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  1. 1. Heart dialysis systemHeart dialysis system  Studying the effect of systemic apoA-1 treatmentStudying the effect of systemic apoA-1 treatment on carotid atherosclerotic plaqueon carotid atherosclerotic plaque  Studying the effect of LDL aphaeresis on LDL,Studying the effect of LDL aphaeresis on LDL, plasma inflammatory markers, and cytokinesplasma inflammatory markers, and cytokines  comparing the effect of local high dose of apoA1comparing the effect of local high dose of apoA1 on atherosclerotic plaque versus systemic therapyon atherosclerotic plaque versus systemic therapy  Comparing the effect of single therapy versusComparing the effect of single therapy versus multiple therapymultiple therapy
  2. 2. Animal studyAnimal study  25 Rabbits25 Rabbits  Cholesterol fed diet (1%)Cholesterol fed diet (1%)  Inducing vascular injury in carotid arteriesInducing vascular injury in carotid arteries  Systemic LDL aphaeresisSystemic LDL aphaeresis  Systemic apoA-1 administrationSystemic apoA-1 administration  Local apoA-1 administrationLocal apoA-1 administration  Studying the effect of apoA-1 on plaque asStudying the effect of apoA-1 on plaque as well as lipid profilewell as lipid profile  Studying the effect of LDL aphaeresis onStudying the effect of LDL aphaeresis on lipid profilelipid profile
  3. 3. Heart Dialysis System In RabbitsHeart Dialysis System In Rabbits 25 (wattanabe) rabbits 1%Cholesterol fed diet Control group: No treatment N#10 Systemic treatment: LDL aphaeresis Systemic apoA1 Local treatment: of apoA1 Systemic LDL aphaeresis Single session therapy N#5 Sacrified after 48 h N#5 Sacrified after 6th w Weekly for 5 w Sacrified at 6th w Sacrified at 6th w N#10N#5
  4. 4. Treatment modalitiesTreatment modalities  Apo A-1m 40 mg/doseApo A-1m 40 mg/dose  Phosphatidylcholine 120 mg/dosePhosphatidylcholine 120 mg/dose  LDL aphaeresisLDL aphaeresis
  5. 5. Measured indicesMeasured indices Biochemical measurementsBiochemical measurements Lipid profileLipid profile LDL, HDL, and TGLDL, HDL, and TG CRPCRP Lp(a)Lp(a) FibrinogenFibrinogen PlasminogenPlasminogen Anti-thrombinAnti-thrombin C3, C4, C1 inhibitorC3, C4, C1 inhibitor Interlukin-1Interlukin-1 TNF alphaTNF alpha EdotoxinsEdotoxins FerritinFerritin CD 14CD 14 Tissue factorTissue factor Before, 1 h, 6h, 24h after treatmentBefore, 1 h, 6h, 24h after treatment Histological studyHistological study Intimal thichnessIntimal thichness Intima/medail ratioIntima/medail ratio Lipid content of the plaqueLipid content of the plaque Macrophage content of theMacrophage content of the plaqueplaque Smooth muscle cell of polaqueSmooth muscle cell of polaque
  6. 6. Local infusion of ApoA-1m in toLocal infusion of ApoA-1m in to carotid artery of rabbitcarotid artery of rabbit  25 rabbits25 rabbits  1.5% cholesterol diet for 90 days1.5% cholesterol diet for 90 days  Perivascular electrical injuryPerivascular electrical injury  G1:salineG1:saline  G2:phospholipid vesicleG2:phospholipid vesicle  G3,4,5:Apo A-1m :250-500-1000 mgG3,4,5:Apo A-1m :250-500-1000 mg  Local delivery through IVUS catheterLocal delivery through IVUS catheter  Ninety minutes infusionNinety minutes infusion Giulia ChiesaGiulia Chiesa
