Transcript Nessun titolo diapositiva

Neurohumoral Activation in CHF
Presence / Extent
Pathophysiological / Clinical significance
Mechanisms / Interrelationships between components
Therapeutic modifications
Unresolved problems - The future
15424 M
Median Plasma Norepinephrine
(pg/ml)
600
Median Plasma Renin Activity
(ng/ml/h)
2
p=0.02
p=0.0003
p=0.0001
400
N = 80
N = 80
N = 151
1
N = 54
p=0.03
200
N = 151
N = 56
0
(pg/ml)
200
Control
(242-450)
Prevention
(312-586)
Treatment
(368-644)
Median Plasma ANF
0
Control
(0.3-0.9)
(pg/ml)
4
Prevention
(0.3-1.6)
Treatment
(0.5-3.8)
Median Plasma AVP
p=0.0001
p=0.0001
N = 80
3
p=0.006
N = 80
p=0.0001
100
2
N = 147
N = 147
N = 54
1
N = 54
0
4749 M
Control
(31-65)
Prevention
(69-139)
Treatment
(91-203)
0
Control
(1.4-2.3)
Prevention
(1.7-3.0)
Treatment
(2.3-4.4)
Francis GS et al., Circulation 1990
Overall Plasma
Noradrenaline Kinetics
Regional
Noradrenaline Kinetics
Spillover Rate Total NE
(pmol/min)
500
Cardiac
250
**
6
Arterial Plasma NE
(pmol/ml)
3
**
0
2000
*
Renal
0
NE Plasma Clearance
(l/min)
2.0
0.25
0
2000
*
Pulmonary
8000
0
4727 M
1000
0
300
Spillover Rate Total NE
(pmol/min)
4000
1000
*
Splanchnic
150
0
Controls Cardiac
failure
Controls Cardiac
failure
Esler M. et al., Circulation
150
mmHg
100
5 sec
4019
MSNA in Mild and Severe CHF
LVEDD
80
mm
** *
LVEF
80
%
MAP
110
mmHg
** **
**
100
60
60
**
40
90
40
80
20
20
HR
100
b/min
90
80
**
70
MSNA
100
bs/100 hb
75
*
** **
**
NE
600
pg/ml
500
** **
**
400
50
70
60
50
300
25
0
Control subjects (n = 17)
3654
200
100
Mild CHF (n = 17)
Severe CHF ( n = 19)
Grassi G. et al., Circulation 1995
Echocardiographic and Sympathetic Resting Values
in Ischemic and Idiopathic Dilated CHF
LVEF
%
80
60
*
*
20
C
IHD
IDC
NE
*
400
4764 M
*°
IHD
IDC
40
20
ng/l
500
*
0
200
40
100
20
IHD (22)
MSNA
*
80
60
C (30)
C
bs/100 hb
100
300
0
*
60
40
0
LVEDD
mm
80
IDC (20)
0
C
IHD
*
IDC
Grassi G. et al., Clin Sci 2001
MAP, BMI, LVEF, MSNA in Patients with Isolated or Combined H, O and CHF
MAP
mmHg
130
**
110
**
**
**
**
BMI
kg/m2
40
**
**
90
**
**
**
30
70
50
C
H
O
CHF
CHF
-H
CHF
-O
CHF
-OH
LVEF
%
100
**
80
**
**
**
20
C
H
O
60
**
CHF
-H
CHF
-O
CHF
-OH
CHF
-O
CHF
-OH
MSNA
bs/100 hb
80
**
CHF
*
*
**
**
* **
60
40
40
20
4766 M
C
H
O
CHF
CHF
-H
CHF
-O
CHF
-OH
20
C
H
O
CHF
CHF
-H
Grassi G. et al., Hypertension 2003
Pathophysiological (although partly compensatory)
Consequences of Neurohumoral Activation
Arteriolar constriction
 Afterload
Venoconstriction
 Preload
Arterial stiffening
 Impedance
Tachycardia
 Cardiac O2 consumption
 Myocardial contractility
 Organ perfusion
 Renal Na+ reabsorption
 Na+ / H2O retention /
venous congestion
 RBF / GFR
Myocardial necrosis
 Ectopic activity
Arrhythmias
Cardiac remodeling
15410 M
ARTERIAL DISTENSIBILITY IN CHF
mmHg
BP
b/min
HEART RATE
LVEDD
mm
80
150
80
p<0.0001
60
60
40
40
20
20
0
0
100
50
0
LVEF
ARTERIAL DISTENSIBILITY
