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LVEDP
*
Mills et al. JACC 1999; 34: 155-162
New diuretics - Conclusions
1. In patients with ADHF, long-term treatment with A1R
antagonists (Rolofillyne), V2R antagonists (Tolvaptan) or
natriuretic peptides (nesiritide):
Decrease body weight and edema, improve dyspnea
Normalized serum sodium (Tolvaptan)
No differences in outcomes (CV death or HF- and renal-
related hospitalizations) as compared to placebo
New natriuretic peptides:
ANPs: Ularitide (proANP 95126), Carperitide (-ANP),
mANP (40-AA peptide mutant ANP)
CD-NP (CNP+15-aa N-terminus of DNP)
BNP: ASBNP.1 (enhances GFR, without the vasoactive properties)
PI3K
RXFP1
Gos
| [Ca
2+
]
i
Goi3
AC
ATP
cAMP
PKA
Relaxin
PKB/Akt
NOS3
NO
PIP3
PKC,
(+)
GC/cGMP
Vasodilation
Regulation of fluid balance
Inhibition of platelet aggregation
Antifibrotic, anti-inflammatory and anti-
apoptotic effects
Relaxins from orphans to therapeutic targets
C. Luteum
Prostata
Cardiovascular Deaths to Day 180
CV Death or Heart/Renal Failure Re-
hospitalizations to Day 60
0.8
0.85
0.9
0.95
1
0 30 60 90 120 150 180
Days
Placebo
Relaxin 10 mcg/kg/d
Relaxin 100 mcg/kg/d
Relaxin 250 mcg/kg/d
Relaxin 30 mcg/kg/d
(p<0.05)
0.8
0.85
0.9
0.95
1
0 10 20 30 40 50 60
Days
Placebo
Relaxin 10 mcg/kg/d
Relaxin 100 mcg/kg/d
Relaxin 250 mcg/kg/d
Relaxin 30 mcg/kg/d
(p=005)
Days Alive and
Out of Hospital to Day 60
Placebo 10 30 100 250
40
41
42
43
44
45
46
47
48
49
50
D
a
y
s
Relaxin (mcg/kg/d)
p=0.05
p=0.16
Worsening Heart Failure
(Physician-Assessed)
0
5
10
15
20
25
6, 12 h 24 h 48 h Day 3 Day 4 Day 5
PL
RLX 10
RLX 30
RLX 100
RLX 250
Relaxin in ADHF (Teerlink et al. Lancet 2009;373:1429-39)
Vasodilation, inhibition of platelet
aggregation, antiremodeling, antiapoptotic
and anti-inflammatory effects
The NO-sGC-cGMP pathway is disrupted in HF
o
|
o
|
o
|
Reduced sGC
Heme Fe
2+
Oxidized sGC
Heme Fe
3+
Heme-free
GTP cGMP GTP
PDE
NO, NO donors
sGC activators
sGC stimulators
(Cinaciguat)
Oxidative
stress
Oxidative
stress
- Boerrigter G et al.
Hypertension. 2008
- Lapp et al. Circulation 2009
Angiotensinogen
Angiotensin I
Angiotensin II
AIII (2-8), AIV (3-8)
Cathepsin G
Kallikrein
Chymase
CAGE
ACE1
tPA
Cathepsin G
Tonin
Trypsin
Kallikrein
Renin Direct renin
inhibitors
Vaccine
Central
(APA)
ACEIs
ARBs AT1/AT2-R
Inhibition of the RAAS
Aldosterone
antagonists
Aldosterone
synthase inhibitors
(Pro)renin
receptor
Ang I
AGT
Ang II
Prorenin
Indirect
effects
Direct
effects
ACEI
Ang II
effects
ARAII
Renin
DRI
ACEI
AT1R
Ang I Ang II PRC PRA
ACEIs + - + +
ARBs + + + +
DRIs - - + -
(+)
TGF|
p42/p44
p42/p44
P
Fibronectina
PAI-1
Colgeno 1
p38 P
p38
hps37
hps37
Actina
Captacin de
3
H-timidina
Hypertrophy, fibrosis,
apoptosis
PLZF
(-)
(P)RR
P
Direct renin inhibitors
ASTRONAUT, ATMOSPHERE,
ESCAPE-SHF, ARIANA-CHF-RD
Aldosterone
Spironolactone
Eplerenone
Improve signs and symptoms
Reduce morbidity and mortality
HF - overexpression
of 11-HSD2
Aldactone
Placebo
1.0
0.9
0.8
0.7
0.6
0.5
0 6 12 18 24
30
36
months
p <0.0001
RALES TRIAL
ALDOSTERONE is an important player
EPHESUS TRIAL
0
HF
(n=4)
5
P=0.03
15
20
Control
(n=3)
C
Y
P
1
1
B
2
/
G
A
P
D
H
(
1
/
1
,
0
2
4
)
10
CYP11B2 gene
Dilated hypertrophy, cardiac fibrosis and failure
(Qin et al. Circ Res 2003)
Yoshimura et al. J Clin Endocrinol Metab 2002
Aldosterone synthase inhibitors
Aldosterone receptor antagonists increase plasma
aldosterone levels, which may result in non-mineralocorticoid
receptor-mediated (non-genomic) adverse effects.
