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Modulation of Cardiac Afferent Signaling: A New Strategy for Heart Failure Therapy?
Irving H. Zucker, Ph.D. Department of Cellular and Integrative P hysiology
University of Nebraska Medical Center Omaha, NE USA
NIH S PARC Workshop February 25, 2015
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Disclosures
• Sorrento Therapeutics Inc. grant recipient
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The Vicious Cycle of Heart Failure
Heart Failure
↓ Cardiac Output
Circulation
Vasoconstriction
Afterload
Myocardial Energy Expenditure
Myocardial Cell Death
Venous return
Preload
LVEDP
Lung edema
Heart
Cytosolic Ca2+
Myocardial Growth
Arrhythmias, Sudden Death
Inotropy / Lusitropy
Myocardial Energy Expenditure
Myocardial Cell Death
Neurohormonal Activation Sympathetic Nervous System
Renin – Angiotensin System
Others
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Sympathetic Nerve Activity in Heart Failure
Cohn,J.N. et al: N.Engl.J.Med. 311: 819, 1984 Ferguson, D. W. et al.: J. Am. Coll. Cardiol., 16:1125, 1990
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Afferent
~ Arterial Baroreflex (-) Arterial Ohemoreflex (+)
A trial Reflex (-) Ventricular vagal Mechano Reflex (
C hemosensitive Reflex ( +)
Cardiac Sym pathetic Afferent Reflex
Efferent
·.J• ~ .. [-7: ....
..-:
Reflex Control in Heart Failure
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The Baroreflex
CVRx.com
Eckberg, D. et al. N. Engl. J. Med. 1971
http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.cvrx.com/usa/patients-us/heart/baroreflex/&ei=hIbnVPqOC4yzyASYqYL4BQ&bvm=bv.86475890,d.aWw&psig=AFQjCNEQzQvSKINK65KdBif2N_o-9IUERg&ust=1424545784509621http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.cvrx.com/usa/patients-us/heart/baroreflex/&ei=hIbnVPqOC4yzyASYqYL4BQ&bvm=bv.86475890,d.aWw&psig=AFQjCNEQzQvSKINK65KdBif2N_o-9IUERg&ust=1424545784509621http:CVRx.com
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Vagal Nerve Stimulation
A Left ventricular volume Indexes p 002
160 140 120
p 0 15 • • •
.. 100
:5 80 E 60
40
20 0
Baseline
- LVEDVI, P: 0.44 (;;] LVESV/ P=O
3 months I
6 months
B Left ventricular ejection fraction P= 0.003
%
35
30
25
20
15
10
5
0
f
1
P= 0.78
P=f.01 f
'\
•
'
•
Baseline
P
-
Chemoreflex Sensitivity
± SD
Normal CRS
High CRS
Chua, T.P. et al. Europ. Heart J. 1997
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Carotid Body Denervation A F,0,6~ 1 FO,o. ii>
aham~: I ~ ~~1~drttfl1~'Hthtt•11 i~· ~t!W•1~tHt~tt+~1t111,t1
B
0..00 0-05 0 10 0 15 0..20 o.2$
Fp,
C Fp1021 F020: 10
&lllr!\-i~ml) I f#NtvWJ#.JV-,WJ..WWW#J.mN.JM fv\WMNJ.,WN~V.. ~ (11'1 )
D
~- =~= ~F.CBD ·~
' 0.10 0 15 0.2
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Cardiac Sympathetic Afferents in Heart Failure: It’s not just about the pain
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Visceral afferent structure
1. Somatic efferent. 2. Somatic afferent. 3,4,5. Sympathetic efferent. 6,7. Sympathetic afferent.
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Thalamus CL VPL
~~ \ POm ' ' \
' I I I I I I
... ~ I I I I
...... ,.,, \ : ''1
I I I
{
ISTT f Tracts mSTT - 1-
S::.;:R:-::T=--- ---- +! I I
A B T2 -;-3
1-1 11 IV
v
l ·· Vil VIII . c
o l IX e C,I
From: Forman, RD. In Reflex Control of the Circulation, Zucker IH and Gilmore JP, CRC Press, 1991
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Stimuli for Cardiac Sympathetic Afferents
• Hydrogen ion • Oxygen radicals • Potassium • Lactate • ATP • Prostaglandins and other AA metabolites • Bradykinin • Substance P • Capsaicin
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5 ug 50 ug
Bradykinin Bradykinin
Wang W and Zucker IH, Am. J. Physiol. 1996
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Epicardial lidocaine reduces SNA in heart failure
Capsaicin (1 O µg/kg, LA) 15
c::=:J Pre-Cap. * # - ~ PostCap. 0 12 (1) ~ en (1) ~ 9 ·a en -s 6 # m
* a:: (1) C> 3 T ... m .c: 0
.!!? 0 c Sham HF
0
Cl -5 :r E .s ~ -10 ~ C::J Sham .= &-15 ~ HF c (ll .t:: ()
0
'2 0 -10 ..... 0
~ ~
~ -20 0:: .= (!)
