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Atherosclerosis and its consequences (plaque rupture and


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Atherosclerosis and its consequences (plaque rupture and

  1. 1. Coronary Dialysis SystemCoronary Dialysis System  Atherosclerosis and its consequencesAtherosclerosis and its consequences  Atherosclerosis and inflammationAtherosclerosis and inflammation  Inflammatory markersInflammatory markers  The role of HDL and its apo A-1The role of HDL and its apo A-1  LDL aphaeresisLDL aphaeresis  Designed Coronary Dialysis SystemDesigned Coronary Dialysis System
  2. 2. Atherosclerosis and itsAtherosclerosis and its consequences (plaque rupture andconsequences (plaque rupture and thrombosis) are the leading causethrombosis) are the leading cause of morbidity and mortality in the USof morbidity and mortality in the US and other industrialized countriesand other industrialized countries
  3. 3. The exact mechanism ofThe exact mechanism of atherosclerosis is unknown, butatherosclerosis is unknown, but evidence suggest that lipoproteinevidence suggest that lipoprotein pathway, injury to the vessel wallpathway, injury to the vessel wall from various stimuli and responsefrom various stimuli and response to injury that include inflammatoryto injury that include inflammatory and immune system responseand immune system response seems to play key roles.seems to play key roles.
  4. 4. Major modes of plaqueMajor modes of plaque disruption:disruption: **The rupture (fracture) of theThe rupture (fracture) of the plaque’s fibrous cap accountingplaque’s fibrous cap accounting for some two thirds of ACSfor some two thirds of ACS **The second mode involves aThe second mode involves a superficial erosion of the intimasuperficial erosion of the intima
  5. 5. Based on Biochemical and EpidemiologicalBased on Biochemical and Epidemiological evidences:evidences: Atherosclerosis is an inflammatoryAtherosclerosis is an inflammatory diseasedisease
  6. 6. Although Acute phase reactantAlthough Acute phase reactant such as CRP is non-specific butsuch as CRP is non-specific but it is very sensitive marker ofit is very sensitive marker of inflammationinflammation
  7. 7. Prospective studies haveProspective studies have consistently demonstrated aconsistently demonstrated a positive association betweenpositive association between hs-CRP and the future coronaryhs-CRP and the future coronary eventsevents
  8. 8. CRP, is not only anCRP, is not only an epiphenomenon of atherosclerosisepiphenomenon of atherosclerosis but a casual relationship has beenbut a casual relationship has been suggested between CRP andsuggested between CRP and inflammatory reaction in the vesselinflammatory reaction in the vessel wallwall
  9. 9. Inflammatory roles of CRPInflammatory roles of CRP activation of complement pathwayactivation of complement pathway enhancement of thrombosisenhancement of thrombosis enhancement of tissue injuryenhancement of tissue injury chemo tactic for monocyteschemo tactic for monocytes facilitation uptake of LDL by MACfacilitation uptake of LDL by MAC induction of adhesion moleculesinduction of adhesion molecules impairment endothelial functionimpairment endothelial function
  10. 10. Each standard deviation increase inEach standard deviation increase in hs-CRP was associated with a 45%hs-CRP was associated with a 45% increase in the relative risk ofincrease in the relative risk of nonfatal MI or sudden cardiacnonfatal MI or sudden cardiac deathdeath
  11. 11. Increased plasma concentration ofIncreased plasma concentration of CRP can be modified by drugsCRP can be modified by drugs such as statins, which by it selfsuch as statins, which by it self reflects the anti inflammatory effect,reflects the anti inflammatory effect, by which only18% reduction ofby which only18% reduction of plasma CRP level can be achievedplasma CRP level can be achieved
  12. 12. Potential preventive therapies for highPotential preventive therapies for high CRP-levelCRP-level Although no specific therapies haveAlthough no specific therapies have been developed to decrease hs-CRPbeen developed to decrease hs-CRP **************************************** ButBut AspirinAspirin andand statinsstatins are effectiveare effective in decreasing the incidence of futurein decreasing the incidence of future coronary events in those with highcoronary events in those with high CRPCRP
  13. 13. These findings suggest:These findings suggest:  Aspirin is not only anti platelet agent butAspirin is not only anti platelet agent but also is an anti-inflammatoryalso is an anti-inflammatory  statins also my has anti-inflammatorystatins also my has anti-inflammatory characteristics in addition to its anti-hypercharacteristics in addition to its anti-hyper lipidemic potentiallipidemic potential
  14. 14. Meta analysis of five primary andMeta analysis of five primary and secondary trials demonstrated thatsecondary trials demonstrated that statin therapy reduces the risk ofstatin therapy reduces the risk of major coronary events by 31% andmajor coronary events by 31% and all cause mortality by 21%.all cause mortality by 21%.
