1. (Dr. Leprán István)1 Modeling myocardial infarction Finding a method: Aim? Appropriate method? - learning curve - validation money – time quality – quantity of results human relevance animals – human (healthy volunteers, patients) subcellular – in vitro (cells, organs) – in vivo Make a compromise!

2. (Dr. Leprán István)2 Modeling myocardial infarction Study endpoints: ? brain, liver, kidney heart – pump function impulse production, -propagation, connective tissue, vascular network size, histology, ultrastructure excitation-contraction ion-movements electric activitybasal function biochemistry – substrate uptake pathology metabolism, regulation pharmacology pump function hemodynamics, contractility gene expression-regulation

3. (Dr. Leprán István)3 Modeling myocardial infarction Study endpoints: ? brain, liver, kidney heart – pump function impulse production, -propagation, connective tissue, vascular network size, histology, ultrastructure excitation-contraction ion-movements electric activitybasal function biochemistry – substrate uptake pathology metabolism, regulation pharmacology pump function hemodynamics, contractility gene expression-regulation

4. (Dr. Leprán István)4 Modeling myocardial infarction Species differences: mice, rat easy bredingsmall heart size short life cyclehigh heart rate mass datashort APD genetic manipulation  I to  I Kr I Ks  collaterals  spontaneous CVD larger animals rabbit dog (variable collaterals – elderly human) pig (no collaterals – young human)

5. (Dr. Leprán István)5 Modeling myocardial infarction Species differences: mice, rat easy bredingsmall heart size short life cyclehigh heart rate mass datashort APD genetic manipulation  I to  I Kr I Ks  collaterals  spontaneous CVD larger animals rabbit dog (variable collaterals – elderly human) pig (no collaterals – young human)

6. (Dr. Leprán István)6 Modeling myocardial infarction Species differences: mice, rat easy bredingsmall heart size short life cyclehigh heart rate mass datashort APD genetic manipulation  I to  I Kr I Ks  collaterals  spontaneous CVD larger animals rabbit dog (variable collaterals – elderly human) pig (no collaterals – young human)

7. (Dr. Leprán István)7 Modeling myocardial infarction Species differences: human The only relevant ‘animal’! new diagnostic methodsethical problems (ECG, Holter, US, NMR, PET) large individual diff. morphologyexpensive in vitro – acute investigations isolated cells patch-clamp tissue (perfused? temperature?) contractility, biochemistry, electrophysiology mol-biol methods ill-defined gene expression Diseased heart!

8. (Dr. Leprán István)8 Modeling myocardial infarction Species differences: human The only relevant ‘animal’! new diagnostic methodsethical problems (ECG, Holter, US, NMR, PET) large individual diff. morphologyexpensive in vitro – acute investigations isolated cells patch-clamp tissue (perfused? temperature?) contractility, biochemistry, electrophysiology mol-biol methods ill-defined gene expression Diseased heart!

9. (Dr. Leprán István)9 Modeling myocardial infarction Species differences: human The only relevant ‘animal’! new diagnostic methodsethical problems (ECG, Holter, US, NMR, PET) large individual diff. morphologyexpensive in vitro – acute investigations isolated cells patch-clamp tissue (perfused? temperature?) contractility, biochemistry, electrophysiology mol-biol methods ill-defined gene expression Diseased heart!

10. (Dr. Leprán István)10 Modeling myocardial infarction In vitro – small animals rat, rabbit, guinea-pig – mice isolated heart – perfused – buffer – blood – Langendorff – working (CO, preload, afterload) hypoxia –ischemia (low flow – complete) global – regional hemodynamics – biochemistry – morphology NMR, surface fluorescence (Ca ++, H + ) monophasic action potential – maping isolated tissue (auricle, ventricle, Purkinje fiber) isolated cell membrane patch (  ischemia !) Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

