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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0681
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 9 5070-5076
Copyright © 2005 by The Endocrine Society

Evidence for Abnormal Left Ventricular Structure and Function in Normotensive Individuals with Familial Hyperaldosteronism Type I

Michael Stowasser, James Sharman, Rodel Leano, Richard D. Gordon, Gregory Ward, Diane Cowley and Thomas H. Marwick

Hypertension Unit (M.S., R.D.G., D.C.) and Cardiovascular Imaging and Research Group (J.S., R.L., T.H.M.), University of Queensland Department of Medicine, and Queensland Health Pathology and Scientific Services (G.W.), Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia

Address all correspondence and requests for reprints to: Assoc. Prof. Michael Stowasser, Hypertension Unit, University of Queensland Department of Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Queensland 4102, Australia. E-mail: m.stowasser{at}uq.edu.au.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Objectives: To explore whether aldosterone excess can induce adverse cardiovascular effects independently of effects on blood pressure (BP), we sought evidence of disturbed cardiovascular structure or function in normotensive individuals with primary aldosteronism.

Methods: Eight normotensive subjects with genetically proven familial hyperaldosteronism type I (FH-I) were compared with 24 age- and sex-matched normotensive controls in terms of BP, biochemical parameters, pulse wave velocity, and echocardiographic characteristics.

Results: Subjects with FH-I demonstrated higher serum aldosterone levels and aldosterone/renin ratios than controls, as expected. Despite having similar 24-h ambulatory BPs, subjects with FH-I demonstrated evidence of concentric remodeling with greater septal (mean ± SD, 9.4 ± 1.1 vs. 7.9 ± 0.9 mm; P < 0.001), posterior wall (9.2 ± 1.7 vs. 7.7 ± 1.0 mm; P < 0.01), and relative wall (0.29 ± 0.03 vs. 0.24 ± 0.02; P < 0.001) thicknesses, and lower mitral early peak velocities (0.74 ± 0.10 vs. 0.90 ± 0.16 m/sec; P < 0.05), ratios of early to late peak diastolic transmitral flow velocity (1.56 ± 0.24 vs. 2.06 ± 0.41; P < 0.01), and myocardial early peak velocities (8.3 ± 1.8 vs. 10.3 ± 2.6 cm/sec; P < 0.05). There were no significant differences in pulse wave velocity or left ventricular ejection fraction, long axis strain rate, peak systolic strain, cyclic variation of integrated backscatter, or posterior wall calibrated integrated backscatter.

Conclusions: Aldosterone excess is associated with increased left ventricular wall thicknesses and reduced diastolic function, even in the absence of hypertension.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
EVIDENCE FROM RECENT experimental and clinical studies has suggested that excessive circulating levels of aldosterone, in the presence of normal or increased body sodium status, can bring about adverse cardiovascular sequelae independently of effects on blood pressure (BP). Chronic administration of aldosterone to salt-fed, uninephrectomized rats leads to the development of cardiac inflammation, remodeling, and fibrosis (1, 2, 3). The presence of fibrosis in both the right and left ventricles suggests that these effects are not dependent on a rise in systemic arterial BP (1, 2, 3). In patients with so-called "essential" hypertension, significant correlations have been reported between aldosterone level and reduced systemic arterial compliance (4), left ventricular (LV) mass (5), and markers of LV dysfunction (6, 7) that were independent of BP. Patients with primary aldosteronism (PAL) have been reported to demonstrate evidence of reduced myocardial perfusion (8, 9) and more severe LV hypertrophy and impairment of diastolic function when compared with patients with essential hypertension matched for age, sex, BP, and duration of hypertension (10, 11). In large trials involving patients with heart failure, (12, 13), treatment with aldosterone antagonist medications (spironolactone or eplerenone) was associated with significant improvements in morbidity and mortality.