  15. 15. Trials which focused primarily on LDL-Trials which focused primarily on LDL- C and its lowering modalities (dietaryC and its lowering modalities (dietary counseling, pharmacotherapy, life stylecounseling, pharmacotherapy, life style modification, and surgery) revealedmodification, and surgery) revealed only a relative risk reduction in CVonly a relative risk reduction in CV mortality of 20% to 40%, so theremortality of 20% to 40%, so there should be other potential reasons forshould be other potential reasons for CV events.CV events.
  16. 16. One such potential target is HDLOne such potential target is HDL and its apoprotein (Apo-A1).and its apoprotein (Apo-A1).
  17. 17. The protective role of HDL againstThe protective role of HDL against atherosclerosis is widely accepted andatherosclerosis is widely accepted and is generally attributed to reverseis generally attributed to reverse cholesterol transport, by which excesscholesterol transport, by which excess cholesterol in peripheral tissues ischolesterol in peripheral tissues is conveyed to the liver for excretionconveyed to the liver for excretion
  18. 18. Effects of HDL on endothelium.Effects of HDL on endothelium.
  19. 19. multiple biological actions of HDL as a potential basismultiple biological actions of HDL as a potential basis for anti-atherothrombotic actions.for anti-atherothrombotic actions.
  20. 20. Table 1. Anti-atherogenic and anti-thrombogenic properties of apo A-I
  21. 21. There is an inverse relation betweenThere is an inverse relation between HDL levels and coronary heart disease.HDL levels and coronary heart disease. There is a similar inverse relationThere is a similar inverse relation between HDL and restenosis afterbetween HDL and restenosis after PTCA.PTCA.
  22. 22. Every 1mg/dl increase in HDL isEvery 1mg/dl increase in HDL is associated with a 2% to 3% lowerassociated with a 2% to 3% lower risk of CAD. Also there is inverserisk of CAD. Also there is inverse relationship between the level ofrelationship between the level of APOA-1 and CAD.APOA-1 and CAD.
  23. 23. Experimental studies have shownExperimental studies have shown that intravenous injection of HDL,that intravenous injection of HDL, inhibited the progression andinhibited the progression and induced regression of early aorticinduced regression of early aortic fatty streaks in cholesterol fedfatty streaks in cholesterol fed rabbitrabbit
  24. 24. In another experimental studyIn another experimental study similar results were achieved insimilar results were achieved in cholesterol fed rabbit receivingcholesterol fed rabbit receiving intravenous apo A-1.intravenous apo A-1.
  25. 25. Intravenous HDL containingIntravenous HDL containing recombinant apoA-1milano alsorecombinant apoA-1milano also showed to prevent progressionshowed to prevent progression or promote regression of aorticor promote regression of aortic atherosclerosis in apoE-nullatherosclerosis in apoE-null micemice
  26. 26. In another experimental study inIn another experimental study in apoE-deficient mice with advancedapoE-deficient mice with advanced atherosclerotic lesion elevatingatherosclerotic lesion elevating HDL-C remodel the plaque byHDL-C remodel the plaque by decreasing MAC and increasingdecreasing MAC and increasing SMCSMC
  27. 27. NOW:NOW: It is the time of development,It is the time of development, implementation, and clinical trials ofimplementation, and clinical trials of this new frontier anti -atherogenicthis new frontier anti -atherogenic policy.policy.
