasma aldosterone was higher (P<0.0001), and the aldosterone/renin ratios were higher (P<0.0001) in the hypertensive subjects. Atrial natriuretic factor was also higher in the hypertensive subjects (P<0.0001). Among blacks, blood pressures did not correlate with plasma renin activity. However, both average daytime and nighttime systolic and diastolic blood pressures were correlated with supine and standing plasma aldosterone and with the aldosterone/renin ratio (P<0.005 or less). In French Canadians, blood pressures tended to be positively correlated with standing plasma renin activity and aldosterone, but not with the aldosterone/renin ratio. Correlations of blood pressure with aldosterone were more consistent and more striking in blacks than in French Canadians. In both ethnic groups, there were inconsistent correlations of blood pressure with atrial natriuretic factor. These observations are consistent with the hypothesis that aldosterone-induced volume expansion is an important contributor to hypertension, especially in blacks.
Key Words: aldosterone • blacks • blood pressure • hypertension • renin
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Introduction |
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Aldosterone is a potent mineralocorticoid that promotes sodium retention and elevation of arterial pressure. Evidence that aldosterone may play a role in blood pressure variation was suggested as early as 1956 when Genest et al reported mild hyperaldosteronism as a frequent finding in "essential hypertension."1 Most of his patients had severe malignant-phase hypertension, and at that time it was not possible to measure renin to determine the driving force for the aldosterone production. Until Conn et al reported the utility of assessing renin activity to distinguish primary from secondary aldosteronism, renin measurements were of little clinical usefulness.2 After studying more referred patients, Conn suggested that elevated blood pressure is related to aldosterone excess in perhaps 20% of patients with essential hypertension. In 1970, Collins et al described 20 of 25 patients with "benign essential hypertension" who had elevated 24-hour urine aldosterone excretion rates that were not suppressed by a high-sodium chloride diet; most had "normal" plasma renin.3 Subsequently, Grim suggested that most of the 25% to 50% of patients with low-renin essential hypertension have a subtle disturbance of aldosterone production that suppresses renin release and increases blood pressure.4 Recent observations that many patients with hypertension have evidence of excess aldosterone production, as reflected by an elevated aldosterone/renin ratio, has led to a surge in interest provoked by the 5- to 15-fold increase in the reported frequency of primary aldosteronism reported in the past few years.5 In a recent report from The Framingham Offspring Study, higher plasma aldosterone concentrations within the physiological range predisposed nonhypertensive participants to the subsequent development of hypertension.6
Extracellular fluid volume is an important contributor to the pathogenesis of low-renin hypertension and to hypertension in blacks.7,8 The purpose of the present report is to describe the relationship of plasma aldosterone to blood pressure in normotensive and hypertensive blacks and whites. Plasma atrial natriuretic factor (ANF) concentrations were measured as an indirect index of extracellular fluid volume.9
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Methods |
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In conjunction with our ongoing protocols for studying the genetic determinants of hypertension, the current studies were performed under carefully controlled standardized conditions at clinical research centers, as previously described.10 Blacks were studied at the Medical College of Wisconsin in Milwaukee. Black ethnic identity was based on self-report that the subject, parents, and grandparents were born in the United States, English was their primary language, and all were identified as black, Negro, or African American, depending on the term used by the participant. French Canadians were studied at Chicoutimi Hospital, located in the Saguenay-Lac St. Jean region of Canada. This population originates from ancestors of French descent who migrated to this region in the early 19th century. Identical protocols were performed at both sites. To ensure standardization of these protocols, periodic exchange visits and teleconferences were held between the investigators at both sites.
We used a case-control design. Controls were those subjects with no history of high blood pressure and an outpatient visit with systolic blood pressure <120 mm Hg and diastolic blood pressure <80 mm Hg. Cases had an outpatient systolic blood pressure 
140 mm Hg and diastolic blood pressure 90 mm Hg, or were using antihypertensive medications. Blood pressures were taken by trained certified personnel according to the American Heart Association guidelines by the Shared Care Method.11 After being seated for at least 5 minutes, 2 readings were taken in each arm and the average of the arm with the higher measurement was used for the visit reading. Outpatient anthropometric measurements included body mass index (BMI), waist circumference, waist-to-hip ratio, and measurement of skin-fold thickness at several sites.
