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Modelling of Cardiac β- adrenoceptor desensitisation to understand heart failure therapy. Karin Lundengård, CMIV Jordi Altimiras, IFM. Outline. Project and groups β AR in the heart and heart failure therapy Modeling methodology The models Future prospects. Altimiras' group at IFM. - PowerPoint PPT Presentation
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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?