the biology and future treatment options - european · pdf filethe biology and future...
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Remodeling the failing heart: : the biology and future treatment options
J-L Balligand (UCL-Brussels, BE)
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• phenotypic plasticity : remodeling is characterized by changes in myocardial structure that happen in response to either mechanical overload or a loss of substance such as that occurring after myocardial infarction.
• Myocardial remodeling is an essential mechanism that allows for cardiac output to be maintained in the presence of chronically abnormal loading conditions or depressed contractility.
Myocardial remodeling: definitions
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Jessup et al N Engl J Med, 2003 (review)
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Jessup et al N Engl J Med, 2003 (review)
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Thick Thick and dilated
Dilated Indeterminate
Normal
Patterns of LV remodeling with cardiac magnetic resonance imaging
Khouri MG et al. Circ Cardiovasc Imaging (2010) 3;164-171
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Harding JD et al Circulation 2001
Reversal of electrical remodeling with LVAD
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Myocyte changes
Extracellular matrix changes
Microvascular changes
Myocardial regeneration
Remodeling involves:
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Hirsch E et al on behalf of WG Myocardial Function ESC Eur J Heart Fail (2013)
Cell-cell cross-talk
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Cardiac myocyte
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Physiological hypertrophy
Concentric hypertrophy
Eccentric hypertrophy
Increased expression of embryonic genes
Normal muscle cell
Growth stimuli
Apoptosis
Autophagy
Patterns of myocyte hypertrophy in myocardial remodeling
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dilated cardiomyopathy
Beuckelmann D et al Circulation 1992
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Serca2a
• Gene therapy (AAV1-Serca2a) • Antagomir (miR-25) • SUMO-ylation
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Del Monte et al Circulation 1999
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Zsebo K…Hajjar R Circ Res 2014
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Myofilaments
• Myosin ATPase: omecantiv mecarbil
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Malik F et al Science 2011
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Malik F et al Science 2011
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Cleland JGF et al Lancet 2011
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Circ Heart Fail. 2015 May 29. pii: CIRCHEARTFAILURE.114.002152. [Epub ahead of print]
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Mitochondria
• Cardiolipin protection by SS peptides
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SS peptides protect mitochondria from oxidative damage
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Membrane receptors
• The beta3-adrenergic receptor
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Balligand et al. Proc Nat Acad Sci USA(1993)
β-adrenergic stimulation of NO Synthase attenuates the inotropic
effect
β1+2-adrenergic receptor blockade unveils a negative inotropic effect of
isoproterenol, a non-specific β-adrenergic agonist
Which β-adrenergic receptor ? By what mechanism ?
Gauthier et al. J Clin Invest (1996)
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β3 AR coupling in mammalian heart
Gauthier et al J Clin Invest 1998:102 (7): 1377 Moniotte et al Circulation 2001: 103 (12); 1649 Dessy et al Circulation 2004;110(8):948 Moniotte et al Eur J Heart Failure 2007; 9 (12): 1163 Hammond J, Balligand JL, JMCC 2012 ; 52(2): 330-340 Belge C et al. Circulation 2014; 129: 451
β3AR
Gαi
NOS
NO
sGC
cGMP
β1AR
Gαs
Effect on remodeling ? 1. hypertrophy 2. coronary vasodilatation 3. fibrosis 4. metabolism ?
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β3AR protects against cardiac hypertrophy PBS PE In vitro
1000
1200
1400
1600
1800
NRC
M a
era
(µm
2 )
AdV:GFP
*
Belge C*, Hammond J*, Dubois-Deruy E* et al, Circulation 2014 129, 451-62 AdV:hβ3AR
#
AdV:hβ3AR AdV:GFP
hβ3AR TG
#
hβ3AR TG
#
hβ3AR TG
#
hβ3AR TG
#
In vivo
Myo
cyte
are
a (µ
m2)
0 100 200 300 400 500 600 700
WT
*
saline Iso 50mg/kg/d
0 100 200 300 400 500 600 700
WT AngII
*
0 100 200 300 400 500 600 700
WT Iso 30mg/kg/d
*
0
250
500
750
WT
*
TAC 9weeks
Belge C et al. Circulation 2014;129:451-462
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β3AR
Gαi
NOS
NO
sGC
cGMP
Targets downstream NOS/cGMP
PKG
Hypertrophy
Titin-P Troponin-I-P
Myocyte/tissue elasticity Myofilament Ca++ sensitivity
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The cardiac fibroblast and myocyte-fibroblast cross-talk
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$
*
Myocardial fibrosis after TAC 9 weeks
WT TG 0
3
9
6
12
β3AR protects against myocardial fibrosis
Myocardial fibrosis after Angiotensin II infusion by minipump (14 days)
Belge C et al. Circulation 2014;129:451-462
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Results in vitro
POTENTIAL PARACRINE FACTORS INVOLVED IN THE ANTIFIBROTIC EFFECT FROM β3-AR CARDIAC MYOCYTES TO CARDIAC FIBROBLASTS
Secretome from cardiac myocytes
B3AR
GFP PE +/-
β3 PE +/-
M. Mayr (King's College London, Cardiovascular Division) Gel-free proteomic analysis
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This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement N° 634559
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Membrane receptors
• Combined AT1-R antagonist and neprilysin inhibitor: LCZ 696
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The endothelial cell and endothelial-myocyte cross-talk
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RBC
EC
CM
Close apposition of cardiac myocytes and capillary endothelial cells
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Lim SL et al Eur Heart J 2015
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That’all
• Questions