Consenting subjects, aged 18 to 55 years, were potential candidates for a 2-day inpatient study. Exclusion criteria included no evidence of secondary hypertension, diastolic blood pressure >110 mm Hg on drug therapy, diabetes mellitus, plasma creatinine >2.2 mg/dL, BMI >34 kg/m2, pregnancy, substance abuse (including alcohol), and myocardial infarction or stroke within 6 months. Among hypertensive subjects, 61% of blacks and 66% of French Canadians had been using antihypertensive medications, and these were withdrawn at least 1 week before study. Diuretics had been used more frequently in blacks (P<0.01), whereas beta-blockers had been used more frequently in French Canadians (P<0.01). There was no difference in the 2 populations in the use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or alpha blockers. Overall, 15% of black women and 30% of French Canadian women were using estrogens at the time of study.
At both sites, over a 2-day period, subjects were placed on a weight-maintaining diet containing 150 mEq sodium and 80 mEq potassium per day. On day 1, blood pressures were measured over a 24-hour period with an Accutracker (Suntech Medical Instruments, Inc) every 30 minutes during the day (6:00 AM to 10:00 PM) and every 60 minutes during the night (10:00 PM to 6:00 AM). Blood pressure results are presented as the average of these daytime and nighttime measurements. Also on day 1, after an overnight fast and insertion of an intravenous catheter into an antecubital vein for obtaining blood samples, plasma renin activity (PRA) and plasma aldosterone were measured after subjects had been supine for 60 minutes and again after quietly standing for 10 minutes. Blood pressure was also measured in response to a standardized math stress test.9 Plasma electrolytes were also measured on day 1, and a 24-hour urine was collected for measurement of sodium, potassium, and cyclic guanine monophosphate (cGMP) excretion. On protocol day 2, plasma ANF and arginine vasopressin (AVP) were measured after an overnight fast; AVP was also measured after a fluid challenge, as previously described.9 Black subjects were reimbursed $25 for the outpatient visit and $200 for their inpatient participation. The protocols were approved by the appropriate Human Research Review Committees at both participating institutions. Informed consent was obtained from all subjects, and the procedures followed were in accordance with institutional guidelines.
PRA, plasma aldosterone, ANF, and AVP were all measured in the same core laboratories at the Medical College of Wisconsin. PRA was measured by a modification of the method of Sealey and Laragh,12 with the use of angiotensin I antisera kindly provided by Dr Jean Sealey (Cornell University Medical Center). Aldosterone was measured by radioimmunoassay with a commercially available assay kit (Coat-a-Count Aldosterone; Diagnostic Products Corp). ANF was extracted from acidified plasma and measured by radioimmunoassay, as previously described.13 Urine cGMP was measured by radioimmunoassay after extraction.14 Plasma AVP was measured by radioimmunoassay.15
Study participants were stratified by their disease status (hypertensive or normotensive) based on outpatient measurements and ethnicity. Two-way analysis of variance (disease status x ethnicity) was used to determine statistical significance for most variables. The significance of gender differences was determined with the 
2 test. Ethnic specific correlates of blood pressures were determined using the Spearman correlation. Multiple linear regression analysis was used to examine the independent associations of aldosterone and ANF with blood pressures after adjusting for age, gender, BMI, PRA, and 24-hour urine sodium excretion. In this analysis, all variables in the model were log-transformed. Means±SE are reported. All tests used a 2-tailed significance level of P<0.05 and were performed using SAS software version 8.0 (SAS Institute, Cary, NC).
