Atherosclerosis is a leading cause of death worldwide. It is a systemic inflammatory disease involving the buildup of plaque in artery walls. Inflammatory markers like C-reactive protein are associated with future coronary events. The authors describe a Cardiac Dialysis System designed to specifically target and remove inflammatory markers from the bloodstream to stabilize vulnerable plaques and prevent acute cardiac events like heart attack.

1. Hossein Eftekhari, MDHossein Eftekhari, MD
Morteza Naghavi, MDMorteza Naghavi, MD

2. Cardiac Dialysis SystemCardiac Dialysis System
 Atherosclerosis and its consequencesAtherosclerosis and its consequences
 Atherosclerosis and inflammationAtherosclerosis and inflammation
 Inflammatory markersInflammatory markers
 Designed Cardiac Dialysis SystemDesigned Cardiac Dialysis System

3. Atherosclerotic cardiovascular diseases is
the leading cause of mortality with over 6.3
million deaths worldwide.
Every year about 1.5 million people in the
United States have heart attacks and more
than half of them die.

4. Mechanisms involved inMechanisms involved in
atherosclerosis:atherosclerosis:
Lipoprotein pathwayLipoprotein pathway
Injury to the vessel wallInjury to the vessel wall
Response to injury includingResponse to injury including
inflammatory and immune systeminflammatory and immune system

5. Atherosclerosis and its consequencesAtherosclerosis and its consequences
((plaque ruptureplaque rupture andand thrombosisthrombosis) are) are
the leading cause of morbidity andthe leading cause of morbidity and
mortality in the US and othermortality in the US and other
industrialized countriesindustrialized countries

6. ATHEROSCLEROSIS IS AATHEROSCLEROSIS IS A
SYSTEMIC DISEASESYSTEMIC DISEASE
BUTBUT
CORONARY ARTERY DISEASECORONARY ARTERY DISEASE
IS THE #IS THE # 11 KILLER OF HUMANKILLER OF HUMAN
BEINGBEING

7. Some of the characteristics ofSome of the characteristics of
atherosclerosisatherosclerosis
 Inflammatory diseaseInflammatory disease
 Slowly progressive diseaseSlowly progressive disease
 Diffuse disease (multi organ involvement)Diffuse disease (multi organ involvement)

8. Coronary Vulnerable Plaque
Killer #1
So, the more specific diagnostic and
therapeutic method the more
effective

10. Proposed Histopathological andProposed Histopathological and
Clinical Criteria for Definition ofClinical Criteria for Definition of
Vulnerable PlaqueVulnerable Plaque
•• MajorMajor Criteria:Criteria:
• Active Inflammation (monocyte/Active Inflammation (monocyte/
macrophage infiltration)macrophage infiltration)
• Thin Cap with Large Lipid CoreThin Cap with Large Lipid Core
• Endothelial Denudation with SuperficialEndothelial Denudation with Superficial
Platelet AggregationPlatelet Aggregation
• Fissured / Wounded PlaqueFissured / Wounded Plaque

11. Proposed Histopathological andProposed Histopathological and
Clinical Criteria for Definition ofClinical Criteria for Definition of
Vulnerable PlaqueVulnerable Plaque
•• MinorMinor Criteria:Criteria:
• Superficial Calcified noduleSuperficial Calcified nodule
• Glistening YellowGlistening Yellow
• Intraplaque HemorrhageIntraplaque Hemorrhage
• Critical StenosisCritical Stenosis
• Positive Remodeling?Positive Remodeling?

12. Major modes of plaqueMajor modes of plaque
disruption:disruption:
**TheThe rupturerupture (fracture) of the(fracture) of the
plaque’s fibrous cap accounting forplaque’s fibrous cap accounting for
some two thirds of ACSsome two thirds of ACS
**The second mode involves aThe second mode involves a
superficial erosionsuperficial erosion of the intimaof the intima

15. Blood FactorBlood Factor
 Antithrombin III deficiencyAntithrombin III deficiency
 Protein C or S deficiencyProtein C or S deficiency
 Resistance to activated protein C (factor VResistance to activated protein C (factor V
Leiden)Leiden)
 Antiphospholipid syndromeAntiphospholipid syndrome
 Nephrotic syndromeNephrotic syndrome
 Platelet polymorphismsPlatelet polymorphisms

16. Myocardial FactorMyocardial Factor
 Different cardiomyopathiesDifferent cardiomyopathies
 Valvular diseaseValvular disease
 Primary electric disturbancesPrimary electric disturbances
 Chest traumaChest trauma
 Anomalous origin of coronary arteriesAnomalous origin of coronary arteries
 MyocarditisMyocarditis
 Myocardial bridgingMyocardial bridging

17. Plaque stabilization strategiesPlaque stabilization strategies
 StatinsStatins
 Anti-inflammatory agentsAnti-inflammatory agents
 ACE inhibitorACE inhibitor
 HDLHDL
 Coated stentsCoated stents
 Gene therapyGene therapy
 Thermal stabilizationThermal stabilization

