Exercise in Adverse Cardiac Remodeling: of Mice and Men

Transcription

1 Exercise in Adverse Cardiac Remodeling: of Mice and Men Dirk J Duncker Experimental Cardiology, Cardiology, Thoraxcenter Cardiovascular Research Institute COEUR Erasmus MC, University Medical Center Rotterdam Rotterdam, The Netherlands

2 Cardiac Remodeling hart Normal Infarction Remodeling Heart Failure Left Ventricle

3 Cardiac Remodeling Myocardial Infarction Aortic Stenosis Physical Exercise Left Ventricular Remodeling Perfusion Function Perfusion Function Physical Exercise

4 Exercise in Adverse Cardiac Remodeling Exercise in Chronic Heart Failure - Evidence - Mechanism(s) of Action Exercise and Acute Myocardial Infarction - Evidence - Mechanism(s) of Action Exercise during Pressure Overload

5 Exercise in Adverse Cardiac Remodeling Exercise in Chronic Heart Failure - Evidence - Mechanism(s) of Action Exercise and Acute Myocardial Infarction - Evidence - Mechanism(s) of Action Exercise during Pressure Overload

6 Exercise Training in Chronic Heart Failure AJ Coats Nat Rev Cardiol 2011

7 JAMA 2009;301: All-Cause Death or Hospitalization CV Death or / HF Hospitalization

8 Exercise Training in Chronic Heart Failure ESC Guidelines May 2012 McMurray et al. Eur Heart J 2012

9 Exercise in Adverse Cardiac Remodeling Exercise in Chronic Heart Failure - Evidence - Mechanism(s) of Action Exercise and Acute Myocardial Infarction - Evidence - Mechanism(s) of Action Exercise during pressure overload

10 Exercise Training in Chronic Heart Failure Mechanisms of Action Peripheral Training Effects - skeletal muscle adaptations Cardiovascular Training Effects - Increased dynamic heart rate range Interaction With Adverse Cardiac Remodeling and Dysfunction Benito & Nattel J Physiol 2009

11 Cardiac Remodeling Myocardial Infarction Aortic Stenosis Physical Exercise Left Ventricular Remodeling Perfusion Function Perfusion Function

12 Exercise in Adverse Cardiac Remodeling Exercise in Chronic Heart Failure - Evidence - Mechanism(s) of Action Exercise and Acute Myocardial Infarction - Evidence - Mechanism(s) of Action Exercise during pressure overload

13 Cardiac Remodeling and Dysfunction Exercise training early after a large MI may aggravate cardiac remodeling and dysfunction Jugdutt et al. JACC 1988 Kubo et al. Am Heart J 2004 Kloner et al. Am Heart J 1983 Gaudron et al. Circulation 1994

14 Mouse Models of Cardiac Remodeling Myocardial infarction 8 wk Myocardial Infarction (MI) permanent LAD coronary artery ligation 45% of the LV becomes infarcted Pressure overload 8 wk Transverse Aorta Constriction (TAC)

15 Exercise 10 Distance (km) Weeks SHEX MIEX de Waard et al Circ Res 2007

16 Methods Echography Left Ventricular (LV) dimensions FS FS = LVD ED-LVD ES LVD ED X 100%

17 Methods Hemodynamics 120 Pressure (mmhg) AoP LV dp/dt (mmhg/s) LVP Time (s) Time (s)

18 Results Pressure Diameter Loop

19 Left Ventricular Pressure-Diameter Relation LV Pressure (mmhg) LV Pressure (mmhg) Sham MI SHAM MI TAC LV LV Diameter diameter (mm)

20 LV Remodeling after MI Sham MI de Waard et al. Circ Res 2007

21 Pressure-Volume relation Pressure (mmhg) MI EX SH EX 0 SH SED MI SED Diameter (mm) de Waard et al. Circ Res 2007

22 Exercise and LV Dysfunction and Remodeling after MI Wildtype Wildtype SED EX de Waard et al Circ Res 2007

23 Exercise and Cardiac Remodeling after MI End-Diastolic Volume Haykowsky et al. Trials 2011

24 Exercise and Cardiac Remodeling after MI Ejection Fraction Haykowsky et al. Trials 2011

25 Conclusions Exercise training starting early after a large MI blunts cardiac remodeling and dysfunction What are the cellular mechanisms underlying the effects of exercise training on function?

