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Modeling myocardial infarction Finding a method: Aim? Appropriate method? - learning curve

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

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Modeling myocardial infarction Finding a method: Aim? Appropriate method? - learning curve

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  1. (Dr. Leprán István) 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) 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 activity basal function biochemistry – substrate uptake pathology metabolism, regulation pharmacology pump function hemodynamics, contractility gene expression-regulation

  3. (Dr. Leprán István) 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 activity basal function biochemistry – substrate uptake pathology metabolism, regulation pharmacology pump function hemodynamics, contractility gene expression-regulation

  4. (Dr. Leprán István) Modeling myocardial infarction Species differences: mice, rat easy breding small heart size short life cycle high heart rate mass data short APD genetic manipulation Ito  IKr IKs  collaterals  spontaneous CVD larger animals rabbit dog (variable collaterals – elderly human) pig (no collaterals – young human)

  5. (Dr. Leprán István) Modeling myocardial infarction Species differences: mice, rat easy breding small heart size short life cycle high heart rate mass data short APD genetic manipulation Ito  IKr IKs  collaterals  spontaneous CVD larger animals rabbit dog (variable collaterals – elderly human) pig (no collaterals – young human)

  6. (Dr. Leprán István) Modeling myocardial infarction Species differences: mice, rat easy breding small heart size short life cycle high heart rate mass data short APD genetic manipulation Ito  IKr IKs  collaterals  spontaneous CVD larger animals rabbit dog (variable collaterals – elderly human) pig (no collaterals – young human)

  7. (Dr. Leprán István) 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) Modeling myocardial infarction Species differences: human The only relevant ‘animal’! new diagnostic methods ethical problems (ECG, Holter, US, NMR, PET) large individual diff. morphology expensive 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) Modeling myocardial infarction Species differences: human The only relevant ‘animal’! new diagnostic methods ethical problems (ECG, Holter, US, NMR, PET) large individual diff. morphology expensive 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) 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) 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) 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) 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) Modeling myocardial infarction In vivo – small animals rat, rabbit, guinea-pig – mice reproducibility small 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 arteryocclusion Healthy heart! Disease models (diabetes, hypertension)! Genetic manipulation (human ill-defined genes)!

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

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

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

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

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

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

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