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1
Neurohumoral Activation in CHF

• Presence / Extent
• Pathophysiological / Clinical significance
• Mechanisms / Interrelationships between
  components
• Therapeutic modifications
• Unresolved problems - The future

15424 M
2
Median Plasma Norepinephrine
Median Plasma Renin Activity
p0.02
p0.0003
p0.0001
N 80
N 80
N 151
p0.03
N 54
N 151
N 56
Median Plasma ANF
Median Plasma AVP
p0.0001
p0.0001
N 80
N 80
p0.006
p0.0001
N 147
N 147
N 54
N 54
Francis GS et al., Circulation 1990
4749 M
3
Regional Noradrenaline Kinetics
Overall Plasma Noradrenaline Kinetics
Spillover Rate Total NE (pmol/min)
500

6
Cardiac
250
Arterial Plasma NE (pmol/ml)

0
3
2000

Renal
0
1000
NE Plasma Clearance (l/min)
2.0
0
2000

0.25
1000
Pulmonary
8000
0
Spillover Rate Total NE (pmol/min)
300

4000
150
Splanchnic
0
0
Controls
Cardiac failure
Controls
Cardiac failure
Esler M. et al., Circulation
4727 M
4
150
mmHg
100
5 sec
4019
5
Increased Sympathetic Nerve Traffic in Heart
Failure
Normal Subjects
CHF Patients
From Liembach WN et al., Circulation 1986 73 913
1892 G
6
MSNA in Mild and Severe CHF
LVEDD
LVEF
MAP
HR
MSNA
NE
Grassi G. et al., Circulation 1995
3654
7
Echocardiographic and Sympathetic Resting Values
in Ischemic and Idiopathic Dilated CHF
LVEF
LVEDD




NE
MSNA




Grassi G. et al., Clin Sci 2001
4764 M
8
Increase in Sympathetic Activity in Hypertension
and Hypertension-related Conditions





bs/100 hb
bs/100 hb
N
MH
SH
C
SDH
ISH










bs/100 hb
bs/100 hb
C
O
H
OH
L No OSA
L OSA
O No OSA
O OSA
Grassi et al Hypertens.1998 J Hypertens 2000
Hypertens 2000 Hypertens 2005
15102 M
9
MAP, BMI, LVEF, MSNA in Patients with Isolated or
Combined H, O and CHF
MAP
BMI
kg/m2
C
H
O
CHF
CHF -H
CHF -O
CHF -OH
C
H
O
CHF
CHF -H
CHF -O
CHF -OH
LVEF
MSNA
C
H
O
CHF
CHF -H
CHF -O
CHF -OH
C
H
O
CHF
CHF -H
CHF -O
CHF -OH
Grassi G. et al., Hypertension 2003
4766 M
10
Pathophysiological (although partly compensatory)
Consequences of Neurohumoral Activation

• Arteriolar constriction
• Venoconstriction
• Arterial stiffening
• Tachycardia
• ? Myocardial contractility
• ? Renal Na reabsorption
• ? RBF / GFR
• ? Ectopic activity

? Afterload ? Preload ? Impedance ? Cardiac O2
consumption ? Organ perfusion ? Na / H2O
retention / venous congestion Myocardial
necrosis Arrhythmias Cardiac remodeling
15410 M
11
ARTERIAL DISTENSIBILITY IN CHF
BP
HEART RATE
LVEDD
mmHg
b/min
mm
plt0.0001
LVEF
ARTERIAL DISTENSIBILITY

CAROTID
AORTA
RA
plt0.0001
plt0.0001
plt0.003
1/mmHg 10-3
1/mmHg 10-2
Means SE
Controls (n30)
CHF (n30)
Giannattasio C. et al., Am J Cardiol 1995
4742 M 037 CG
12
Increase in Arterial Distensibility after
Removal of Sympathetic Influences
Vessel Radial artery (man) Femoral artery
(man) Femoral artery (man) Carotid artery
(rat) Femoral artery (rat)
Procedure Brachial plexus anesthesia Spinal cord
hemianesthesia Unilateral lumbar
sympathectomy 6-OH-dopamine 6-OH-dopamine
Distensibility 36 47 26 59 62
Failla et al., J Hypert 1999 17 1117 - Mangoni
et al., Hypertension 1997 30 1085
15427 M
13
Radial Artery in Hand Transplantation 6 Months
Follow-Up
Surgical Intervention end of October
Diameter
Distensibility
1/mmHg.10-3
mm
Giannattasio et al., Hypertension 2005 45 608
4741 M
14
Adverse Prognostic Significance in CHF Shown for
Most (All?) Components of Neurohumoral Activation

