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HFA Congress 2015
Basic Mechanisms to improve systolic function
Christoph Maack, MD
Klinik für Innere Medizin IIIUniversitätsklinikum des Saarlandes
Homburg/Saar, Germany
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Conflicts of Interest
Speaker honoraria from:Bayer, Berlin-Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Servier, Pfizer, Stealth Biotherapeutics.
Scientific advisor to:Stealth Biotherapeutics.
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Myocardialinfarction
Arrhythmia &loss of myocardium
Remodelling
LVdilation
ChronicHeart Failure
Death
Coronarythrombosis
Myocardialischemia
CAD
Atherosclerosis, LVH
Risk factors
Modified fromDzaru & Braunwald,1991
HypertensionCholesterolDiabetesNicotine
The cardiovascular continuum
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SystolicHeart Failure
(HFrEF)LVH
HypertensiveCardiopathy
DiastolicHeart Failure(HFpEF)
AcuteHeart Failure
Risk factorsHypertensionCholesterolDiabetesNicotine
Myocardialinfarction
Arrhythmia &loss of myocardium
Remodelling
LVdilation
Death
Coronarythrombosis
Myocardialischemia
CAD
Atherosclerosis
Modified fromDzaru & Braunwald,1991
The cardiovascular continuum
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Neuroendocrine activationReduced compliance (diuretics, fluid intake)Medication (NSAR etc.)
H2O
Pulmonary Congestion
Afterload Blood pressure Aortic stenosis
C.O.
Ischemia
Arrhythmia
Preload
MyocarditisTako-Tsubo
Diuretics
Inotropes
Vasodilators
Myocardial protection agents
Renal preservation agents
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C.O.
Inotropes
Nieminen et al., Eur Heart J 2006;27:2725-2736
CardiogenicShock (4%)
Gheorghiade et al., JAMA 2006;296:2217-2226
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Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+Sarcoplasmic Reticulum (SR)
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
Oxidative Phosphorylation
Physiology: Excitation-contraction coupling and mitochondrial energetics
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Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
Chronic Heart Failure:Defects in EC Coupling
ATP
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Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
Chronic Heart Failure:Defects in EC Coupling
ATP
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Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
Chronic Heart Failure:Defects in EC Coupling
ATP
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Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
Chronic Heart Failure:Defects in EC Coupling
(Ca2+)
ATP
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Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
Chronic Heart Failure:Defects in EC Coupling
(Ca2+)
Contraction/Relaxation
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Ca2+Ca2+
ATP
Ca2+
Ca2+
NCX
Na+
Ca2+
Na+
ICa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
T-tu
bule
ETC
1-AR
cAMP
INa
NKA
K+ K+
Ca2+
Leck
PKAPDEs +
O2 H2O
Actin-myosincross bridges
OMECAMTIV
SERCA2a GENE-THERAPY
DOBUTAMINE
HNO
RYCALS
ISTAROXIME
ISTAROXIME
BENDAVIA
RyR
+ +
+ENOXIMONEMILRINONE
DIGITALIS
+
+Troponin C
Ca2+
+
LEVOSIMENDAN
Strategies to improve systolic function
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Ca2+Ca2+
ATP
Ca2+
Ca2+
NCX
Na+
Ca2+
Na+
ICa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
T-tu
bule
ETC
1-AR
cAMP
INa
NKA
K+ K+
Ca2+
Leck
PKAPDEs +
O2 H2O
Actin-myosincross briges
OMECAMTIV
SERCA2a GENE-THERAPY
DOBUTAMINE
HNO
RYCALS
ISTAROXIME
ISTAROXIME
BENDAVIA
RyR
+ +
+ENOXIMONEMILRINONE
DIGITALIS
+
+Troponin C
Ca2+
+
LEVOSIMENDAN
Strategies to improve systolic function
![Page 15: Basic mechanisms to improve systolic function](https://reader031.vdocuments.site/reader031/viewer/2022030312/58ed9a461a28ab282e8b4579/html5/thumbnails/15.jpg)
