Presentation is loading. Please wait.

Presentation is loading. Please wait.

Reversing HF: LVAD & clenbuterol LVAD with biological therapies for the reversal of HF. Myth or reality? Sir Magdi Yacoub, FRS Imperial College London.

Similar presentations


Presentation on theme: "Reversing HF: LVAD & clenbuterol LVAD with biological therapies for the reversal of HF. Myth or reality? Sir Magdi Yacoub, FRS Imperial College London."— Presentation transcript:

1 Reversing HF: LVAD & clenbuterol LVAD with biological therapies for the reversal of HF. Myth or reality? Sir Magdi Yacoub, FRS Imperial College London Harefield Heart Science Centre 5th STEM CELL THERAPY Madrid 2008

2 Reversing HF: LVAD & clenbuterol Chronology –Beneficial and harmful effects of LVAD unloading –? optimal length of time for LVAD-induced functional recovery –? link between structural and functional reverse remodelling –The role of clenbuterol –Translational research (Harefield protocol) –Clinical results

3 Reversing HF: LVAD & clenbuterol Benefits of unloading –Experimental (heterotopic Tx in murine models of HF) Whole heart function Cellular Molecular ECM –Clinical Bridge to Tx Bridge to recovery

4 Reversing HF: LVAD & clenbuterol Benefits of unloading –Experimental (heterotopic Tx in murine models of HF) Whole heart function –in-vivo pressure-volume relationship of unloaded failing rabbit heart Tevaerai et al, JTCVS 2002 Unloading improves contractile dysfunction restores cardiac responsiveness to mechanical and β-AR stimulation.

5 Reversing HF: LVAD & clenbuterol Benefits of unloading –Experimental (heterotopic Tx in murine models of HF) Whole heart function –in-vivo pressure-volume relationship of unloaded failing rabbit heart ± β 2 -AR overexpression Tevaerai et al, Circulation 2002 Unloading improves contractile dysfunction β 2 -AR overexpression enhances functional improvement

6 Reversing HF: LVAD & clenbuterol Benefits of unloading –Experimental (heterotopic Tx in murine models of HF) Whole heart function –Ex-vivo pressure-volume relationship Soppa et al, Circulation 2006 (Abstract) [A] [B] [C] [D]

7 Reversing HF: LVAD & clenbuterol Benefits of unloading –Experimental (heterotopic Tx in murine models of HF) Whole heart function Cellular –Cardiomyocyte size –Contractility –Ca 2+ transient kinetics Molecular ECM

8 Reversing HF: LVAD & clenbuterol Benefits of unloading –Experimental (heterotopic Tx in murine models of HF) Whole heart function Cellular –Cardiomyocyte size »1 week - ↓21% in cell area Soppa et al, Circulation 2006 (Abstract) »2weeks – ↓23% in myocyte diameter Tsuneyoshi et al, ASAIO 2005 »2 weeks – ↓27%, 4 weeks – ↓41%, 8 weeks – ↓56% in myocyte diameter Oriyanhan et al, JHLT 2007 –Contractility –Ca 2+ transient kinetics Molecular ECM

9 Reversing HF: LVAD & clenbuterol Benefits of unloading –Experimental (heterotopic Tx in murine models of HF) Whole heart function Cellular –Cardiomyocyte size –Contractility »Time-dependent improvement followed by deterioration of papillary function and contractile reserve Oriyanhan et al, JHLT 2007 »Improved myocyte contractility after 2 weeks Takaseya et al, JACC 2004 »Unchanged myocyte contractility after 1 week Soppa et al, Circulation 2006 (Abstract) –Ca 2+ transient kinetics Molecular ECM

10 Reversing HF: LVAD & clenbuterol Benefits of unloading –Experimental (heterotopic Tx in murine models of HF) Whole heart function Cellular –Cardiomyocyte size –Contractility –Ca 2+ transient kinetics »Normalization of deranged Ca 2+ transient kinetics after 2 weeks unloading Takaseya et al, JACC 2004 »Unaffected deranged Ca 2+ transient kinetics after 1 week unloading Soppa et al, Circulation 2006 (Abstract) Molecular ECM

11 Reversing HF: LVAD & clenbuterol Benefits of unloading –Experimental (heterotopic Tx in murine models of HF) Whole heart function Cellular –Cardiomyocyte size –Contractility –Ca 2+ transient kinetics Molecular –Gene and protein expression »↑SERCA2a Tsuneyoshi et al, ASAIO 2005; Takaseya et al, JACC 2004 »normalization of ↑BNP Tsuneyoshi et al, ASAIO 2005 »↑β 2 -AR Tsuneyoshi et al, ASAIO 2005 ECM

