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Hypertension Unit, University Department of Medicine, Greenslopes Hospital, Brisbane 4120, Australia
Address all correspondence and requests for reprints to: Prof. Richard D. Gordon, Hypertension Unit, University Department of Medicine, Greenslopes Hospital, Brisbane 4120, Australia. E-mail: med.gslopes{at}mailbox.uq.edu.au
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Abstract |
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1 medication required to control
hypertension, no history of stroke, age >18 yr when studied) with
those of 17 subjects with severe hypertension (onset before 15 yr, or
systolic blood pressure >180 mm Hg or diastolic blood pressure >120
mm Hg at least once, or 
2 medications, or history of stroke). Severe
hypertension was more frequent in males (11 of 13 males
vs. 6 of 13 females; P < 0.05). All
4 subjects still normotensive after age 18 yr were females. Of 10 other
affected, deceased individuals (7 males and 3 females) from a single
family, all six who died before 60 yr of age (4 by stroke) were males.
Biochemical studies were conducted in 6 mild and 16 severe subjects.
The 2 groups were similar in terms of urinary sodium excretion. Mild
subjects tended, although not significantly, to have lower urinary
18-oxo-cortisol (mean ± SD, 27.4 ± 9.0
vs. 35.2 ± 12.9 nmol/mmol creatinine·day),
higher plasma potassium (4.0 ± 0.3 vs. 3.6 ±
0.4 mmol/L), and lower recumbent (0800 h after overnight recumbency)
plasma aldosterone levels (498 ± 279 vs. 744
± 290 pmol/L). Upright (midmorning after 2–3 h of upright posture)
plasma aldosterone levels were similar (mild, 485 ± 150; severe,
474 ± 188 pmol/L). In 1 normotensive female, upright PRA was much
higher, and the upright aldosterone/PRA ratio was much lower than that
in the other subjects. The remaining mild subjects had similar upright
PRA levels (mild, 2.8 ± 1.4; severe, 3.7 ± 3.2
pmol/L·min) and aldosterone/PRA ratios (mild, 199.5 ± 133.4;
severe, 200.6 ± 150.9) as severe subjects. During angiotensin II
(AII) infusion studies (n = 6 mild and 10 severe), performed
during recumbency, aldosterone levels were lower in the mild group both
basally (404 ± 144 vs. 843 ± 498 pmol/L;
P < 0.05) and after 60 min AII (2 ng/kg·min;
261 ± 130 vs. 520 ± 330 pmol/L;
P < 0.05). Aldosterone was unresponsive (rose by
<50%) to AII in all subjects. Day curve studies (blood collected
every 2 h for 24 h; n = 2 mild and 7 severe)
demonstrated abnormal regulation of aldosterone by ACTH rather than by
AII in both groups. In conclusion, in this series of patients with
FH-I, males had more severe hypertension, and the degree of hybrid
gene-induced aldosterone overproduction may have contributed to the
severity of hypertension. |
Introduction |
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We have previously shown that in untreated FH-I, the hybrid gene dominates in terms of aldosterone production over the wild-type genes (2), which are presumably in a state of dormancy resulting from chronic suppression of the renin-AII system caused by long-term mineralocorticoid excess. As a result, aldosterone production in FH-I is regulated by ACTH rather than by AII (2, 3, 4, 5, 6, 7, 8). Plasma aldosterone is therefore unresponsive to the assumption of upright posture after overnight recumbency or to an infusion of AII (and, in fact, usually falls, because ACTH levels are falling during the early morning hours when these studies were conducted) (3, 4), can be stimulated by continuous ACTH for at least 4 days instead of the usual transient increase followed by suppression (5), is markedly suppressed by dexamethasone (0.5 mg every 6 h) for several days to weeks in contrast to the transient suppression observed normally (6, 7, 8), and demonstrates tight correlation of its diurnal rhythm with that of plasma cortisol, but not with that of PRA (2).