%
80
0.2
p<0.0001
RA
0.4
CAROTID
60
40
p<0.003
1/mmHg 10-2
1/mmHg 10-3
p<0.0001
0.1
p<0.006
0.3
0.2
0.1
20
0.0
0.0
0
Means ± SE
4742 M = 037 CG
AORTA
Controls (n=30)
CHF (n=30)
Giannattasio C. et al., Am J Cardiol 1995
Increase in Arterial Distensibility
after Removal of Sympathetic Influences
Vessel
Procedure
Radial artery (man)
Brachial plexus anesthesia
+36%
Femoral artery (man)
Spinal cord hemianesthesia
+47%
Femoral artery (man)
Unilateral lumbar sympathectomy
+26%
Carotid artery (rat)
6-OH-dopamine
+59%
Femoral artery (rat)
6-OH-dopamine
+62%
15427 M
Distensibility
Failla et al., J Hypert 1999; 17: 1117 - Mangoni et al., Hypertension 1997; 30: 1085
Radial Artery in Hand Transplantation:
6 Months Follow-Up
Surgical Intervention: end of October
Diameter
mm
Distensibility
1/mmHg.10-3
5
1.2
4
1.0
0.8
3
0.6
2
0.4
1
0.2
0
0
Dec
Jan
Feb
RA, transplanted hand
4741 M
Mar Apr May
Dec
RA, controlateral hand
Jan
Feb
Mar Apr May
Homolateral, high, native RA
Giannattasio et al., Hypertension 2005; 45: 608
Adverse Prognostic Significance in CHF Shown
for Most (All?) Components of Neurohumoral Activation
15408 M
PRA
Sympathetic nerve activity
Angiotensin II
Vasopressin
Aldosterone
ANP
Plasma NE
BNP
Effect of PVC in Healthy Controls and CHF
Healthy Controls
ECG
CHF Patients
ECG
200
200
BP
BP
100
100
0
0
MSNA
MSNA
Post-PVC MSNA burst
Post-PVC MSNA burst
 DBP Overshoot
30
msec
**
20
20000
10
0
Duration of MSNA Inhibition
30000
mmHg
1573 G
5 sec
**
10000
C
CHF
0
C
CHF
Grassi G. et al., Hypertension 2002
+
Insulin Resistance
+
Lembo G et al., J Clin Invest 1992; 90: 24
Jamerson et al., Hypertension 1993; 21: 618
Sympathetic Nerve Activity
Insulinemia
+
Anderson EA et al., J Clin Invest 1991; 87: 2246
7189 M
Relationships between MSNA and Insulin Sensitivity
4
Central obesity
Peripheral obesity
HOMA (a.u.)
3
2
1
r =0.59
p < 0.001
r = 0.51
p < 0.001
0
20
9712 M = 2062 G mod
30
40
50
60
70
MSNA (bs/100 hb)
80
90
Grassi G. et al., J Hypertens 2004
Interactions between SNS and RAS
Plasma catecholamines
Renal vasoconstriction
Renin secretion
+
AG II
SNS
+
Central VC influences
Ganglionic transmission
NE release
Adrenergic receptor
7195 M
Effect of AgII on Diving-Induced Coronary Vasoconstriction in Man
% 60
Phentolamine
i.v. (n=5)
RPP
CVR
**
40
20
0
% 45
Ag II i.c.
(n=8)
% 45
ACEI p.o.
(n=9)
RPP
CVR
**
30
15
C
Phe
RPP
C
Phe
0
C ACEI
C ACEI
CVR
**
30
15
0
C
AgII
C
AgII
Saino A. et al., EHJ 1992 - Perondi R. et al., Circulaion 1992 - Saino A. et al., Circulation 1997 - Saino A. et al., Circulation 2000
4003
LVEF
80
%
** **
HR
100
b/min
90
*
60
**
MSNA
100
bs/100 hb
75
*
80
50
70
40
25
60
20
Control
Mild
CHF
50
Severe
CHF
Control
Mild
CHF
-12
-8
**
5
* p < 0.05;
** p < 0.01
4746 M
8
4
-12
**
-8
-40
-80
-15
-120
Mild CHF (n = 21)
12  MAP (mmHg)
8
-4
-10
Controls (n = 14)
Severe
CHF
40
12
-4
-5
Mild
CHF
80
*
4
Control
 MSNA (% i.a.)