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Results |
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Comparing overall results of hypertensive versus normotensive subjects in the combined black and French Canadian participants (Table 1), hypertensive subjects were older (P<0.0001), had higher mean BMI (P=0.0003), waist circumference (P=0.001), and waist/hip ratio (P<0.0001) than normotensive subjects. Overall, the magnitude of the nighttime systolic blood pressure dip and the increment of systolic blood pressure in response to math stress were greater in the hypertensive subjects (P<0.05 and P<0.0001, respectively). Plasma sodium concentration was slightly higher in the hypertensive subjects (P<0.0001). Among the blacks, plasma potassium was lower in hypertensive than in normotensive subjects (P<0.01). Urine sodium and potassium excretion did not differ in the overall hypertensive and normotensive groups of subjects. Supine and standing PRAs were lower (P
0.01), plasma aldosterone concentrations were higher (P<0.0001), and the aldosterone/renin ratios were higher in the hypertensive subjects (P<0.0001). Plasma ANF concentrations were higher in the hypertensive subjects (P<0.0001); 24-hour urinary cGMP excretion was also higher in the hypertensive subjects (P=0.006). Both before and after the combined oral water load and NaCl infusion, plasma AVP concentrations were lower in the hypertensive subjects (P<0.0001).
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Comparing overall results in blacks and French Canadians by combining results of normotensive and hypertensive subjects within each ethnic group, overall, blacks had higher BMI (P<0.0001), waist circumference (P=0.0001), and percent body fat (P<0.0001) than French Canadians. The waist-to-hip ratio was lower in blacks (P=0.001). The 24-hour urine sodium excretion tended to be higher in blacks (P<0.07), although there was no difference in the 2 ethnic groups after adjusting for BMI (P=0.42) or 24-hour urine creatinine excretion (P=0.71). Nighttime blood pressures were also higher in the blacks (P<0.02 or less); the nighttime blood pressure dip and the blood pressure increment in response to math stress were each attenuated in the blacks (P<0.0001) compared with the French Canadians. Blacks had lower PRA (P0.0005), higher plasma aldosterone/renin ratios (P<0.001), and lower potassium excretion (P<0.0001) than the French Canadians. There was no significant effect of hormone use or previous antihypertensive therapy on PRA or aldosterone. Overall, plasma aldosterone was positively correlated with plasma sodium concentration (P<0.01) and inversely correlated with 24-hour urinary sodium excretion (P<0.001) and with the urine sodium/potassium ratio (P<0.01). Aldosterone was not significantly correlated with plasma potassium concentration or potassium excretion. Plasma AVP concentrations were higher in the blacks (P<0.0001).
Among French Canadians, blood pressures were significantly correlated (P<0.005 or less) with BMI, waist circumference, and waist/hip ratio (Table 2). In contrast, blood pressures were not correlated with these measures of body size in blacks. Also in contrast to blacks, among French Canadians standing plasma aldosterone was correlated with BMI (r=0.15; P=0.02), waist circumference (r=0.19; P=0.02), and waist/hip ratio (r=0.19; P=0.002) after adjusting for age. However, after also adjusting for PRA, these correlations were no longer significant. Standing PRA was also correlated with waist circumference (r=0.16; P=0.01) and waist/hip ratio (r=0.19; P=0.003) in French Canadians.
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Among blacks, there were no significant correlations between blood pressures and either supine or standing PRA. However, both daytime and nighttime systolic and diastolic blood pressures were consistently correlated with supine and standing plasma aldosterone (P<0.005 or less) and with the aldosterone/renin ratio (P<0.005 or less). In French Canadians, blood pressures tended to be positively correlated with both standing PRA (P<0.05) and standing plasma aldosterone (P<0.05 or less), but not with the aldosterone/renin ratio.
In blacks, daytime systolic blood pressure was positively correlated with ANF (P<0.01), and in both racial groups there were several significant correlations between blood pressures and 24-hour urine cGMP excretion. ANF accounted for 9.7% and 14.4% of the variability of cGMP excretion in blacks and French Canadians, respectively (P<0.0003 for each). Also in both racial groups, there were inverse correlations between several blood pressures and plasma AVP concentrations, both before and after the fluid challenge (P<0.05).
In blacks, nighttime and daytime systolic and diastolic blood pressures were strikingly correlated (P<0.004 or less) with both supine and standing and plasma aldosterone, after adjustment for age, gender, BMI, PRA, and 24-hour urinary sodium excretion (Table 3, Figure). Among French Canadians, these correlations were less striking and less consistent. In both ethnic groups, there were also inconsistent correlations of blood pressure with ANF.
