Interactions of biventricular pacing with alterations in heart failure

Transcription

1 2008 NBCR Summer Institute La Jolla, August 11 th, 2008 Interactions of biventricular pacing with alterations in heart failure

2 Cardiac Resynchronization Therapy Heart failure: 250,000 deaths/year in US alone Patients with HF and conduction abnormalities such as bundle branch block have the worst prognosis Cardiac resynchronization therapy (CRT) improves timing between LV and RV contraction improves quality of life* reduces mortality* ~30% of patients do not respond to CRT, especially those with myocardial infarcts Lack of experimental in-vivo data on regional electrical activation and mechanical function No objective protocols to optimize pacing *Cleland, 2005

3 Objective To develop patient-specific and animalspecific multi-scale models of ventricular electromechanics in the failing heart for predicting functional outcomes of cardiac resynchronization therapy

4 Systems Physiology Models Finite element and boundary element models Constitutive Models Cell Systems models Coronary ostia pressure Coronary artery flows substrates Coronary artery flow Tissue perfusion Circulatory system dynamics Ventricular systolic pressures and cardiac output Intramyocardial pressure and volume Crossbridge interactions Mitochondrial metabolism Ventricular filling pressures and output impedance Wall stress and strain Myofilament tension adenosine Regulation of peripheral resistances, fluid volumes, HR Torso bioelectric fields Whole ventricular electromechanics Regional wall stresses, strains, displacements Myofilament activation Purine metabolism Neurohumoral regulation Epicardial potential fields Transmembrane potentials Action potential propagation Calcium handling Total transmembrane ionic current Cell signaling Autonomic mediators Ionic currents Circulation Torso Ventricles Myocardium Myocyte

5 Outline Model Development Cellular models Electrophysiology Biomechanics Electromechanics Anatomy Applications to heart failure Scar Physiologically-based sensitivity analysis Clinical study design

6 Modeling from cell to system Tissue Organ System Cell Baro-reflex and back again

7 Heart Failure at the cell level Control CHF Sham 8 wk 16 wk β 1 -AR: -75% SERCA: -30% CHF Sham Oudit, G. Y., et al. (2003). Circulation 108(17): Zarain-Herzberg, et al. (1996). Mol Cell Biochem : Sjaastad, I., et al. (2002). Acta Physiol Scand 175(4): NCX: +55% 7

8 Heart Failure at the cell level 0.7 Normal CHF Ca 2+ (µm) 0.1 Holt, ET et al. (1998) J Mol Cell Cardiol 30(8): Xiao RP et al. (2003) Circulation 108(13):

9 Electrophysiology at cell/tissue level Action Potential (mv) Epi M-Cell Endo time (ms) Currents Densities (ms/µf) Epi Endo Mid Transient outward K +, Gto Rapid delayed rectifier K +, GKr Slow delayed rectifier K +, GKs Plateau K +, GKp Sodium, GNa % % % Saucerman JJ, Healy SN, Belik ME, Puglisi JL, McCulloch AD. Circ Res. 2004;95:

10 Purkinje System Auckland Canine Heart Purkinje Fibers Activation Times LV Endocardial Model (Usyk et al, 2002, CVS) Time (ms) 1200

11 Biomechanics Models filament crossbridge regulatory unit ventricles myocardial tissue myofilament lattice

12 Myocyte Excitation-Contraction Coupling Model STIMULUS Flaim et al, 2006 (Ca 2+ RELEASE, REUPTAKE, BUFFERING, ETC) Ca 2+ (Ca 2+ BUFFERING BY TnC) (Cordeiro et al. 2004) Rice et al, 2008 UNLOADED CELL SHORTENING ACTION POTENTIAL Ca 2+ TRANSIENT UNLOADED CELL SHORTENING

13 Mid- and Endo- Cells Display Similar Ca 2+ - Shortening Dynamics experiment Ca 2+ TRANSIENT UNLOADED SHORTENING (Campbell et al. 2008)

14 Ventricular Wall Mechanics Conservation of mass, momentum and energy Pressure boundary conditions from hemodynamic model Myofiber angle and sheet distributions 3-D mechanical properties

15 Stress-strain relations for myocardium Passive Stress (kpa) Fiber stress Stress normal to sheet Cross-fiber stress Strain Normal Failing

16 64-slice ECG-gated CT Anatomic Model DTMRI Helm et al, 2006

17 FE model in circulation, modified for dog Circulation model by Lu et al (AJP 2001)

18 Kerckhoffs RCP, Neal M, Gu Q, Bassingthwaighte JBB, Omens JH, McCulloch AD. Ann Biomed Eng 2007;35(1):1-18

19 Lu et al (AJP 2001) Control of blood pressure

20 Hemodynamics from FE model Left ventricular Pressure [mmhg] Right ventricular Pressure [mmhg] Left ventricular Volume [ml] Right ventricular Volume [ml] Aortic & mitral flow [lit/sec] Pulmonary artery & tricuspid flow [lit/sec]

