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SUPPLEMENTAL MATERIAL
Prevalence and Clinical Phenotype of Primary Aldosteronism in Primary Care Hypertensives
Silvia Monticone, MD, PhD1*, Jacopo Burrello, MD1*, Davide Tizzani, MD1, Chiara Bertello, MD1,
Andrea Viola, MD1, Fabrizio Buffolo1, MD, Luisa Gabetti, MD2, Giulio Mengozzi, MD3, Tracy A.
Williams, PhD1,4, Franco Rabbia, MD1, Franco Veglio, MD1, Paolo Mulatero, MD1
1 University of Torino, Department of Medical Sciences, Division of Internal Medicine and
Hypertension Unit, Via Genova 3, 10126, Torino, Italy.
2 Azienda Sanitaria Locale- Primary Care Trust- Torino 1, Via San Secondo 29, 10128, Torino,
Italy
3University of Torino, Clinical Chemistry Laboratory, Corso Bramante 88, 10126, Torino, Italy.
4Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-
Universität München, Munich, Germany
*equal contribution
[email protected], [email protected], [email protected],
[email protected], [email protected], [email protected],
[email protected], [email protected], [email protected],
[email protected], [email protected], [email protected]
Word count: 4,660
Brief title: hyperaldosteronism in primary care
N° of figures and tables: 2 figures, 4 tables, 8 supplemental tables
Acknowledgments
We are indebted with all the GPs who participated to the PATO study and in particular Beatrice M.
Amosso, Luisa M. Gabetti, Donata Tarello, Carmen Usai, Laura Morselli, Manuela Ruffa, Denise
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Marri, Marco Giovannone, Maria L. Bracco, Giuseppe Tafuri, Piero Verdi, Claudio Nocentini,
Laura Cecchetto, Teresita M. Bracci, Maurizio Milletarì, Maria C. Mercadante, Paola Livorno,
Vincenzo Surgo, Claudia Matrella. We thank the society EVOLUS Srl for providing some patients
data using the NEXT MMG software.
Funding: the study was supported by grants from Regione Piemonte 2008-I and 2008-II; P.M. and
S.M. are in receipt of a grant from the Italian Ministry of the Instruction, University and Research
(ex-60% 2013 and 2014 P.M.; ex-60% 2014 and 2015 S.M).
Corresponding author:
Paolo Mulatero, MD, Division of Internal Medicine and Hypertension, Department of Medical
Sciences, University of Torino, Via Genova 3, 10126, Torino, Italy.
e-mail: [email protected]
Phone: +390116336959 Fax: +390116336931
Supplemental Methods
Selection of the Patients
We screened for PA in hypertensive patients with age less than 60 years to avoid the risk of acute
volume expansion in a population at increased risk of renal/heart failure/arterial stiffness.
Furthermore, because of the decrease in renin with age, the rate of false positive ARR is increased
in older patients (1); older patients are less frequently willing to undergo subtype differentiation
with AVS and prefer to be treated medically; finally, unilateral adrenalectomy does not obtain cure
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of hypertension in unilateral PA forms in most cases in elderly patients (1), thereby reducing the
benefit of large scale screening of this form.
3272 hypertensive patients were invited to participate to the study. 1672 (51%) agreed to participate
and were included in the protocol. We were able to retrieve some information from 503/1600 (31%)
patients that were not recruited: this cohort displayed age, sex distribution, blood pressure and
potassium levels not significantly different from the cohort of patients included in the study
(supplemental table S1).
Only in a few cases a partial or complete screening for secondary forms of hypertension had been
already performed in the recruited patients. We decided to include these patients regardless of
previous findings.
Whenever possible patients were studied under no treatment or before the beginning of the anti-
hypertensive therapy. When necessary blood pressure was controlled using doxazosin (up to 12
mg/day) and verapamil (up to 240 mg/day) alone or in combination. In few cases (n=23), it was
necessary to add a dihydropiridine calcium channel blocker (lercanidipine up to 20 mg/day) to have
an acceptable blood pressure control.
Evaluation of target organ damage and metabolic syndrome.