  28. 28. Demonstration of the effect of the apoA-Demonstration of the effect of the apoA- 1milano on aorta of apo E deficient mice1milano on aorta of apo E deficient mice
  29. 29. Effect of apo A-1milano/PC, PC-free apo A-1milano, and PC onlyEffect of apo A-1milano/PC, PC-free apo A-1milano, and PC only on cholesterol efflux, expressed as fraction released per 4 hourson cholesterol efflux, expressed as fraction released per 4 hours
  30. 30. EKO mice were fed WD for 6 months to developEKO mice were fed WD for 6 months to develop advanced lesions in thoracic aortaadvanced lesions in thoracic aorta
  31. 31. Histological appearances of atherosclerotic lesions in experimentalHistological appearances of atherosclerotic lesions in experimental groupsgroups
  32. 32. Smooth muscle -actin content of atherosclerotic lesions inSmooth muscle -actin content of atherosclerotic lesions in experimental groupsexperimental groups..
  33. 33. Macrophage content of atherosclerotic lesions in experimentalMacrophage content of atherosclerotic lesions in experimental groupsgroups
  34. 34. Content of macrophage-related products inContent of macrophage-related products in atherosclerotic lesions in experimental groupsatherosclerotic lesions in experimental groups
  35. 35. NO standard treatment has beenNO standard treatment has been established for patient who continues toestablished for patient who continues to maintain LDL-c level in excess of 160 mg/dlmaintain LDL-c level in excess of 160 mg/dl after diet and drug therapy. To date therapyafter diet and drug therapy. To date therapy has consisted of a variety of measureshas consisted of a variety of measures including combination drug therapy,including combination drug therapy, plasmapheresis, and partial ileal by passplasmapheresis, and partial ileal by pass and even liver transplantation.and even liver transplantation.
  36. 36. The LDL aphaeresis wasThe LDL aphaeresis was developed to provide therapy fordeveloped to provide therapy for patients who fail to responds topatients who fail to responds to provided therapy especiallyprovided therapy especially when patients who have existingwhen patients who have existing CAD.CAD.
  37. 37. Treatment efficacy result of LDL aphaeresisTreatment efficacy result of LDL aphaeresis weeklyweekly BeforeBefore AfterAfter ChangeChange ChangeChange MeanMean mg/dlmg/dl MeanMean mg/dlmg/dl MeanMean mg/dlmg/dl Percent%Percent% Total-CTotal-C 287287 144144 -134-134 -47-47 LDL-CLDL-C 200200 8989 -111-111 -54-54 Apolipo-BApolipo-B 164164 7676 -88-88 -52-52 TriglycerideTriglyceride 188188 9898 -90-90 -49-49 HDL-CHDL-C 4242 3636 -6-6 -14-14 Apo A-1Apo A-1 123123 100100 -22-22 -18-18 FibrinogenFibrinogen 270270 112112 -158-158 -58-58
  38. 38. Weekly vs. biweekly parameter changesWeekly vs. biweekly parameter changes Pre-Pre- treatment(%)treatment(%) Post-Post- treatment(%)treatment(%) Change (mg/dl)Change (mg/dl) Change (%)Change (%) LDL-CLDL-C 202202 242242 9191 104104 -111-111 -138-138 -53-53 -55-55 Total-CTotal-C 277277 318318 144144 156156 -133-133 -161-161 -47-47 -49-49 Apolipo-BApolipo-B 170170 184184 7777 8080 -92-92 -104-104 -53-53 -56-56 HDL-CHDL-C 4141 4040 3535 3434 -6-6 -6-6 -15-15 -15-15 Apo A-1Apo A-1 118118 119 9797 100 -22-22 -19 -18-18 -16
