Modelling of Cardiac β-adrenoceptor desensitisation to understand heart failure therapy Karin Lundengård, CMIV Jordi Altimiras, IFM

2 Outline Project and groups β AR in the heart and heart failure therapy Modeling methodology The models Future prospects

3 Altimiras' group at IFM Phenotypic plasticity of cardiovascular function during fetal development: mechanisms and consequences Research Interests:

4 Project collaboration  Collaboration with Gunnar Cedersund, IKE/IMT and Elin Nyman, IKE  LCSB

5 Outline Project and groups β AR in the heart and heart failure therapy Modeling methodology The models Future prospects

6 β-adrenoceptors in the heart Catecholamines are key stimulators of cardiac function (positive chronotropic and inotropic effects) by binding to  -adrenoceptors Loss of βAR sensitivity to adrenergic agonists occurs in heart failure

7 Cardiac function Release of catecholamines Chronic β-AR stimulation Receptor desensitisation Cardiac function HEART FAILURE!

8 Baspresentation LiU Heart failure therapy Based on ACE inhibitors and β-blockers β-blockade substantially improves pump function in the long term

9 « An entire explanation for improved cardiac function in patients using β-blockers is unknown… » « … and, in fact may be quite complicated, considering the numerous intracellular signaling pathways associated with β- adrenergic receptors » Tilley and Rockman. Expert Rev.Cardiovasc.Ther. 4:417 (2006) Aims of our work Collect experimental data on βAR desensitization Construct and optimize a βAR signaling model

10 Outline Project and groups β AR in the heart and heart failure therapy Modeling methodology The models Future prospects

11 Modelling Methodology Mechanistic model, ODEs Time series data Iteratively with experiments HypothesisModel Optimization Experiments

12 Outline Project and groups β AR in the heart and heart failure therapy Modeling methodology The models Future prospects

13 d(B1)/dt = k1d*B1int + k1c*B1p - kbas1*B1 - B1*(kiso+kip1)*H1 d(B1act)/dt = kbas1*B1 + B1*(kiso+kip1)*H1 - k1a*B1act*(kGRK*GRKact+PKAact) d(B1p)/dt = k1a*B1act*(kGRK*GRKact+PKAact) - (k1b+k1c)*B1p d(B1int)/dt = k1b*B1p – k1d*B1int d(B2)/dt = k2d*B2int + k2c*B2p - kbas2*B2 - B2*(kiso+kip2+kter)*H2 d(B2act)/dt = kbas2*B2 + B2*(kiso+kip2+kter)*H2 - k2a*B2act*(kGRK*GRKact+PKAact) d(B2p)/dt = k2a*B2act*(kGRK*GRKact+PKAact) - (k2b+k2c)*B2p d(B2int)/dt = k2b*B2p - k2d*B2int d(Gs)/dt = k3b*Gsact - k3a*Gs*(B1act+B2act) d(Gsact)/dt = k3a*Gs*(B1act+B2act) - k3b*Gsact d(Gi)/dt = k3d*Giact - k3c*B2p*Gi d(Giact)/dt = k3c*B2p*Gi - k3d*Giact d(AC)/dt = k4b*ACact - k4a*Gsact/(kinh+Giact)*AC d(ACact)/dt = k4a*Gsact/(kinh+Giact)*AC - k4b*ACact d(cAMP)/dt = cAMP0 + ACact*k5 – kPKA*PKAact*cAMP d(GRK)/dt = - cAMP*k6a*GRK + k6b*GRKact d(GRKact)/dt = cAMP*k6a*GRK - k6b*GRKact d(PKA)/dt = - cAMP*k6c*PKA + k6d*PKAact d(PKAact)/dt = cAMP*k6c*PKA - k6d*PKAact

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32 Theoretical data Return of signal Experimental data Predict resting time Original model Minimal models All smaller models

33 Outline Project and groups β AR in the heart and heart failure therapy Modeling methodology The models Future prospects

34 Future prospects Study β-AR desensitization and beta-blocker effects in the murine myocardial infarction model in collaboration with Prof. de Muinck, Clinical Physiology Further development of the model to account for the effects of beta- blockade Why don’t fetal βARs desensitize?

Thank you for your attention! Questions?