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2469 Mo
Il ruolo dell’aldosterone
nell’ipertensione arteriosa
Alberto Morganti
U.O. Medicina Generale e Centro Ipertensione Arteriosa
Ospedale San Giuseppe, Università di Milano
Congresso ASIAM
Firenze 16-18 , 2011
Tumore Surrenalico Bilaterale: Immagine TAC
298
ALDOSTERONE
Escrezione
renale di K+
Ritenzione
renale di Na+
Volume circolante
Liberazione di renina
Apparato juxtaglomerulare
Bilancio
intracellulare di K+
A II
A I
Pressione di
perfusione renale
309
PA
ACTH
2724 Mo
Comparison of ARRs calculated with PRA and DRA
in patients with APA, IHA and EH
Rossi GP et al., J Hypertens 2010; 28: 1892-1899
ARR-P ARR-D
ng/dl
ng/ml/h
ng/dl
U/dl
0
60
120
180
240
0
50
100
150
200
APA 16
IHA 17
EH 218
APA 16
IHA 17
EH 218
*
* *
*
n=
1310 Mo
Number of Diagnosed Cases of PA per Year
Before and After Using ARR for Screening
Mulatero P et al., J Clin Endocrinol Metab 2004; 89: 1045-1050
Torino Rochester Brisbane Singapore Santiago0
10
20
30
40
50
60
70
80
90
Before ARR
After ARR
1307 Mo
Prevalence of Primary Hyperaldosteronism in Italy
PAPI Study
Diagnostic criteria
PRA / Aldo before and after acute ACEI inhibition
(captopril 50 mg p.o.)
PRA / Aldo before and after volume expansion
(2 l saline infusion in 4 hrs)
Adrenal imaging (TC, RMN)
Adrenal vein sampling
Rossi GP et al., Abstract 22° Congresso SISA 2005
1308 Mo
Prevalence of Primary Hyperaldosteronism in Italy
PAPI Study
Patients recruited
Primary hyperaldosteronism
Aldosteronoma
Adrenal hyperplasia
(mono / bilateral)
Rossi GP et al., Abstract 22° Congresso SISA 20054
1121
118 (10.5%)
49 (41%)
69 (59%)
1287 Mo
Prevalence of the More Relevant Secondary Forms
of Hypertension
Disease
RVH
Primary hyperaldosteronism
RST
Licorice ingestion
“Pill” hypertension
Prevalence
5-10%
7-10%
Rare
0.1%?
1%
Affected patients (Italy)
1-2 mls
1.5-2 mls
?
20.000?
200.000?
Calculation based on the assumption of 30-35% prevalence of HT in the general population
(20 mls pts)
322
Aldosterone: Possibili Meccanismi di Danno Cardiovascolare
• Ritenzione di sodio con espansione volume plasmatico
• Perdita di potassio e magnesio
• Potenziamento dell’attività nervosa simpatica
• Effetto parasimpaticolitico
• Vasocostrizione diretta
• dell’attività AII ( dei recettori AII, conversione AI-AII)
• Alterazione funzione barocettiva
• Alterazione compliance arteriosa
• espressione pompe di membrana
• Sviluppo fibrosi miocardica e vascolare
324
Fibrosi interstiziale cardiaca e perivascolare
Alterazioni di membrana
Rimodellamento cardiovascolare
Aldosterone come Fattore di Rischio Cardiovascolare
compliance
ventricolare
Disfunzione diastolica
Scompenso
rete capillare
e disfunzione
endoteliale
Ischemia
Squilibri elettrolit.
e disregolazione
orto/parasimp.
