New therapeutic targets in heart Failure

Juan Tamargo
Department of Pharmacology, School of Medicine
Universidad Complutense, 28003 Madrid, Spain

Heart Failure a major public health problem

1. A major challenge for a clinician

Over 15 million patients in Europe (30 million in 2020)

Leading cause of hospitalization in the elderly

Lower QoL than patients suffering from any other chronic disease

High mortality rates ( 40% of HF patients will die within 1 y)

2. Healthcare costs - $39.2 billion (US), 2% NHB (UK)

Higher costs than any other diagnosis (Medicare)

ESC Guidelines 2008

HF - General goals of the treatment

1. Reduce MORBIDITY

Relieve signs and symptoms (dyspnea, fatigue)

Improve hemodynamics
Increase stroke volume and cardiac output
Reduce PCWP and LV filling pressures

Improve the QoL

2. Exert favourable effects on OUTCOMES

Reduce the length of stay in-hospital, readmissions and

mortality

Retard the progression of HF once LV dysfunction is established

Stop it at the start; its late for medicine to be prepared when disease has
grown strong through long delays (Ovid, Remedia Amoris)

Development of new drugs for HF

INOTROPICS

1946 - DIGOXIN
1957 - HCTZ

DIURETICS

1961 SPIRONOLACTONE
1965 FUROSEMIDE

1974 - NITROGLYCERIN
1982 - NITROPRUSSIDE
1985 - DA, DOBUTAMINE
1987 - ACEIs
1988 CALCIUM ANTAGONIST
1996 - BLOCKERS
1999 - ARBs, ALDOSTERONE ANTAGONISTS

VASODILATATORS

1999 - NESIRITIDE
2000s - A1R ANTAGONISTS
LEVOSIMENDAN
AVP ANTAGONISTS
TNF INHIBITORS, ET-1 INH.
ULARITIDE, SILDENAFIL

NEUROHUMORAL
INHIBITION
INFLAMMATION,
APOPTOSIS,
METABOLISM
REMODELING.....

2008 - ISTAROXIME, OMECAMTIV, IVABRADINE

2009 - RELAXIN, ALISKIREN, CINACIGUAT
2010 - CXL-1020, RANOLAZINE, 11-HSD2 INH, GENE THERAPY

Mortality and morbidity remain substantial

EHS on Survey
Heart Failure II
II: (2007)
Euro Heart
Mortality
according totonumber
of prescribed
medications
Mortality
according
number
of prescribed
drugs
(BB, ACE-I/ARB, Aldosterone
Aldosterone antagonists)
(BBs, ACEIs/ARBs,
antagonists)
1.0

Survival

0.9

0 drugs
1 drug
2 drugs
3 drugs

0.8

0.7

log-rank test p < 0.001

0.6
Patients at risk
n=2973
2528

2201

2061

0.5
0

12

Months
after
discharge
Months
after
discharge

1.

2.

3.
4.

Relieve symptoms, improve survival and reduce

hospitalisation for HF:
ACE inhibitors, ARBs, -adrenoceptor antagonists,
Aldosterone receptor antagonists
Neutral effect on mortality:
Digoxin, Nitrates, Warfarin, Aspirin, Amlodipine
Unknown effect on prognosis: Diuretics
Increase mortality: inotropics

2008

AHA/ACC

New diuretics under development

Goals - more effective natriuresis and preserve renal function

1.

Adenosine A1 receptor antagonists:

BG9719 (CVT-124), Tonapofylline, FK 838, Rolofillyne

2.

Vasopressin receptor antagonists:

V1A: OPC-21268, Relcovaptan, SR-49059

V2: Lixivaptan, Mozavaptan, RWJ-351647, Satavaptan,
Tolvaptan, VP-343
V1A/V2: CL-385004, Conivaptan, JTV-605, RWJ-676070

3.

Natriuretic peptides:

mANP (40-AA mutant ANP), Carperitide (-ANP), Ularitide

(proANP 95126),
Nesiritide (hrBNP), ASBNP.1
CD-NP (CNP+15 AA N-terminus of DNP),

Tamargo et al. Current Med Chem 2010

Time to death or CV or
renal rehospitalization

Adenosine A1 receptor antagonists PROTECT trial

Clinical signs and

symtoms

Rolofylline 30 mg
N = 1356

Placebo
N = 677

Success, % (n)

40.6 (551)

36.0 (244)

Unchanged, % (n)

37.5 (509)

44.2 (299)

Failure, n (%)

21.8 (296)

19.8 (134)

25.7

25.6

Re-hospitalization

An excess in stroke (3 vs 16) and seizures (0 vs 11)

Metra M.
ESC 2009

Vasopressin antagonists - EVEREST Trial

Death or HF Hospitalization

25.9% vs 26.3%

42% vs 40.2%

Proportion Alive

1.0

Proportion Without Event

All-Cause Mortality

HR 0.98; 95%CI (.87-1.11)