120
10
**
0
Severe
CHF
 HR (b/min)
15
*
** ** **
**
Severe CHF (n = 17)
Grassi G. et al., Circulation 1995
Comparison of the Effects of Bilateral Cervical Vagal Cold Block
at Different Carotid Sinus Pressures in 6 Dogs with Aortic Nerves Cut
Mean aortic
pressure
mmHg
300
mmHg
300
200
200
Pulse
pressure
Renal
blood flow
ml/min
300
200
PRA
aorta
ng/ml/h
60
40
PRA
renal vein
ng/ml/h
60
40
Renin
release
ng/min
6000
4000
Sinus pressure maintained
at the level of the
mean aortic blood pressure
before vagal block
Sinus pressure maintained
at 40 mmHg
Block
Control
7385 M
100
100
100
20
20
2000
0
0
0
0
0
0
Mancia G et al , Circ Res 1975; 36: 529-535
 MAP (mmHg)
 HR (b/min)
3
12
12
2
9
9
6
6
3
3
0
0
-3
-3
-3
-4
-6
-6
0
-1
-2
 FVR (units)
*
30
25
20
15
10
5
0
-5
-10
-15
*
*
*
Normotensive s (n = 10)
 NE (pg/ml)
150
120
90
60
30
0
-30
-60
-90
-120
**
*
 PRA (ng/ml/h)
1
*
0,8
0,6
0,4
0,2
0
-0,2
-0,4
*
1
Uncomplicated HT (n = 10)
*
 CVP (mmHg)
HT with LVH (n = 12)
* p < 0.05, **p < 0.01
4007
Grassi G. et al., Hypertension 1988, 12: 227-237
Baroreflex in Heart Transplantation
Baroreflex slope
msec/mmHg
15
msec/mmHg
20
15
10
10
5
5
0
Normals
(n = 6)
1902 G
Heart
Cardiac
Failure Transplantation
(n = 11)
(n = 20)
0
Pre
Transplant
Post
Transplant
Ellenbogen et al., Circulation 1989
Neurohumoral Activation in CHF
Presence / Extent
Pathophysiological / Clinical significance
Mechanisms / Interrelationships between components
Therapeutic modifications
Unresolved problems - The future
15424 M
Ag II
24
pg/ml
18
LVEF
55
%
45
*
MSNA
80
bs/100 hb
65
*
12
35
50
6
25
35
0
Baseline
15
8 wk ACEI
20
Baseline
*
75
**
4
50
2
25
4
8
12
-4
4
-12
-2
-4
**
-8
-4
-25
*
*
-50
-6
-8
4772 M
8 wk ACEI
 MSNA (% i.a.)
100
6
-8
Baseline
8 wk ACEI
 HR (b/min)
8
-12
*
**
8
**
12  MAP (mmHg)
*
-75
Baseline
8 weeks ACEI
-100
Grassi G. et al., Circulation 1997
LVEF
MSNA
50
%
40
80
bs/100 hb
65
30
50
20
35
10
0
B
20
8 wks Amlo
B
8 wks Amlo
 MSNA (% i.a.)
 HR (b/min)
12
20
15
8
10
4
5
4
-12
-8
8
12
-4
4
-12
-8
8 MAP12(mmHg)
-4
-5
-4
-10
-8
CHF NYHA Class II/III
n = 14
4774 M
-12
-15
Baseline
8 weeks Amlodipine
-20
Grassi G. et al., Hypertension 1999
Relationship between Neurohumoral Deactivation
by Treatment and Prognosis
Beta-blockers
ACE inhibitors
AgII receptor antagonists
Ventricular synchronization
Calcium antagonists
Phosphodiesterase inhibitors
15431 M
Neurohumoral
activation
Mortality /
Clinical endpoints












Effects of Cardiac Resynchronization Therapy by BV Pacing
BP
140
mmHg
120
*
*
%
30
100
20
80
10
60
0
IV
LVEF
40
NYHA class
**
MSNA
80
**
bs/100 hb
III
60
II
40
I
C
1901 G
Tr (2 mo)
20
C
Tr (2 mo)
Grassi et al., Hypertension 2004
Relationship between Neurohumoral Deactivation
by Treatment and Prognosis
Beta-blockers
ACE inhibitors
AgII receptor antagonists
Ventricular synchronization
Calcium antagonists
Phosphodiesterase inhibitors
Digitalis
Central agents
Alpha-blockers
15432 M
Neurohumoral
activation
Mortality /
Clinical endpoints















 (?)


