שינויים מולקולאריים ומבניים באי ספיקת לב אפשרויות לטיפול עתידני

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1 שינויים מולקולאריים ומבניים באי ספיקת לב אפשרויות לטיפול עתידני פרופ יהונתן ליאור 1

2 Braunwald s Heart Disease 8th Edition Chapter 21 Mechanisms of Cardiac Contraction and Relaxation Chapter 22 Pathophysiology of Heart failure Chapter 29 Emerging therapies 2

3 ספרות Cardiac Plasticity Joseph A. Hill, M.D., Ph.D., and Eric N. Olson, Ph.D N Eng J Med Volume 358: March 27,

4 שאלה מדידה שלו בדם 6 שעות מהסמנים ומנבאת פרוגנוזה לאחר אוטם שריר הלב )ברנוולד פרק ( טרופונין T טרופונין I נטריורטיק פפטיד קולגן

5 שאלה יעכב הכל למעט )סמן תשובה לא ACE מתן מעכבי ( נכונה Beta-adrenergic desensitization Fetal gene expression Myocyte necrosis MMP activation E-C coupling

6 Main Topics 1. LV remodeling -cellular and molecular level 2. Extracellular matrix 3. Regeneration 6

7 Myocardium 1. Cardiomyocytes and nonmyocyte cells 2. Extracellular Matrix 3. Vessels 7

8 Myocardial Cells Jugdutt & al. Circulation

9 The Sarcomere Figure 19-1 Braunwald

10 10

11 Cardiac Damage and Repair 11

12 Apoptosis vs. Necrosis 12

13 Myocyte Cell Death Necrosis Apoptosis Autophagy 13

14 Healing Nomenclature Regeneration Repair Damaged tissue is Damaged tissue is replaced from replaced by parenchyma. fibrous scar tissue. 14

15 Ventricular remodeling, comprising changes in mass, volume, shape, and composition, constitutes one of the principal mechanisms by which the heart compensates for an increased load 15

16 16

17 LV Dilatation 17

18 Cardiac Support Device Figure

19 19

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21 Cellular Events Triggered by Altered Workload. A complex interplay of biomechanical and neurohumoral stress responses culminates in hypertrophic gene regulation and cell growth Hill & Olson NEJM 2008

22 Pathogenesis of heart failure

23 23

24 Overview of the pathophysiology of myocardial remodeling Figure

25 Cellular Hypertrophy 25

26 Cardiac myocyte remodeling Increased myocyte length and width 26

27 cardiac hypertrophy Figure

28 Autophagy 28

29 Small RNAs in a big heart

30 Figure 69-6 The flow of genetic information. Transcription in the nucleus creates a complementary ribonucleic acid copy from one of the DNA strands in the double helix. mrna is transported into the cytoplasm, where it is translated into protein

31 MicroRNAs as Mediators MicroRNAs as Mediators Mann D. N Engl J Med 2007;356:

32 Human mutations affecting Ca2+ cycling proteins J. Clin. Invest. 115: (2005) Braunwald p

33 Calcium Hemostasis in Failing Human Myocardium Intracellular Calcium levels Basal (diastolic) Peak (systolic) Rate of fall with diastole From Braunwald pp 33

34 Alterations in beta-adrenergic pathways in the failing heart 34

35

36 Braunwald Table

37 Braunwald Table 29-6 Effect of Gene Polymorphisms on the Pharmacological Treatment of Heart Failure 37

38 38

39 Extra Cellular Matrix 39

40 MMP activity site Extra cellular matrix degradation causes cardiomyocyte realignment wall thinning LV dilatation heart failure 40

41 The regulation of extracellular matrix degradation Figure

42 Factors responsible for diastolic dysfunction Figure

43 FIGURE 22-4 The systemic and tissue components of the renin-angiotensin system 43

44 Angiotensin II and Myocardium Myocyte hypertrophy Myocyte apoptosis Fibrosis Matrix remodeling (collagen deposition) Inflammation Oxidative stress 44

45 Summary LV Remodeling at the molecular and cellular level 1. Myocyte growth or hypertrophy. 2. Changes in myocyte phenotype with reexpression of fetal gene programs. 3. Alterations in proteins involved in excitationcontraction coupling and contraction. 4. Myocyte death due to necrosis and apoptosis 5. Changes in the extracellular matrix. 6. Abnormalities in energetics. 45

46 Processes Occurring in Ventricular Remodeling (2) Continued expansion of infarct zone Dilation and reshaping of the left ventricle Myocyte hypertrophy Ongoing myocyte loss Excessive accumulation of collagen in the cardiac interstitium 46

47 Table 22-5

48 Myocardial regeneration and repair 48

49 Stem Cell Self renewal Give rise to specialized cells. 49

50 Embryonic and Adult Stem Cells Zipori

51 Cardiac Stem cells 51

52 Myocardial repair Figure

53 Induced Pluripotent Stem cells ips 53

54 Possible mechanisms for successful cardiac regenerative therapy Boyle et al Circulation 2006 Prof. Jonathan Leor, NCRI 54

55 FIGURE 29-3 Proposed mechanisms of action of stem/progenitor cells in cardiovascular repair. 55

56 Future directions Braunwald future therapies will likely be focused on reversing and/or stabilizing the downstream biological consequences of neurohormonal activation, rather than on neurohormonal activation per se. 56

57 Sleeping Student: Take home message 57

58 Overview of the pathophysiology of myocardial remodeling Figure