0.9
0.8
0.7
0.6

Median follow-up: 9.9 mos

0.5
0.4
0

12

15

18

21

24

TLV 30 mg
PLACEBO

1.0
0.9
0.8

HR 1.04; 95%CI (.95-1.14)

0.7
0.6
0.5
0.4
0

Months In Study

Secondary end points

CV death or hospitalization
CV mortality
Worsening of HF (death, hospitalization
or unscheduled visits
8

12

15

18

21

Months In Study

Tolvaptan
(n = 2072)

Placebo
(n = 2061)

48.5%
20.3%

46.4%
19.8%

0.52
0.67

36.5%

35.8%

0.62

24

Change from baseline (%)

Nesiritide increased of 30-Day Mortality and the

Risk of Developing Worsening Renal Function
Placebo
Nesiritide

60
*

40
20

*
*

0
-20
-40

SV CO HR

*
LVEDP

Mills et al. JACC 1999; 34: 155-162

Sackner-Bernstein et al. Circulation 2005; 111:

14871491; JAMA. 2005; 293: 19001905

In the FUSION I and II and BNP-CARDS trials nesiritide did not

increase mortality or worsened renal function as compared to placebo

Yancy and Singh. Am J Cardiol 2006

Yancy CW et al. Am Heart J 2007;153:478-484
Witteles et al. J Am Coll Cardiol 2007; 50: 1835-1840

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 renalrelated 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)

Relaxins from orphans to therapeutic targets

C. Luteum
Prostata

Relaxin
RXFP1
Gs

AC

Gi3
PI3K

ATP

cAMP

PIP3
PKB/Akt

(+)
PKA

NOS3

PKC
GC/cGMP

NO

Vasodilation
[Ca2+]i

Regulation of fluid balance

Inhibition of platelet aggregation
Antifibrotic, anti-inflammatory and antiapoptotic effects

Relaxin in ADHF (Teerlink et al. Lancet 2009;373:1429-39)

Days Alive and
Out of Hospital to Day 60

Worsening Heart Failure

(Physician-Assessed)
25

PL
RLX 10
RLX 30
RLX 100
RLX 250

15
10
5

0
6, 12 h 24 h

48 h

Days

20

p=0.16

50
49
48
47
46
45
44
43
42
41
40

p=0.05

Placebo

Day 3 Day 4 Day 5

CV Death or Heart/Renal Failure Rehospitalizations to Day 60

1

10

30

100

250

Relaxin (mcg/kg/d)

Cardiovascular Deaths to Day 180

Relaxin 30 mcg/kg/d
(p<0.05)
Relaxin 10 mcg/kg/d
Relaxin 100 mcg/kg/d

1
Relaxin 30 mcg/kg/d
(p=005)
0.95

0.95
Relaxin 250 mcg/kg/d

Relaxin 250 mcg/kg/d

Relaxin 100 mcg/kg/d

0.9

Relaxin 10 mcg/kg/d

0.9

Placebo

0.85

0.85
Placebo

0.8

0.8
0

10

20

30

Days

40

50

60

30

60

90
Days

120

150

180

The NO-sGC-cGMP pathway is disrupted in HF

NO, NO donors

sGC stimulators

sGC activators

(Cinaciguat)

Oxidative
stress

Reduced sGC
Heme Fe2+
GTP

Oxidized sGC
Heme Fe3+

Oxidative
stress

Heme-free

cGMP

GTP

PDE

Vasodilation, inhibition of platelet

aggregation, antiremodeling, antiapoptotic
and anti-inflammatory effects

- Boerrigter G et al.
Hypertension. 2008
- Lapp et al. Circulation 2009

Inhibition of the RAAS

Angiotensinogen
tPA
Cathepsin G
Tonin
Trypsin
Kallikrein

Renin
Angiotensin I
Cathepsin G
Kallikrein
Chymase
CAGE

ACE1

Angiotensin II
AIII (2-8), AIV (3-8)

Aldosterone
antagonists

AT1/AT2-R
Aldosterone
synthase inhibitors

Direct renin
inhibitors

ACEIs
Vaccine
Central
(APA)
ARBs

Direct renin inhibitors

(+)

Prorenin

Renin
Indirect

Direct
effects

DRI

ACEI

effects

ACEI
AGT

Ang I

ARAII

(Pro)renin
receptor

(-)
PLZF

Ang II
effects

(P)RR

p38

p42/p44

Captacin de
3H-timidina

AT1R

Ang II

p42/p44
TGF
P

Fibronectina
PAI-1
Colgeno 1

p38 P

Ang I Ang II PRC

PRA

hps37
hps37 P
Actina

Hypertrophy, fibrosis,
apoptosis

ACEIs
ARBs
DRIs

+
+
-

+
-

+
+
+

+
+
-

ASTRONAUT, ATMOSPHERE,
ESCAPE-SHF, ARIANA-CHF-RD

ALDOSTERONE is an important player

Aldosterone

HF - overexpression
of 11-HSD2

Spironolactone
Eplerenone
Improve signs and symptoms
Reduce morbidity and mortality