12 Reversing HF: LVAD & clenbuterol Benefits of unloading –Experimental (heterotopic Tx in murine models of HF) Whole heart function Cellular Molecular ECM –↑fibrosis Oriyanhan et al, JHLT 2007

13 Reversing HF: LVAD & clenbuterol Harmful effects of unloading –Experimental (heterotopic Tx in murine models of HF) Whole heart function – unchanged at 1 week Soppa et al, Circulation 2006 (Abstract) Cellular –Contractility »Unchanged at 1 week Soppa et al, Circulation 2006 (Abstract) »Time dependent reduction in contractile function and contractile reserve Oriyanhan et al, JHLT 2007 –Ca 2+ transient kinetics »Unchanged at 1 week Soppa et al, Circulation 2006 (Abstract) Molecular – not known ECM –↑fibrosis Oriyanhan et al, JHLT 2007

14 Reversing HF: LVAD & clenbuterol Benefits of unloading –Clinical Bridge to Tx –Whole heart – improved ex-vivo LV function Klotz et al, Circulation 2005

15 Reversing HF: LVAD & clenbuterol Benefits of unloading –Clinical Bridge to Tx –Whole heart »Improved LVEF, off-pump Frazier et al, ATS 1996; Muller et al, Circulation 1997 »Low incidence of myocardial functional recovery (4-24%) Frazier et al, ATS 1999; Mancini et al, Circulation 1998; Dandel et al, Circulation 2005 –Cellular »Reduction in cell size Zafeiridis et al, Circulation 1998; Bruckner et al, JHLT 2001 »Improved EC coupling

16 Reversing HF: LVAD & clenbuterol 1. Harding et al., Circulation Terracciano et al., Circulation Chen et al., Circ Res Marx et al., Cell Terracciano et al., Eur Heart J Dipla et al., Circulation Chaudhary et al., JACC Frazier et al., ATS Heerdt et al., Circulation Improved EC coupling

17 Reversing HF: LVAD & clenbuterol Benefits of unloading –Clinical Bridge to Tx –Whole heart –Cellular –Molecular »Improved β-AR responsiveness and receptor density Dipla et al, Circulation 1998; Ogletree-Hughes et al, Circulation 2001 »↑Ca 2+ cycling gene & protein Heerdt et al, Circulation 2000 »Changes in cytokine milieu Torre-Amione et al, Circulation 1999 »Changes in gene transcription patterns Margulies et al, Circ Res 2005 »Improved mitochondrial function Heerdt et al, ATS 2002, Lee et al, JTCVS 1998 »Cytoskeletal protein changes Vatta et al, Lancet 2001 »Alterations in MAPK activity Flesch et al, Circulation 2001

18 Reversing HF: LVAD & clenbuterol Benefits of unloading –Clinical Bridge to Tx –Whole heart –Cellular –Molecular –ECM - ? controversial »↓ collagen content Bruckner et al, JHLT 2001; Thompson et al, J Surg Res 2005; Akgul et al, JHLT 2004 »↑collagen content Klotz et al, Circulation 2005; Li et al, Circulation 2001; Bruggink et al, JHLT 2006 »Alterations in MMPs & TIMPs Felkin et al, JHLT 2006; Klotz et al, Circulation 2005; Li et al, Circulation 2001

19 Reversing HF: LVAD & clenbuterol Chronology –Beneficial and harmful effects of LVAD unloading –? optimal length of time for LVAD-induced functional recovery –? link between structural and functional reverse remodelling –The role of clenbuterol –Translational research (Harefield protocol) –Clinical results

20 Reversing HF: LVAD & clenbuterol ? optimal length of time for LVAD-induced functional recovery (Circulation. 2007;115: )

21 Reversing HF: LVAD & clenbuterol SR Ca 2+ content Donor heart Idiopathic dilated cardiomyopathy Idiopathic dilated cardiomyopathy - post LVAD ? link between structural and functional reverse remodelling –specific changes in EC coupling, and not regression of cellular hypertrophy Terracciano et al, Circulation 2004

22 Reversing HF: LVAD & clenbuterol Translational research (Harefield protocol) “…. on its own, unloading appears to be inadequate. We therefore evolved a strategy of combination therapy, aiming at inducing maximal regression of pathological hypertrophy, followed by induction of physiological hypertrophy of both cardiac and skeletal muscle (using clenbuterol).” Evolution of a concept MH Yacoub