Another characteristic biochemical finding in FH-I is the presence of elevated urinary levels of the hybrid steroids, 18-hydroxy- and 18-oxo-cortisol, thought to result from the aberrant expression of aldosterone synthase activity in zona fasciculata, where 11-desoxy-cortisol and cortisol are available as substrates (1, 9, 10).
Although hypertension in FH-I is often of early onset and may be of sufficient severity as to result in early death, commonly due to intracerebral hemorrhage (11, 12, 13), the presence and severity of hypertension vary considerably between affected individuals within any given age group, even among affected members of a single family (14, 15, 16, 17, 18). Individuals demonstrating only mildly elevated, or even normal, blood pressure levels have been increasingly recognized since the availability and application among affected families of genetic tests capable of reliably detecting the hybrid gene in peripheral blood DNA (19, 20). Some individuals have remained normotensive until well into the fifth decade of life despite demonstrating biochemical evidence of excessive, abnormally regulated aldosterone production characteristic of hypertensive individuals with the disorder (21). In the current study we sought to identify factors contributing to this marked phenotypic variability by comparing clinical and biochemical characteristics of individuals who were mildly affected with those of subjects who were severely affected in terms of blood pressure levels.
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Materials and Methods |
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In all subjects studied, the diagnosis of FH-I was confirmed by demonstrating the presence of the hybrid gene in peripheral blood leukocyte DNA using a long PCR-based method developed in this laboratory (19, 20) and validated against the Southern blot technique (1).
Designation of patients as having mild or severe hypertension
Patients categorized as having mild hypertension were normotensive or, if hypertensive, were not known to have developed hypertension until after the age of 15 yr, had never had documented blood pressure levels over 160/100 mm Hg, did not require more than one antihypertensive medication for control, and did not have a past history of stroke. Those categorized as having severe hypertension had been found to have hypertension before the age of 15 yr, had documented blood pressure levels over 180 mm Hg systolic or 120 mm Hg diastolic on at least one occasion, required at least two antihypertensive medications for control, or had a past history of stroke. Although these criteria were clearly arbitrary, they nevertheless permitted clear separation of the study subjects into one or the other group.
Blood pressure was measured using a mercury sphygmomanometer after subjects had been quietly seated for at least 5 min. Three measurements, separated by at least 1 min, were recorded. Subjects were regarded as normotensive (if not receiving any antihypertensive treatment) or as having controlled hypertension (if receiving antihypertensive treatment) if the mean of the last two systolic and diastolic measurements was within the normal range for age and sex (22).
The study involved 33 affected subjects derived from 5 different families. By the criteria defined above, 16 of the 33 subjects were categorized as having mild hypertension, and the remaining 17 as having severe hypertension. Of those with mild hypertension, 7 who had not yet reached 18 yr of age were excluded on the basis that there was still a reasonable chance that they may develop either hypertension by the age of 15 yr (4 subjects <15 yr of age) or more severe hypertension later in life. The remaining 9 with mild hypertension and all 17 with severe hypertension were included in the study.
Medication use and dietary salt intake during biochemical studies
Biochemical studies were conducted in 22 subjects (6 mild and 16 severe). At the time of assessment, 4 of the 6 mild subjects were not taking any regular medications. One female subject (patient 3) was receiving a combination oral contraceptive medication (cyproterone acetate/ethinyl estradiol), and another woman (patient 7) was receiving hormone replacement therapy with transdermal estradiol. Of the 16 severe subjects who underwent biochemical studies, 6 were not taking any regular medications, and the remaining 10 (patients 11, 13–17, 21, and 23–26) were receiving antihypertensive treatment with fosinopril, lisinopril, enalapril, verapamil, felodipine, amlodipine, hydralazine, labetolol, or metoprolol, either singly or in combination. Patient 26 was also receiving salazopyrine and ketoprofen as treatment for rheumatoid arthritis. None of the 22 subjects undergoing biochemical studies was receiving diuretics at the time of assessment. In the 7 patients who had previously received diuretic treatment, diuretics were stopped for 2 weeks (patient 17) or at least 4 weeks (patients 13, 14, 16, 18, 22, and 23) before blood collection. During the biochemical studies, dietary salt intake was unrestricted.