Evidence of Possible Harmful Effects of
Excessive Neurohumoral Deactivation by Treatment
High doses of a central sympathetic inhibitor
(moxonidine) associated with further
impairment in cardiac function / increased
mortality
Triple RAS blockade in VALUE detrimental
15430 M
Combined Morbidity / Mortality in Subgroups
FAVOURS VALSARTAN
% Patients
FAVOURS PLACEBO
All Patients 100
47
< 65
≥ 65
53
Male
80
Female
20
EF < 27
50
50
EF ≥ 27
ACEI (Yes) 93
ACEI (No)
7
BB (Yes)
35
BB (No)
65
IHD (Yes)
57
IHD (No)
43
0.3
15428 M
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
1.2
1.3
1.4
Combined All Cause Mortality and Morbidity
Sub-group Without ACEI Background Therapy
Event-free probability
1.0
44.5%
RISK REDUCTION
P = 0.0002
0.8
0.6
VALSARTAN (N = 185)
PLACEBO (N = 181)
0.4
0
3
6
9
12
15
18
21
Time since randomization (months)
15429 M
24
27
Residual morbidity and mortality remains
high despite treatment with ACEIs/ARBs
16
Atenolol
14
Losartan
12
10
8
Residual
6
Risk
4
2
0 0 6 12 18 24 30 36 42 48 54 60 66
Months
SOLVD: CV death
14.6%
Relative Risk
Reduction
50
Proportion died (%)
Proportion of patients with
first event (%)
LIFE: CV death, stroke & MI
Placebo
Enalapril
40
30
20
Residual
Risk
10
0
0
30
25
12%
Relative Risk
Reduction
20
15
10
Residual
Risk
5
00
0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
6
12 18 24 30 36 42 48
Months
HOPE: CV death, stroke & MI
Proportion of patients
Proportion died (%)
CHARM-Overall: CV death
Placebo
Candesartan
16% Relative
Risk Reduction
0.20
0.15
Placebo
Ramipril
22%
Relative Risk
Reduction
0.10
0.5
00
Residual
Risk
500
1000
1500
Days of follow-up
Dahlöf et al 2002; SOLVD Investigators 1991; Pfeffer et al 2003; Yusuf et al 2000
Inhibition of the BP response to Ang I
at trough
Losartan
*
90
n = 10
% inhibition
80
*
n=5
100
ns
n=5
n = 10
70
60
50
40
77%
30
76%
40
0
0
Lis: lisinopril
100 mg
od+ Lis
n = 10
50
10
100 mg
bid
n=5
60
10
200 mg
od
n=5
*
70
20
35%
100 mg
od
n = 10
79%
30
54%
20
80
ns
*
90
% inhibition
100
Telmisartan
57%
59%
160 mg
od
80 mg
bid
36%
80 mg
od
80 mg
od+ Lis
Forclaz et al. Hypertension. 2003;41:31–6
Angiotensin II Escape With Long-Term ACEI
Treatment
100
75
Plasma ACE 50
(nmoL/mL/min)
25
*
*
0
30
Plasma
20
angiotensin II
(pg/mL)
10
*
*
*
*
*
*
1
2
3
4
5
6
*
0
Placebo 4 hr
24 hr
Time (mos)
*P<0.001 vs placebo.
Biollaz J et al. J Cardiovasc Pharmacol. 1982;4:966-972.
Change in Aldosterone From
Baseline (pg/mL)
Aldosterone “Escape” Despite
Angiotensin II Blockade and ACE Inhibition
50
Candesartan 4 mg
40
Candesartan 8 mg
30
20
Candesartan 16 mg
10
0
Candesartan 4 mg
+ enalapril 20 mg
-10
-20
Candesartan 8 mg
+ enalapril 20 mg
-30
-40
Enalapril 20 mg
17 Weeks
43 Weeks
Adapted from McKelvie et al. Circulation. 1999;100:1056-1064.
