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Pancoronary Therapy withPancoronary Therapy with
Intrapericardial Drug DeliveryIntrapericardial Drug Delivery
Sergio Waxma...
Case HistoryCase History
60%
50%
50%
60%
Coronary angiogramCoronary angiogram
40%
80%
95%
Treatment planTreatment plan
 Stenting of 2 “tightest” lesions in RCAStenting of 2 “tightest” lesions in RCA
 Aggressive...
But… what about those lesions leftBut… what about those lesions left
behind?behind?
 2.5 to 3.5 non-culprit TCFA’s per MI...
Treatment Paradigms for VPTreatment Paradigms for VP
 SystemicSystemic
 OralOral
 IntravenousIntravenous
 LocalLocal
...
Rationale for IP Drug Delivery forRationale for IP Drug Delivery for
Local Cardiac TherapyLocal Cardiac Therapy
 Natural ...
Rationale for IP DeliveryRationale for IP Delivery
 Therefore, it should be possible to:Therefore, it should be possible ...
Pericardial FluidPericardial Fluid
May Be More than Just An Innocent BystanderMay Be More than Just An Innocent Bystander
...
Elevated bFGF in Pericardial Fluid ofElevated bFGF in Pericardial Fluid of
Patients with Unstable AnginaPatients with Unst...
Delayed Clearance of RadiolabeledDelayed Clearance of Radiolabeled
Agents from Pericardial Space: SizeAgents from Pericard...
Residual Radioactivity FollowingResidual Radioactivity Following
Delivery ofDelivery of 131131
I-labeled NONO-albuminI-lab...
Persistent coronary vasodilatation induced byPersistent coronary vasodilatation induced by
intrapericardial nitroglycerini...
Higher Concentrations AchievedHigher Concentrations Achieved
with Pericardial vs IV Deliverywith Pericardial vs IV Deliver...
Fractional intramuralFractional intramural deliverydelivery andand retentionretention inin
the coronary artery ofthe coron...
Inhibition of neointima formation withInhibition of neointima formation with
intrapericardial paclitaxel after balloon ove...
VEGF levels following intrapericardialVEGF levels following intrapericardial
adenoviral-mediated gene transferadenoviral-m...
Pericardially delivered EPC Migrate toPericardially delivered EPC Migrate to
Areas of Ischemic MyocardiumAreas of Ischemic...
Intrapericardial drug delivery:Intrapericardial drug delivery:
Potential pancoronary therapeutic applicationsPotential pan...
How do we get there?How do we get there?
 Direct surgical approachDirect surgical approach
 ““Outside” inOutside” in
 S...
PerduCer™ device for intrapericardialPerduCer™ device for intrapericardial
accessaccess
Courtesy of Comedicus Inc.
Transventricular pericardial access usingTransventricular pericardial access using
a helical tipped cathetera helical tipp...
Transatrial Access into Pericardial SpaceTransatrial Access into Pericardial Space
Verrier, Waxman, et al, Circulation 199...
Transatrial Access into Pericardial SpaceTransatrial Access into Pericardial Space
 Guide positioning inGuide positioning...
Transatrial Access into Pericardial SpaceTransatrial Access into Pericardial Space
 Advancement of infusionAdvancement of...
Implantable chronic deliveryImplantable chronic delivery
systems?systems?
Use of polymers in the pericardial space for drugUse of polymers in the pericardial space for drug
deliverydelivery
Waxman...
ConclusionsConclusions
 The pericardial space may be an appropriate platformThe pericardial space may be an appropriate p...
Intrapericardial DeliveryIntrapericardial Delivery
ChallengesChallenges
 What agents?What agents?
 How practical is it? ...
AcknowledgementsAcknowledgements
 Center for TranslationalCenter for Translational
Cardiovascular Research, Tufts-Cardiov...
Distribution ofDistribution of 125125
I bFGF after 5 differentI bFGF after 5 different
routes of deliveryroutes of deliver...
Luciferase expression at 3 days following geneLuciferase expression at 3 days following gene
transfer with intrapericardia...
