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Stem cell therapy in cardiac practice

Stem cell therapy in cardiac practice. Dr Sajeer K T Senior resident, Department of Cardiology, Govt. Medical College, Kozhikode. Background. Cardiovascular disease ➔ leading cause of morbidity and mortality worldwide Despite advances in Mx and cath-based therapy for AMI

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Stem cell therapy in cardiac practice

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  1. Stem cell therapy in cardiac practice Dr Sajeer K T Senior resident, Department of Cardiology, Govt. Medical College, Kozhikode.

  2. Background • Cardiovascular disease ➔ leading cause of morbidity and mortality • worldwide • Despite advances in Mx and cath-based therapy for AMI • 1-year mortality: 13% • 5-year prognosis for patients with HF: 50%. • LV systolic dysfunction: • major determinant of prognosis • associated with significant loss of cardiomyocytes • (Irreversible ➔heart post mitotic organ) Abdul M. Mozid et al. British Medical Bulletin 2011; 98: 143–159

  3. Stem cell therapy • Clinical trials focused on 3 main situations: • Acute MI (with the hope of preventing LVSD) • Chronic heart failure secondary to previous MI • DCM (non ischemic cardiomyopthy) • Areas of discussion: • 1. Stem cell types used in cardiac repair • 2. Methods of cell delivery in clinical practice • 3. Clinical trial evidence to date

  4. Stem cell ? • Stem cell • a cell with a unique capacity to produce • unaltered daughter cells (self-renewal) & to • generate specialized cell types (potency) • Self-renewal • symmetric division: • two stem cells • two cells destined for differentiation • asymmetric division: • one stem cell and one differentiating cell

  5. Signature characteristic of the stem cell

  6. Types of stem cells • Stem cells : 2 types • Somatic stem cells : • BM, brain, liver, skeletal & dermal tissue • in vitro proliferative ability is limited • Pluripotent stem cells : • Embryonic stem cells, embryonic germ cells • embryonic carcinoma cells, induced pluripotent stem (iPS) • Exhibit pluripotency

  7. Traditional view ➲ Current evidence • Traditional view: • heart is a terminally differentiated post mitotic organ • Current evidence: • heart is not a terminally differentiated post mitotic organ • 4 sources of cells : for new cardiomyocytes after birth 1. Adult cardiomyocytes (mononucleated) 2. Bone marrow–derived cardiac stem or progenitor cells 3. Embryonic epicardium derived cells 4. Niches of cardiac stem or cardiac progenitor cells (CPCs) Stem Cells  2007; 25:589. Cell 2009 138;257–270.

  8. Different cell types investigated for use in cardiac repair Abdul M. Mozid et al. British Medical Bulletin 2011; 98: 143–159

  9. Heart - self-renewing organ • Myocyte regeneration occurs throughout organism lifespan • Cardiac niches contain stem cells ➔ after activation • ➔ give rise to myocytes and vascular structures Piero Anversa, Jan Kajstura, Annarosa Leri. Circulation. 2006;113:1451-1463

  10. Cardiac Stem or Progenitor cells (CSC or CPC) • niche of primitive cells present in human heart • possess the ability to form cardiomyocytes, endothelial cells • (ECs), smooth muscle cells (SMCs) Different classes of CPCs : based on cell surface markers • c-Kit+ cells • 2. Sca-1+ cells • 3. side population cells (SP) • 4. cells expressing the protein Islet-1 (transcription factor)

  11. Cardiac progenitor cell classes • c-kit positive cell • Sca-1 positive cell • SP cells • Cardiospheres • Epicardial progenitors

  12. Hierarchy of CPC growth and differentiation • Asymmetrical division of a CSC ➨ a daughter • CSC and a daughter cardiac progenitor (CPg) • CPg gives rise to • - Myocyte progenitor (MPg )& precursor (MPr) • - EC progenitor (EPg) & precursor (EPr) • - SMC progenitor (SMPg) & precursor (SMPr) • Precursors ➨ transient amplifying cells ➨ divide • and differentiate into mature myocytes, ECs, and • SMCs. • CSCs are lineage-negative cells : express only • c-kit, MDR1, or Sca-1. • Progenitors express stem cell antigens and • transcription factors of cardiac cells but do not • exhibit specific cytoplasmic proteins • Precursors possess stem cell antigens, • transcription factors, membrane& cytoplasmic • proteins typical of myocytes, ECs, and SMCs

  13. Hierarchy of CPC growth and differentiation

  14. Cardiac Stem Cells and Myocardial Diseases • Role of cardiac stem cells in the advanced stages of HF: • - to modulate endogenous CPCs to regenerate cardiac muscle • and to create new blood vessel formation • Ventricular remodeling ➔ progressive chamber dilation and thinning of the walls • Myocardial regeneration ➔ reverse this process • ➔ transforming a dilated failing heart into a normal, functionally • competent organ