The role of aldosterone in the genesis of abnormal cardiovascular structure or function would be optimally investigated in subjects without hypertension or overt cardiovascular disease. One such group are normotensive individuals with the familial, glucocorticoid-remediable variety of PAL [familial hyperaldosteronism type I (FH-I)]. In FH-I, inheritance of a corticotrophin (ACTH)-regulated "hybrid" 11ß-hydroxylase/aldosterone synthase gene (14) leads to excessive, ACTH-regulated production of aldosterone, levels of which are markedly suppressed throughout several days of dexamethasone administration (unlike the normal transient suppression followed by recovery), (15, 16) and demonstrate tight correlation during hormone day-curve studies with those of cortisol [and not plasma renin activity (PRA)], (17) consistent with predominant regulation by ACTH rather than by renin-angiotensin. The availability of genetic testing for this subtype (14, 18) has allowed us to identify several affected individuals who were normotensive during genetic screening of families known to have that condition (17).

In the current study, we sought evidence of non-BP-dependent adverse cardiovascular effects of aldosterone excess by comparing serum levels of procollagen type III amino-terminal propeptide (PIIINP) (a marker of cardiovascular fibrosis), pulse wave velocities (PWVs), and echocardiographic parameters in normotensive individuals with FH-I with those in normotensive control subjects matched for age, sex, and BP.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

The study included eight normotensive subjects (five females, three males; age range, 14–48 yr; median ± SD, 19.5 ± 13.7 yr) with FH-I. All subjects were consistently normotensive (BP < 140/90 mm Hg) in clinic, hospital ward, or home environments. All were healthy, with no past history of cardiovascular disease. None were receiving medications apart from oral contraceptive agents [namely combination preparations of either ethynylestradiol (35 mg) and levonorgestrol (150 mg) (subject 5) or ethynylestradiol (30 mg) and cyproterone acetate (2 mg) (subjects 6 and 7)]. Subjects 1–7 were members of a single large family that included 14 other known affected individuals; two had also demonstrated consistently normal BPs up until the time of this study but elected not to participate. The remaining 12 had hypertension that was well controlled on low-dose glucocorticoid treatment. Subject 8 belonged to a different family with one other known affected member who had hypertension well controlled on low-dose dexamethasone. The clinical and biochemical characteristics of these families have been described in detail previously (16, 19).

Twenty-four controls were recruited from the local community with no past history of hypertension or other cardiovascular or metabolic disorders and receiving no antihypertensive medications or other drugs known to have significant effects on the cardiovascular system (apart from oral contraceptive agents). They were matched, three per each study subject, for gender and age (within 1 yr for study subjects <20 yr of age and within 5 yr for those >20 yr) and had BPs less than 140/90 mm Hg when measured in the sitting position at the time of initial assessment.

All procedures received approval from the Princess Alexandra Hospital Ethics Committee, and participants provided informed consent.

Ambulatory BP monitoring

This was performed on a regular work or school day using fully automatic machines (model TM-2420; A & D, Tokyo, Japan) with readings every 30 min between 0600 and 2200 h and every 60 min between 2200 and 0600 h. Before commencing each study, BP was measured in both arms using a mercury sphygmomanometer. The 24 h ambulatory BP cuff was always applied to the nondominant arm except when mercury readings (systolic) on the dominant arm exceeded those on the other side by at least 10 mm Hg, in which case the dominant arm was chosen. Choice of cuff size (standard or large) was dependent on the subject’s arm circumference and was in accordance with currently accepted guidelines (20).

Biochemical studies

During the biochemical studies, dietary salt intake was unrestricted. Levels of sodium were measured in a 24-h urine collection as an indicator of dietary sodium intake.

Midmorning upright plasma potassium, serum aldosterone, and PRA levels

Levels of plasma potassium, serum aldosterone, PRA, and aldosterone/PRA ratios were measured in blood carefully collected (21) midmorning after at least 2 h of upright posture. After each collection, the blood was centrifuged, and the plasma component was snap frozen on dry ice and stored at –20 C pending assay.

Aldosterone, PRA, and cortisol day-curve studies

Hormone day-curve studies were performed on each subject with FH-I. For each 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 1000 to 2200 h for measurement of serum aldosterone, PRA, plasma 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.

Serum procollagen levels

Serum levels of PIIINP were measured in serum collected midmorning from nonfasting subjects.