Midmorning upright plasma potassium, aldosterone, and PRA, and recumbent plasma aldosterone and urinary sodium and 18-oxo-cortisol levels
Levels of plasma potassium, plasma aldosterone, PRA, and aldosterone/PRA ratios were measured in blood collected without stasis midmorning after at least 2 h of upright posture. Plasma aldosterone was also measured at 0800 h after overnight recumbency. Immediately after each collection, the blood was centrifuged, and the plasma component was snap-frozen on dry ice and stored at -20 C pending assay. Levels of sodium and 18-oxo-cortisol (corrected for creatinine excretion) were measured in a 24-h urine collection.
Angiotensin II (AII) infusion studies
AII infusion studies were performed during midmorning hours after at least 30 min of recumbency. AII was infused at a rate of 2 ng/kg·min, and blood was collected basally and 60 min after commencement of the infusion for measurement of plasma aldosterone. Aldosterone was considered responsive to AII if levels rose by at least 50% during the infusion.
Aldosterone, PRA, and cortisol day curve studies
For each day curve study, a cannula was inserted into a forearm vein in the cubital fossa for blood sampling. Blood (15 ml) was collected every 2 h for 24 h from 2200–1000 h for measurement of plasma aldosterone, PRA, potassium, and plasma cortisol. Posture was unrestricted until midnight, after which subjects remained recumbent until 0800 h and then assumed an upright posture until the completion of the day curve at 1000 h.
Assays
Plasma aldosterone was measured by RIA (Coat-A-Count 125I-Aldosterone RIA Kit, Diagnostic Products, Los Angeles, CA) in a modification of the method of Mayes et al. (23), with intra- and interassay coefficients of variation of 4.0% and 6.0%, respectively, and a lower detection limit of 69 pmol/L. PRA was measured by RIA (Gamma Coat [125I] Plasma Renin Activity RIA Kit, INCSTAR Corp., Stillwater, MN) of generated angiotensin I in a modification of the method of Haber et al. (24), with intra- and interassay coefficients of variation of 4.3% and 7.2%, respectively, and a lower detection limit of 1.3 pmol/L·min. Plasma cortisol was measured by RIA (Quanticoat 125I-Cortisol RIA Kit, Kallestad Diagnostics, Chaska, MN), with intra- and interassay coefficients of variation of 4.5% and 9.6%, respectively, and a lower detection limit of 28 nmol/L. Urinary 18-oxo-cortisol levels were determined by RIA using a method previously described (10).
Data analysis
Group data are presented as the mean ± SD
unless otherwise indicated. Means were compared by Mann-Whitney U test,
and proportions were determined by 
2 analysis.
For each day curve study, Spearman rank correlation coefficients were
determined for correlations between aldosterone and cortisol levels as
a reflection of ACTH-dominated aldosterone regulation and between
aldosterone and PRA levels as a reflection of AII-dominated regulation
of aldosterone.
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Results |
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)There was no difference in mean age of the mild (40.9 ± 13.4 yr) vs. the severe (39.5 ± 21.6 yr) hypertension groups. However, the 2 groups differed significantly (P < 0.05) in gender proportion, with females comprising 7 (78%) of the 9 with mild hypertension compared with only 6 (35%) of the 17 with severe hypertension. All 4 subjects who have remained normotensive into adulthood (patients 1, 3, 7, and 9 who are now 23, 43, 43, and 39 yr old, respectively) are females. Of 10 other deceased individuals (7 males and 3 females) from a single large family, who were identified as being affected based on the pattern of inheritance of FH-I within that family, all 6 who died before the age of 60 yr (in 4 of them by stroke) were males.
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Parental origin of the hybrid gene was unable to be determined in 2 subjects (an adopted 14-yr-old male and a 78-yr-old female). Among the remaining 24 subjects, the mild group did not differ significantly from the severe group in terms of the proportion of subjects who inherited the hybrid gene from their mothers [4 of 9 (44%) vs. 6 of 15 (40%)].
