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

Disclosures

• Sorrento Therapeutics Inc. grant recipient

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

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

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

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

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

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

Cardiac Sympathetic Afferents in Heart Failure: It’s not just about the pain

Visceral afferent structure

1. Somatic efferent. 2. Somatic afferent. 3,4,5. Sympathetic efferent. 6,7. Sympathetic afferent.

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

Stimuli for Cardiac Sympathetic Afferents

• Hydrogen ion • Oxygen radicals • Potassium • Lactate • ATP • Prostaglandins and other AA metabolites • Bradykinin • Substance P • Capsaicin

5 ug 50 ug

Bradykinin Bradykinin

Wang W and Zucker IH, Am. J. Physiol. 1996

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

TRPV1

Euphorbia resinifera 16 Billion Scoville Units

Resineferitoxin (RTX)

RTX X

PGP 9.5 TRPV1 Merge

Sham

+Veh

icle

Sham

+RTX

180µm

*P

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

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

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

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

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

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

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