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Discussion |
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Based on average 24-hour blood pressure measurements, obtained under controlled standardized conditions, several differences were observed in blood pressure–related phenotypes in these 2 culturally and genetically distinct groups of subjects. Blood pressures were correlated with anthropometric measurements in the French Canadians, but not in the blacks. Conceivably, the absence of a correlation between blood pressure and BMI in the blacks may be related to the relatively high BMI in the blacks. In a preliminary study that included smaller numbers of black and French Canadian hypertensive subjects, and no normotensive subjects, we reported that plasma aldosterone correlated with blood pressures in the blacks, but not in the French Canadians.16 The present report extends these findings by increasing the numbers of hypertensive subjects and by adding a large number of normotensive subjects studied under identical circumstances. The results indicate that plasma aldosterone correlates with blood pressure, more consistently and to a greater extent in the blacks. Additionally, in both populations, plasma ANF was higher in the hypertensive subjects than in the normotensive subjects and inconsistently correlated with blood pressure. Despite statistical adjustment for age, gender, BMI, PRA, and sodium excretion, we cannot exclude the possibility that these traits, or any of a number of other unmeasured traits, rather than ethnicity per se, may account for the closer association of blood pressure with aldosterone in the blacks than in the French Canadians. Nevertheless, these observations are consistent with the hypothesis that aldosterone induced volume expansion is an important contributor to stage 1 hypertension.
The concept that aldosterone contributes to hypertension is not new. Soon after its discovery >50 years ago, it was suggested that human arterial hypertension is a state of mild chronic hyperaldosteronism.1 Subsequently, it has been proposed that idiopathic aldosteronism caused by bilateral adrenal hyperplasia and low-renin essential hypertension are not distinct clinical entities but rather are pathogenetically related and differ only in the level of aldosterone production.17 Perhaps of relevance to this concept is an earlier observation based on an autopsy series of an association between hypertension and adrenal cortical abnormalities (adenoma and hyperplasia), particularly in blacks.18 Recently, similar polymorphisms of the aldosterone synthase gene have been described in patients with idiopathic primary aldosteronism and in patients with low-renin essential hypertension.19 However, a number of studies, primarily in white subjects, have not found an elevation of aldosterone in hypertension,6,20,21 and recent reports indicate either no correlation or weakly positive correlations between plasma aldosterone and blood pressure in white patients with essential hypertension.22,23 Most of these studies were based on isolated blood pressure measurements and did not use careful control of time, diet, and posture. Further suggesting a role for aldosterone in the pathogenesis of hypertension, addition of low-dose spironolactone to the antihypertensive regimen has been reported to provide significant additive blood pressure reduction in black and white subjects with resistant hypertension, whether or not they have primary aldosteronism.24 It has recently been reported that the selective aldosterone antagonist, eplerenone, is a more effective antihypertensive agent than the angiotensin II receptor blocker, losartan, in patients with mild to moderate hypertension, particularly in blacks.25
In normotensive children and adults, PRA, plasma aldosterone, and urine aldosterone excretion have been found to be either no different or lower in blacks than in whites, although the aldosterone/renin ratio is higher.26,27 Among hypertensive subjects, however, several reports indicate that despite the suppression of PRA in blacks, plasma aldosterone and/or urine aldosterone excretion do not differ between blacks and whites.17,28 In the present study, we also noted that normotensive blacks had lower plasma aldosterone concentrations than normotensive French Canadians, whereas among hypertensive subjects, plasma aldosterone was higher in blacks. Higher plasma aldosterone, despite suppressed PRA, suggests that a subtle variant of primary aldosteronism may contribute to hypertension in blacks.
Conceivably, the higher plasma aldosterone despite lower PRA in blacks may be related to increased adrenal sensitivity to angiotensin II, obesity, or potassium. Patients with low-renin essential hypertension have an increased adrenal sensitivity to angiotensin II;17,29 however, this observation has not been confirmed in blacks.30 Other investigators have reported an association between plasma aldosterone and obesity, particularly visceral obesity.31,32 Goodfriend et al have speculated that visceral fat may in some way promote adrenal steroidogenesis,33 possibly caused by stimulation by oxidized derivatives of polyunsaturated fatty acids.34 In the current study, however, there was no relationship of plasma aldosterone to body size in the blacks. In the French Canadians, although there were significant correlations of aldosterone with BMI, waist circumference, and waist/hip ratio, these correlations were not significant after adjusting for PRA. Although potassium is an important regulator of aldosterone secretion, there was also no correlation of aldosterone with either serum or urine potassium. Further, serum potassium concentrations did not differ in black and white subjects, and in the blacks serum potassium was slightly lower in the hypertensive subjects.