Midmorning upright plasma potassium, aldosterone, and PRA, and
recumbent plasma aldosterone and urinary 18-oxo-cortisol and sodium
levels (Table 1
)
Mean plasma potassium levels did not differ significantly between the 2 groups, but levels tended to be lower in the severe group. All 6 subjects with levels below the lower limit of the normal range (3.5–5.0 mmol/L) belonged to the severe group. Three of these belonged to family 4. Although none of these subjects was taking diuretics at the time of testing, 4 of the 6 hypokalemic patients had received diuretics within 2 months of testing. By comparison, only 1 of the remaining 10 severely hypertensive subjects and only 1 of the 6 mildly hypertensive subjects had received diuretics within the previous 2 months. Of the 16 individuals who had never received diuretics, the 2 who were hypokalemic both belonged to the severely hypertensive group.
Upright plasma aldosterone levels were similar in the two groups (mild, 485 ± 150; severe, 474 ± 188 pmol/L). The mild hypertension group demonstrated lower recumbent plasma aldosterone levels (498 ± 280 vs. 744 ± 290 pmol/L), but the difference did not reach statistical significance.
In one normotensive female (patient 3) who was receiving a combined estrogen/antiandrogen medication, the upright PRA level (99.0 pmol/L.min) was much higher and the upright aldosterone/PRA ratio (6.5) was consequently much lower than in the other subjects. Other biochemical findings in the patient (elevated 24-h urinary 18-oxo-cortisol levels, failure of aldosterone to respond during AII infusion, and tight correlation of circadian plasma aldosterone levels with those of cortisol, but not with PRA levels) were similar to those of the other subjects with FH-I. These findings have been discussed in detail in previous reports (2, 21), in which it was concluded that the high PRA levels in this patient could be explained on the basis of estrogen treatment or of a genetic mutation resulting in a state of relative resistance to aldosterone. The remaining subjects with mild hypertension had upright PRA levels (mild, 2.8 ± 1.4; severe, 3.7 ± 3.2 pmol/L·min) and aldosterone/PRA ratios (199.5 ± 133.4 vs. 200.6 ± 150.9) similar to those of subjects with severe hypertension.
Mean 24-h urinary 18-oxo-cortisol levels did not differ significantly between the two groups (27.4 ± 9.0 vs. 35.2 ± 12.9 nmol/mmol creatinine), but there was a tendency for the severe subjects to show higher levels. The two groups did not differ in terms of urinary sodium excretion (7.2 ± 3.5 vs. 6.8 ± 4.6 mmol/mmol creatinine).
AII infusion studies (Table 2)
AII infusion studies were performed in 16 subjects (6 mild and 10 severe) during recumbency. Aldosterone levels were lower in the mild aldosterone group both basally (404 ± 144 vs. 843 ± 498 pmol/L; P < 0.05) and after 60 min of AII (2 ng/kg·min; 261 ± 130 vs. 520 ± 330 pmol/L; P < 0.05). Aldosterone was unresponsive to AII in all 16 subjects.
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)Nine subjects (two mild and seven severe) underwent day curve studies. In all nine, circadian levels of aldosterone correlated strongly with those of cortisol (r = 0.69–0.99; mean, 0.88 ± 0.11; P < 0.05–0.001), but not with circadian PRA levels (r = -0.42 to 0.39; mean, 0.05 ± 0.27; all P = NS). The small number of mild subjects studied did not permit statistical comparison between the two groups. The two mild subjects, however, demonstrated aldosterone/cortisol r values among the lowest recorded for the combined group of nine subjects.
Mean day curve plasma aldosterone levels in the two subjects with mild hypertension were among the lowest, and mean day curve PRA levels were among the highest for the combined group.
