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Turning Heart Failure into Success
David A. Kass, M.D.
Abraham and Virginia Weiss Professor of Cardiology
Professor of Medicine, Professor of Biomedical Engineering
Director, Institute of CardioScience
Division of Cardiology, Department of Medicine
Johns Hopkins Medical Institutions, Baltimore, MD
The Problem
 6 Million
 620 Thousand
 25 Million
 39 Billion
 50%
 53%
“Tonight, we’re going to let the statistics speak for themselves.”
What is Heart “Failure” and how do we treat it?
Normal Heart
Contraction
Ischemia
Hypertension
Genetics
Toxins
Valve Disease
Blah blah blah
Heart Failure
↑ Filling Pressures
↑ Cardiac Volumes
↓Cardiac Output
Fluid
Work Load
↑ RAAS
↑ Na and H2O
Retention
Vasoconstriction
↑ RAAS
↑ Sympathetic
Vasoconstriction
Three Postcards – What we are working on to fix Heart Failure
Oxidative Stress and the Heart
Antioxidants
ROS
Antioxidants
It’s all about the location and where it’s coming from
So what stimulates Oxidative Stress in the Heart?
?
Adrenaline
Renin-Angiotensin
Cytokines
Mechanical Stress
Protein Kinase G: A masterful anti-stress Brake
TRPC
TGFb
R2
R1
RGS2/4
Smads
MKK(K)s
PGC1a
Mudd and Kass Nature 2008
MKKs
What happens if you oxidize a critical anti-stress heart-Brake
Sham
Pressure-Overload
WT
KI
Left Ventricular Mass (mg)
200
*§
†
100
0
(Wk)
Burgoyne et al. Science 2007
0
1
2
3
Nakamura et al JCI 2015: in press
When PKG is oxidized, it moves away from the outer membrane
leaving key disease-causing proteins unblocked
Nakamura et al JCI 2015: in press
Baseline
H2O2
CON
3wk TAC
ET1
PKG1aWT
Rcan1/Gapdh
4
*
*
P<0.01
*
3
PKG1aC42S
2
1
0
TRPC6mut
-
WT
+
-
C42S
+
What can PKG do better at the outer membrane when it’s not
oxidized? It blocks an ion channel called – TRPC6
So why should we care?
• TRPC6 is major regulator of fibrosis and
muscle growth in the heart.
• TRPC6 is a key factor in the abnormal
heart muscle response to stress in
Duchenne Muscular Dystrophy
• PKG activation looks like a potent way to
suppress it, as in vivo drugs against
TRPC6 remain elusive.
Three Postcards – What we are working on to fix Heart Failure
Basic Science
Clinical Therapy
Cardiac Resynchronization
Cardiac Resynchronization Therapy (CRT)
Pacemaker
RV Lead
LV Lead
Neubauer and Redwood, NEJM, 2014; 370:1164-66
Cardiac Resynchronization Therapy
increases the heart motor-protein’s
sensitivity to calcium
Kirk et al. (J Clin Invest, 2014 ;124:129-38).
When is the therapy you want to achieve actually the opposite
of what it seems that you are doing to achieve it?
Neurostimulation
for Pain Control
Vaccination to
induce immunity
Transient Heart Ischemia
to induce Pre-conditioning
Pacemaker
Induced
Transient
Asynchrony
How is it done?
Pace the Right Ventricle from midnight to 6 AM
Pace the Atrium the rest of the day
I
t
Why do we care?
• ~60% of heart failure patients do not have
the type of heart failure that can be treated
with cardiac resynchronization therapy.
• Now we might have a new treatment that
is rather easy to implement – bit of new
software will do it (light switch timer).
• This may open up a major new therapy for
heart failure.
Three Postcards – What we are working on to fix Heart Failure
Viagra’s Cousin
Natriuretic
Peptide Receptor
Nitric Oxide
Synthase
NOS
sGC
rGC
cGMP
PKG
PDE?
Do Stuff
cGMP
PKG
PDE5A
Putting out a
Casting Call
Natriuretic
Peptide Receptor
Nitric Oxide
Synthase
NOS
rGC
cGMP
PKG
ROS
sGC
PDE9
PDE?
cGMP
Do Joint
Stuff
PKG
PDE5A
PDE9a KO mice are protected against Sustained
Pressure-overload (Trans-aortic constriction – TAC)
a
b
PDE9A-/-
WT
Sham
TAC
Sham
TAC
Sham (7) TAC-WT (12)
Sham PDE9A-/- (9)
FS (%)
LV-ESD (mm)
80
60
*
40
20
4
250
3
200
*
50
7
14
21
0
0
Days
c
Sham
-WT
TAC
-WT
100
0
0
Sham
PDE9A-/-
*
150
2
1
0
TAC-PDE9A-/- (18)
LV mass (mg)
7
14
21
0
7
Days
TAC
PDE9A-/-
Days
Interstitial fibrosis (%)
10
*
8
#
6
MT
14
4
2
0
400
Myocyte CSA (mM2)
300
WGA
*
#
200
100
0
n= 5
Lee et al, Nature 2015: 519, 472–476
6
5
6
21
Are
Inonly
Vivomuch
effectsifworks
ofNOS-cGMP
PDE5ifinhibition
the same
with PDE9 inhibition?
are
available
ButPretty
PDE9
NOS sources
function
isassuppressed
Fractional Shortening (%)
70
Treatment Started
60
50
Control
Control + TAC
40
Control + TAC + PDE9A
Control + TAC + SIL
30
20
0
7
14
21
28
35
Days
Fractional Shortening (%)
70
60
Control
L-Name
50
L-Name + TAC
40
L-Name + TAC + PDE9A
L-Name + TAC + SIL
30
20
0
7
Lee et al, Nature 2015: 519, 472–476
14
21
Days
28
35
PDE9A Protein Expression is increased in
Human DCM and particularly HFpEF
NF
DCM
PDE9A
n=10
n=10
3
†
*
PDE9A activity/mg prot.
PDE9A/GAPDH
GAPDH
2
1
NF
DCM
10
PDE9A/actin
NF
NF
AS
NF
NF
8
AS
AS
HFPEF
HFPEF
NF
HFPEF
NF
NF
NF
HFPEF
HFPEF
Actin
NF
DCM
n=
PDE9A
10
0
0
NF
20
DCM
12
8
* ‡
6
*
4
2
0
NF
Lee et al, Nature 2015: 519, 472–476
HFPEF
AS
Why are we excited?
• HF-preserved ejection fraction is ½ of all
heart failure, no current effective therapy
other than diuretics and treat HTN.
• Post-menopausal women and others where
estrogen declines may benefit as the NO
signaling pathway is less active.
• Opens up an entirely new pathway with a
clinical drug that is already tested in humans.