11. (Dr. Leprán István)11 Modeling myocardial infarction In vitro – small animals rat, rabbit, guinea-pig – mice isolated heart – perfused – buffer – blood – Langendorff – working (CO, preload, afterload) hypoxia –ischemia (low flow – complete) global – regional hemodynamics – biochemistry – morphology NMR, surface fluorescence (Ca ++, H + ) monophasic action potential – maping isolated tissue (auricle, ventricle, Purkinje fiber) isolated cell membrane patch (  ischemia !) Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

12. (Dr. Leprán István)12 Modeling myocardial infarction In vitro – small animals rat, rabbit, guinea-pig – mice isolated heart – perfused – buffer – blood – Langendorff – working (CO, preload, afterload) hypoxia –ischemia (low flow – complete) global – regional hemodynamics – biochemistry – morphology NMR, surface fluorescence (Ca ++, H + ) monophasic action potential – maping isolated tissue (auricle, ventricle, Purkinje fiber) isolated cell membrane patch (  ischemia !) Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

13. (Dr. Leprán István)13 Modeling myocardial infarction In vitro – small animals rat, rabbit, guinea-pig – mice isolated heart – perfused – buffer – blood – Langendorff – working (CO, preload, afterload) hypoxia –ischemia (low flow – complete) global – regional hemodynamics – biochemistry – morphology NMR, surface fluorescence (Ca ++, H + ) monophasic action potential – maping isolated tissue (auricle, ventricle, Purkinje fiber) isolated cell membrane patch (  ischemia !) Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

14. (Dr. Leprán István)14 Modeling myocardial infarction In vivo – small animals rat, rabbit, guinea-pig – mice reproducibilitysmall liability to arrhyth. inexpensivegp < mice < rabbit < rat large numberspontaneous defibr. tolerate surgeryrabbit < rat < mice chronic invest. conscious – anesthetized acute surgery (open chest) – chronic surgery chemical arrhythmia models (aconitine, BaCl, ouabain) coronary artery occlusion Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

15. (Dr. Leprán István)15 Modeling myocardial infarction In vivo – small animals rat, rabbit, guinea-pig – mice reproducibilitysmall liability to arrhyth. inexpensivegp < mice < rabbit < rat large numberspontaneous defibr. tolerate surgeryrabbit < rat < mice chronic invest. conscious – anesthetized acute surgery (open chest) – chronic surgery chemical arrhythmia models (aconitine, BaCl, ouabain) coronary artery occlusion Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

16. (Dr. Leprán István)16 Modeling myocardial infarction In vivo – small animals rat, rabbit, guinea-pig – mice reproducibilitysmall liability to arrhyth. inexpensivegp < mice < rabbit < rat large numberspontaneous defibr. tolerate surgeryrabbit < rat < mice chronic invest. conscious – anesthetized acute surgery (open chest) – chronic surgery chemical arrhythmia models (aconitine, BaCl, ouabain) coronary artery occlusion Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

17. (Dr. Leprán István)17 Modeling myocardial infarction In vivo – large animals dog, pig reproducibility?variable arrhythmogen expensivecollaterals few animalsless tolerate surgery chronic invest. conscious – anesthetized acute surgery (open chest) – chronic surgery rtg, pacemaker, intracavital electrophysiology coronary artery occlusion – baloon catheter Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

18. (Dr. Leprán István)18 Modeling myocardial infarction In vivo – large animals dog, pig reproducibility?variable arrhythmogen expensivecollaterals few animalsless tolerate surgery chronic invest. conscious – anesthetized acute surgery (open chest) – chronic surgery rtg, pacemaker, intracavital electrophysiology coronary artery occlusion – baloon catheter Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

19. (Dr. Leprán István)19 Modeling myocardial infarction In vivo – large animals dog, pig reproducibility?variable arrhythmogen expensivecollaterals few animalsless tolerate surgery chronic invest. conscious – anesthetized acute surgery (open chest) – chronic surgery rtg, pacemaker, intracavital electrophysiology coronary artery occlusion – baloon catheter Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

20. (Dr. Leprán István)20 Thank you for your attention !