Consistent with previous reports, in the current study, urinary potassium excretion was lower in the blacks.35 We also observed that plasma sodium concentrations were lower in the blacks. Also consistent with previous observations of others,36 in the current study, plasma AVP concentrations were higher in the blacks, and conceivably this may account for the lower serum sodium concentrations. In apparent contrast to earlier observations of others, we found that AVP concentrations were lower in the hypertensive than in the normotensive subjects in both populations, both before and after a fluid challenge.
ANF is a natriuretic and vasorelaxant peptide that is released from the atria in response to volume expansion and/or atrial wall tension/stretch, typically from pressure or volume overload.9 Cyclic GMP is a second messenger for both ANF and nitric oxide, and urine cGMP excretion reflects both ANF and nitric oxide activity.37 Circulating levels of ANF are increased in experimental models of volume-dependent hypertension. Mean ANF concentrations are reported to be similar, higher, or even lower in patients with essential hypertension, compared with normotensive subjects.9,38 In the current study, in both populations, mean plasma ANF concentrations and urine cGMP excretion were higher in hypertensive than in normotensive subjects. Other investigators have also reported elevated ANF concentrations in patients with low-renin essential hypertension, as well as in patients with primary aldosteronism, possibly as a marker of an expanded vascular volume.39–42 However, we cannot exclude the possibility that subtle alterations of atrial function and/or left ventricular function may account for the higher ANF concentrations in the hypertensive subjects
Perspectives
Based on the correlations of blood pressure with aldosterone, we hypothesize that aldosterone contributes to the pathogenesis of hypertension, particularly in blacks. This has important implications for the treatment of hypertension, including an expanded role for the use of aldosterone antagonists. We suggest that additional studies be conducted to develop approaches for identifying those hypertensive patients with an elevated plasma aldosterone/renin ratio who should be further evaluated for a surgically correctable form of primary aldosteronism.
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Acknowledgments |
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This study was supported by U.S. Public Health Service grants P50 HL-54998, HL-70111, and 5-M01-RR-00058 (General Clinical Research Center).
Received October 10, 2004; first decision October 20, 2004; accepted December 15, 2004.
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G. E. Umpierrez, P. Cantey, D. Smiley, A. Palacio, D. Temponi, K. Luster, and A. Chapman Primary Aldosteronism in Diabetic Subjects With Resistant Hypertension Diabetes Care, July 1, 2007; 30(7): 1699 - 1703. [Abstract] [Full Text] [PDF]
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S. Kidambi, J. M. Kotchen, C. E. Grim, H. Raff, J. Mao, R. J. Singh, and T. A. Kotchen Association of Adrenal Steroids With Hypertension and the Metabolic Syndrome in Blacks Hypertension, March 1, 2007; 49(3): 704 - 711. [Abstract] [Full Text] [PDF]
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 D. A. Calhoun Aldosterone and Cardiovascular Disease: Smoke and Fire Circulation, December 12, 2006; 114(24): 2572 - 2574. [Full Text] [PDF]
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 D. A. Calhoun Aldosteronism and Hypertension Clin. J. Am. Soc. Nephrol., September 1, 2006; 1(5): 1039 - 1045. [Abstract] [Full Text] [PDF]
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M. Bochud, J. Nussberger, P. Bovet, M. R. Maillard, R. C. Elston, F. Paccaud, C. Shamlaye, and M. Burnier Plasma Aldosterone Is Independently Associated With the Metabolic Syndrome Hypertension, August 1, 2006; 48(2): 239 - 245. [Abstract] [Full Text] [PDF]
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J. D. Spence Letter to the Editor: Individualized Therapy for Hypertension Hypertension, March 1, 2006; 47(3): e11 - e11. [Full Text] [PDF]
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