• PRA
• Angiotensin II
• Aldosterone
• Plasma NE

• Sympathetic nerve activity
• Vasopressin
• ANP
• BNP

15408 M
15
Close Relationship between Sympathetic
Activation (Plasma NE) and Prognosis
1.0
0.8
0.6
Probability of survival
0.4
Plasma norepinephrine
200 pg/ml
400 pg/ml
0.2
700 pg/ml
1000 pg/ml
1200 pg/ml
0
0
10
20
30
40
50
60
Elapsed time in months
Cohn et al., NEJM 1984 311 819
11983 M
16
Effect of PVC in Healthy Controls and CHF
Healthy Controls
CHF Patients
ECG
ECG
BP
BP
5 sec
MSNA
MSNA
Post-PVC MSNA burst
Post-PVC MSNA burst
Duration of MSNA Inhibition
? DBP Overshoot


Grassi G. et al., Hypertension 2002
1573 G
17
Lembo G et al., J Clin Invest 1992 90
24 Jamerson et al., Hypertension 1993 21 618

Sympathetic Nerve Activity
Insulin Resistance


Insulinemia
Anderson EA et al., J Clin Invest 1991 87 2246
7189 M
18
Relationships between MSNA and Insulin Sensitivity
Central obesity Peripheral obesity
HOMA (a.u.)
r 0.59 p lt 0.001 r 0.51 p lt 0.001
MSNA (bs/100 hb)
Grassi G. et al., J Hypertens 2004
9712 M 2062 G mod
19
Interactions between SNS and RAS
Plasma catecholamines Renal vasoconstriction Renin
secretion Central VC influences Ganglionic
transmission NE release Adrenergic receptor

SNS
AG II

7195 M
20
Effect of AgII on Diving-Induced Coronary
Vasoconstriction in Man
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
21
Effect of Benazeprilat Infusion on Angiotensin II
Mean values
Individual values



Benazepril
P lt 0.05
Saino A. et al., Circulation 2000
4767 M
22
Effect of AgII on Diving-Induced Coronary
Vasoconstriction in Man
RPP
CVR
RPP
CVR
?
?


Phentolamine i.v. (n5)
ACEI p.o. (n9)
C
Phe
C
Phe
C
ACEI
C
ACEI
?
?
RPP
CVR
RPP
CVR
Ag II i.c. (n8)
ACEI i.c. (n8)


Dose that reduced AgII in coronary sinus but
not in aorta
C
AgII
C
AgII
C
ACEI
C
ACEI
Saino A. et al., EHJ 1992 - Perondi R. et al.,
Circulation 1992 - Saino A. et al., Circulation
1997 - Saino A. et al., Circulation 2000
4003
23
Mechanisms Responsible for Sympathetic Activation
in CHF Hypothesis
Reflex Dysfunction
Humoral Activation (? RAAS)
? SNS
Metabolic Abnormalities (Hyperinsulinemia, Hyperle
ptinemia)
Hypoxia (Chemoreceptor stimulation)
Ionic Alterations (Metaboreceptor stimulation)
1166 G
24
LVEF
HR
MSNA
Control
Mild CHF
Severe CHF
Control
Mild CHF
Severe CHF
Control
Mild CHF
Severe CHF
? HR (b/min)
? MSNA ( i.a.)