Target organ damage was defined in agreement with the guidelines of the European Society of
Hypertension (2). In particular, left ventricular hypertrophy assessed by electrocardiography was
defined by a Sokolow–Lyon index >3.5 mV; left ventricular mass index was calculated with the
formula: 0.8 * 1.04* [(interventricular septum + left ventricular internal diameter + inferolateral
wall thickness)3 - left ventricular internal diameter3] + 0.6 gr; left ventricular hypertrophy assessed
by echocradiography was defined by a left ventricular mass index >115 g/m2 for men and >95 g/m2
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for women; for obese subjects left ventricular mass was indexed for height (left ventricular
hypertrophy was defined by a left ventricular mass index >50 g/m2.7) (3); microalbuminuria was
defined between 30–300 mg/24 h or by an albumin to creatinine ratio of 30–300 mg/g. Metabolic
syndrome was defined according to the definition of ATPIII (4).
Results
We decided to reduce the ARR and aldosterone level cut-offs compared to our usual clinical
approach in order to maximize the sensitivity of the screening test. Using a more stringent cut-off
(ARR>40 and aldosterone > 15 ng/dL) would reduce the number of positive screening tests as
follows: 197 patients would have had a positive screening test (93 PA and 104 EH after
confirmatory test), instead of 232 positive screening tests (99 PA and 133 EH after confirmatory
testing). The six PA patients missed using a higher cut-off would have been 5 BAH, no APA and 1
undetermined PA subtype.
We also performed an analysis using different post-SIT aldosterone level cut-offs. Using a post-SIT
aldosterone level cut-off of 6.8 ng/dL, the number of missed PA diagnoses would have been 15
(including no APAs) resulting in a PA prevalence of 5%; using a post-SIT aldosterone level cut-off
of 7.5 ng/dL, the number of missed PA diagnoses would have been 20 (including no APAs)
resulting in a PA prevalence of 4.7%.; using a post-SIT aldosterone level cut-off of 10 ng/dL, the
number of missed PA diagnoses would have been 36 (including 3 APA) resulting in a PA
prevalence of 3.8%.
Reducing the ARR cut-off from 30 to 20 would result in doubling the number of positive screening
tests from 232 to 463. Of course we cannot exclude that a very small number of these patients could
have been PA. However, we are confident that, if any, a very small number of APAs would have
been comprised in this group. In fact, increasing the ARR cut-off from 30 to 40 (and absolute
aldosterone levels from 10 to 15 ng/dL) result in a reduction of 35 positive screening tests. Among
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the 35 patients missed by the increased cut-off, only 6 resulted to be affected by PA but no patients
had unilateral PA, that is APA.
We analyze the rate of positive screening tests and final diagnoses if ARR measurement was
performed only in the subgroup of hypertensive stage 2 or higher: we would have screened 539
patients, with a final diagnosis of 55 PA (18 APA / 34 BAH/ 3 undetermined subtype) and 484 non-
PA (apparent essential hypertensives), therefore missing 44 PA patients of which 9 with APA. If the
screening test was performed only in patients with target organ damage, we would have screened
544 patients with a final diagnosis of 60 PA (19 APA / 39 BAH) and 484 non-PA, therefore missing
39 PA patients of which 8 with APA; if the screening test was performed only in patients with
previous cardiovascular events, we would have screened 109 patients with a final diagnosis of 15
PA (3 APA / 12 BAH) and 94 non-PA (apparent essential hypertensives), therefore missing 84 PA
patients of which 24 with APA;
If the screening test had been performed only in patients with one of the conditions described above
(hypertension stage 2 or higher, and/or target organ damage, and/or previous cardiovascular events),
we would have screened 893 patients with a final diagnosis of 78 PA (22 APA / 53 BAH, 3
undetermined PA subtype) and 815 non-PA (apparently essential hypertensives), therefore missing
21 PA patients of which 5 with APA.
A subdivision of the type of events according with the subgroup of hypertensive patients is
provided in the supplemental table S3.
Discussion
The main pathological effects of aldosterone excess in the heart and kidney are vascular and
perivascular inflammation, fibrosis and cellular hypertrophy (5-8). Thus left ventricular hypertrophy
(9), inappropriate left ventricular mass (10,11), microalbuminuria and reduced renal function 5
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(12,13) are observed more frequently in patients with PA than in essential hypertensives. In
addition, aldosterone excess has been shown to promote insulin resistance, thereby participating in
the pathogenesis and progression of metabolic syndrome and diabetes mellitus (14,15).