FAD286, LCI699 , SL125
|
Inotropics in HF - Effect on survival
Study Inotropic Result
Xamoterol Xamoterol Increase mortality
Enoximone Enoximone Increase mortality
PROMISE Milrinone Increase mortality
PROFILE Flosequinan Increase mortality
OPTIME-CHF Milrinone Increase mortality
VEST I Vesnarinone Increase mortality
VEST II Vesnarinone Increase mortality
PICO Pimobendan Increase mortality
PRIME 2 Ibopamine Increase mortality
SURVIVE/REVIVE Levosimendan Neutral effects
DIG Digoxin Neutral effect
Ahmed et al. Eur Heart J 2006
Istaroxime (PST-2744)
A luso-inotropic agent without chronotropic effects
ATPase Na
+
K
+
Pump
Na+ Ca++
Exchange
K
+
Na
+
Ca
++
Ca
++
Ca
++
Ca
++
+ Troponin C
Ca
++
Na
+
Tropomyosin Myosin-ATPase
ATP
Ca
++
Ca
++
Phospholamban
SERCA2
ATP
Na
+
/K
+
-ATPase inhibitor
Sarcoplasmic reticulum Ca
2+
pump (SERCA2a) activator
HORIZON-HF trial
n =120, ADHF and LVEF 35%
Gheorghiade M et al. JACC 2008
Cardiac-specific myosin activators increase
myofibril ATPase activity to enhance contractility
Omecamtiv
mecarbil
CK-0689705
CK-1122534
CK-1213296
Myosin
Cardiac Myosin Activators - Omecamtiv mecarbil
0.7
0.9
1.1
1.3
F
u
r
a
r
a
t
i
o
C
e
l
l
l
e
n
g
t
h
m
)
Basal
CK-1827452
No change in Ca
2+
transient
-9
-6
-3
0
-20
0
20
40
60
80
C
h
a
n
g
e
f
r
o
m
b
a
s
e
l
i
n
e
(
%
)
Cardiac myosin activator 15 min
Cardiac myosin activator 3-4 h
FS CO
Bolus 0.5 mg/kg plus 0.5
mg/kg/h for 6 h
*
*
*
*
*
*
SV
HR TPR
*
*
MVO
2
*
LVEDP
*
Increases contractility without changes in [Ca
2+
]
I
Prolongs the systolic ejection time (Phase IIa)
Beta-blocks do not inhibit the inotropic effect
Tamargo et al 2009
Anormalities in Ca
2+
handling
AC
|1AR
o|
|2AR
cAMP
PMCA
Na/Ca
exchange
Ca
2+
Na
+
Ca
2+
ATP
RyR2
Ca
2+
Ca-CSQ
P
P
P
PLB
Ca
2+
SERCA2a
PLB
C
o
n
t
r
a
c
t
i
o
n
Mitochondria
?
L-type
channel
P
Gi
|ARK
SERCA2a
overexpression
PLB inhibition
Fixing SR Ca
2+
leak
The CUPID trial (First-in-man gene therapy
trial in chronic HF) (Heart Failure, Berlin 2010)
Improves 6MWT and NYHA, preserves LVEF
Decreases CV hospitalisation for high-dose group (0.20.7 vs 2.13 days)
Antibodies against AAV in 40% of patients with chronic HF
Oxidative posttranslational modifications decrease SERCA activity
Calcium release channel stabilizers in HF
S44121
H
F
+
S
4
4
1
2
1
H
F
N
O
R
M
A
L
1. RyR2 channels regulate Ca
2+
handling
2. PKA phosphorylation of
Ser
2808
reduces the binding
affinity of the channel-
stabilizing subunit calstabin2,
resulting in leaky RyR2
channels:
+ contractility (HF)
Arrhythmias (CRVT)
3. S 44121, DP2114-2149:
Stabilize the channel complex
and prevent Ca
2+
leak during
diastole in HF
Ser
2808
Cardiac remodeling after MI
Ang II, aldosterone
GFs (TGF|1, CTGF)
cytokines, integrins
PREMIER. JACC 2006;48:15-20
INCREASED
MORTALITY (?)