? MAP (mmHg)


p lt 0.05 p lt 0.01
Grassi G. et al., Circulation 1995
4746 M
25
Relationship Between BRS Gain and MSNA Responses
to PVC in C and CHF
20000
n 34 r 0.89 p lt 0.001
? MSNA inhibition post PVC (msec)
16000
12000
8000
4000
0
? MSNA (i.a.) / ? MAP (mmHg)
Grassi G. et al., Hypertension 2002
4001
26
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
Pulse pressure
Renal blood flow
PRA aorta
Renin release
PRA renal vein
mmHg
mmHg
ml/min
ng/ml/h
ng/min
ng/ml/h
300
300
300
60
60
6000
Sinus pressure maintained at the level of
the mean aortic blood pressure before vagal
block Sinus pressure maintained at 40 mmHg
200
200
200
40
40
4000
Block
Control
100
100
100
20
20
2000
0
0
0
0
0
0
Mancia G et al , Circ Res 1975 36 529-535
7385 M
27
? MAP (mmHg)
? CVP (mmHg)
? HR (b/min)
? NE (pg/ml)
? FVR (units)
? PRA (ng/ml/h)



p lt 0.05, p lt 0.01
Grassi G. et al., Hypertension 1988, 12 227-237
4007
28
Baroreflex Impairment in CHF - Possible Mechanisms

• Large artery stiffening
• Na / Water retention
• Smooth muscle contraction
• Baroreceptor degeneration (?)
• Central factors (?)
• Reduced adrenergic / vagal responsiveness
• Prevalence of functional over structural
  (irreversible) alterations

15415 M
29
Baroreflex in Heart Transplantation
Baroreflex slope
Normals (n 6)
Heart Failure (n 11)
Cardiac Transplantation (n 20)
Pre Transplant
Post Transplant
Ellenbogen et al., Circulation 1989
1902 G
30
Neurohumoral Activation in CHF

• Presence / Extent
• Pathophysiological / Clinical significance
• Mechanisms / Interrelationships between
  components
• Therapeutic modifications
• Unresolved problems - The future

15424 M
31
Ag II
LVEF
MSNA



? HR (b/min)
? MSNA ( i.a.)


? MAP (mmHg)






Grassi G. et al., Circulation 1997
4772 M
32
LVEF
MSNA
? MSNA ( i.a.)
? HR (b/min)
? MAP (mmHg)
CHF NYHA Class II/III n 14
Grassi G. et al., Hypertension 1999
4774 M
33
Relationship between Neurohumoral Deactivation
by Treatment and Prognosis
Beta-blockers ACE inhibitors AgII receptor
antagonists Ventricular synchronization Calcium
antagonists Phosphodiesterase inhibitors
Neurohumoral activation ? ? ? ? ?? ?
Mortality / Clinical endpoints ? ? ? ? ?? ?
15431 M
34
Effects of Ventricular Resynchronization on
Hemodynamic and Functional Parameters
BP
QRS
HR
mmHg
b/min
msec
DTDVS
NYHA
EF
mm

msec
VO2 max
Minnesota
6MWT
mt
ml/kg/min
Grassi G et al., Hypertension 2004
15416 M
35
Effects of Cardiac Resynchronization Therapy by
BV Pacing
BP
LVEF


NYHA class
MSNA
IV


III
II
I
C
Tr (2 mo)
C
Tr (2 mo)
Grassi et al., Hypertension 2004
1901 G
36
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
Neurohumoral activation ? ? ? ? ?? ? ? ? ?
Mortality / Clinical endpoints ? ? ? ? ?? ? ?
(?) ? ?
15432 M
37
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
38
Combined Morbidity / Mortality in Subgroups
FAVOURS VALSARTAN
FAVOURS PLACEBO
Patients
All Patients
100
47
lt 65
65
53
Male
80
Female
20
EF lt 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
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
1.2
1.3
1.4
15428 M
39
Combined All Cause Mortality and
MorbiditySub-group Without ACEI Background
Therapy
1.0
44.5RISK REDUCTIONP 0.0002

0.8
Event-free probability
0.6
VALSARTAN (N 185)
PLACEBO (N 181)
0.4
3
6
9
12
21
18
15
24
27
0
Time since randomization (months)
15429 M
40
Residual morbidity and mortality remains high
despite treatment with ACEIs/ARBs
Dahlöf et al 2002 SOLVD Investigators 1991
Pfeffer et al 2003 Yusuf et al 2000
41
Inhibition of the BP response to Ang I at trough
Lis lisinopril
Forclaz et al. Hypertension. 200341316
42
Angiotensin II Escape With Long-Term ACEI
Treatment
Plasma ACE(nmoL/mL/min)