21 Baroreflex from FE model

22 Sympathetic nerve endings in the heart are heterogeneously distributed Munch, G. et al. Circulation 2000;101:

23 beta-ar is distributed heterogeneously transmurally in heart failure β 1 and β 2 density subepicardium subendocardium NF F NF F SL Beau et al. Circulation 1993;88;

24 Applications: Multi-scale models of heart failure ~30% of HF patients undergoing CRT classified as non-responders Most of these had a prior myocardial infarct Investigate relation between myocardial scar and CRT

25 Effects of Myocardial Scars 0 40% 0 60% Inferior infarct Anterior infarct

26 Relative improvement in global function with LV pacing was independent of scar size But relative improvement in regional function with LV pacing decreased with increasing scar size

27 Anterior scar of increasing size

28 Models of dilated dyssynchronous HF with scar Kerckhoffs et al, Medical Image Analysis, 2008, in press

29 Regional function independent of scar size Kerckhoffs et al, Medical Image Analysis, 2008, in press

30 PV loops of non-failing heart and failing heart with LBBB Pressure [mmhg] LV RV Volume [ml]

31 Applications: Physiological sensitivity analysis - What is each alteration s contribution to a change in regional/ global function? - How does biventricular pacing interact with alterations?

32 Non-failing vs failing In the numerical models, there are four alterations from normal to failing: geometry normal vs. dilated force generation normal vs. reduced twitch duration normal vs. longer activation sequence LBBB vs. BIV pacing V LV /V wall =0.25 V LV /V wall =0.53

33 Non-failing vs. failing In the numerical models, there are four alterations from normal to failing: geometry normal vs. dilated force generation normal vs. reduced (r) twitch duration normal vs. longer activation sequence LBBB vs. BIV pacing myofiber stress [kpa] -27% *Pieske et al. J Clin Invest 88:765, 1996

34 Non-failing vs. failing In the numerical models, there are four alterations from normal to failing: geometry normal vs. dilated force generation normal vs. reduced twitch duration normal vs. longer (l) activation sequence LBBB vs. BIV myofiber stress [kpa] +17% *Pieske et al. J Clin Invest 88:765, 1996

35 In the numerical models, there are four alterations from normal to failing: geometry normal vs. dilated force generation normal vs. reduced twitch duration Non-failing vs. failing normal vs. longer activation sequence LBBB vs. BIV pacing (b)

36 Write cardiac function parameter as function of alteration parameter Stroke Volume Stroke Volume For normal heart Change in stroke volume for change in geometry Third order interactions Fourth order interaction Change in Stroke Volume owing to interaction between geometry and reduced force Results in 16 coefficients

37 Bunch of simulations for all possible combinations Simulation name Alteration Peak Twitch Impulse Geometry stress duration conduction (d) (r) (l) (b) Comment simulation baseline Non-failing heart + LBBB b Non-failing heart + BIV l lb r br rl rlb d db dl dlb dr drb drl Failing heart + LBBB drlb Failing heart + BiV

38 Effects on dp/dt max [%] the %change in dp/dt max owing to BIV pacing Interaction effect between BIV pacing and a prolonged relaxation Large effects of all alterations on dp/dt max

39 Large interaction between dilation and reduced peak stress [%] large effects of peak stress large interaction between the two large effects of dilation

40 [%] results in more uniform contraction large positive interaction with BIV and dilation more mechanical synchronous contraction dilation induces dyssynchrony and non-uniformity

41 Patient-specific Study Design Two patient groups with dilated cardiomyopathy at San Diego VAMC indicated for CRT First group is considered probable responders without infarcts Second group has an infarct or other indication of less probable response rate Multi-slice CT imaging prior to implantation LV and RV electroanatomic mapping (NavX) and right and left heart cardiac catheterization during implantation procedure with and without pacing Echo two weeks after implantation with pacing on and off Retrospective model building and analysis 3-month clinical follow-up

42 Acknowledgements CMRG: Collaborators: Andrew McCulloch Sanjiv Narayan, UCSD VAMC Sarah Flaim David Krummen, UCSD VAMC Stuart Campbell Don Bers, Loyola University Chicago Anushka Michailova Jose Puglisi, Loyola University Chicago Jeff Omens Wayne Giles, University of Calgary Stuart Campbell Chae Hun Leem,, University of Ulsan Jun Shin Larry Frank, UCSD Radiology Jazmin Aguado Paul Stark, UCSD VAMC Radiology Vincent Forster Helen Saad Ben Coppola Elliot Howard Fred Lionetti

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