* g> -30 (ll .c ()
0
~ -3 ~ 0:: I -6 .= (!) O> c ~ -9 ()
Zucker et al. In: Spinale FG. Pathophysiology of Tachycardia-Induced Heart Failure, 1996
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TRPV1
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Euphorbia resinifera 16 Billion Scoville Units
Resineferitoxin (RTX)
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RTX X
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PGP 9.5 TRPV1 Merge
Sham
+Veh
icle
Sham
+RTX
180µm
-
*P
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Hemodynamic and morphological data in sham and CHF rats treated with vehicle or RTX
Sham+Vehicle
(n=21)
Sham + RTX
(n=20)
CHF+Vehicle
(n=23)
CHF + RTX
(n=25)
Body weight, g 429 ± 7 430 ± 7 452 ±8 440 ± 8
Heart weight, mg 1438 ± 28 1430 ± 30 2239 ± 61* 1650 ± 49*†
HW/BW, mg/g 3.4± 0.1 3.3 ± 0.1 5.0 ± 0.1 * 3.8 ± 0.1*†
WLW/BW, mg/g 4.4± 0.1 4.5 ± 0.1 8.7 ± 0.3 * 5.1 ± 0.2*†
MAP, mmHg 103.5 ± 2.4 105.0 ± 3.1 96.7 ± 2.0* 101.3 ± 2.1
LVEDP mmHg 5.0± 0.4 4.8± 0.4 21.3± 1.0* 8.3± 0.7*†
HR, bpm 357.3 ± 6.1 362.0 ±6.8 368.9 ± 5.1 348.3± 5.5†
dp/dtmax 9108±324 8601±224 5137 ± 180 * 5446 ± 173*
dp/dtmin -8458±235 -8088±196 -3452±113* -4643±149*†
Infarct size, % 0 0 42.5± 1.4 * 39.1 ± 1.2 *
*P
-
A
S+V
S+RTX
C+V
B . '
. ' .. "~ /.
· i.}~' ~ '1/' I • - ...r:
-
Basal lso -0-- Sham+Vehicle
12000 = Sham+Vehicle 10000 - Sham+RTX - Sham+RTX -?---- CHF+Vehicle
- CHF+Vehicle c: --V-- CH F+RTX -0 = CHF+RTX "'C VJ ..... 8000 - -"t:J c. 0 l* - * "'C -c.. + CV "t:J c: I/) 5000 + c: CV 0
4000 C> c.. ]t c: I/) nJ CV .c: a... 0
0 0
0.01 0.1 1.0
0 0.01 0.1 1.0 0
c: ....,
-4000 ·-o
~"t:J .:0 VJ - --c.. c.. 0 "t:J * "'C -I I CV -1500 -8000 t c: I/) ·- c:
CV 0
= Sham+Vehicle C> c.. c: I/) - Sham+RTX
nJ CV -0-- Sham+Vehicle .c: a... -12000 - CHF+Vehicle 0 - Sham+RTX = CHF+RTX -3000 -?---- CHF+Vehicle ~ CHF+RTX
Wang, HJ. et al. Hypertension, 2014
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A
c
E
0:: > a.
"' w
o; :I: E
200
.s 100 ~ :I ..., ...,
-
A Sham+Vehicle Sham+RTX CHF+RTX
IVS '\
c CHF+RTX CHF+Vehicle
30 = Shant-Veticle I/) - Shcrn+R1X ·u; - - Of+Vehicle * 0 CV ..... l!! = Of+RTX :e CV
* L1. - * uS 15 * CV 0 t ·- -"E ~ CV -(.)
0 IVS LVremote
c Left Ventricle Septum
S+V S+RTX C+V C+RTX S+V S+RTX C+V C+RTX
= Sh ~ .s 0 0
"" "' 0:: 0
Septum
S+V S+RTX C+V C+RTX
= Sham+Vehlcle - Sham+RTX - CHF+Vehlcle = CHF+RTX
* t
= Sham+Vehlcle - Sham+RTX - CHF+Vehlcle = CHF+RTX
* t
G
Wang, HJ. et al. Hypertension, 2014
-
A
~ ~ ~
.!!! Qi u OJ > ::: 'iii 0 a. I
...J w z :::> I-
D
Q)
(,)
..t::.