  7. 7. plaque lipid contentplaque lipid content Right carotid Left carotidRight carotid Left carotid Saline 85.30±8.06 80.70±7.14Saline 85.30±8.06 80.70±7.14 DPPC 83.74±6.19 71.34±15.16DPPC 83.74±6.19 71.34±15.16 AIM 250 75.45±7.83 70.62±10.87AIM 250 75.45±7.83 70.62±10.87 AIM 500 64.21±2.60 61.56±4.01AIM 500 64.21±2.60 61.56±4.01 AIM 1000 53.30±10.18 51.82±6.87AIM 1000 53.30±10.18 51.82±6.87 Giulia ChiesaGiulia Chiesa
  8. 8. Study protocolStudy protocol IVUS study 0, 30m, 60m, 90mIVUS study 0, 30m, 60m, 90m Blood sample 0, 45,90m , 6,24,48,72hBlood sample 0, 45,90m , 6,24,48,72h Histologic examination on both carotidsHistologic examination on both carotids Giulia ChiesaGiulia Chiesa
  9. 9. Plasma HDL 72 h after infusionPlasma HDL 72 h after infusion Giulia ChiesaGiulia Chiesa
  10. 10. Plaque areaPlaque area Giulia ChiesaGiulia Chiesa
  11. 11. Inhibition of carotid intimal thickening by apoA-1mInhibition of carotid intimal thickening by apoA-1m in rabbitsin rabbits  New Zealand white rabbitsNew Zealand white rabbits  1% cholesterol-fed1% cholesterol-fed  Flexible collar application at 21Flexible collar application at 21stst dayday of dietof diet  EPC+A-1m(119+40mg)EPC+A-1m(119+40mg) EPC(119mg)EPC(119mg) Maurizio and SomaMaurizio and Soma
  12. 12. Study protocolStudy protocol Maurizio andMaurizio and SomaSoma NZWR 1% cholesterol diet EPC+A-!m EPC control Significant intimal thickening Drug before injury Sig decrease in intima Drug the day of injury No sig change No decrease in intima
  13. 13. Effect of various regimensEffect of various regimens Maurizio and SomaMaurizio and Soma I/M ratio Control 0.63+/-o.11 EPC treated 0.50+/-0.14 A-1m treated 0.26+/-0.19
  14. 14. Reduction of intima thickening inReduction of intima thickening in hypercholesterolemic rabbithypercholesterolemic rabbit  1% Cholesterol fed rabbits1% Cholesterol fed rabbits  Balloon injured ileofemoral arteriesBalloon injured ileofemoral arteries  G1: apoA-1m+phospholipidG1: apoA-1m+phospholipid  G2: phospholipidG2: phospholipid  G3: controlG3: control PK Shah et allPK Shah et all
  15. 15. Intimal thicknessIntimal thickness PK Shah et allPK Shah et all Control 1.69+/-0.43 mm2 Carrier treated 1.14+/-0.38 mm2 A-1m treated o.49+/-0.29 mm2
  16. 16. Intima-Media RatioIntima-Media Ratio  Control:2.1+/-0.1Control:2.1+/-0.1  Carrier :1.5+/-0.5Carrier :1.5+/-0.5  Apo1-A:0.7+/-0.2Apo1-A:0.7+/-0.2 PK Shah et allPK Shah et all
  17. 17. Intimal lesion covered by macrophagesIntimal lesion covered by macrophages  Carrier treated:59.3+/-12.3%Carrier treated:59.3+/-12.3%  ApoA-1 treated:25.3+/-17%ApoA-1 treated:25.3+/-17% PK Shah et allPK Shah et all
  18. 18. conclusionconclusion Apo A-1m significantlyApo A-1m significantly Reduces intimal thickeningReduces intimal thickening Reduces macrophage contentReduces macrophage content PK Shah et allPK Shah et all
  19. 19. ApoA-1m in EKO miceApoA-1m in EKO mice  EKO mice fed with high cholesterolEKO mice fed with high cholesterol  G1:Control(saline treated)G1:Control(saline treated)  G2:Carrier (Phosphatidylcholine)G2:Carrier (Phosphatidylcholine)  G3:Apoa-1 treated+phospholipidG3:Apoa-1 treated+phospholipid PK ShahPK Shah
  20. 20. ResultsResults  1.6-fold increase in tissue cholesterol1.6-fold increase in tissue cholesterol mobilization in apoA-1 groupmobilization in apoA-1 group  40%-50% decrease in plaque lipid40%-50% decrease in plaque lipid content in apoA-1 groupcontent in apoA-1 group  29%-36% decease in macrophage29%-36% decease in macrophage content in apoA-1 groupcontent in apoA-1 group PK Shah et allPK Shah et all