Consistently, in our study we observed a higher prevalence of left ventricular hypertrophy,
microalbuminuria and metabolic syndrome in PA patients compared to non-PA hypertensives.
Up to 30% of the hypertensive patients display the LREH (44), a clinical condition characterized by
suppressed renin and “normal” aldosterone levels. The distinction between LREH and mild forms
of PA can be challenging and relies on arbitrary cut-off values chosen to define failure of
aldosterone suppression after confirmatory/exclusion testing. According to the Endocrine Society
guidelines, no clear recommendations are provided on the optimal cut-off levels that determine
positive confirmatory test results (4, 5). In our Hypertension Unit, the saline infusion test was
regarded as positive when serum aldosterone levels were >5 ng/dL (or for a captopril challenge test
when the ARR was >30 ng/dL/ng·mL-1·h-1). Accordingly, we allocated our low-renin patients into
three categories: 1) PA, 2) LREH with a negative ARR test result and 3) LREH with a positive
ARR test but with a negative confirmatory test result. Interestingly, patients with LREH and a
positive screening test did not differ significantly in terms of clinical, metabolic and biochemical
parameters (except for hormonal values, as expected), organ damage or cardiovascular events at
diagnosis, from patients with LREH and negative screening test, consistent with confirmatory
testing efficiently discriminating between PA and LREH.
References
1) Funder JW, Carey RM, Mantero F, et al. The Management of Primary Aldosteronism: Case
Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J. Clin.
Endocrinol. Metab. 2016;101:1889-916.
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2) Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification
by echocardiography in adults: an update from the American Society of Echocardiography and the
European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28:1-39.
3) Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH / ESC Guidelines for the management of
arterial hypertension. Eur. Heart J. 2013:2159–219.
4) National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and
Treatment of High Blood Cholesterol in Adults: Executive Summary of the Third Report of the
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486
–2497.
5) Rocha R, Rudolph AE, Frierdich GE, et al. Aldosterone induces a vascular inflammatory
phenotype in the rat heart. Am. J. Physiol. Heart Circ. Physiol. 283:H1802–H1810.
6) Rocha R, Martin-Berger CL, Yang P, Scherrer R, Delyani J, McMahon E. Selective aldosterone
blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinology
143:4828–36.
7) Rocha R, Chander PN, Zuckerman a, Stier CT. Role of aldosterone in renal vascular injury in
stroke-prone hypertensive rats. Hypertension 1999;33:232–7.
8). Brilla CG, MAtsubara LS, Weber KT. Anti-aldosterone treatment and the prevention of
myocardial fibrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol 1993;25:563–
75.
9) Rossi GP, Sacchetto A, Visentin P, et al. Changes in Left Ventricular Anatomy and Function in
Hypertension and Primary Aldosteronism. Hypertension 1996;27:1039–45.
10) Rossi GP, Cesari M, Cuspidi C, et al. Long-term control of arterial hypertension and regression
of left ventricular hypertrophy with treatment of primary aldosteronism. Hypertension 2013;62:62–7
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9.
11) Muiesan ML, Salvetti M, Paini A, et al. Inappropriate left ventricular mass in patients with
primary aldosteronism. Hypertension 2008;52:529–34.
12) Sechi LA, Novello M, Lapenna R, et al. Long-term renal outcomes in patients with primary
aldosteronism. Jama-journal Am. Med. Assoc. 2006;295:2638–45.
13) Rossi GP, Bernini G, Desideri G, et al. Renal damage in primary aldosteronism: Results of the
PAPY study. Hypertension 2006;48:232–8.
14) Hanslik G, Wallaschofski H, Dietz A, et al. Increased prevalence of diabetes mellitus and the
metabolic syndrome in patients with primary aldosteronism of the German Conn’s Registry. Eur. J.
Endocrinol. 2015;173:665–75.
15) Sowers JR, Whaley-connell A, Epstein M. Narrative Review: The Emerging Clinical
Implications of the Role of Aldosterone in the Metabolic Syndrome and Resistant Hypertension.
Ann. Intern. Med. 2010;150:776–83.