  39. 39. Effect of 31 LDL aphaeresis treatments onEffect of 31 LDL aphaeresis treatments on CRP and low density cholesterol (LDL)CRP and low density cholesterol (LDL) concentrations in serum of 13 CHD patientsconcentrations in serum of 13 CHD patients VariableVariable BeforeBefore aphaeresisaphaeresis AfterAfter aphaeresisaphaeresis P valueP value CRPCRP (mg/dl)(mg/dl) 3.093.09 1.071.07 <0.001<0.001 LDL-CLDL-C (mmol/l)(mmol/l) 5.05.0 1.81.8 <0.001<0.001
  40. 40. Six-month trend analysis of pre- and post-Six-month trend analysis of pre- and post- treatmenttreatment hs-CRPhs-CRP levels for four patients onlevels for four patients on chronic LDL apheresis therapy.chronic LDL apheresis therapy. 6-month6-month
  41. 41. Change in lipid, fibrinogen, CRP across 6 months of LDLChange in lipid, fibrinogen, CRP across 6 months of LDL aphaeresisaphaeresis Parameter (mg/dl)Parameter (mg/dl) BaselineBaseline Mean decrease perMean decrease per treatment(%)treatment(%) change afterchange after 6months(%)6months(%) Total-CTotal-C 359 +/-77359 +/-77 56%56% -5%-5% LDL-CLDL-C 275 +/-69275 +/-69 64%64% -9%-9% HDL-CHDL-C 46 +/-1446 +/-14 25%25% +12%+12% TriglycerideTriglyceride 190 +/-64190 +/-64 34%34% +8%+8% FibrinogenFibrinogen 332 +/-46332 +/-46 65%65% -25%-25% CRPCRP 9 +/-89 +/-8 64%64% -49%-49%
  42. 42. Effects of a single dose therapyEffects of a single dose therapy Variables saline DPPC ApoA-1mVariables saline DPPC ApoA-1m Before treatmentBefore treatment Total-CTotal-C 818+/_126818+/_126 729+/_199729+/_199 696+/_312696+/_312 1 hour after1 hour after Total-CTotal-C 703+/_131703+/_131 993+/_352993+/_352 1377+/_3451377+/_345 48 hour after48 hour after Total-CTotal-C 621+/_158621+/_158 656+/_190656+/_190 1085+/-2631085+/-263 Cholesterol efflux%Cholesterol efflux% At 1 hourAt 1 hour 25+/_325+/_3 18+/_218+/_2 40+/_340+/_3 Plaque lipid contentPlaque lipid content % at 48 hour% at 48 hour 19.6+/_6.319.6+/_6.3 18.1+/_4.718.1+/_4.7 10.1+/_4.210.1+/_4.2 Plaque macrophagePlaque macrophage %content at 48 hour%content at 48 hour 10.4+/_3.410.4+/_3.4 9.3+/_5.89.3+/_5.8 6.4+/_2.06.4+/_2.0
  43. 43. Heparin-induced exteracoporealHeparin-induced exteracoporeal LDL-PrecipitationLDL-Precipitation Other co-precipitated plasma proteins :Other co-precipitated plasma proteins : 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
  44. 44. Safety-adverse eventsSafety-adverse events No=23 ptsNo=23 pts Total no. ofTotal no. of eventsevents NumberNumber weekly(575weekly(575 treatments)treatments) Number biNumber bi weekly(276weekly(276 treatments)treatments) Access problemAccess problem 3131 2020 44 HypotensionHypotension 2020 1010 44 FatigueFatigue 88 22 22 Prolonged PTT orProlonged PTT or ACTACT 77 77 00 ChillsChills 55 33 22 NauseaNausea 44 22 00 FeverFever 33 11 11 DizzinessDizziness 33 22 00 AcheAche 22 00 11
  45. 45. GOALGOAL Integration of:Integration of:  LDL aphaeresisLDL aphaeresis::  Decrease LDLDecrease LDL  Decrease CRPDecrease CRP  Decrease apo(a)Decrease apo(a)  Decrease fibrinogenDecrease fibrinogen  Decrease cytokinesDecrease cytokines  Local TherapyLocal Therapy::  High dose HDLHigh dose HDL  Chelating agentsChelating agents  Gene deliveryGene delivery  ThermotherapyThermotherapy
  46. 46. The coronary dialysis systemThe coronary dialysis system
  47. 47. The coronary dialysis systemThe coronary dialysis system