Etanercept, Infliximab TNFo inhibitors
NO EFFECT Oxipurinol Antioxidants
NO EFFECT Alagebrium AGEP breakers
NO EFFECT Poli-caspase inhibitors Antiapoptotic drugs
NO EFFECT
PG-116800, PG-530742, PD 166793, CP-471,474 MPP Inhibitors
Small, E. M. et al. Circulation 2010;121:1022-1032
MicroRNAs are dominant players in cardiac remodeling
Negative regulators of gene expression by inhibiting mRNA translation or promoting mRNA degradation
Oxidative stress
DL Mann FC06.4.1
Strategies alter microRNA expression/function
A. Cells express a miRs profile that can become altered in HF
Antisense oligonucleotides can capture miRs for knockdown or sequestrate
inappropriately overexpressed miRs
Antagomirs, sponges and erasers to reduce miRs levels
Artificial miRs to overexpress miRs
B. Masks and gene-specific miR mimics can affect single targets specifically
A B
The hopes of today, the future of tomorrow
" Failure is the opportunity to begin again with more intelligence "
Target Drugs under development
Cardiac remodeling/
hypertrophy
Calcineurin inhibitors: AKAP1, atrogin, MCIP1
PI3K/protein kinase B (Akt)/GSK 3 cascade modulators
CaMKII inhibitors (KN93)
Histone deacetylase inhibitors: trichostatin A, SAHA
Neuregulin (rhNRG-1)
Matrix
modulation
MMPs inhibitors (selectivity, time)
Matricellular proteins: thrombospondins, osteopontin, periostin, tenascins
Mannose-binding lectins (IL-6)
Anti-inflammatory drugs Pentraxins (PTX3): cytokine-inducible genes
PI3K inhibitors: LY294002
Immuno-adsorption (anti-|1R/anti-TnI antibodies)
Iron, Erythropoietins rHuEpo, darbopoetina-o, ferric carboxymaltose
Bradycardic agents Ivabradin (SHIFT)
Metabolic modulators Perhexiline, Trimetazidine
Sildenafil (PDE5Is) HF associated with pulmonary hypertension
Late sodium current Ranolazine
Nitroxyl (HNO) donors
CXL-1020
Antidiabetics Metformin, DPP-IV inhibitors, GLP-1 analogs
Conclusions
HF remains a major clinical challenge
Increasing prevalence, substantial morbidity and mortality
A heterogeneous syndrome with different pathophysiology
Different drugs for different syndromes ?
There are too many possible targets
Epiphenomena vs real therapeutic targets
We need better animal models of HF
None of the new drugs have shown to improve outcomes
Limited understanding of the pathophysiology
Heterogeneous populations, doses and duration of the treatment
RCT: end points should be standardized (FDA/EMEA)
New RCT trials should answer important questions
Mechanistic hypotheses to identify real therapeutic targets
Post-discharge outcomes
Urodilatin (hrUlaritide) SIRIUS II trial
Reduced PCWP, SVR and N-terminal pro-BNP
Improved dyspnea score
It did not worsen renal function and shortened length of hospital stay
Decreased SBP (at 30 ng/kg/min - 16%of patients experienced hypotension)
Mitrovic et al. Eur Heart J 2006; 27:2823-2832
221 patients with
ADHF
PCPW > 18 mm Hg,
CI s 2.5 L/min/m
2
24 h i.v. infusion
Effects of istaroxime HORIZON-HF trial
Patients hospitalized with HF and LVEF 35%
Effects dissipated over 1-2 hours
GI symptoms and injection site pain
No changes in neurohormones, creatinine, or TnI
g/kg/min
Parameter 0.5
n=29
1.0
n=30
1.5
n=30
Placebo,
n=31
PCWP
a
(mm Hg) -3.2
a
-3.3
a
-4.7
a
0.0
LVEDV (mL) +2.9 -6.4 -14.1
a
+3.9
HR (bpm) -3.7 -4.3 -7.5
a
-0.6
MAP (mm Hg) +2.2 +3.3 +7.5
a
+0.9
QTc (ms) -25.7
a
-38.0
a
-49.2
a
-2.4
Gheorghiade M et al. J Am Coll Cardiol 2008; 51:2276-2285.
Inflammation as a target in heart failure
TNFo
ILs (1|, 6, 18)
Chemokines (MCP-1, IL-8)
Cardiotrophin-1
Disappointing results:
Etanercept: RENEWAL, RENAISSANCE, RECOVER
Infliximab: ATTACH
New alternatives:
Pentraxins (PTX3): cytokine-inducible genes
PI3K inhibitors: LY294002
Immuno-adsorption (anti-|1R/anti-TnI antibodies)
Strategies used to alter microRNA expression
28 miRs were upregulated >2.0-fold in CHF, with nearly complete normalization of the
HF miR signature by left ventricular assist device treatment
Matkovich, S. J. et al. Circulation 2009;119:1263-1271
The hopes of today, the future of tomorrow
AC2592 (PROCLAIM)
ACRX-100
Aliskiren
ATMOSPHERE, ESCAPE-
SHF, ARIANA-CHF-RD
Allopurinol
Alprostadil
Ambrisentan
Benznidazole
Bosentan (BADDHY)
Cinaciguat
Clevipidine (PRONTO)
CXL-1020
Diuretics
Darbopoetin alpha (RED-HF)
Diuretics
Dopamine (DAD-HF I and II)
Exenatide
Iron
Ivabradine (SHIFT)
JNT-39588146
Levosimendan
LCZ696
Lixivaptan
Metformin (TYASIDE)
Micronutrients (MINT-HF)
Natriuretic peptides
Carperitide, CD-NP,
nesiritide, urocortins
Omecantiv
Omega-3
Perhexiline
Relaxin (Relax-AHF)
RLY5016 (PEARL-HF)
Sildenafil (RELAX, SIDEMI)
Sitagliptin
Statins
Thiamin
Spironolactone (EMPHASIS,
TOPCAT, ALBATROSS)
Vildagliptin
Vitamine D..