Comparison of females vs. males
In view of the difference in gender proportion between the mild and severe hypertension groups, characteristics of the 13 female study subjects were compared to those of the 13 males. Although the women tended to be older (mean age, 46.4 ± 18.7 vs. 33.5 ± 17.4 yr), the difference was not statistically significant. There were no differences between females and males in terms of mean upright plasma potassium (3.5 ± 0.4 vs. 3.7 ± 0.4 mmol/L), upright plasma aldosterone (481 ± 189 vs. 473 ± 173 pmol/L), upright PRA [14.9 ± 31.8 (or with patient 3 excluded, 4.3 ± 4.2) vs. 3.0 ± 1.6 pmol/L·min], or upright aldosterone/PRA ratio [155.7 ± 138.1 (or with patient 3 excluded, 174.4 ± 135.0) vs. 216.3 ± 151.8]. However, women demonstrated lower recumbent plasma aldosterone levels (women, 498 ± 232; men, 801 ± 288 pmol/L; P < 0.05), lower aldosterone levels measured basally (503 ± 266 vs. 783 ± 517 pmol/L; P = NS), and after 60 min of AII (243 ± 119 vs. 530 ± 323 pmol/L; P < 0.01) at the time of the AII infusion studies, lower mean day curve plasma aldosterone levels (396 + 91 vs. 611 ± 121 pmol/L; P < 0.05), higher mean day curve PRA levels [12.2 ± 18.9 (or with patient 3 excluded, 4.6 ± 4.1) vs. 1.1 ± 0.4 pmol/L·min; P < 0.05] and lower r values for correlation of day curve aldosterone with cortisol levels (0.84 ± 0.11 vs. 0.98 ± 0.01; P < 0.05). Mean day curve plasma cortisol levels did not differ significantly between females and males (296 ± 89 vs. 234 ± 40 nmol/L).
Blood pressure responses to glucocorticoid treatment
After completion of the above studies, patients 2, 4, and 5 from the mild group and patients 10–23 and 26 from the severe group were started on glucocorticoid treatment. In all treated patients, hypertension became well controlled without requiring other antihypertensive medications.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Other investigators reported more severe hypertension to be associated with lower urinary kallikrein levels (25) and with maternal origin of the hybrid gene (15), but a lack of association of hypertension severity with urinary sodium excretion (11), urinary hybrid steroid levels (25), degree of hyperaldosteronism (15, 25), or position of the hybrid gene cross-over point (15, 25).
Jamieson and co-workers (15) observed a paternal origin of the gene in all five normotensive subjects in their series and reported that subjects who inherited FH-I from their mothers had higher basal mean arterial pressure than those who had inherited the hybrid gene from their fathers. In contrast to these findings, the current study did not find an association between parental origin of the hybrid gene and hypertension severity in FH-I.
The greater incidence of hypokalemia among the more severely hypertensive patients in the current study raises the possibility that the severity of hypertension in patients with FH-I may be dependent, at least in some individuals, upon the degree of hyperaldosteronism, as reflected by the severity of the resulting biochemical abnormalities. Alternatively, previous treatment with diuretics in some of these patients may have rendered them more prone to developing hypokalemia.
Although upright plasma aldosterone levels were similar in the mild and severe groups, the more severely hypertensive subjects in the current study tended to demonstrate higher recumbent levels, a difference that achieved statistical significance when recumbent levels measured at the time of the AII infusion studies were compared. This finding adds further support to the idea that the degree of excessive aldosterone production may influence the likelihood of developing hypertension in FH-I.
Recumbent plasma aldosterone levels are usually higher than upright levels in FH-I (2, 3) because they are collected earlier in the morning, when ACTH levels are higher, and they fall, despite the assumption of upright posture, in response to the fall in ACTH that normally occurs as the morning progresses. Early morning recumbent aldosterone levels may therefore better reflect the overall daily load of ACTH-regulated aldosterone production. This may help to explain why hypertension severity in FH-I demonstrated a better correlation with recumbent levels collected at 0800 h than with upright levels collected at 1000 h. Levels measured basally and at 60 min after commencement of AII infusion also showed correlation with hypertension severity despite the fact that these samples were collected later in the morning (at approximately 1030 and 1130 h, respectively) than the upright samples. Presumably, other processes that occur in association with the assumption of upright posture and are capable of modifying aldosterone levels (for example, alterations in rate of aldosterone metabolism resulting from changes in hepatic blood flow or effects of endogenous renin/AII level on wild-type CYP11B2 expression) may serve to obscure a relationship between plasma aldosterone level and hypertension severity.