CYP11B2 gene

RALES TRIAL
0.9

0.8

Aldactone

0.7

0.6

p < 0.0001

0.5

P=0.03

20
15
10
5
0

HF

Control

(n=4)

(n=3)

Placebo

months
0

CYP11B2 / GAPDH (1/1,024)

1.0

12

18

24

EPHESUS TRIAL

30

36

Dilated hypertrophy, cardiac fibrosis and failure

(Qin et al. Circ Res 2003)
Yoshimura et al. J Clin Endocrinol Metab 2002

Aldosterone synthase inhibitors

FAD286, LCI699 , SL125

Aldosterone receptor antagonists

increase plasma
aldosterone levels, which may result in non-mineralocorticoid
receptor-mediated (non-genomic) adverse effects.

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+ Na+ Ca++
Exchange
Pump
Ca++

Na+

Na+

Na+/K+-ATPase inhibitor
Sarcoplasmic reticulum Ca2+
pump (SERCA2a) activator

ATP
Ca++
Ca++

K+

Ca++
Ca++

ATP
Phospholamban

Ca+++ Troponin C
Tropomyosin

Ca++

SERCA2

Myosin-ATPase

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

Myosin

Omecamtiv
mecarbil
CK-0689705
CK-1122534
CK-1213296

Cardiac Myosin Activators - Omecamtiv mecarbil

Cardiac myosin activator 15 min

80
0

-3

-6

Fura ratio

-9
1.3

No change in Ca2+
transient

Cardiac myosin activator 3-4 h

CK-1827452
Change from baseline (%)

Cell length (m)

Basal

*
*
60

Bolus 0.5 mg/kg plus 0.5

mg/kg/h for 6 h

*
40

*
*

*
20

1.1
0.9
0.7

-20
FS

SV

CO

MVO2

*
HR

TPR

Increases contractility without changes in [Ca2+]I

Prolongs the systolic ejection time (Phase IIa)
Beta-blocks do not inhibit the inotropic effect
Tamargo et al 2009

*
LVEDP

Anormalities in Ca2+ handling

PMCA

Na/Ca
exchange

?
L-type
channel

ATP

AC

Ca2+

Na+

Ca2+

Mitochondria

cAMP

Ca2+
P

SERCA2a

Ca2+

PLB
P

Gi
ARK

RyR2
Contraction

1AR2AR

Ca-CSQ

PLB
SERCA2a
overexpression
PLB inhibition
Fixing SR Ca2+ 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

NORMAL

1. RyR2 channels regulate Ca2+

handling
2. PKA
phosphorylation
of
Ser2808 reduces the binding
affinity
of
the
channelstabilizing subunit calstabin2,
resulting in leaky RyR2
channels:

HF

Ser2808

contractility (HF)

Arrhythmias (CRVT)

HF+S44121

S44121

3. S 44121, DP2114-2149:
Stabilize the channel complex
and prevent Ca2+ leak during
diastole in HF

Cardiac remodeling after MI

PREMIER. JACC 2006;48:15-20

PG-116800, PG-530742, PD 166793, CP-471,474

NO EFFECT

Poli-caspase inhibitors

NO EFFECT

Alagebrium

NO EFFECT

Antioxidants

Oxipurinol

NO EFFECT

TNF inhibitors

Etanercept, Infliximab

INCREASED
MORTALITY (?)

MPP Inhibitors
drugs
Ang Antiapoptotic
II, aldosterone
GFs (TGF1, CTGF)
AGEP breakers
cytokines,
integrins

MicroRNAs are dominant players in cardiac remodeling

Negative regulators of gene expression by inhibiting mRNA translation or promoting mRNA degradation

Oxidative stress

Small, E. M. et al. Circulation 2010;121:1022-1032

DL Mann FC06.4.1

Strategies alter microRNA expression/function

A

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

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

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-, 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

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)

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

221 patients with

ADHF
PCPW 18 mm Hg,
CI 2.5 L/min/m2
24 h i.v. infusion

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

Effects of istaroxime HORIZON-HF trial

Patients hospitalized with HF and LVEF 35%

g/kg/min
Parameter

0.5

1.0

1.5

Placebo,

n=29

n=30

n=30

n=31

PCWPa (mm Hg)

-3.2a

-3.3a

-4.7a

0.0

LVEDV (mL)

+2.9

-6.4

-14.1a

+3.9

HR (bpm)

-3.7

-4.3

-7.5a

-0.6

MAP (mm Hg)

+2.2

+3.3

+7.5a

+0.9

-25.7a

-38.0a

-49.2a

-2.4

QTc (ms)

Effects dissipated over 1-2 hours

GI symptoms and injection site pain
No changes in neurohormones, creatinine, or TnI
Gheorghiade M et al. J Am Coll Cardiol 2008; 51:2276-2285.

Inflammation as a target in heart failure

TNF
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, ESCAPESHF, 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..