Basic mechanisms to improve systolic function

HFA Congress 2015

Basic Mechanisms to improve systolic function

Christoph Maack, MD

Klinik für Innere Medizin IIIUniversitätsklinikum des Saarlandes

Homburg/Saar, Germany

Conflicts of Interest

Speaker honoraria from:Bayer, Berlin-Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Servier, Pfizer, Stealth Biotherapeutics.

Scientific advisor to:Stealth Biotherapeutics.

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

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

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

C.O.

Inotropes

Nieminen et al., Eur Heart J 2006;27:2725-2736

CardiogenicShock (4%)

Gheorghiade et al., JAMA 2006;296:2217-2226

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

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


RyR2

K+

Chronic Heart Failure:Defects in EC Coupling

ATP

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


RyR2

K+


ATP

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


RyR2

K+


ATP

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


RyR2

K+


(Ca2+)

ATP

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


RyR2

K+


(Ca2+)

Contraction/Relaxation

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

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


DOBUTAMINE

HNO

RYCALS

ISTAROXIME

ISTAROXIME

BENDAVIA

RyR

+ +

+ENOXIMONEMILRINONE

DIGITALIS

+

+Troponin C

Ca2+

+

LEVOSIMENDAN


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


RyR

DIGITALIS

Troponin C

Ca2+


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


RyR2

K+

Digitalis increases Na+ and Ca2+ by inhibiting the Na+ /K+-ATPase

Digitalis

ATP

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


RyR2

K+

Digitalis

ATP


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


RyR2

K+

Digitalis

ATP


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


RyR2

K+

Digitalis

ATP


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


RyR2

K+

Digitalis

NCENa+

Ca2+ ATP

Elevating cytosolic Na+ triggers oxidative stress from mitochondria

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


RyR2

K+

Digitalis

NCENa+

Ca2+ ATPKohlhaas,Circ 2010

CGP

Liu,JMCC 2010

Elevating cytosolic Na+ triggers oxidative stress from mitochondria

ROS

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


RyR2

K+

Digitalis

NCENa+

Ca2+

Der Klassiker: Digitalis

DIG Trial, NEJM 1997

All-cause Mortality

Death or Hospitalization due to HF

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


RyR

DIGITALIS

Troponin C

Ca2+


DOBUTAMINE+

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


RyR2

K+

-AR

AC

PKA

AMP

Agonist

PP P

P

PDE

PDE-Inhibitors

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)

Eugene Braunwald

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

Hemodynamic effects of dobutamine

„First in man“

Jewitt et al., Lancet 1974

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

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)

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

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

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


RyR

DIGITALIS

Troponin C

Ca2+


DOBUTAMINE+ENOXIMONEMILRINONE

LEVOSIMENDAN

Acto-myosin interaction.

Hasenfuss & Teerlink, Eur Heart J 2011;32:1838-1845

Ca2+Ca2+ sensitizers +

Acto-myosin Interaction

Brixius et al., Cardiovasc Drugs Ther 2006

The „pure“ Calcium-Sensitizer

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

Mebazaa et al., JAMA 2007;297:1883-91

Levosimendan does not improve outcome despite favourable hemodynamic effects

NT-proBNP Survival

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

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

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


RyR

DIGITALIS

Troponin C

Ca2+



LEVOSIMENDAN

OMECAMTIV +

LEVOSIMENDAN

Mode of action of cardiac myosin activators.

Hasenfuss & Teerlink, Eur Heart J 2011;32:1838-1845

Myosin Activators: Mechanism

n=8 n=5>

Omecamtiv Control/Placebo

„More hands pulling on a rope“

Actin filament

Myosin heads

Omecamtiv Mecarbil prolongs contractionwithout increasing Ca2+

Malik et al., Science 2011;331:1439-1443

Rat cardiac myocytes

Omecamtiv Mecarbil: Dose-dependent increase ofsystolic function in rats and dogs

Echocardiography in dogs and rats in vivo


Hemodynamic profile of Omecamtiv Mecarbil in dogs with or without heart failure

Wache Hunde in vivo


Normal Hearts Heart Failure

WT – wall thickeningSET – Systolic ejection time

Omecamtiv Mecarbil: positive inotropic effectswithout increasing O2 consumption

Concious instrumented Dogs in vivo

Shen et al., Circ Heart Fail 2010;3:522-7

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


RyR

DIGITALIS

Troponin C

Ca2+



LEVOSIMENDAN

OMECAMTIV +

SERCA2a GENE-THERAPY+

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

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

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

Jessup et al. Circulation 2011;124:304-313

CUPID: Phase II trial with SERCA gene therapy







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


RyR

DIGITALIS

Troponin C

Ca2+



LEVOSIMENDAN

OMECAMTIV +

SERCA2a GENE-THERAPY+ HNO +

SH

R

R

SH

HNO

Mild oxidation = “nitroXylation”

S

R

R

S+ 2H+ + 2e-

Disulfide

Protein Structure Protein function?

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+

CXL-1020 in normal and failing mice myocytes

Sabbah et al, Circ Heart Fail 2013

CXL-1020 in conscious failing dogs


CXL-1020 in patients with symptomatic HF


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


OMECAMTIV


DOBUTAMINE

HNO

RYCALS

ISTAROXIME

ISTAROXIME

BENDAVIA

RyR

+ +

+ENOXIMONEMILRINONE

DIGITALIS

+

+Troponin C

Ca2+

+

LEVOSIMENDAN


Thank you!

Christoph Maack, MDKlinik für Innere Medizin III

Kardiologie, Angiologie und Internistische IntensivmedizinUniversitätsklinikum des Saarlandes

Homburg/[email protected]

Healthcare

Basic mechanisms to improve systolic function