Ca2+Ca2+
ATP
Ca2+
Ca2+
NCX
Na+
Ca2+
Na+
ICa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
T-tu
bule
ETC
1-AR
cAMP
INa
NKA
K+ K+
Ca2+
Leck
PKAPDEs +
O2 H2O
Actin-myosincross bridges
RyR
DIGITALIS
Troponin C
Ca2+
Strategies to improve systolic function
![Page 16: Basic mechanisms to improve systolic function](https://reader031.vdocuments.site/reader031/viewer/2022030312/58ed9a461a28ab282e8b4579/html5/thumbnails/16.jpg)
Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
Digitalis increases Na+ and Ca2+ by inhibiting the Na+ /K+-ATPase
Digitalis
ATP
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Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
Digitalis
ATP
Digitalis increases Na+ and Ca2+ by inhibiting the Na+ /K+-ATPase
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Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
Digitalis
ATP
Digitalis increases Na+ and Ca2+ by inhibiting the Na+ /K+-ATPase
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Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
Digitalis
ATP
Digitalis increases Na+ and Ca2+ by inhibiting the Na+ /K+-ATPase
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Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
Digitalis
NCENa+
Ca2+ ATP
Elevating cytosolic Na+ triggers oxidative stress from mitochondria
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Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
Digitalis
NCENa+
Ca2+ ATPKohlhaas,Circ 2010
CGP
Liu,JMCC 2010
Elevating cytosolic Na+ triggers oxidative stress from mitochondria
ROS
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Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
Mito
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
Digitalis
NCENa+
Ca2+
Der Klassiker: Digitalis
DIG Trial, NEJM 1997
All-cause Mortality
Death or Hospitalization due to HF
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Ca2+Ca2+
ATP
Ca2+
Ca2+
NCX
Na+
Ca2+
Na+
ICa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
T-tu
bule
ETC
1-AR
cAMP
INa
NKA
K+ K+
Ca2+
Leck
PKAPDEs +
O2 H2O
Actin-myosincross bridges
RyR
DIGITALIS
Troponin C
Ca2+
Strategies to improve systolic function
DOBUTAMINE+
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cAMP
Ca2+
Ca2+Ca2+
Ca2+ATPCa2+ Ca2+
Ca2+
NKA
NCX
Na+
Ca2+
Na+
ICa
INa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
T-tu
bulu
s
Cytosol Myofilaments
RyR2
K+
-AR
AC
PKA
AMP
Agonist
PP P
P
PDE
PDE-Inhibitors
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Adrenergic receptor efficacy of catecholamines
Endogenous catecholamines• Adrenaline (adrenal gland)• Noradrenaline (cardiac sympathetic neurons)• Dopamine (CNS)
Synthetic catecholamines• Isoproterenol (1-/ 2-AR agonist)• Dobutamine (1-AR agonist)• Phenylephrine (-AR agonist)
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Eugene Braunwald
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Hemodynamic effects of dobutamine
Vatner et al., J Clin Invest 1974;53:1265-73
Concious instrumented dogs
Kindermann & Maack et al., Circulation 2004;109:3182-3190
Healthy volunteers
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Hemodynamic effects of dobutamine
„First in man“
Jewitt et al., Lancet 1974
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O`Connor et al., Am Heart J 1999
Adverse long-term effects of dobutamine
FIRST (Flolan International Randomized Survival Trial)471 patients with AHF, NYHA IIIb-IV(n=80 on dobutamine, n=391 controls)
Controls
Dobutamine
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Adverse long-term effects of dobutamine
Jewitt et al., Lancet 1974
FIRST (Flolan International Randomized Survival Trial)471 patients with AHF, NYHA IIIb-IV(n=80 on dobutamine, n=391 controls)
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AC
cAMP
1-AR
5'-AMPPKA
Ca2+ Handling
PDE4
NE, Dobutamine etc.