23 Reversing HF: LVAD & clenbuterol Translational research (Harefield protocol) Pharmacological therapy –Phase 1: intended to enhance reverse remodeling Digoxin ACE inhibition – SAVE, SOLVD, HOPE (Lisinopril) Angiotensin II inhibition - RESOLVD (Losartan) Aldosterone receptor blockade - RALES (Spironolactone) β-blockade (Carvedilol)

24 Reversing HF: LVAD & clenbuterol Translational research (Harefield protocol) Pharmacological therapy –Phase 2: intended to limit unloading-induced atrophy. β 2 stimulation (Clenbuterol)

25 Reversing HF: LVAD & clenbuterol The role of clenbuterol

26 Reversing HF: LVAD & clenbuterol

27 The role of clenbuterol On skeletal muscle –‘Physiological’ hypertrophy –Increased power Petrou et al, Circulation 1999; Maltin et al, Clin Sci (Lond) 1993 –Faster contraction & relaxation Petrou et al, Circulation 1999 –Induction of IGF1 On cardiac muscle –‘Physiological’ hypertrophy Wong et al, Card Res 1998; Petrou et al, Circulation 1995 –Enhancement of systolic & diastolic function in small & large animal models Wong et al, Card Res 1998; Hon et al, JTCVS 2001; Hon et al, Acta Physiol Scand 2001 –Prevents fibrosis following banding of the aorta & PA Hon et al, JTCVS 2001 –Gene expression (physiological hypertrophy) Wong et al, Card Res 1998; Petrou et al, Circulation 1995

28 Reversing HF: LVAD & clenbuterol The role of clenbuterol RV pressure-volume loops Hon et al, JTCVS 2001 SalineClenbuterol

29 Reversing HF: LVAD & clenbuterol The role of clenbuterol Clenbuterol induces myofibrillogenesis Clenbuterol 10µMUntreated

30 Reversing HF: LVAD & clenbuterol The role of clenbuterol

31 Reversing HF: LVAD & clenbuterol Clenbuterol produces cardiac hypertrophy with altered EC coupling in normal rat hearts Soppa et al, Am. J. Physiol, 2005 saline clenbuterol Clenbuterol prolongs APD Amplitude ratio (0.02 units) Ca transient Clenbuterol increases Ca transient amplitude 100 ms 2000 ms SR Ca content Amplitude ratio (0.02 units) Clenbuterol increases SR Ca content Western blotting: clenbuterol increases the expression of SERCA and NCX

32 Reversing HF: LVAD & clenbuterol The role of clenbuterol Clenbuterol limits unloading-induced myocyte atrophy in normal and failing heart Clen-Tx Sal-Tx Clen-Rec Sal-Rec 50 µm 50  m Sham+Sal HF+Sal HF+Clen HF+UN+Sal HF+UN+Clen Normal rat heart Soppa et al, Biophys J 2005 (Abstract) Failing rat heart Soppa et al, Circulation 2006 (Abstract)

33 Reversing HF: LVAD & clenbuterol Representative 2D and M-mode recordings showing development of LV dysfunction [A, B and C]. Graph [D] showing the effect of treatment with Sal or Clen on LVEF assessed by 2D short-axis views at the mid- papillary level. HF+SalSham+SalHF+Clen [A][B][C] The role of clenbuterol Clenbuterol improves LVEF of failing rat hearts Soppa et al, Circulation 2006 (Abstract)

34 Reversing HF: LVAD & clenbuterol The role of clenbuterol Unloading+clenbuterol improves ex-vivo contractility of failing rat hearts Soppa et al, Circulation 2006 (Abstract)

35 Reversing HF: LVAD & clenbuterol 0.05 ratio units 0.05 µm 200 ms HF+Sal HF+UN+Clen Unloading+clenbuterol normalises EC coupling in normal & failing hearts Unloading + Clen normalises delayed TTP shortening. Sal Tx Sal Rec Clen Tx Unloading + Clen normalises delayed sarcomere relaxation. Unloading + Clen normalises delayed TTP Normal rat heart Soppa et al, Biophys J 2005 (Abstract) Unloading + Clen normalises increased Ca transient amplitude Unloading + Clen normalises delayed decay Ca transient Unloading + Clen normalises amplitude & speed of sarcomere shortening Unloading + Clen normalises delayed Sarcomere relaxation Failing rat heart Soppa et al, Circulation 2006 (Abstract)