Plasma angiotensin II(pg/mL)

Placebo
4 hr
24 hr
1
2
3
4
5
6
Time (mos)
Plt0.001 vs placebo. Biollaz J et al. J
Cardiovasc Pharmacol. 19824966-972.
43
Aldosterone Escape DespiteAngiotensin II
Blockade and ACE Inhibition
50
40
30
20
10
Change in Aldosterone From Baseline (pg/mL)
0
-10
-20
-30
-40
17 Weeks
43 Weeks
Adapted from McKelvie et al. Circulation.
19991001056-1064.
44
Limitations of Available Therapeutic
Interventions on RAS
Beta-blockers Only oppose neurally dependent
renin secretion
ACE inhibitors Ang II formatiom from non-ACE
pathways Increase bradykinin levels
Ang II antagonists High PRA/Ang II levels may
break through AT1 blockade AT2 receptor
stimulation
Potentially harmful?
Potentially beneficial?
45
How to Improve on RAS Blockade
Aldosterone secretion depends on AgII but also
on other factors Secretion only partly
reduced Anti-aldosterone drugs
Blockade at two levels (2 drug combination) BB
ACEI BB ARB ACEI ARB
Renin inhibitors
Increased doses of ARB
10106 M
46
Unlike ACEIs and ARBs, aliskiren reducesAng I,
Ang II and PRA
Direct renin inhibitor
Angiotensinogen
Renin
Ang I
ACEIs
Feedback Loop
Ang II
ARBs
AT1 Receptor
PRA
Renin
Ang II
Ang I
?
?
?
?
ACEI
?
?
?
?
ARB
?
?
?
?
Aliskiren
Azizi M et al. 2006 Adapted from Müller DN
Luft FC. 2006
47
Neurohumoral Measurements in NYHA II-IV Patients
(ALOFT)
p 0.010 0.016 0.90 0.015 lt0.0001 lt0.0001
Ratio Aliskiren / Placebo 0.75 (0.61-0.94) 0.75
(0.59-0.95) 0.99 (0.93-1.18) 0.79
(0.66-0.96) 2.60 (1.97-3.44) 0.23 (0.17-0.31)
NT-proBNP BNP Aldosterone Urinary
aldosterone Plasma renin concentration PRA
3 month treatment on top of ARB (or ACEI) BB
McMurray JJV et al., Circulation 2008 1 17
12917 M
48
(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
Vessels

• Vasoconstriction
• Remodelling

(Pro)reninreceptor
Nguyen G, et al. 2001
49
PRA predicts the incidence of MIInterrelation
between PRA and CV risk factors
For every 2-unit increase in PRA, there is an
overall 25 increase in MI incidence
MI rate/1000 person-years
Plasma renin activity (PRA)
High
Normal
Low
Low
Moderate
High
Risk status
Association strongest in white menRisk status
high, ?2 risk factors (smoking, cholesterol,
LVH) moderate, 1 risk factor low, no risk
factors.Alderman MH et al. Am J Hypertens
19971018
50
Aliskiren provides significant reductions inBNP
levels compared with placebo
Optimal HF therapy Aliskiren 150 mg
Optimal HF therapy Placebo
0
n137
n148
-10
-12.2
-20
-30
-40
-50
-60
-61.0
p0.0160
-70
Mean change from baseline in BNP at Week 12
(pg/mL)
McMurray JJV. ESC 2007 (ALOFT)
Baseline BNP concentration 291 pg/mL
51
Cumulative Hospitalization-free Survival
according to NT-proBNP Plasma Level at Admission
and Discharge
Admission
Discharge
1.0
1.0
0.8
0.8
0.6
0.6
p 0.11
p lt 0.0001
Cum. hospitalization-free survival
0.4
0.4
NT-proBNP below median NT-proBNP above median
NT-proBNP below median NT-proBNP above median
0.2
0.2
0.0
0.0
0
100
200
0
100
200
Time (days)
Time (days)
Bettencourt P et al., Circulation 2004 110 2168
13220 M