PDE3
5'-AMP
Phospho-diesterases
ContractilityCaMKII
Hypertrophy Apoptosis Arrhythmias
Nucleus Mitochondria
GRK2
P
PDE-Inhibitors,(Levosimendan)
Myofilaments
-arrestinEPAC
CaMKII
1-AR stimulation induces cardiomyocyte hypertrophy
and apoptosis
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Engelhardt et al., PNAS 1999; 96:7059-64
Chronic 1-AR stimulation causes LV hypertrophy and failure
LV Hypertrophy
WT 1-AR TG
Myocyte hypertrophy LV contractility LVEF
15-fold overexpressionof the human 1-AR
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Ca2+Ca2+
ATP
Ca2+
Ca2+
NCX
Na+
Ca2+
Na+
ICa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
T-tu
bule
ETC
1-AR
cAMP
INa
NKA
K+ K+
Ca2+
Leck
PKAPDEs +
O2 H2O
Actin-myosincross bridges
RyR
DIGITALIS
Troponin C
Ca2+
Strategies to improve systolic function
DOBUTAMINE+ENOXIMONEMILRINONE
LEVOSIMENDAN
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Acto-myosin interaction.
Hasenfuss & Teerlink, Eur Heart J 2011;32:1838-1845
Ca2+Ca2+ sensitizers +
Acto-myosin Interaction
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Brixius et al., Cardiovasc Drugs Ther 2006
The „pure“ Calcium-Sensitizer
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Hasenfuss et al., Circulation 1998;98:2141-2147
0.3 µmol/L
1 µmol/L
Human LV Myocardium – in vitro
Inotropic and lusitropic effects of levosimendan
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Mebazaa et al., JAMA 2007;297:1883-91
Levosimendan does not improve outcome despite favourable hemodynamic effects
NT-proBNP Survival
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Orstavik et al., Br J Pharmacol 2014;171:5169-81
Human failing LV Myocardium – in vitro
Positive inotropic effects of levosimendan are mediated by PDE-inhibition
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Human failing LV Myocardium – in vitro
Orstavik et al., Br J Pharmacol 2014;171:5169-81
Positive inotropic effects of levosimendan are mediated by PDE-inhibition
PLOS One, 2015
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Ca2+Ca2+
ATP
Ca2+
Ca2+
NCX
Na+
Ca2+
Na+
ICa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
T-tu
bule
ETC
1-AR
cAMP
INa
NKA
K+ K+
Ca2+
Leck
PKAPDEs +
O2 H2O
Actin-myosincross bridges
RyR
DIGITALIS
Troponin C
Ca2+
Strategies to improve systolic function
DOBUTAMINE+ENOXIMONEMILRINONE
LEVOSIMENDAN
OMECAMTIV +
LEVOSIMENDAN
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Mode of action of cardiac myosin activators.
Hasenfuss & Teerlink, Eur Heart J 2011;32:1838-1845
Myosin Activators: Mechanism
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n=8 n=5>
Omecamtiv Control/Placebo
„More hands pulling on a rope“
Actin filament
Myosin heads
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Omecamtiv Mecarbil prolongs contractionwithout increasing Ca2+
Malik et al., Science 2011;331:1439-1443
Rat cardiac myocytes
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Omecamtiv Mecarbil: Dose-dependent increase ofsystolic function in rats and dogs
Echocardiography in dogs and rats in vivo
Malik et al., Science 2011;331:1439-1443
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Hemodynamic profile of Omecamtiv Mecarbil in dogs with or without heart failure
Wache Hunde in vivo
Malik et al., Science 2011;331:1439-1443
Normal Hearts Heart Failure
WT – wall thickeningSET – Systolic ejection time
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Omecamtiv Mecarbil: positive inotropic effectswithout increasing O2 consumption
Concious instrumented Dogs in vivo
Shen et al., Circ Heart Fail 2010;3:522-7
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Ca2+Ca2+
ATP
Ca2+
Ca2+
NCX
Na+
Ca2+
Na+
ICa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