Assays

Serum aldosterone was measured by RIA (Coat-A-Count 125I-Aldosterone RIA Kit; Diagnostic Products, Los Angeles, CA). PRA was measured by RIA (Gamma Coat [125I] Plasma Renin Activity RIA Kit; DiaSorin, Stillwater, MN) of generated angiotensin I. For the purpose of calculating aldosterone/PRA ratios, PRA levels that were undetectable were taken to be 0.15 ng/ml·h, which was the lower limit of detection with this assay technique. Plasma cortisol was measured by chemiluminescent immunoassay (ADVIA Centaur; Bayer HealthCare, Melbourne, Australia). PIIINP was measured by RIA (Type III Procollagen INTACT PIIINP RIA Kit; Orion Diagnostica, Espoo, Finland).

Arterial PWV

Carotid-femoral (CF) and carotid-radial (CR) PWV were measured using the Complior device (Colson, Garges les Genosse, France). Pressure-sensitive transducers were placed over the right carotid, right femoral, and right radial arteries. The PWV was calculated by dividing the distance separating the two sensors by the time corresponding to the period separating the start of the rising phase of the carotid pulse wave and that of the femoral pulse wave for CF PWV and the radial pulse wave for CR PWV (22). At least 10 correct single measurements were averaged to obtain the PWV. Mean PWV values that demonstrated a SD of less than 10% among the single measurements were accepted for analysis in this study.

Echocardiography

A detailed two-dimensional and Doppler echocardiogram (Vivid Five; GE Vingmed, Horton, Norway) was performed in all study subjects. LV M-mode measurements of wall thickness, end-diastolic, and end-systolic diameters were used for calculation of fractional shortening and LV mass (23), which was indexed to body surface area (LVMI). LV ejection fraction was determined by a modified Simpson’s method. Assessment of LV diastolic function included transmitral pulsed-wave Doppler from the apical four-chamber view and mitral annular velocities with tissue Doppler echocardiography. The transmitral peak early (E) and peak late (A) diastolic velocities were recorded. Systolic and early (Em) and late (Am) diastolic velocities were measured at the medial and lateral mitral annulus with pulsed-wave tissue Doppler in the apical four-chamber view with gains minimized to allow for a clear tissue signal. Isovolumetric relaxation time, defined as the time between aortic valve closure and the beginning of transmitral flow, was also recorded. Measurements were performed off-line and averaged from three to five consecutive cardiac cycles. Satisfactory measurements were obtained with all modalities.

Strain rate imaging and integrated backscatter

Strain rate (SR) imaging and cyclic variation (CV) of integrated backscatter (IB) are sensitive echocardiographic techniques that provide quantitative assessment of regional myocardial systolic function (24, 25). These techniques are able to detect subtle myocardial dysfunction in early hypertensive heart disease (26) and other preclinical cardiomyopathies (27, 28). Three consecutive cardiac cycles of color Doppler data were digitally recorded in each of six LV regions (inferior septum and lateral wall, anterior and inferior walls, anterior septum, and posterior wall) in three standard apical views.

Strain and SR are sensitive measures of long-axis systolic LV function that represent dimensionless descriptions of length changes due to the deformation of tissue caused by applied or developed force. The rate of regional myocardial deformation (SR) was derived from instantaneous differences in myocardial velocities within an 11 mm region of interest (29), using commercially available software (Echopac 6.1; GE Vingmed, Milwaukee, WI). Percentage deformation of the segment (myocardial strain) was obtained by integration of the SR curve. Mean SR and peak systolic strain were calculated in each subject by averaging the results of the basal segment of each wall.

Long-axis systolic LV function was also assessed by CV of IB as a means of corroborating the strain rate results. Gray scale loops of three consecutive cardiac cycles were acquired at frame rates 80–120 frames/sec in three standard apical views, saved in raw data format and analyzed off-line (Echopac 6.1; GE Vingmed). The IB information in the three cycles was averaged, and then CV of IB during systole was determined for each of the six basal LV segments by tracking a fixed 11 x 11 pixel region of interest in the midmyocardium in each frame. The magnitude of CV was determined by the difference between the minimal and maximal values of IB in a cardiac cycle (30). Mean CV was calculated in each patient by averaging the results of individual segments.

