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