Remodeling the failing heart: : the biology and future treatment options

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1 Remodeling the failing heart: : the biology and future treatment options J-L Balligand (UCL-Brussels, BE) jl.balligand@uclouvain.be

2 Myocardial remodeling: definitions 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.

3 Jessup et al N Engl J Med, 2003 (review)

4 Jessup et al N Engl J Med, 2003 (review)

5 Patterns of LV remodeling with cardiac magnetic resonance imaging Thick Thick and dilated Normal Indeterminate Dilated Khouri MG et al. Circ Cardiovasc Imaging (2010) 3;

6 Reversal of electrical remodeling with LVAD Harding JD et al Circulation 2001

7 Remodeling involves: Myocyte changes Extracellular matrix changes Microvascular changes Myocardial regeneration

8 Cell-cell cross-talk Hirsch E et al on behalf of WG Myocardial Function ESC Eur J Heart Fail (2013)

9 Cardiac myocyte

10 Patterns of myocyte hypertrophy in myocardial remodeling Apoptosis Physiological hypertrophy Growth stimuli Normal muscle cell Concentric hypertrophy Increased expression of embryonic genes Autophagy Eccentric hypertrophy

11 Beuckelmann D et al Circulation 1992 dilated cardiomyopathy

13 Serca2a Gene therapy (AAV1-Serca2a) Antagomir (mir-25) SUMO-ylation

14 Del Monte et al Circulation 1999

15 Zsebo K Hajjar R Circ Res 2014

19 Myofilaments Myosin ATPase: omecantiv mecarbil

20 Malik F et al Science 2011

21 Malik F et al Science 2011

22 Cleland JGF et al Lancet 2011

23 Circ Heart Fail May 29. pii: CIRCHEARTFAILURE [Epub ahead of print]

25 Mitochondria Cardiolipin protection by SS peptides

26 SS peptides protect mitochondria from oxidative damage

29 Membrane receptors The beta3-adrenergic receptor

β-adrenergic stimulation of NO Synthase attenuates the inotropic effect β1+2-adrenergic receptor blockade unveils a negative inotropic effect of isoproterenol, a

30 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? Balligand et al. Proc Nat Acad Sci USA(1993) Gauthier et al. J Clin Invest (1996)

31 β3 AR coupling in mammalian heart β 1 AR G αs β 3 AR NOS G αi NO Effect on remodeling? 1. hypertrophy 2. coronary vasodilatation 3. fibrosis 4. metabolism? sgc cgmp 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): Belge C et al. Circulation 2014; 129: 451

β3ar protects against cardiac hypertrophy PBS PE In vitro NRCM aera (µm 2 ) 1800 1600 1400 1200 1000 * AdV:GFP # AdV:hβ 3 AR

500 400 300 200 100 0 WT * saline # hβ 3 AR TG 700 600 500 400 300 200 100 0 Iso 50mg/kg/d * # WT hβ 3 AR TG AngII 700 600 500

32 β3ar protects against cardiac hypertrophy PBS PE In vitro NRCM aera (µm 2 ) * AdV:GFP # AdV:hβ 3 AR AdV:GFP Belge C*, Hammond J*, Dubois-Deruy E* et al, Circulation , AdV:hβ 3 AR In vivo Myocyte area (µm2) WT * saline # hβ 3 AR TG Iso 50mg/kg/d * # WT hβ 3 AR TG AngII * # WT hβ 3 AR TG Iso 30mg/kg/d * # WT hβ 3 AR TG TAC 9weeks Belge C et al. Circulation 2014;129:

33 Targets downstream NOS/cGMP β 3 AR G αi NOS sgc NO cgmp PKG Troponin-I-P Titin-P Myofilament Ca++ sensitivity Hypertrophy Myocyte/tissue elasticity

34 The cardiac fibroblast and myocyte-fibroblast cross-talk

Angiotensin II infusion by minipump (14 days) 12 9 6

35 β3ar protects against myocardial fibrosis Myocardial fibrosis after TAC 9 weeks Myocardial fibrosis after Angiotensin II infusion by minipump (14 days) * $ 3 0 WT TG Belge C et al. Circulation 2014;129:

Results in vitro POTENTIAL PARACRINE FACTORS

+/- β3 PE +/- Gel-free proteomic analysis M.

36 Results in vitro POTENTIAL PARACRINE FACTORS INVOLVED IN THE ANTIFIBROTIC EFFECT FROM β3-ar CARDIAC MYOCYTES TO CARDIAC FIBROBLASTS B 3 AR Secretome from cardiac myocytes GFP PE +/- β3 PE +/- Gel-free proteomic analysis M. Mayr (King's College London, Cardiovascular Division)

37 This project has received funding from the European Union s Horizon 2020 research and innovation programme under grant agreement N

38 Membrane receptors Combined AT1-R antagonist and neprilysin inhibitor: LCZ 696

42 The endothelial cell and endothelial-myocyte cross-talk

43 Close apposition of cardiac myocytes and capillary endothelial cells CM EC RBC

45 Lim SL et al Eur Heart J 2015

47 Questions That all

In Vivo Animal Models of Heart Disease. Why Animal Models of Disease? Timothy A Hacker, PhD Department of Medicine University of Wisconsin-Madison

In Vivo Animal Models of Heart Disease Timothy A Hacker, PhD Department of Medicine University of Wisconsin-Madison Why Animal Models of Disease? Heart Failure (HF) Leading cause of morbidity and mortality