Online Table S1. Comparison of clinical and biochemical parameters of included and not
recruited hypertensive patients.
Variable Included (n = 1672) Not-recruited (n=503) P value
Sex (male/female) 945/727
(56.5/43.5%)
274/229 (54.5/45.5%) 0.224
Age (years) 46 ± 9.2 46.2 ± 10 0.735
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Systolic BP (mmHg) 147.3 ± 14.6 147.1 ± 15.2 0.774
Diastolic BP (mmHg) 94.2 ± 8 93.7 ± 7.4 0.217
Serum K+ (mEq/L) 4.23 ± 0.41 4.26 ± 0.47 0.172
Hypokalemia (yes/no) 106/1566 (6.3%) 34/469 (6.8%) 0.402
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Online Table S2. Clinical and biochemical parameters of included patients, according to the duration of hypertension.
Variable Newly diagnosed
hypertensives (n=569)
Known hypertensives
(n=1072)
P value
Sex (male/female) 316/253 610/462 0.6
Age (years) 44 ± 10 47 ± 9 <0.001
Systolic BP (mmHg) 146 ± 14 148 ± 15 <0.001
Diastolic BP (mmHg) 94 ± 7 95 ± 8 0.1
Serum K+ (mEq/L) 4.3 ± 0.4 4.2 ± 0.4 0.018
PRA (ng/mL/h) 1.6 [0.7-2.6] 1.4 [0.7-2.5] 0.3
Serum aldosterone (ng/dL) 18.9 [13.4-28.0] 19.0 [12.5-26.3] 0.3
Serum creatinine (mg/dL) 0.88 ± 0.18 0.89 ± 0.20 0.2
BMI (Kg·m-2) 25.6 ± 4.3 26.4 ± 4.3 0.001
Total cholesterol (mg/dL) 205 ± 39 208 ± 40 0.08
HDL (mg/dL) 57 ± 18 55 ± 15 0.06
Triglycerydes (mg/dL) 116 ± 76 123 ± 74 0.1
LDL (mg/dL) 125 ± 35 129 ± 36 0.022
Diabetes (Y/N) 23/490 (4.5%) 35/932 (3.6%) 0.4
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LVH ECG (Y/N) 50/397 (11.2%) 81/738 (9.9%) 0.5
LVH Echo (Y/N) 130/305 (29.9%) 304/566 (34.9%) 0.07
Microalbuminuria (Y/N) 64/379 (14.4%) 104/686 (13.2%) 0.5
CV events at diagnosis (Y/N) 18/551 (3.2%) 88/984 (8.2%) <0.001
PA diagnosis (Y/N) 33/536 (5.8%) 66/1006 (6.2%) 0.8
BP= blood pressure; K+= potassium; PRA= plasma renin activity; BMI= body mass index; HDL= high density lipoprotein; LDL= low density
lipoprotein; LVH= left ventricular hypertrophy; CV events= cardiovascular events; PA= primary aldosteronism. Variables are indicated as mean ±
standard deviation (if normally distributed) or as median [25th -75th] (for variables without normal distribution), unless otherwise indicated.
Online Table S3. Type of events in the different subgroups of hypertensive patients.
Non-PA BAH APA Und
No events 1479 52 24 8
CAD 19 (1.3%) 4 (7.7%) 0 0
Atrial fibrillation 20 (1.4%) 3 (5.8%) 2 (8.3%) 0
Stroke 53 (3.6%) 5 (9.6%) 1 (4.2%) 0
Heart failure 2 (0.1%) 0 0 0
Total events 94 (6.4%) 12 (23.1%) 3 (12.5%) 0
Total patients 1573 64 27 8
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PA=primary aldosteronism, BAH = bilateral adrenal hyperplasia; APA= aldosterone-producing adenoma; Und= undetermined PA subtype, CAD=
coronary artery disease.
Online Table S4. Multivariate logistic regression analysis of variables independently associated with cardiovascular events in our
hypertensive population.