T-tu
bule
ETC
1-AR
cAMP
INa
NKA
K+ K+
Ca2+
Leck
PKAPDEs +
O2 H2O
Actin-myosincross bridges
RyR
DIGITALIS
Troponin C
Ca2+
Strategies to improve systolic function
DOBUTAMINE+ENOXIMONEMILRINONE
LEVOSIMENDAN
OMECAMTIV +
SERCA2a GENE-THERAPY+
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del Monte et al., Circulation 1999
1s
0
15
1.5
1.0
Non-Failing Myocyte+ Ad.GFP
Failing Myocyte + Ad.GFP
Failing Myocyte + Ad.SERCA2a
[Ca2+]i (mM)
% shortening
Gene transfer of SERCA2a restores contractility in human failing myocytes
Cardiac myocyte,Field stimulation
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Lyon et al., Circ Arrhythmia Electrophysiol 2011;4:362-372
Gene transfer of SERCA2a prevents arrhythmiasin rats with heart failure
Isoproterenol-induced ventricular tachycardia (VT) in rats in vivo
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HealthyControl
HeartFailure
HeartFailure
+ SERCA2aGene Therapy
T-tubule Density
C HF HF+S0
25
50
75
100
T-tu
bule
Den
sity
(Cor
rect
ed to
con
trol
(AU
)) ** *
Lyon et al., Circ Heart Fail 2012;5;357-365
C HF HF+S0.00
0.25
0.50
0.75
1.00
Z G
RO
OVE
IND
EX
*** ***
Z Groove Index
Gene transfer of SERCA2a restores surface- and t-tubular structure in rats with heart failure
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Jessup et al. Circulation 2011;124:304-313
CUPID: Phase II trial with SERCA gene therapy
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Jessup et al. Circulation 2011;124:304-313
CUPID: Phase II trial with SERCA gene therapy
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Jessup et al. Circulation 2011;124:304-313
CUPID: Phase II trial with SERCA gene therapy
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Jessup et al. Circulation 2011;124:304-313
CUPID: Phase II trial with SERCA gene therapy
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Ca2+Ca2+
ATP
Ca2+
Ca2+
NCX
Na+
Ca2+
Na+
ICa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
T-tu
bule
ETC
1-AR
cAMP
INa
NKA
K+ K+
Ca2+
Leck
PKAPDEs +
O2 H2O
Actin-myosincross bridges
RyR
DIGITALIS
Troponin C
Ca2+
Strategies to improve systolic function
DOBUTAMINE+ENOXIMONEMILRINONE
LEVOSIMENDAN
OMECAMTIV +
SERCA2a GENE-THERAPY+ HNO +
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SH
R
R
SH
HNO
Mild oxidation = “nitroXylation”
S
R
R
S+ 2H+ + 2e-
Disulfide
Protein Structure Protein function?
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LTCCRyR2
SERCA2a
PLN
Ca2+
Myofilaments
Diastole Systole
Ca2+
HNO …
• enhances Ca2+ cycling at the SR level• sensitizes myofilaments• does not increase diastolic Ca2+ or SR Ca 2+
load • does not recruit extracellular Ca2+
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CXL-1020 in normal and failing mice myocytes
Sabbah et al, Circ Heart Fail 2013
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CXL-1020 in conscious failing dogs
Sabbah et al, Circ Heart Fail 2013
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CXL-1020 in patients with symptomatic HF
Sabbah et al, Circ Heart Fail 2013
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Ca2+Ca2+
ATP
Ca2+
Ca2+
NCX
Na+
Ca2+
Na+
ICa
Ca2+
SERCA SERCA
ADP
Ca2+ Ca2+SR
T-tu
bule
ETC
1-AR
cAMP
INa
NKA
K+ K+
Ca2+
Leck
PKAPDEs +
O2 H2O
Actin-myosincross bridges
OMECAMTIV
SERCA2a GENE-THERAPY
DOBUTAMINE
HNO
RYCALS
ISTAROXIME
ISTAROXIME
BENDAVIA
RyR
+ +
+ENOXIMONEMILRINONE
DIGITALIS
+
+Troponin C
Ca2+
+
LEVOSIMENDAN
Strategies to improve systolic function
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Thank you!
Christoph Maack, MDKlinik für Innere Medizin III
Kardiologie, Angiologie und Internistische IntensivmedizinUniversitätsklinikum des Saarlandes
Homburg/[email protected]