Mean upright PRA levels and aldosterone/PRA ratios did not differ between the mild and severe hypertension groups. Comparisons of very low PRA levels such as those encountered in this study, which were very often close to or below the limit of detection by the RIA method used, should be made with caution, however. Increasing the generation time of angiotensin I from 3 to 18 h has been reported to enhance the assay at the lower end of the range (26) and might have been expected to facilitate detection of differences between the two groups. Furthermore, chronic treatment with diuretic medication can release the renin/AII system from suppression in patients with primary aldosteronism, an effect that could persist for many weeks and may have resulted in higher PRA levels in those hypertensive subjects who had previously received long-term diuretic treatment. Comparison of PRA levels between the two groups is further complicated by the fact that at the time of the study, many of the hypertensive subjects were receiving treatment with other medications that are known to affect PRA levels (27, 28, 29).
Although not statistically significant, there was a tendency for the more severely hypertensive subjects to have higher urinary levels of 18-oxo-cortisol. Although an elevated urinary level of 18-oxo-cortisol is a sensitive biochemical marker of FH-I (10, 11), this steroid has only weak mineralocorticoid activity (30) and is believed not to play a major role in the development of hypertension in this condition. Nevertheless, a higher urinary level of 18-oxo-cortisol would be consistent with a higher level of hybrid gene expression, which, in turn, would be likely to result in a more pronounced degree of aldosterone overproduction.
Regardless of hypertension severity, all subjects studied demonstrated failure of plasma aldosterone to rise normally during AII infusion and a strong tendency for circadian levels of aldosterone to tightly follow those of cortisol rather than PRA levels, findings consistent with aldosterone production being predominantly regulated by ACTH rather than by AII. We recently reported similar findings in 10 normotensive individuals with FH-I (21). The absence of hypertension in such individuals, therefore, cannot be attributed merely to a complete lack of expression of the hybrid gene. This does not exclude the possibility, however, that variable degrees of hybrid gene expression could contribute to the variability in hypertension severity observed in this disorder.
We and others (21, 25) have hypothesized that other genes involved in blood pressure regulation may influence the phenotypic expression of the hybrid gene in patients with FH-I. Mutations in the mineralocorticoid receptor or second messenger genes involved in aldosterone action, for example, might modify the biochemical and blood pressure sequelae of increased aldosterone production caused by expression of the hybrid gene. The presence of such a mutation could explain the normal blood pressure and raised PRA levels that were observed, despite biochemical evidence of effective hybrid gene expression, in patient 3. Treatment with an estrogen-containing preparation in this patient, however, could also have contributed to her high PRA levels (31, 32).
Shared genetic traits predisposing to increased hypertension severity might help to explain why all four members of family 4 exhibited hypertension of severe degree. These four individuals also demonstrated plasma potassium levels that were either at (one subject) or below (three subjects) the lower limit of the normal range, raising the possibility that genetic factors predisposing them to increased hypertension severity might have exerted their influence by way of increased hybrid gene expression and more severe hyperaldosteronism. Levels of other biochemical indicators of hybrid gene expression, however, did not indicate a propensity to greater biochemical disturbance in these individuals.
In conclusion, in this group of 26 patients with FH-I, 1) the severity of hypertension was related to gender, with females relatively protected against the development of early onset or severe hypertension and its complications; and 2) the degree of hybrid gene expression may have influenced hypertension severity.
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Footnotes |
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Received October 22, 1999.
Revised March 3, 2000.
Accepted March 11, 2000.
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References |
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