Calibrated IB, a marker of ultrasound reflectivity shown previously to correspond with biopsy evidence of fibrosis (31), was obtained from the posterior wall in the parasternal view by subtracting average pericardial IB intensity from average myocardial IB intensity.

Statistical methods

Grouped data are expressed as means ± SD. Means were compared by t test. For each hormone day-curve study, Spearman’s 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 angiotensin II-dominated aldosterone regulation. Because one of the three normal controls matched to FH-I subject 5 refused blood collection, the missing biochemical (plasma potassium, creatinine and renin activity, and serum aldosterone and PIIINP) data for that individual were derived from the mean of the data from the other two corresponding matched control subjects.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The current study depends on demonstration that subjects with FH-I had biochemical evidence of excessive, abnormally regulated aldosterone production. All demonstrated tight correlation (r values all > 0.7; P < 0.05 in each case) of serum aldosterone with plasma cortisol but not PRA levels during hormone day-curve studies, consistent with aldosterone production being regulated, abnormally, by ACTH rather than by renin-angiotensin II (Table 1Go and Fig. 1Go). Suppressed PRA levels and elevated aldosterone/PRA ratios were observed in all except one of these individuals (subject 7) during clinical workup and in five of them at the time of the current study (Table 1Go). All had normal (defined as 3.5–5.0 mmol/liter) plasma potassium levels (lower limit of normal in two).


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  		TABLE 1. Clinical and biochemical characteristics of subjects with FH-I1

 


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  		FIG. 1. Results of hormone day-curve study in subject 2 with FH-I demonstrating excellent correlation (Spearman’s rank correlation coefficient, r = 0.91; P < 0.001) of plasma aldosterone (Aldo, circles) with plasma cortisol (squares) (A), but lack of correlation (r = –0.43; not significant) of aldosterone with PRA (triangles) (B), levels of which were all suppressed (<1.0 ng/ml·h). Note the particularly tight correlation of aldosterone with cortisol, but not with PRA, during the early morning hours at the end of the study (between 0200 and 0800 h). These results are consistent with aldosterone production being excessive (causing renin suppression) and abnormally regulated (by adrenocorticotrophic hormone rather than by renin-angiotensin II) in this subject.

 
A comparison of clinical, biochemical, and PWV data between the FH-I subjects and controls is shown in Table 2Go. The two groups were well matched for age, sex, and 24 h ambulatory systolic and diastolic BP levels. There were no differences in mean weight, height, body mass index, waist or hip circumferences, or 24 h urinary sodium excretion rates. As expected, FH-I subjects had slightly lower mean plasma potassium levels and significantly higher upright serum aldosterone levels (20.3 ± 15.1 vs. 11.5 ± 8.0 ng/100 ml; P < 0.05) and aldosterone/renin ratios (79.2 ± 116.6 vs. 7.2 ± 5.1; P < 0.01) than controls. Subjects with FH-I also tended to have lower PRA levels, but the difference did not reach statistical significance.


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  		TABLE 2. Clinical, biochemical, and PWV characteristics for normotensive subjects with FH-I and in age- and sex-matched normotensive controls

 
The two groups did not differ significantly in terms of mean serum PIIINP levels, CF PWV, or CR PWV.

Echocardiographic data for the two groups are shown in Table 3Go. Subjects with FH-I demonstrated significantly greater septal [interventricular septal dimension (IVSD); 9.4 ± 1.2 vs. 7.9 ± 0.9 mm; P < 0.001] and posterior wall [posterior wall dimension (PWD); 9.2 ± 1.7 vs. 7.7 ± 1.0 mm; P < 0.01] thicknesses and greater relative wall thicknesses (RWTs) [defined as (IVSD + PWD)/(IVSD + PWD + LV end-diastolic diameter); 0.29 ± 0.03 vs. 0.24 ± 0.02; P < 0.001]. LVMI values tended to be greater among FH-I subjects, but the difference in mean values did not reach statistical significance because LV end-diastolic diameters tended to be lower. Subjects with FH-I exhibited lower mitral E peak velocities (0.74 ± 0.10 vs. 0.90 ± 0.16 m/sec; P < 0.05), lower ratios of E to A peak diastolic transmitral flow velocity (E/A ratios; 1.56 ± 0.24 vs. 2.06 ± 0.41; P < 0.01), and lower myocardial early peak velocities (Em; 8.3 ± 1.8 vs. 10.3 ± 2.6 cm/sec; P < 0.05). There were no significant differences between the two groups in terms of parameters of LV systolic function (including LV ejection fraction, peak systolic strain, SR, or CV of IB) or myocardial calibrated IB in the posterior wall.