18. statinsstatins
 StatinStatin therapy reduces the risk of majortherapy reduces the risk of major
coronary events by 31%coronary events by 31%
 Patients intolerancePatients intolerance
 Systemic side effectsSystemic side effects

19. Stent limitationStent limitation
 Re-stenosisRe-stenosis
 Inaccessibility of lesions (more than 50%)Inaccessibility of lesions (more than 50%)
 More than one stent may be neededMore than one stent may be needed
 High costHigh cost

20. Based on Biochemical and EpidemiologicalBased on Biochemical and Epidemiological
evidencesevidences
Atherosclerosis is an inflammatory diseaseAtherosclerosis is an inflammatory disease

21. Although Acute phase reactantAlthough Acute phase reactant
such assuch as CRPCRP is non-specific but itis non-specific but it
is very sensitive marker ofis very sensitive marker of
inflammationinflammation

22. Prospective studies haveProspective studies have
consistently demonstrated aconsistently demonstrated a
positive association between hs-positive association between hs-
CRPCRP and the future coronary eventsand the future coronary events

23. Each standard deviation increase in hs-Each standard deviation increase in hs-
CRPCRP was associated with a 45%was associated with a 45%
increase in the relative risk of nonfatalincrease in the relative risk of nonfatal
MI or cardiac deathMI or cardiac death

24. CRPCRP is not only an epiphenomenonis not only an epiphenomenon
A casual relationship has beenA casual relationship has been
suggested betweensuggested between CRPCRP andand
inflammatory reaction in the vesselinflammatory reaction in the vessel
wallwall

25. Inflammatory roles ofInflammatory roles of
CRPCRP
Activation of complement pathwayActivation of complement pathway
Enhancement of thrombosisEnhancement of thrombosis
Enhancement of tissue injuryEnhancement of tissue injury
Chemotactic for monocytesChemotactic 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

28. Potential preventive therapies forPotential preventive therapies for
high CRP-levelhigh CRP-level
Although no specific therapies have beenAlthough no specific therapies have been
developed to decreasedeveloped to decrease hs-CRPhs-CRP
****************************************
ButBut AspirinAspirin andand statinsstatins are effective inare effective in
decreasing the incidence of future coronarydecreasing the incidence of future coronary
events in those with highevents in those with high CRPCRP

29. CRPCRP level can be modified bylevel can be modified by
statins, which reflects the antistatins, which reflects the anti
inflammatory effect by 18%inflammatory effect by 18%
reduction of plasmareduction of plasma CRPCRP

31. These findings suggest:These findings suggest:
 Statins also may has anti-inflammatoryStatins also may has anti-inflammatory
characteristics in addition to its anti-hypercharacteristics in addition to its anti-hyper
lipidemic potentiallipidemic potential
 Aspirin is not only anti platelet agent but alsoAspirin is not only anti platelet agent but also
is an anti-inflammatoryis an anti-inflammatory

32. StatinStatin therapy reduces the risk oftherapy reduces the risk of
major coronary events bymajor coronary events by
31%,all cause mortality by 21%31%,all cause mortality by 21%

33. Focusing primarily on LDL-CFocusing primarily on LDL-C
lowering revealed only 20% to 40%lowering revealed only 20% to 40%
relative risk reduction in CV mortalityrelative risk reduction in CV mortality
so there should be other potentialso there should be other potential
reasons for CV events.reasons for CV events.

34. NO standard treatment has been established forNO standard treatment has been established for
patient who continues to maintain LDL-c levelpatient who continues to maintain LDL-c level
in excess of 160 mg/dl after diet and drugin excess of 160 mg/dl after diet and drug
therapy.therapy.
To date therapy has consisted of a variety ofTo date therapy has consisted of a variety of
measures including combination drug therapy,measures including combination drug therapy,
plasmapheresis, and partial ileal by pass andplasmapheresis, and partial ileal by pass and
even liver transplantation.even liver transplantation.

35. NOW!NOW! It is the time of developing,It is the time of developing,
implementing, and clinical trials ofimplementing, and clinical trials of
new frontier anti -atherogenic policynew frontier anti -atherogenic policy

36. TheThe LDL aphaeresisLDL aphaeresis waswas
developed to provide therapy fordeveloped to provide therapy for
patients who fail to responds topatients who fail to responds to
provided therapy especially whenprovided therapy especially when
patients who have existing CADpatients who have existing CAD

37. 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
Adhesion moleculesAdhesion molecules
C3, C4, C1 inhibitorC3, C4, C1 inhibitor
ChemokinesChemokines
Interlukin-1Interlukin-1
TNF alphaTNF alpha
EdotoxinsEdotoxins
FerritinFerritin
CD 40LCD 40L

38. Treatment efficacy result of LDL aphaeresisTreatment efficacy result of LDL aphaeresis
-58-58-158-158112112270270FibrinogenFibrinogen
-18-18-22-22100100123123Apo A-1Apo A-1
-14-14-6-636364242HDL-CHDL-C
-49-49-90-909898188188TriglycerideTriglyceride
-52-52-88-887676164164Apolipo-BApolipo-B
-54-54-111-1118989200200LDL-CLDL-C
-47-47-134-134144144287287Total-CTotal-C
Percent%Percent%MeanMean mg/dlmg/dlMeanMean mg/dlmg/dlMeanMean mg/dlmg/dl
ChangeChangeChangeChangeAfterAfterBeforeBeforeweeklyweekly

