modeling myocardial infarction finding a method: aim? appropriate method? - learning curve

(Dr. Leprán István) 1

Modeling myocardial infarction

Finding a method:

Aim?

Appropriate method?- learning curve- validationmoney – timequality – quantity of resultshuman relevance

animals – human (healthy volunteers, patients)subcellular – in vitro (cells, organs) – in vivo

Make a compromise!

(Dr. Leprán István) 2

Modeling myocardial infarction

Study endpoints:? brain, liver, kidneyheart – pump function

impulse production, -propagation, connective tissue, vascular network

size, histology, ultrastructureexcitation-contraction

ion-movementselectric activity basal function biochemistry – substrate uptake pathology

metabolism, regulation pharmacologypump function

hemodynamics, contractilitygene expression-regulation

(Dr. Leprán István) 3

Modeling myocardial infarction

Study endpoints:? brain, liver, kidneyheart – pump function

impulse production, -propagation, connective tissue, vascular network

size, histology, ultrastructureexcitation-contraction

ion-movementselectric activity basal function biochemistry – substrate uptake pathology

metabolism, regulation pharmacologypump function

hemodynamics, contractilitygene expression-regulation

(Dr. Leprán István) 4

Modeling myocardial infarction

Species differences:mice, rat

easy breding small heart sizeshort life cycle high heart ratemass data short APDgenetic manipulation Ito IKr IKs

collaterals spontaneous CVD

larger animalsrabbitdog (variable collaterals – elderly human)pig (no collaterals – young human)

(Dr. Leprán István) 5

Modeling myocardial infarction

Species differences:mice, rat

easy breding small heart sizeshort life cycle high heart ratemass data short APDgenetic manipulation Ito IKr IKs

collaterals spontaneous CVD

larger animalsrabbitdog (variable collaterals – elderly human)pig (no collaterals – young human)

(Dr. Leprán István) 6

Modeling myocardial infarction

Species differences:mice, rat

easy breding small heart sizeshort life cycle high heart ratemass data short APDgenetic manipulation Ito IKr IKs

collaterals spontaneous CVD

larger animalsrabbitdog (variable collaterals – elderly human)pig (no collaterals – young human)

(Dr. Leprán István) 7

Modeling myocardial infarction

Species differences:human

The only relevant ‘animal’!new diagnostic methods ethical problems

(ECG, Holter, US, NMR, PET) large individual diff.

morphology expensivein vitro – acute investigations

isolated cellspatch-clamp

tissue (perfused? temperature?)contractility, biochemistry, electrophysiology

mol-biol methodsill-defined gene expression

Diseased heart!

(Dr. Leprán István) 8

Modeling myocardial infarction

Species differences:human

The only relevant ‘animal’!new diagnostic methods ethical problems

(ECG, Holter, US, NMR, PET) large individual diff.

morphology expensivein vitro – acute investigations

isolated cellspatch-clamp

tissue (perfused? temperature?)contractility, biochemistry, electrophysiology

mol-biol methodsill-defined gene expression

Diseased heart!

(Dr. Leprán István) 9

Modeling myocardial infarction

Species differences:human

The only relevant ‘animal’!new diagnostic methods ethical problems

(ECG, Holter, US, NMR, PET) large individual diff.

morphology expensivein vitro – acute investigations

isolated cellspatch-clamp

tissue (perfused? temperature?)contractility, biochemistry, electrophysiology

mol-biol methodsill-defined gene expression

Diseased heart!

(Dr. Leprán István) 10

Modeling myocardial infarction

In vitro – small animalsrat, rabbit, guinea-pig – miceisolated heart – perfused – buffer – blood

– Langendorff – working (CO, preload, afterload)

hypoxia – ischemia (low flow – complete)global – regionalhemodynamics – biochemistry – morphology

NMR, surface fluorescence (Ca++, H+)monophasic action potential – maping

isolated tissue (auricle, ventricle, Purkinje fiber)isolated cellmembrane patch ( ischemia !)

Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

(Dr. Leprán István) 11

Modeling myocardial infarction

In vitro – small animalsrat, rabbit, guinea-pig – miceisolated heart – perfused – buffer – blood

– Langendorff – working (CO, preload, afterload)

hypoxia – ischemia (low flow – complete)global – regionalhemodynamics – biochemistry – morphology

NMR, surface fluorescence (Ca++, H+)monophasic action potential – maping

isolated tissue (auricle, ventricle, Purkinje fiber)isolated cellmembrane patch ( ischemia !)

Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

(Dr. Leprán István) 12

Modeling myocardial infarction

In vitro – small animalsrat, rabbit, guinea-pig – miceisolated heart – perfused – buffer – blood

– Langendorff – working (CO, preload, afterload)

hypoxia – ischemia (low flow – complete)global – regionalhemodynamics – biochemistry – morphology

NMR, surface fluorescence (Ca++, H+)monophasic action potential – maping

isolated tissue (auricle, ventricle, Purkinje fiber)isolated cellmembrane patch ( ischemia !)

Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

(Dr. Leprán István) 13

Modeling myocardial infarction

In vitro – small animalsrat, rabbit, guinea-pig – miceisolated heart – perfused – buffer – blood

– Langendorff – working (CO, preload, afterload)

hypoxia – ischemia (low flow – complete)global – regionalhemodynamics – biochemistry – morphology

NMR, surface fluorescence (Ca++, H+)monophasic action potential – maping

isolated tissue (auricle, ventricle, Purkinje fiber)isolated cellmembrane patch ( ischemia !)

Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

(Dr. Leprán István) 14

Modeling myocardial infarction

In vivo – small animalsrat, rabbit, guinea-pig – mice

reproducibility small liability to arrhyth.inexpensive gp < mice < rabbit < ratlarge number spontaneous defibr.tolerate surgery rabbit < rat < mice chronic invest.

conscious – anesthetizedacute surgery (open chest) – chronic surgerychemical arrhythmia models

(aconitine, BaCl, ouabain)coronary artery occlusion

Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

(Dr. Leprán István) 15

Modeling myocardial infarction

In vivo – small animalsrat, rabbit, guinea-pig – mice

reproducibility small liability to arrhyth.inexpensive gp < mice < rabbit < ratlarge number spontaneous defibr.tolerate surgery rabbit < rat < mice chronic invest.

conscious – anesthetizedacute surgery (open chest) – chronic surgerychemical arrhythmia models

(aconitine, BaCl, ouabain)coronary artery occlusion

Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

(Dr. Leprán István) 16

Modeling myocardial infarction

In vivo – small animalsrat, rabbit, guinea-pig – mice

reproducibility small liability to arrhyth.inexpensive gp < mice < rabbit < ratlarge number spontaneous defibr.tolerate surgery rabbit < rat < mice chronic invest.

conscious – anesthetizedacute surgery (open chest) – chronic surgerychemical arrhythmia models

(aconitine, BaCl, ouabain)coronary artery occlusion

Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

(Dr. Leprán István) 17

Modeling myocardial infarction In vivo – large animals

dog, pigreproducibility ? variable arrhythmogenexpensive collateralsfew animals less tolerate surgerychronic invest.

conscious – anesthetizedacute surgery (open chest) – chronic surgeryrtg, pacemaker, intracavital electrophysiologycoronary artery occlusion – baloon catheter

Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

(Dr. Leprán István) 18

Modeling myocardial infarction In vivo – large animals

dog, pigreproducibility ? variable arrhythmogenexpensive collateralsfew animals less tolerate surgerychronic invest.

conscious – anesthetizedacute surgery (open chest) – chronic surgeryrtg, pacemaker, intracavital electrophysiologycoronary artery occlusion – baloon catheter

Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

(Dr. Leprán István) 19

Modeling myocardial infarction In vivo – large animals

dog, pigreproducibility ? variable arrhythmogenexpensive collateralsfew animals less tolerate surgerychronic invest.

conscious – anesthetizedacute surgery (open chest) – chronic surgeryrtg, pacemaker, intracavital electrophysiologycoronary artery occlusion – baloon catheter

Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

(Dr. Leprán István) 20

Thank you for your attention !