Disturbi conduzione
Aritmie
1314 Mo
Values of Plasma Aldosterone, LVMI and PQ Interval Duration
in Patients according to K+ Levels
Rossi GP et al., Circulation 1997; 95: 1471-1478
Plasma Aldosterone LV Mass Index PQ Interval
200
180
160
140
120
140
120
100
80
60
2000
1600
1200
800
400
0
(pmol/l) (g/m2) (msec)
< 3.2 > 3.2
< 4.1
> 4.1
Serum K+ (mmol/l)
< 3.2 > 3.2
< 4.1
> 4.1 < 3.2 > 3.2
< 4.1
> 4.1
Serum K+ (mmol/l) Serum K+ (mmol/l)
p < 0.05
p < 0.05
p < 0.05
p < 0.05
p < 0.05
2337 Mo
Pulse Wave Velocity in Patients with Primary Aldosteronism vs
Patients wih Essential Hypertension and Controls
AJH 2006; 19
4
6
8
10
12
14P
WV
(m
s/s)
Controls
n = 20
Essential
Hypertension
n = 28
Primary
Aldosteronism
n = 36
1313 Mo
Carotid Artery Intimal-Medial Thickenings and Plaques
in Patients with PA and EH
Rossi GP et al., Am J Hypertens 1993; 6: 8-14
Int-med thickening Plaques0
2
4
6
8
10
12
14PA (n = 17)
EH (n = 17)
NS
NS
0
2
4
6
8
10
12
14p=0.001 p=0.005 p=0.0001
%
Cardiovascular Events in Patients with
Primary Aldosteronism vs Essential Hypertensives
PA EHT PA EHT PA EHT
Stroke Myocardial
Infarction
Atrial
Fibrillation
Milliez P et al. J Am Coll Cardiol 2005 3 years follow-up
2485 Mo
Neurohormonal stages in hypertension
Lim P et al., J Hypertension 2002; 20: 11-15
Sa
lt s
ensi
tivit
y
AT
II a
dre
nal
sen
siti
vit
y
Age and log ARR
IHA
10-15%
Low renin hypertension
25-33%
Essential hypertension
/ = PRA
= ARR
PRA
ARR
PRA
ARR
2486 Mo
Association between resistant hypertension and
low-renin / high aldosterone profile
Characteristic
Clinic SBP/DBP (mmHg)
No. of BP medications
Potassium (mEq/l)
Plasma aldosterone (mg/dl)
Plasma renin activity (ng/ml.h)
Plasma ARR
Gaddam KK et al., Arch Interm Med 2008; 168: 1159-1164
Patients with
resistant hypertension
(n = 279)
146/86
4.1 *
3.9 *
13.0 *
2.3 *
22 *
Controls
(n = 53)
125/79
0.5
4.3
8.4
3.8
6
0 12 24 36 48 60 72 84 96 108 120
0
20
40
60
80
100
2335 Mo
Probability of Reaching Blood Pressure Control (<140/90)
in Patients with EH, Aldosterone Associated Hypertension (AAH)
and IHA
Sartori M et al., AJH 2006; 19: 373-379
Cu
mu
lati
ve
pro
bab
ilit
y o
f
rea
chin
g s
tud
y e
nd
-poin
t (%
)
Months of follow-up
EH, n = 160
AAH, n = 91
IHA, n = 58
2327 Mo
Mean BP Before and During Spironolactone Treatment
In Obese Patients with Resistant Hypertension (ASCOT trial)
Chapman N et al., Hypertension 2007; 49: 839-845
Mea
n B
P (
mm
Hg)
Pre 0
20
40
60
80
100
120
140
160
Post-Spiro Pre Post-Spiro
SBP DBP
156.9
135.1
85.3
75.8
n = 1411, Spiro median dose 25 mg/day,
BMI 29.4 F.U. 1.3 yr
2634 Mo
Effect of spironolactone treatment on office and 24h BP
in obese patients with resistant hypertension (m
mH
g)
n = 175, FU 7 months
De Souza F et al., Hypertension 2010; 55: 147-152
Baseline BMI 30.2
Spiro 25-50 mg/day
SBP DBP
50
100
150
200
250
20
50
80
110
140
Office 24h Daytime Nighttime Office 24h Daytime Nighttime
All p < 0.001 All p < 0.001
2494 Mo
Effects of spironolactone addition on BP
in obese patients with resistant hypertension - The ASPIRANT
Trial
Vaclavik J et al., Hypertesion online May 2011
SB
P (
mm
Hg
)
Office blood pressure
ABPM (daytime)
-20
-15
-10
-5
0
-20
-15
-10
-5
0
DB
P (
mm
Hg
)
ABPM (nighttime)
Spiro
(n = 55)
Placebo
(n = 56)
Spiro
(n = 55)
Placebo
(n = 56)
Spironolactone addition: 25 mg/day
Follow-up: 9 weeks BMI 32.3
2489 Mo
Effects of eplerenone and enalapril alone and in combination
on blood pressure in hypertensive patients with LVH
Pitt B et al., Circulation 2003; 108: 1831-1838