Parameter OR 95% CI P value
Age (years) 1.09 1.06-1.13 <0.001
Duration of hypertension (years) 1.04 1.02-1.07 0.002
SBP (mmHg) 1.02 1.00-1.03 0.01
BMI (Kg·m-2) 1.00 0.95-1.10 0.89
HDL cholesterol (mg/dL) 0.94 0.97-1.00 0.06
PA diagnosis (Y) 2.08 1.10-3.93 0.025
Male sex (Y) 1.07 0.66-1.73 0.78
Smoking habit (Y) 1.14 0.68-1.89 0.63
Diabetes (Y) 1.01 0.34-2.98 0.98
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OR= odds ratio; CI= confidence interval; SBP= systolic blood pressure; BMI= body mass index; HDL= high density lipoprotein; PA= primary
aldosteronism.
Online Table S5. Multivariate logistic regression analysis of variables independently associated with left ventricular hyperplasia in our
hypertensive population.
Parameter OR 95%CI P value
Age (years) 1.05 1.03-1.06 <0.001
Duration of hypertension (years) 1.03 1.01-1.04 0.006
SBP (mmHg) 1.02 1.01-1.03 <0.001
PA diagnosis (Y) 2.09 1.35-3.25 0.001
OR= odds ratio; CI= confidence interval; SBP= systolic blood pressure; PA= primary aldosteronism.
Online Table S6. Multivariate logistic regression analysis of variables independently associated with microalbuminuria in our hypertensive
population.
Parameter OR 95% CI P value
Age (years) 0.99 0.97-1.01 0.2
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Duration of hypertension (years) 1.01 0.99-1.04 0.4
SBP (mmHg) 1.01 1.003-1.024 0.01
Diabetes (N) 0.8 0.5-1.3 0.4
PA diagnosis (Y) 2.6 1.5-4.4 0.001
OR= odds ratio; CI= confidence interval; SBP= systolic blood pressure; PA= primary aldosteronism.
Online Table S7. Clinical and biochemical parameters according to the renin profile and final diagnosis.
Variable LREH (n=464) PA (n=99) Normal – high
renin (n=1109)
Overall
p-value
P value
LREH vs
PA
P value LREH
vs normal –
high renin
P value PA vs
normal –
high renin
Sex (male/female) 224/240 59/40 662/447 <0.001 0.04 n.s. <0.001
Age (years) 48±8 49±7 45±10 <0.001 0.9 <0.001 <0.001
Duration of hypertension (years) 3 [1-7] 5 [1-10] 3 [1-7] 0.2 n.s. n.s. n.s.
Systolic BP (mmHg) 149±15 153±17 146±14 <0.001 0.007 0.02 <0.001
Diastolic BP (mmHg) 94±8 97±9 94±8 0.002 0.003 1 0.002
Serum K+ (mEq/L) 4.2±0.4 3.8±0.5 4.3±0.4 <0.001 <0.001 0.6 <0.001
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PRA (ng/mL/h) 0.5 [0.37-0.7] 0.3 [0.2-0.5] 2.1 [1.5-3.0] <0.001 0.05 <0.001 <0.001
Serum aldosterone (ng/dL) 14.2 [9.1-19.9] 31.0 [22.0-42.9] 20.7 [14.4-28.3] <0.001 <0.001 <0.001 <0.001
BMI (Kg·m-2) 25.8±4 26.8±4.7 26.2±4.3 0.06 0.08 0.4 0.4
Glucose (mg/dL) 92±17 97±25 93±22 0.1 0.1 1.0 0.2
Total cholesterol (mg/dL) 208±40 203±38 207±40 0.6 0.9 1 1.0
HDL (mg/dL) 57±15 53±18 56±16 0.1 0.1 1 0.2
Triglycerydes (mg/dL) 113±62 132±79 122±79 0.023 0.073 0.07 0.7
Diabetes (Y/N/IFG) 118/362/46 5/76/12 820/37/131 0.7 n.s. n.s. n.s.