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  		TABLE 3. Echocardiographic data for normotensive subjects with FH-I and in age- and sex-matched normotensive controls

 
Among the group with FH-I, the use of oral contraceptive agents by three subjects did not appear to be associated with greater disturbances in BP levels or in biochemical or echocardiographic parameters. Conversely, mean 24 h ambulatory BP levels in these three subjects (range of systolic, 105–120 mm Hg; range of diastolic 62–76 mm Hg) were well within the normal range, and their PRA levels (2.6–7.7 ng/ml·h) and peak mitral E wave velocities (0.81–0.90 m/sec) were higher and aldosterone/PRA ratios (2.0–5.9), LV septal wall thickness (8.1–9.3 mm), and posterior wall thickness (7.3 - 9.0 mm) lower than the means for these parameters among the FH-I group.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the current study, subjects with FH-I, a familial variety of PAL, demonstrated thicker LV walls with increased RWT and evidence of reduced diastolic LV function, with lower mean peak mitral E wave velocities, mitral E/A velocity ratios, and myocardial Em peak velocities compared with controls matched for age, sex, and 24 h ambulatory BP levels. These findings occurred in association with higher serum aldosterone levels but in the absence of hypertension and would therefore be consistent with aldosterone excess having adverse effects on the myocardium independently of, and predating, its effects on raising BP.

As far as we are aware, this is the first report describing evidence of such effects in subjects without established hypertension or clinically apparent cardiac dysfunction. Several groups have reported abnormalities in cardiac morphology or function in hypertensive patients with PAL that appeared to be out of proportion to the elevation in BP, including greater LVMIs and more severely impaired diastolic function (10, 11) [both of which markedly improved after specific treatment of PAL (10)], lower myocardial perfusion at rest on thallium scanning, (8) greater exercise-induced ischemia on 99mTc-sestamibi single-photon emission tomography scanning and echocardiography (9), and higher degrees of myocardial backscatter (32) compared with matched essential hypertensives.

Impaired LV diastolic filling is commonly associated with LV hypertrophy (other than that associated with endurance training) (33), but may also be influenced by aging, systolic dysfunction, heart rate, myocardial fibrosis, preload, and afterload (34, 35, 36). In the current study, effects of aging and heart rate can be discounted. Evidence of reduced diastolic function in our subjects with FH-I occurred in association with increased LV wall thicknesses and RWT compared with age-matched controls, perhaps indicating an early stage in the development of concentric LV hypertrophy. There was no evidence of systolic dysfunction (by either traditional M-mode or newer, more sensitive tissue Doppler techniques) or altered heart rate and no evidence of myocardial fibrosis using serum PIIINP and myocardial backscatter as markers. The lack of differences in PIIINP level and myocardial backscatter was somewhat unexpected. Cardiac fibrosis is a consistent finding in animal models of hyperaldosteronism (1, 2, 3), and postmortem studies have been reported to demonstrate fibrosis within the heart and other organs in patients with adrenal adenoma who were considered likely to have PAL (based on the presence of hypertension and low-normal to frankly low plasma potassium levels) during life (37). Previous studies have demonstrated good correlations of myocardial collagen content with degree of diastolic dysfunction in both animal (38) and human (39) models. It is possible that measurement of serum PIIINP and myocardial backscatter is not sensitive enough to detect early degrees of fibrosis or that sample size in the current study was not sufficient to detect differences in the measured parameters.