  15. Bone marrow stem cells • Bone marrow–derived stem cells: • - best studied cells • - used in clinical trials in MI and/or idiopathic DCM • Bone marrow progenitor cells: • - hematopoietic stem cells (HSCs) • - side population cells (SP cells) • (expression of the Abcg2 transporter and allowing • export of Hoechst dye) • - mesenchymal stem cells (MSCs) • - multipotential adult progenitor cells (MAPCs)

  16. Inducible Pluripotent Stem Cells (iPSCs) • Adult stem cells ➔ successfully reprogrammed back to an • undifferentiated pluripotent state • (by inserting 4 genes: Oct3/4, Sox2, KL4 and c-Myc into differentiated • somatic cells) • Morphological phenotype of ES cells • Same differentiation potential as ES cells ( in vivo and in vitro) • - able to form all three germ layers • Functioning cardiomyocytes ➔ produced from iPSCs

  17. Inducible Pluripotent Stem Cells (iPSCs) Generation of iPS cells from somatic cells • Reprogramming factors ➨ introduced in vitro • Established iPS cells ➨ differentiate into various cell types Circulation. 2010;122:80-87

  18. iPS demonstrate pluripotent features Circulation. 2009;120:408-416

  19. Cell types and mode of delivery of cells for cardiac repair A : Cell types used for cardiovascular repair B: Delivery strategies used in the clinical setting for cell therapy EPCs = endothelial progenitor cells iPS cells = induced pluripotent SCs MSCs = mesenchymal stem cells SP cells = side population cells

  20. Summary of cell types used in clinical trials and future perspective Circulation. 2010;121:325-335

  21. Method of delivery of stem cells • Intracoronary infusion of cells: • - most popular mode of cell delivery - after AMI • Intramyocardial injection: • - performed in patients with chronic heart failure • secondary to IHD • - transendocardial injections (catheter-based) • - transepicardial injections (during open heart surgery)

  22. Mechanisms of action Progenitor cells: improve functional recovery of infarcted or failing myocardium 1. Direct or indirect improvement of revascularization 2. Paracrine factors released by progenitor cells may inhibit cardiac apoptosis, affect remodeling, or enhance endogenous repair (eg: by tissue-resident PCs) 3. Differentiation into cardiomyocytes may contribute to cardiac regeneration.

  23. Homing of BM-derived stem cells to the myocardium • Homing of BM-derived stem cells to the myocardium: • - fate of bone marrow-derived stem cells is determined by the • microenvironment that they enter

  24. Mobilization and homing • Homing is mediated by : • Adhesion • Transmigration • Invasion

  25. Prerequisite for cell-based therapies Summary of prerequisite for cell-based therapies Circulation. 2010;121:325-335

  26. Stem cell therapy in acute MI

  27. Stem cell therapy in acute myocardial infarction • Most of the trials used intracoronary delivery of BMSCs following • successful stenting of the infarct-related artery • Surrogate markers used to assess efficacy of cell therapy: • - Improvements in the LVEF • - Reduction in size of scar tissue • - Reduction in cardiac volume • Post infarction heart failure: • - results from ventricular remodeling processes • - characterized by progressive expansion of the infarct area and • dilation of the LV cavity

  28. Major goal to reverse LV remodeling: • - enhancement of regeneration of cardiac myocytes • - stimulation of neovascul. within the infarct area • 4 main randomized controlled trials (RCTs) • - published with positive findings • 1. TOPCARE-AMI ( Circulation- 2002) • 2. BOOST trial ( Lancet - 2004) • 3. REPAIR-AMI trial ( EJM - 2006) • 4. FINCELL (Eur Heart - 2008)

  29. Randomized control trials of intracoronary BMSC therapy following acute myocardial infarction

  30. TOPCARE-AMI :Transplantation of Progenitor Cells and Regeneration Enhancement in AMI Birgit Assmus et al. Circulation. 2002;106:3009-3017

  31. LV Function Assessed by Analysis of LV Angiography in the Cell Therapy Group • Demonstrated potential beneficial effect of BSMC therapy following AMI with improvement in the LVEF from 51.6+ 9.6% to 60.1+8.6% at 4 months

  32. TOPCARE-AMI :Transplantation of Progenitor Cells and Regeneration Enhancement in AMI Left panel (A): LV angiography before CPC therapy Right panel (B): at 4-month follow-up Birgit Assmus et al. Circulation. 2002;106:3009-3017

  33. TOPCARE-AMI :Transplantation of Progenitor Cells and Regeneration Enhancement in AMI Echocardiographic wall motion score index at rest (initial basal) and during low-dose dobutamine stimulation (initial 10 g dobutamine) at baseline before progenitor cell therapy and at rest at 4-month follow-up (follow-up basal). Birgit Assmus et al. Circulation. 2002;106:3009-3017