~ + L1. :::c (,)
>< ..... 0:: + L1. :::c (,)
6
4
2
0
~ 3 ~ ~
.!!! Qi u 2 OJ > ~ Cl)
0 1 CL I
...J w z :::>
0 I-
= Sham+Vehicle * - Sham+RTX - CHF+Vehicle - CHF+RTX
-=---LV infarct area
= Sham+Vehicle - Sham+RTX - CHF+Vehicle - CHF+RTX
*
LV remote area
c = Sham+Vehicle 4 - Sham+RTX ~ - CHF+Vehlcle * ~ t .!!! 3 - CHF+RTX Qi
* u OJ > 2 t ::: 'iii * 0 CL I 1 ...J
w z :::>
0 I-LV peri-infarct area
E = Sham+Vehicle ~ 3 - Sham+RTX * ~ - CHF+Vehicle ~ .!!! - CHF+RTX Qi u 2 OJ .? := Cl) 0 1 t a. I
...J w * z _lllil_ :::> r=---, -I- 0 IVS
B
Wang, HJ. et al. Hypertension, 2014
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Peripheral tissues
~a \0:/{)
:w lllJJlf.
0
-
Hypothesis: Local CSAR afferent endings containing pro-
inflammatory neuropeptides play a critical role in deleterious
cardiac remodeling in CHF
Myocardial Infarction
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TNFa
lpha
in c
ardi
ac c
onte
nt(p
g/m
g pr
otei
n)
0
50
100 Sham+Vehicle Sham+RTX C+V periinfarct C+V remote C+R periinfarct C+R remote
10-12 week post MI
* *
* * † †
-
A
C
-
N=19
N=20
Survival
Long
term
sur
viva
l rat
e (%
) 100
80
60
40
CHF+Vehicle CHF+RTX
n = 19
n = 20
0 5 10 15 20 25
Weeks 30
-
Epidural T1-T4 DRG application
of RTX
-
A RTX B
-
-C'> 40 :::c E E -a.. ~ 20 c: ·-GI C'> c: * ~ o .LL...L•a_ 0
--~ 240 -t'U
.Q ~ 0 - 160 -
-
Ci 200 CHFSham 200 :::c E
E-
0 1.0
-1.0 ......._______...:......_ -1.0 --------
Ci 200 :::c
CHF+Epicardial RTX 200 CHF+Epidural RTX
E E-D.. ~ 0 ~---------- 1.0 >-
-
A -Epicardial application
C)-~ 100 Q) cu -'- 80 cu >·~ 60 ::::s en E 40' Q)-Cl c: 20 0
...J
n=190000000000 b ooooooooooo
--.- CHF+Vehicle n=20 -·o ·- CHF+RTX
0 5 10 15 20 25 30 Weeks
Epidural T1-T4 DRGs
-C) ~ 100 Q) -'-cu
80 -cu >·> 60'::::s en E 40 -'Q) Cl c: 20 0
...J
OOOOOOOOOOOOOQ n=9 \ 0000000000
•
- ·c()
CHF+Vehicle · CHF+RTX
0 5 10 15 20 25 30 Weeks
B
-
ral i
RAS i ECM Infarct scar MMPj d eg rad-;--+ expansion ~
~
/ Cardiac_~ t __-" fibrosis ............_
, ~Cardiac \ apoptosis
Cardiac .hypertrophy
NE I
..
TRPV1-expressi Cardiac afferents
TR V·------> • Substance P
82
A
.....-... ~....,.. Cardia
Capillary j permability
Plasma !
Extravasation
! onocytes and
Myoc~umj ..lnflam~ion
leukocytes
immigrate intocardiac tissue
• CGRP • Other peptides
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Future Directions Animal Models
• Ischemic • Non-ischemic (cardiomyopathy) • Diastolic Heart Failure (HFpEF) • Large animal models (pig, dog)
Proof of Principle strategies
• Modulation of DRG neuronal activity • Channel Rhodopsin • Halo Rhodopsin • Substance P antagonism
Specificity
• Thoracic DRG • Lumbar DRG • Epicardial
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Therapeutic windows
Mechanisms
•Central pathways mediating sympatho-excitation in response to sympathetic afferent activation. •Molecular regulation of TRPV1 protein in DRG •Cardiac sympathetic afferent activation and arrythmogenesis •Mechanisms of afferent neuropeptide regulation of cardiac remodeling •Understanding of the “physiological role” of cardiac sympathetic afferents •Autonomic regulation •Permeability •Inflammation •Blood flow regulation
Clinical Studies
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Acknowledgements
Johnnie Hackley Pamela Curry Kaye Talbitzer Richard Robinson
Kurtis G. Cornish, Ph.D. Hanjun Wang, M.D.
P01 HL-62222, R01 HL-116608 Sorrento Therapeutics, Inc. American Heart Association
http://www.nhlbi.nih.gov/index.htmhttp://www.nhlbi.nih.gov/index.htm
Modulation of Cardiac Afferent Signaling: �A New Strategy for Heart Failure Therapy?DisclosuresSlide Number 3Slide Number 4Slide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Slide Number 19Slide Number 20Slide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27Slide Number 28Slide Number 29Slide Number 30Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Slide Number 36Slide Number 37Slide Number 38Slide Number 39