Although aldosterone excess might be expected to induce a state of increased preload by promoting sodium and fluid retention, this is unlikely to explain the observed echocardiographic changes because end-diastolic volumes were not higher and, in fact, tended to be lower (possibly because of the impairment in diastolic LV filling) in FH-I subjects vs. controls. Aldosterone-induced increased peripheral vascular resistance, previously observed in PAL (40), may have contributed to our findings by inducing increases in afterload. Although peripheral vascular resistance was not specifically measured in our study, the fact that 24-h ambulatory BP levels and PWV were no different between the two groups would argue against this as being the sole explanation for our results.

Because aldosterone excess causes renal potassium wasting, leading to reduced intracellular potassium and eventually to frank hypokalemia, could minor changes in potassium balance have contributed to the echocardiographic abnormalities observed here? This would appear to be most unlikely, because none of our subjects with FH-I were hypokalemic (mean potassium of 3.8 mmol/liter) and previous echocardiographic studies on patients with chronic hypokalemia due to PAL, Gitelman’s syndrome, Bartter’s syndrome, and congenital renal alkalosis found no evidence of abnormal systolic or diastolic cardiac function (41, 42). Abnormalities in diastolic function reported in PAL in association with acute potassium depletion (mean plasma potassium of 3.1 mmol/liter) induced by oral administration of a thiazide diuretic and sodium chloride (43) are not relevant to the current study, in which the subjects were in a stable state.

Chhokar et al. (44) have proposed that excessive renal excretion of calcium and magnesium ions, by inducing a state of secondary hyperparathyroidism, in turn leading to calcium loading of cardiomyocytes, could explain the development of cardiac remodeling in patients with PAL. Although serum calcium and magnesium levels were within the normal range in the subjects with FH-I included in the current study (data not shown), we cannot exclude subtle abnormalities in renal handling because renal clearance of these ions and serum levels of parathyroid hormone were not measured. Levels of growth hormone, thyroxine, or catecholamines (other endocrine factors that could promote cardiomyocyte hypertrophy) were also not determined in the current study but have not been reported, as far as we are aware, to be elevated in FH-I or other forms of PAL.

Several groups of investigators have reported on the marked degree of variability in severity of hypertension observed among individuals with FH-I, ranging from normal BP levels, as seen in the subjects studied herein, to severe, resistant hypertension of early onset, sometimes leading to early death from hypertensive stroke (17, 45, 46, 47). Reported contributors to such variability have included patient gender (47), gender of the parent of origin (46), degree of biochemical disturbance (47), and position of the hybrid gene crossover point (48), but environmental factors and variations in expression of other genes that might affect phenotypic expression of the hybrid gene (for example, by altering responses to the actions of aldosterone) are probably also involved (45, 47). Similar factors may also explain variability in the degree of renin suppression, as was observed among our study subjects. The ability to screen families for FH-I by genetic testing has helped to expand the spectrum of phenotypic expression further by facilitating the detection of affected individuals in early, preclinical phases of development, including the normotensive subjects described in the current report.

Could treatment with oral contraceptive medications explain the differences in echocardiographic findings between the FH-I and control subjects? All three of the eight subjects with FH-I who were taking these medications at the time of this study were on combination preparations with an estrogen (ethynylestradiol) and an agent with progestational actions (levonorgestrol or cyproterone acetate), one of which (cyproterone) also has antiandrogenic properties. Hypertension resulting from treatment with oral contraceptives is well documented, but two of the three subjects receiving these medications had the lowest mean 24-h BP levels of the group, and we are unaware of reports implicating such agents in the development of LV remodeling and diastolic dysfunction in the absence of hypertension. Treatment with oral contraceptives has also been reported to be associated with elevations in PRA (49, 50), thought to be due to enhancement (by estrogens) of hepatic renin substrate synthesis with a possible contribution from the anti-mineralocorticoid action of progestational agents. Indeed, PRA levels were higher in the three subjects receiving these agents than in the others with FH-I. Conceivably, the expected associated rise in circulating angiotensin II levels might have rendered these individuals relatively prone to LV remodeling. However, the fact that LV wall thicknesses in all three of these subjects were below and peak mitral E wave velocities above the means for these parameters among the group with FH-I makes this highly unlikely.

