Modelling of Cardiac β-adrenoceptor

desensitisation to understand heart failure therapy

Karin Lundengård, CMIV

Jordi Altimiras, IFM

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Outline

Project and groups

βAR in the heart and heart failure therapy

Modeling methodology

The models

Future prospects

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Altimiras' group at IFM

Phenotypic plasticity of cardiovascular function during fetal development: mechanisms and consequences

Research Interests:

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Project collaboration

Collaboration with Gunnar Cedersund, IKE/IMT and Elin Nyman, IKE

LCSB

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Outline

Project and groups

βAR in the heart and heart failure therapy

Modeling methodology

The models

Future prospects

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β-adrenoceptors in the heartCatecholamines are key stimulators of cardiac function (positive

chronotropic and inotropic effects) by binding to β-adrenoceptors

Loss of βAR sensitivity to adrenergic agonists occurs in heart failure

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Cardiac function

Release of catecholamines

Chronic β-AR stimulation

Receptor desensitisation

Cardiac functionHEART FAILURE!

8Baspresentation LiU

Heart failure therapyBased on ACE inhibitors and β-blockers

β-blockade substantially improves pump function in the long term

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« 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 workCollect experimental data on βAR desensitization

Construct and optimize a βAR signaling model

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Outline

Project and groups

βAR in the heart and heart failure therapy

Modeling methodology

The models

Future prospects

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Modelling Methodology

Mechanistic model, ODEs

Time series data

Iteratively with experiments

Hypothesis Model

Optimization

Experiments

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Outline

Project and groups

βAR in the heart and heart failure therapy

Modeling methodology

The models

Future prospects

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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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Theoretical data

Return of signal

Experimental data

Predict resting time

Original model

Minimal models

All smaller models

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Outline

Project and groups

βAR in the heart and heart failure therapy

Modeling methodology

The models

Future prospects

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Future prospectsStudy 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?

www.liu.se

Thank you for your attention!

Questions?