36 Reversing HF: LVAD & clenbuterol The role of clenbuterol Clenbuterol normalises depressed myofilament sensitivity to Ca 2+ of failing rat hearts, with and without unloading Soppa et al, Circulation 2006 (Abstract)

37 Reversing HF: LVAD & clenbuterol The role of clenbuterol Clenbuterol normalises unloading-induced reduction of G αi protein expression Soppa et al, JMCC 2007 (Abstract) Sham+SalHF+SalHF+ClenHF+UN+SalHF+UN+Clen 45 kDa

38 Reversing HF: LVAD & clenbuterol The role of clenbuterol β 2 -G i sinalling has been shown to be cardioprotective Xiao et al, Trends Pharmacol Sci 2004 Does clenbuterol activate the β 2 -G i pathway?

39 Reversing HF: LVAD & clenbuterol Fluo-4 fluorescence (F/F 0 ) (r.u. 0.2) 500 ms control3x10 -5 M10 -4 Mwash out clenbuterol Sarcomere length (  m) wash out 3 x10 -5 M10 -4 M ## # The role of clenbuterol Acute clenbuterol application is –vely inotropic Siedlecka et al, AHA 2007 (Abstract No )

40 Reversing HF: LVAD & clenbuterol The role of clenbuterol Acute clenbuterol application is –vely inotropic and reduces contractility of ventricular myocytes via a Gi-mediated pathway Siedlecka et al, AHA 2007 (Abstract No )

41 Reversing HF: LVAD & clenbuterol

42 Translational research (Harefield protocol) Explantation criteria –LV dimensions with device off EDD <60mm, ESD <50 mm, –EF >45% –LVEDP <12 mmHg –Resting CI >2.8 L/min/m 2 –mVO 2 >20 ml/kg/min & VE/VCO 2 slope <34

43 Reversing HF: LVAD & clenbuterol Drug Therapy For Myocardial Recovery

44 Reversing HF: LVAD & clenbuterol

45 Tx (n = 1) Explantation BiV (n = 1) Birks et al. N Engl J Med 2006;355:

46 Reversing HF: LVAD & clenbuterol Birks et al. N Engl J Med 2006;355:

47 Reversing HF: LVAD & clenbuterol Benefits of unloading+clenbuterol –Clinical Bridge to Recovery –Whole heart »↑LVEF and CI Birks et al NEJM 2006; Dandel et al, Circulation 2005; Frazier et al, ATS 1999 –Cellular »↓size & normalised EC coupling Terracciano et al, Circulation 2004; Terracciano et al, EHJ 2003 –Molecular »Specific changes in cytoskeletal genes and proteins Latif et al, JHLT 2007; Birks et al, Circulation 2005 »Specific changes EPAC2, Integrin signalling pathway Hall et al, EHJ 2007 »AGAT – creatine synthesis Cullen et al, Circulation 2006 »↑IGF-1 expression Barton et al, Circulation 2005 »↑Apelin receptor expression Farkasfalvi et al, Circulation 2006 (Abstract) –ECM – not known

48 Reversing HF: LVAD & clenbuterol Conclusions Reversal of HF using LVAD + Clen in non-ischemic DCM has given encouraging results (single centre) The molecular & cellular mechanisms responsible have been partially studied experimentally & clinically A multicentre study of the ‘Harefield protocol’ (HARPS) is on the way Need to evaluate the combination therapy in –Ischemic DCM –With continuous flow pumps

49 Reversing HF: LVAD & clenbuterol HARPS Investigator’s Meeting Boston, MA April 10, 2008

50 Reversing HF: LVAD & clenbuterol Study Site Status IND IRB ApprovalContractsSIV # Enrolled Cleveland Clinic Not submittedWorking on it Michigan 2 Montefiore 2 (3) Northwestern 2 Ohio State 2 Pennsylvania ConditionalSubmitted Texas Heart 2 UAB ? Working on it Washington 1

51 Reversing HF: LVAD & clenbuterol Enrollment Summary N=12 (includes pending MO & TX patients) 2 withdrawn

52 Reversing HF: LVAD & clenbuterol


Download ppt "Reversing HF: LVAD & clenbuterol LVAD with biological therapies for the reversal of HF. Myth or reality? Sir Magdi Yacoub, FRS Imperial College London."

Similar presentations


Ads by Google