We have described a second familial form of PAL (familial hyperaldosteronism type II) that is not glucocorticoid remediable and not associated with the hybrid gene mutation and in which biochemical screening by aldosterone/PRA ratio testing of affected families permitted detection of affected members who were not yet hypertensive (51, 52). Fardella et al. (53) detected three individuals with raised aldosterone/PRA ratios, with PAL confirmed in each case by fludrocortisone suppression testing (and FH-I in one of these individuals by genetic testing), among 205 normotensive subjects studied in Chile. It is therefore likely that a normotensive phase exists in all forms of PAL, whether familial or apparently sporadic. With recent evidence suggesting that PAL is a common condition (53, 54, 55, 56, 57), it is possible that significant numbers of normotensive individuals may have early, subclinical forms.

It appears that non-BP-dependent deleterious cardiovascular effects of aldosterone excess can be ameliorated by treatments that antagonize mineralocorticoid action in humans as well as in experimental animals, and, in the present study, this raises the question whether normotensive subjects with FH-I would be better treated with mineralocorticoid receptor blockade than with glucocorticoids suppressing ACTH. In rats, mineralocorticoid-induced cardiac inflammation and fibrosis were prevented by the administration of spironolactone (58) or eplerenone (59) in doses that only partially attenuated the rise in BP. Addition of spironolactone to angiotensin converting enzyme (ACE) inhibitor treatment was reported (60) to result in a greater reduction in LVMI in essential hypertensives than that induced by ACE inhibitors alone, despite a similar reduction in BP in the two study groups. In the Randomized Aldactone Evaluation Study, treatment with relatively small doses (mean 26 mg/d) of spironolactone in patients with severe heart failure who were already receiving ACE inhibitors and loop diuretics (with or without digoxin) was associated with a 30% reduction in mortality after only 12 months follow-up (12). A substudy of the Randomized Aldactone Evaluation Study found baseline levels of PIIINP in patients with severe heart failure to correlate significantly with mortality and to fall significantly in patients randomized to receive spironolactone (but not in those who received placebo), and that the benefit of spironolactone on mortality was significant only in those with above-median baseline PIIINP levels (61). In the EPHESUS trial (Eplerenone’s Neurohormonal Efficacy and Survival Study), treatment with eplerenone led to a 15% reduction in mortality in patients with LV failure after myocardial infarction (13). More recently, we reported that treatment with spironolactone (25 mg daily given for 6 months) in patients with hypertension and LV diastolic dysfunction was associated with improvements in sensitive echocardiographic parameters of LV systolic function (SR, peak systolic strain, and CV of IB), despite there being no significant change in mean 24 h ambulatory BP levels (62).

The findings of the current study and of others that have reported evidence of non- BP-dependent adverse effects of aldosterone excess raise the question as to whether normotensive subjects with FH-I or other varieties of PAL should receive treatment to either lower aldosterone levels or block aldosterone effect even before hypertension develops. In light of these observations, additional studies aimed at addressing this issue by assessing long-term clinical outlook in these individuals and the effects of specific intervention would appear to be warranted.


   Footnotes
 
This work was supported in part by a Centres of Clinical Research Excellence Grant, National Health and Medical Research Council (Canberra, Australia).

First Published Online June 7, 2005

Abbreviations: A, Mitral late peak velocity; ACE, angiotensin converting enzyme; BP, blood pressure; CF, carotid femoral; CR, carotid radial; CV, cyclic variation; E, mitral early peak velocity; FH-I, familial hyperaldosteronism type I; IB, integrated backscatter; IVSD, interventricular septal dimension; LV, left ventricular; LVMI, left ventricular mass index; PAL, primary aldosteronism; PIIINP, procollagen type III amino-terminal propeptide; PRA, plasma renin activity; PWD, posterior wall dimension; PWV, pulse wave velocity; RWT, relative wall thickness; SR, strain rate.

Received April 1, 2005.

Accepted May 26, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Aldosterone, Normotension, and Diastolic Dysfunction
J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5500 - 5501.
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