  34. TOPCARE-AMI :Transplantation of Progenitor Cells and Regeneration Enhancement in AMI Birgit Assmus et al. Circulation. 2002;106:3009-3017

  35. BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST trial) Lancet 2004; 364: 141–48

  36. BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST trial) Lancet 2004; 364: 141–48

  37. BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST trial) Lancet 2004; 364: 141–48

  38. BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST trial) Lancet 2004; 364: 141–48

  39. BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST trial) • Representative colour-coded • images showing systolic wall • motion at baseline and 6 months' • follow-up in two patients. • Both patients had A/C AWMI. • Bright colours: good systolic • wall motion. • Dark colours : poor wall motion • (expressed in mm). • Note improved functional recovery • in patient treated with BMCs. Lancet 2004; 364: 141–48

  40. Reinfusion of Enriched Progenitor Cellsand Infarct Remodeling in Acute Myocardial Infarction(REPAIR-AMI) trial Enrollment and outcomes N Engl J Med 2006;355:1210-21.

  41. Reinfusion of Enriched Progenitor Cellsand Infarct Remodeling in Acute Myocardial Infarction(REPAIR-AMI) trial N Engl J Med 2006;355:1210-21.

  42. Reinfusion of Enriched Progenitor Cellsand Infarct Remodeling in Acute Myocardial Infarction(REPAIR-AMI) trial P value Placebo n=92 BMC n=95 N Engl J Med 2006;355:1210-21.

  43. Reinfusion of Enriched Progenitor Cellsand Infarct Remodeling in Acute Myocardial Infarction(REPAIR-AMI) trial N Engl J Med 2006;355:1210-21.

  44. Reinfusion of Enriched Progenitor Cellsand Infarct Remodeling in Acute Myocardial Infarction(REPAIR-AMI) trial Panel A: Interaction between baseline LVEF and the absolute change in LVEF Panel B: Interaction between the timing of intracoronary infusion of BMC or placebo after reperfusion therapy and the absolute change in LVEF N Engl J Med 2006;355:1210-21.

  45. Reinfusion of Enriched Progenitor Cellsand Infarct Remodeling in Acute Myocardial Infarction(REPAIR-AMI) trial Conclusion • Intracoronary administration of BMC is associated with improved • recovery of left ventricular contractile function in patients with acute • myocardial infarction N Engl J Med 2006;355:1210-21.

  46. Effects of I/C injection of mononuclear BMCs on LV function, arrhythmia risk profile, and restenosis after lytic therapy of AMI - FINCELL Investigators Aim: To assess the efficacy and safety of bone marrow cell (BMC) therapy after thrombolytic therapy of an acute STEMI Methods: Patients with STEMI treated with thrombolysis followed by PCI (2–6 days after STEMI ) Intracoronary BMCs (n= 40) placebo medium (n= 40) (collected & prepared 3–6 h prior PCI) Injected into the infarct artery immediately after stenting European Heart Journal (2008) 29, 2723–2732

  47. Effects of I/C injection of mononuclear BMCs on LV function, arrhythmia risk profile, and restenosis after lytic therapy of AMI - FINCELL Investigators • Efficacy assessed by : • measurement of global LVEF - LV angiography • - 2-D echo • Safety by measuring arrhythmia risk variables • Restenosis of the stented vessel by IVUS • At 6 months: • BMC group : greater absolute increase of global LVEF than placebo • (measured by angiography or 2-D echo) • No differences observed between the groups in • - adverse clinical events • - arrhythmia risk variables • - MLD of stented coronary lesion European Heart Journal (2008) 29, 2723–2732

  48. Effects of I/C injection of mononuclear BMCs on LV function, arrhythmia risk profile, and restenosis after lytic therapy of AMI

  49. Effects of I/C injection of mononuclear BMCs on LV function, arrhythmia risk profile, and restenosis after lytic therapy of AMI - FINCELL Investigators Conclusion : Intracoronary BMC therapy is associated with an improvement of global LVEF and neutral effects on arrhythmia risk profile and restenosis of the stented coronary lesions in patients after lytic therapy of STEMI European Heart Journal (2008) 29, 2723–2732

  50. RCTs with neutral findings • LEUVEN-AMI study1: • - No changes in global LVEF after BMSC infusion • ASTAMI trial2 : • - No significant effect on the LVEF, LV volumes, or infarct size • HEBE trial3 : • - No changes in global or regional LV systolic function • after BMSC therapy 1Janssens et al. Lancet 2006;367:113–21 2 Lunde K et al. N Eng J Med 2006;355:1199–209 3Alexander Hirsch et al. Eur Heart J 2010

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