39. Weekly vs. biweekly parameter changesWeekly vs. biweekly parameter changes
-18-18
-16-16
-22-22
-19-19
9797
100100
118118
119119
Apo A-1Apo A-1
-15-15
-15-15
-6-6
-6-6
3535
3434
4141
4040
HDL-CHDL-C
-53-53
-56-56
-92-92
-104-104
7777
8080
170170
184184
Apolipo-BApolipo-B
-47-47
-49-49
-133-133
-161-161
144144
156156
277277
318318
Total-CTotal-C
-53-53
-55-55
-111-111
-138-138
9191
104104
202202
242242
LDL-CLDL-C
Change (%)Change (%)Change (mg/dl)Change (mg/dl)Post-Post-
treatment(%)treatment(%)
Pre-Pre-
treatment(%)treatment(%)

40. Effect of 31 LDL aphaeresis treatments onEffect of 31 LDL aphaeresis treatments on
CRPCRP and low density cholesterol (LDL)and low density cholesterol (LDL)
concentrations in serum of 13 CHD patientsconcentrations in serum of 13 CHD patients
<0.001<0.0011.81.85.05.0LDL-CLDL-C
(mmol/l)(mmol/l)
<0.001<0.0011.071.073.093.09CRPCRP
(mg/dl)(mg/dl)
P valueP valueAfterAfter
aphaeresisaphaeresis
BeforeBefore
aphaeresisaphaeresis
VariableVariable

41. Six-month trend analysis of pre- andSix-month trend analysis of pre- and
post-treatmentpost-treatment hs-CRPhs-CRP levels for fourlevels for four
patients on chronic LDL apheresispatients on chronic LDL apheresis
therapy.therapy.
6-month6-month

42. Time course of CRP and LDL recoverTime course of CRP and LDL recover
between H.E.L.Pbetween H.E.L.P E.WielandE.Wieland

43. Change in lipid, fibrinogenChange in lipid, fibrinogen,, CRPCRP across 6 months of LDLacross 6 months of LDL
aphaeresisaphaeresis
-49%-49%64%64%9 +/-89 +/-8CRPCRP
-25%-25%65%65%332 +/-46332 +/-46FibrinogenFibrinogen
+8%+8%34%34%190 +/-64190 +/-64TriglycerideTriglyceride
+12%+12%25%25%46 +/-1446 +/-14HDL-CHDL-C
-9%-9%64%64%275 +/-69275 +/-69LDL-CLDL-C
-5%-5%56%56%359 +/-77359 +/-77Total-CTotal-C
change afterchange after
6months(%)6months(%)
Mean decrease perMean decrease per
treatment(%)treatment(%)
BaselineBaselineParameter (mg/dl)Parameter (mg/dl)

44. How to increase the efficiency ofHow to increase the efficiency of
LDL aphaeresis machine?LDL aphaeresis machine?
 Increasing the spectrum of its clinical useIncreasing the spectrum of its clinical use
 Implementing other techniques for IncreasingImplementing other techniques for Increasing
its capacity to remove more harmful factorsits capacity to remove more harmful factors
from plasmafrom plasma

45. CLINICALAPPLICATION OF LDLCLINICALAPPLICATION OF LDL
APHAERESISAPHAERESIS
Acute coronary syndromeAcute coronary syndrome
Chronic coronary artery diseaseChronic coronary artery disease

46. CLINICAL TRIALCLINICAL TRIAL
Inclusion criteria:Inclusion criteria:
Acute coronary syndromeAcute coronary syndrome
Unstable anginaUnstable angina
Acute myocardial infarctionAcute myocardial infarction
Anti ischemic treatmentAnti ischemic treatment
LDL-C> 200 mg/dlLDL-C> 200 mg/dl

47. End pointsEnd points
Primary end point:Primary end point:
MACEMACE
Secondary end points:Secondary end points:
Lipid profileLipid profile
CRPCRP
FibrinogenFibrinogen
Tissue factorTissue factor
CytokinesCytokines
IL-1, IL-6IL-1, IL-6
TNFTNF
CD40/LCD40/L

48. CLINICAL TRIALCLINICAL TRIAL
Patient with ACS
HELP + Statin Statin
One HELP therapy Weekly HELP for 4w
MACE
Biochemical changes
MACE
Biochemical changes
MACE
Biochemical changes

49. Safety-adverse eventsSafety-adverse events
110022AcheAche
002233DizzinessDizziness
111133FeverFever
002244NauseaNausea
223355ChillsChills
007777Prolonged PTT orProlonged PTT or
ACTACT
222288FatigueFatigue
4410102020HypotensionHypotension
4420203131Access problemAccess problem
Number biNumber bi
weekly(276weekly(276
treatments)treatments)
NumberNumber
weekly(575weekly(575
treatments)treatments)
Total no. ofTotal no. of
eventsevents
No=23 ptsNo=23 pts