(mm
Hg
)
Eplerenone
(n = 64)
Follow-up: 3 months
Eplerenone 200 mg/day, Enalapril 40 mg/day, Epl + Enal 200 + 10 mg/day
-30
-20
-10
0
-30
-20
-10
0
-30
-20
-10
0 SBP DBP
Enalapril
(n = 71)
SBP DBP
EPL + ENAL
(n = 67)
SBP DBP
2331 Mo
Percent Changes in Median UACR Induced by Eplerenone over
Time and by Quartile of Baseline eGFR and Treatment Group
Epstein M et al., Clin J Am Nephrol 2006; 1: 940-951
Med
ian
% c
han
ge
in U
AC
R
< 61 61-63 74-84 > 85
-60
-50
-40
-30
-20
-10
0
10
Week 4 Week 8 Week 12
-60
-50
-40
-30
-20
-10
0
Placebo EPL 50 EPL 100
Baseline eGFR (ml/min/1.73m2)
*
* *
* *
* * †
†
* ‡
2490 Mo
Changes in ACR (%) after therapy with eplerenone and
amlodipine in patients without and with MA
White WB et al., Hypertension 2003; 41: 1021-1026
Ch
an
ge
fro
m b
ase
lin
e in
UA
CR
(%
)
-80
-60
-40
-20
0
Eplerenone (n = 134)
Amlodipine (n = 135)
MA at baseline
< 30 mg/g
MA at baseline
≥ 30 mg/g
Follow-up: 24 weeks
2492 Mo
Changes in pulse wave velocity
after therapy with eplerenone and amlodipine
Eplerenone 50-200 mg/day (n = 134)
Amlodipine 2.5-10 mg/day (n = 135)
Ch
an
ge
fro
m b
ase
lin
e (m
/s)
White WB et al., Hypertension 2003; 41: 1021-1026
Carotid-femoral PWV Carotid-radial PWV
-3
-2
-1
0
-3
-2
-1
0
Eplerenone Amlodipine Eplerenone Amlodipine
Week 14
Week 24
Staessen J et al, J Endocrinol 1981; 91: 457
Escape of aldosterone to ACEI treatment in hypertensive patients
0
5
10
15
20
25
30
35 Angiotensin II
AldosteroneAngiotensin II
(pg/ml)Aldosterone(pg/ml)
MonthsCaptopril(mg/24h)
1
200
2
400
3
400
6
500
9
600
12
600
160
120
80
40
0
018
2514 Mo
Incidence of aldosterone “escape” phenomenon
during treatment with RAS inhibitors
Definition
Any increase from baseline
Aldosterone above levels
in healthy subjects
In patients with CHF
In patients without CHF
Bomback AS et al., Nat Clin Prac Nephrol 2007; 3: 486-492
6 months
40%
10%
10%
40%
12 months
53%
38%
38%
53%
556 patients from 8 studies
Duration of treatment
0
2
4
6
8
0
20
40
60
80
100
2332 Mo
Aldosterone Escape during RAS Blockade is Associated with
Enhanced GFR Decline
Schjoedt KJ et al., Diabetologia 2004; 47: 1936-1939
pg/ml
Plasma Aldo Decline in GFR
ml/min/year
B = Baseline L = Losartan 100 mg/day (35 months) Aldo escape Aldo non-escape
B L B L
*
*
*
2487 Mo
Percent of patients with resistant hypertension
controlled by dual blockade and spironolactone
Alvarez-Alvarez B et al., J Hypertension 2010; 28: 2329-2335
0 20 40 60 80 100%
Control Not control
SPR + single blockade
ABPM
SPR + single blockade
Office BP
Dual blockade
ABPM
Dual blockade
Office BP
2325 Mo
Changes in Blood Pressure, Left Ventricular Mass and Urinary Albumin Excretion
in Hypertensive Patients with Type 2 Diabetic Nephropathy
on Treatment with ACEI after Addition of Spironolactone
Sato A et al., Hypertension 2003; 41: 64-68
Blood pressure LVMI UAE
DBP
SBP
150
100
50
0
PostPre
600
400
200
0
PostPre
150
100
50
0
PostPre
mmHg g/m2 mg/g creatinine
*
*
2685 Mo
Conclusioni
Gli iperaldosteronismi primari ( adenomi o iperplasie) sono
causa non rara di ipertensione secondaria.
Gli elevati valori di aldosterone sono causa di danno cardio
vascolare con eventi più frequenti che nell’HT essenziale
Alti livelli di aldosterone con renina soppressa si osservano
anche nell’HT resistente che risponde meglio agli
antialdosteronici che alle altre classi di farmaci
Gli antialdosteronici possono essere utili anche nei pazienti in
cui la secrezione dell’aldosterone sfugge ai bloccanti del RAS