43
Limitations of Available Therapeutic
Interventions on RAS
Beta-blockers
ACE inhibitors
Ang II antagonists
Only oppose
neurally
dependent
renin secretion
Ang II
formatiom
from non-ACE
pathways
High PRA/Ang II
levels may break
through AT1
blockade
Increase
bradykinin
levels
AT2 receptor
stimulation
Potentially
harmful?
Potentially
beneficial?
How to Improve on RAS Blockade
Increased
doses of
ARB
Aldosterone secretion
depends on AgII but
also on other factors
Secretion only partly
reduced
Anti-aldosterone drugs
10106 M
Blockade
at two levels
(2 drug
combination)
BB + ACEI
BB + ARB
ACEI + ARB
Renin inhibitors
Unlike ACEIs and ARBs, aliskiren reduces
Ang I, Ang II and PRA
Direct renin inhibitor
Angiotensinogen
Renin
Ang I
Non ACE pathways
ACE
ACEIs
Feedback Loop
Ang II
ARBs
AT1 Receptor
Ang I
ACEI
ARB
Aliskiren
↑
↑
↓
Ang II
↓
↑
↓
Renin
↑
↑
↑
PRA
↑
↑
↓
Azizi M et al. 2006; Adapted from: Müller DN & Luft FC. 2006
Neurohumoral Measurements in NYHA II-IV Patients
(ALOFT)*
Ratio Aliskiren / Placebo
p
NT-proBNP
0.75 (0.61-0.94)
0.010
BNP
0.75 (0.59-0.95)
0.016
Aldosterone
0.99 (0.93-1.18)
0.90
Urinary aldosterone
0.79 (0.66-0.96)
0.015
Plasma renin concentration
2.60 (1.97-3.44)
<0.0001
PRA
0.23 (0.17-0.31)
<0.0001
* 3 month treatment on top of ARB (or ACEI) + BB
12917 M
McMurray JJV et al., Circulation 2008; 1: 17
(Pro)renin receptor may play an important role in
cardiovascular disease
(Pro)renin receptor actions:
Binding of (pro)renin
Increased renin catalytic activity
Activates VSMC ERK1/2
Direct renin inhibitor
Angiotensinogen
Renin
Ang I
Non ACE pathways
ACE
Feedback Loop
Ang II
Direct renin inhibitor
AT1 Receptor
Heart
Kidney
Aliskiren binds
to renin
Target cell
(Pro)renin
receptor
Vessels
 Vasoconstriction
 Remodelling
Nguyen G, et al. 2001
PRA predicts the incidence of MI:
Interrelation between PRA and CV risk factors
MI rate/1000 person-years
40
For every 2-unit increase in PRA, there is
an overall 25% increase in MI incidence*
Plasma renin activity (PRA)
High
Normal
Low
30
20
10
0
High
Moderate
Risk status†
Low
*Association strongest in white men
†Risk status: high, 2 risk factors (smoking, cholesterol, LVH); moderate, 1 risk factor; low, no risk factors.
Alderman MH et al. Am J Hypertens 1997;10:1–8
Aliskiren provides significant reductions in
BNP levels compared with placebo
0
−10
Optimal HF therapy +
Aliskiren 150 mg
Optimal HF therapy +
Placebo
n=148
n=137
−12.2
−20
−30
−40
−50
−60
−61.0
p=0.0160
−70
Mean change from baseline in BNP at Week 12 (pg/mL)
Baseline BNP concentration = 291 pg/mL
McMurray JJV. ESC 2007 (ALOFT)
Cumulative Hospitalization-free Survival according to
NT-proBNP Plasma Level at Admission and Discharge
Cum. hospitalization-free
survival
Admission
1.0
1.0
0.8
0.8
0.6
0.6
p = 0.11
0.4
p < 0.0001
0.4
NT-proBNP below median
NT-proBNP above median
NT-proBNP below median
NT-proBNP above median
0.2
0.0
0.2
0
100
Time (days)
13220 M
Discharge
200
0.0
0
100
200
Time (days)
Bettencourt P et al., Circulation 2004; 110: 2168