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Contractile dysfunction in human heart failure

VU University Medical Center. Contractile dysfunction in human heart failure. Jolanda van der Velden Ger Stienen. Institute for Cardiovascular Research. Introduction. Force measurements in permeabilized cardiomyocytes & contractile protein composition. Establish methods.

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Contractile dysfunction in human heart failure

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  1. VU University Medical Center Contractile dysfunctionin human heart failure Jolanda van der Velden Ger Stienen Institute for Cardiovascular Research

  2. Introduction Force measurements in permeabilized cardiomyocytes & contractile protein composition • Establish methods • Calcium sensitivity is increased in end stage failing hearts • Effects of myosin light chain 2 phosphorylation • Functional effects of PKC • Atrial Fibrillation • Diastolic versus systolic heart failure

  3. Force transducer Motor 40 m Force measurements in cardiomyocytes

  4. Isoform composition F D -MHC F D MHC - C-protein - -MHC  -actinin - -MHC Actin - -MHC -TnT tropomyosin - TnI - TnT MLC-1 - MLC-2 - TnI

  5. 16-3-2000 0.6 mgr sample patient 11 2D gel electrophoresis Isoelectric point pH 4.5 5.5 ATP synthase Desmin Actin TnT Molecular weight Tm MLC1 MLC2

  6. sarcolemma cytoplasm myofibrils PKC MLCK PKA CaM kinase Ryanodine receptor SERCA 2 SR phospholamban 2+ 2+ 2+ Ca Ca Ca Protein phosphorylation

  7. Calcium sensitivity of force development van der Velden et al Basic Res Cardiol (2002)

  8. Effect of PKA on Force Relativeforce van der Velden et al Cardiovasc Res (2000)

  9. Effects of MLC2-dephosphorylation Donor Failing Relative force pCa pCa van der Velden et al Cardiovasc Res (2004)

  10. PKA after PKC van der Velden et al Cardiovasc Res (2005)

  11. PKC after PKA

  12. PKC and PKA

  13. EF LVEDP LVEDP norm. EF norm. Systolic and diastolic dysfunction

  14. *P<0.05 Diastolic Heart Failure Myofilament dysfunction in diastolic heart failure? Ventricular endomyocardial biopsies from patients: • with normal cardiac function: Control (n=8) • with pure diastolic dysfunction: DHF (n=12) Borbély et al. Circulation (2005)

  15. 4.5 5.8 9.0 9.0 9.0 9.0 Force recordings Length Force pCa

  16. DD Total force (kN/m2) +PKA Calcium sensitivity of force development in DD patients Passive force (kN/m2) Borbély et al. Circulation (2005)

  17. Patient groups • 9 Patients with sinus rhythm (SR) • 11 Patients with SR and atrial dilation (SR + AD) • Patients with persistent atrial fibrillation (AF) • Methods: • Atrial dimensions by Doppler Imaging. • Protein composition by 1D- and 2D-gel electrophoresis. • Force measurements in skinned cardiomyocytes (Fmax;pCa50;Ktr).

  18. Mean atrial dimensions Eiras et al JMCC (in press)

  19. SR SR+AD AF Myosin heavy chain composition SR AF kD - MHC 150 - 100 - 75 - 50 -  - desmin  - actin  - troponin T 37 - 25 -  - ALC-1 20 -  - ALC-2

  20. 2D-gel electrophoresis SR Molecular weight ApoA1 IEF 4.5 5.5

  21. Alterations in protein composition

  22. Protein (%) ANOVA SR SR+AD AF b-MHC * 22.64.3# 27.04.0 41.55.0 TnTD * 26.13.0 26.70.8# 20.21.3 TnTP * 61.92.4# 62.91.1 70.42.2 TnTPP 12.12.0 10.51.0 9.41.6 TnT/actin 21.01.7 20.42.5 18.62.4 ALC-1D 90.61.4 87.11.9 89.41.8 ALC-1P 9.41.4 12.91.9 10.61.8 ALC-1/actin 45.25.2 44.73.2 35.73.1 ALC-2D 71.34.3 68.22.6 68.22.8 ALC-2P 25.13.4 27.52.3 26.22.4 ALC-2PP 3.51.5 4.80.8 5.61.1 ALC-2/actin * 38.05.0 39.23.3 28.62.5 ALC-1/ALC-2 12511 1179 13511 Desmin/actin * 23.03.1# 22.02.7# 39.32.9 ApoA-I* 13.12.4 16.32.7 10.11.6 ApoA-I/actin 19.42.8 14.82.6 9.92.3 Alterations in protein composition

  23. Alterations in contractile function

  24. Conclusions • Atrial dilatation per se does not predispose nor cause • the alterations in contractile protein composition and function in • atrial fibrillation. • Slowing of contraction might reduce ventricular filling.

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