26 Exercise and LV Dysfunction and Remodeling after MI Wildtype Wildtype SED EX de Waard et al Circ Res 2007

27 Sham MI Ca 2+ Ca 2+ Ca 2+ Ca 2+ channel Noradrenaline b - AR g b a P s b - ARK camp AC ATP Sarcolemma g a i b Ca 2+ Ca 2+ Ca 2+ Ca 2+ SERCA PLB SR PKA ser P T - tubule Ca 2+ channel Tn - C P Tn - I Tn - T MI MI SED SED actin filament Ca 2+ MI EX MI EX tropomyosin myosin filament de Waard et al Circ Res 2007; Bito et al Cardiovasc Res 2010

28 A 25 B 25 Force (kn/m 2 ) C Ca Ca Ca 2+ Ca Ca 2+ Ca 2+ Ca 2+ Ca 2+ channel 5.5 pca Noradrenaline b - AR g b a P s b - ARK SH SED camp 5.0 SERCA PLB P<0.05 MI SED 4.5 SR AC PKA Force (kn/m 2 ) D ATP Sarcolemma g a i b pca 5.0 SH SED MI SED SH EX MI EX 4.5 Relative Force T - tubule pca 50 = ± Ca 2+ channel 6.0 Ca ser P SH SED MI SED 4.5 Relative Force Tn - C P Tn - I Tn - T pca myosin filament actin filament 5.0 SH SED MI SED SH EX MI EX tropomyosin 4.5 de Waard et al Circ Res 2007

29 Conclusions Exercise training after a large MI attenuates global left ventricular dysfunction This occurs likely as a result of decreased: - interstitial fibrosis - apoptosis - cardiomyocyte dysfunction What are the molecular mechanisms underlying these beneficial effects of exercise training?

30 Molecular Mechanisms of Cardiac Remodeling Mudd & Kass Nature 2008

31 Cardiac Remodeling by Exercise Training Mann & Rosenzweig Circulation 2012

32 enos transgenic mice van Haperen et al. J Biol Chem 2002 Jones et al. PNAS 2003

33 Exercise and LV Dysfunction and Remodeling after MI Endothelial Nitric Oxide Synthase Overexpression LV Hypertrophy Fibrosis LV dp/dt P30 % Shortening Jones et al. PNAS 2003; de Waard et al. Am J Physiol 2009

34 Conclusions Exercise training attenuates interstitial fibrosis, apoptosis, and cardiomyocyte and global left ventricular dysfunction after MI de Waard et al Circ Res 2007 These effects of exercise are mimicked, in part, by enos overexpression Jones et al PNAS 2003 de Waard et al Am J Physiol 2009

35 de Waard et al J Mol Cell Cardiol 2010 Exercise and LV Dysfunction and Remodeling after MI Endothelial Nitric Oxide Synthase knockout Wildtype Wildtype SED EX *P<0.05 vs Sham P<0.05 vs SED P<0.05 vs Wildtype

36 Conclusions Exercise training attenuates interstitial fibrosis, apoptosis, and cardiomyocyte and global left ventricular dysfunction after MI de Waard et al Circ Res 2007 These effects of exercise are mimicked, in part, by enos overexpression Jones et al PNAS 2003 de Waard et al Am J Physiol 2009 These effects of training appear to be fully dependent on intact enos expression de Waard et al J Mol Cell Cardiol 2010

37 Exercise in Adverse Cardiac Remodeling Exercise in Chronic Heart Failure - Evidence - Mechanism(s) of Action Exercise and Acute Myocardial Infarction - Evidence - Mechanism(s) of Action Exercise during pressure overload

38 Mouse Models of Cardiac Remodeling Myocardial infarction 8 wk Myocardial Infarction (MI) permanent LAD coronary artery ligation Pressure overload 8 wk Transverse Aorta Constriction (TAC) mtac: 25G stac: 27G 37± 3 mmhg 57± 4 mmhg

39 Effects of exercise in TAC versus MI % Shortening Filling Pressure Fibrosis Lung Edema Maximum Force Passive Force Ca 2+ Sensitivity SERCA Van Deel et al J Mol Cell Cardiol 2011

40 Conclusions The effects of exercise training on left ventricular dysfunction appear critically dependent on the underlying cause of hypertrophy / remodeling These divergent effects may be due to intrinsic differences in the remodeling phenotype or the different hemodynamic responses to exercise enos overexpression: The benefit of exercise without the hemodynamic overloading?

41 Mann & Rosenzweig Circulation 2012

42 Acknowledgements Erasmus University MC Rotterdam Experimental Cardiology Elza van Deel Martine de Boer Monique de Waard Ewout Jan van den Bos Biochemistry Dick Dekkers Jos Lamers Cell Biology and Genetics Rini de Crom Rien van Haperen Frank Grosveld Free University MC Amsterdam Jolanda van der Velden Nicky Boontje Ger Stienen Maastricht University An Moens Catholic University of Leuven Karin Sipido Virginie Bito Liesbeth Biesmans Emory University David Lefer Funding Netherlands Organization of Scientific Research (ZonMW / NWO) Royal Netherlands Academy of Arts and Sciences (KNAW) Netherlands Heart Foundation (NHS)