Metabolic syndrome (Y/N) 129/309 (29.5%) 44/53 (45.4%) 312/728 (30%) 0.006 0.04 n.s. 0.03
LVH ECG (Y/N) 23/326 (6.6%) 20/68 (22.7%) 90/746 (10.8%) <0.001 <0.001 0.04 0.005
LVH Echo (Y/N) 130/238 (35.3%) 50/43 (53.8%) 260/601 (30.2%) <0.001 0.038 n.s. 0.002
Microalbuminuria (Y/N) 39/301 (11.5%) 22/60 (26.8%) 111/717 (13.4%) 0.001 0.003 n.s. 0.007
CV events at diagnosis (Y/N) 35/429 (7.5%) 15/84 (15,2%) 59/1050 (5,3%) <0.001 0.002 0.09 <0.001
LREH= low renin essential hypertensives; PA= primary aldosteronism; BP= blood pressure; K+= potassium; PRA= plasma renin activity; BMI=
body mass index; HDL= high density lipoprotein; LVH= left ventricular hypertrophy; CV events= cardiovascular events. Variables are indicated as
mean ± standard deviation (if normally distributed) or as median [25th -75th] (for variables without normal distribution), unless otherwise indicated
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Online Table S8. Clinical and biochemical parameters according to the renin profile and the final diagnosis.
Variable PA
(n=99)
LREH ST (+)
CET (-) (n=133)
LREH ST (-)
(n=331)
Overall
P-value
PA vs
LREH ST
(+) CET (-)
PA vs
LREH ST
(-)
LREH ST (+)
CET (-) vs
LREH ST (-)
Sex (male/female) 59/40 61/72 163/168 0.1 n.s. n.s. n.s.
Age (years) 49±7 49±7 48±9 0.08 n.s. n.s. n.s.
Duration of hypertension (years) 5 [1-10] 3 [1-7] 3 [1-8] 0.3 n.s. n.s. n.s.
Systolic BP (mmHg) 153±17 150±17 148±14 0.003 0.5 0.03 0.2
Diastolic BP (mmHg) 97±9 95±9 94±8 0.001 0.3 0.001 0.2
Serum K+ (mEq/L) 3.8±0.5 4.2±0.4 4.3±0.4 <0.001 <0.001 <0.001 0.3
PRA (ng/mL/h) 0.3 [0.2-0.5] 0.3 [0.2-0.5] 0.6 [0.46-0.8] < 0.001 1.0 <0.001 <0.001
Serum aldosterone (ng/dL) 31 [22.0-42.9] 21.9 [18.0-28.2] 11.4 [8.1-15.6] <0.001 0.005 <0.001 <0.001
BMI (Kg·m-2) 26.9±4.7 25.4±3.8 25.9±4.3 0.045 0.040 0.2 0.8
Glucose (mg/dL) 97 ± 25 93 ± 20 92 ± 15 0.057 0.3 0.051 1.0
Total cholesterol (mg/dL) 203±38 210 ± 38 207 ± 41 0.4 n.s. n.s. n.s.
HDL (mg/dL) 53 ± 17 57 ± 15 57 ± 15 0.1 n.s. n.s. n.s.
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Triglycerydes (mg/dL) 132 ± 79 110 ± 61 (n=126) 114 ± 63 0.03 0.039 0.065 1.0
Diabetes (Y/N/IFG) 5/76/12 8/101/16 261/10/30 0.5 n.s. n.s. n.s.
Metabolic syndrome (Y/N) 44/53 (45.4%) 36/89 (28.8%) 93/220 (29.7%) 0.01 0.08 0.05 1.0
LVH ECG (Y/N) 20/68 (22.7%) 9/88 (9.3%) 14/240 (5.5%) <0.001 0.03 <0.001 0.2
LVH Echo (Y/N) 50/43 (53.8%) 32/74 (30.2%) 98/164 (37.4%) 0.002 0.03 0.08 0.4
Microalbuminuria (Y/N) 22/60 (26,8%) 13/93 (12,3%) 26/208 (11,1%) 0.002 0.04 0.005 0.8
CV events at diagnosis (Y/N) 15/84 (15,2%) 5/128 (3,8%) 30/301 (9,1%) 0.01 0.005 0.1 0.07
PA= primary aldosteronism; LREH= low renin essential hypertensives; ST: screening test; CET: confirmatory/exclusion test; BP= blood pressure;
K+= potassium; PRA= plasma renin activity; BMI= body mass index; HDL= high density lipoprotein; IFG= impaired fasting glucose; LVH= left
ventricular hypertrophy; CV events= cardiovascular events. Variables are indicated as mean ± standard deviation (if normally distributed) or as
median [25th -75th] (for variables without normal distribution), unless otherwise indicated
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