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Pancoronary therapy with ipdd

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Pancoronary therapy with ipdd

  1. 1. Pancoronary Therapy withPancoronary Therapy with Intrapericardial Drug DeliveryIntrapericardial Drug Delivery Sergio Waxman, M.D. Lahey Clinic Medical Center Tufts University School of Medicine
  2. 2. Case HistoryCase History 60% 50% 50% 60%
  3. 3. Coronary angiogramCoronary angiogram 40% 80% 95%
  4. 4. Treatment planTreatment plan  Stenting of 2 “tightest” lesions in RCAStenting of 2 “tightest” lesions in RCA  Aggressive medical therapy: statins,Aggressive medical therapy: statins, aspirin, clopidogrel, smoking cessationaspirin, clopidogrel, smoking cessation Pre Post
  5. 5. But… what about those lesions leftBut… what about those lesions left behind?behind?  2.5 to 3.5 non-culprit TCFA’s per MI patient2.5 to 3.5 non-culprit TCFA’s per MI patient  20% risk of thrombosis/lesion/2 years20% risk of thrombosis/lesion/2 years  Only 1 in 3 thrombotic lesions will lead to ACSOnly 1 in 3 thrombotic lesions will lead to ACS  20% chance of ACS within 2 years20% chance of ACS within 2 years  40% risk reduction with statins, 50% with40% risk reduction with statins, 50% with combined medRx, still 12% risk of ACS within 2combined medRx, still 12% risk of ACS within 2 yearsyears  Risk of a DES in focal lesion: 0.5% SAT, 3%Risk of a DES in focal lesion: 0.5% SAT, 3% restenosisrestenosis
  6. 6. Treatment Paradigms for VPTreatment Paradigms for VP  SystemicSystemic  OralOral  IntravenousIntravenous  LocalLocal  IntracoronaryIntracoronary  InjectionInjection  BalloonBalloon  StentStent  RadiationRadiation  PDTPDT  ExtracorporealExtracorporeal  Focused energyFocused energy  IntrapericardialIntrapericardial
  7. 7. Rationale for IP Drug Delivery forRationale for IP Drug Delivery for Local Cardiac TherapyLocal Cardiac Therapy  Natural barrier action ofNatural barrier action of the pericardiumthe pericardium  Possible regulatory role inPossible regulatory role in myocardial and coronarymyocardial and coronary tissuetissue  Limited or delayedLimited or delayed absorption into systemicabsorption into systemic circulationcirculation  Increased residence timeIncreased residence time in pericardial space andin pericardial space and exposure to target tissue(s)exposure to target tissue(s)
  8. 8. Rationale for IP DeliveryRationale for IP Delivery  Therefore, it should be possible to:Therefore, it should be possible to:  Deliver small dosesDeliver small doses  Obtain high local tissue concentrationsObtain high local tissue concentrations  Limit side effectsLimit side effects Target tissues
  9. 9. Pericardial FluidPericardial Fluid May Be More than Just An Innocent BystanderMay Be More than Just An Innocent Bystander PF Serum P Na+ , mmol/L 139±1 138 ±0 NS K+ , mmol/L 4.1±0.1 3.9±0.2 .02 Glucose, mmol/L 5.4±0.2 6.8 ±0.2 .001 Osmolarity, mOsm/L 250±4 255 ±3 .001 Protein, g/L 26±2 65 ±2 .001 FGF2, g/L 565 ±120 pg/mL 18±2 pg/mL .001 TGF-ß, g/L 1.1±0.2 ng/mL 13.2 ±2.5 ng/mL .001 Endothelin-1, pg/mL 3.4 ±0.4 4.4±0.4 NS Angiotensin II, pg/mL 58±9 147 ±36 .04 ANF, pg/mL 137±38 69 ±24 .02 Corda S et al, Circ Res 1997;81:679-87
  10. 10. Elevated bFGF in Pericardial Fluid ofElevated bFGF in Pericardial Fluid of Patients with Unstable AnginaPatients with Unstable Angina Fujita et al, Circulation 1996;94:610-13
  11. 11. Delayed Clearance of RadiolabeledDelayed Clearance of Radiolabeled Agents from Pericardial Space: SizeAgents from Pericardial Space: Size MattersMatters MW 479 Da MW 74 kDa Baek SH et al. Circulation 2002;105:2779-84
  12. 12. Residual Radioactivity FollowingResidual Radioactivity Following Delivery ofDelivery of 131131 I-labeled NONO-albuminI-labeled NONO-albumin T 1/2=2.5-3.9 hrs T 1/2=22.2 hrs Stoll HP et al. Clinical Cardiology 1999;22(Suppl I):10-16
  13. 13. Persistent coronary vasodilatation induced byPersistent coronary vasodilatation induced by intrapericardial nitroglycerinintrapericardial nitroglycerin Waxman S et al, JACC 1999;33:2073-7
  14. 14. Higher Concentrations AchievedHigher Concentrations Achieved with Pericardial vs IV Deliverywith Pericardial vs IV Delivery Hermans et al. JPET 2002;301:672-78
  15. 15. Fractional intramuralFractional intramural deliverydelivery andand retentionretention inin the coronary artery ofthe coronary artery of 125125 I labeled agentsI labeled agents Stoll HP et al. Clinical Cardiology 1999;22(Suppl I):10-16 Uniform Concentration Persistent Concentration
  16. 16. Inhibition of neointima formation withInhibition of neointima formation with intrapericardial paclitaxel after balloon overstretchintrapericardial paclitaxel after balloon overstretch Control Paclitaxel, 10 mg Paclitaxel, 50 mg Hou et al, Circulation 2000;102:1575
  17. 17. VEGF levels following intrapericardialVEGF levels following intrapericardial adenoviral-mediated gene transferadenoviral-mediated gene transfer (AdCMV.VEGF, AdRSV.β-gal) in a canine model(AdCMV.VEGF, AdRSV.β-gal) in a canine model of chronic ischemiaof chronic ischemia Lazarous et al, Cardiovascular Research 1999;44:299
  18. 18. Pericardially delivered EPC Migrate toPericardially delivered EPC Migrate to Areas of Ischemic MyocardiumAreas of Ischemic Myocardium 0 100 200 300 400 500 600 AW AS IP Lung Liver 7d +EPC 7d control 21d +EPC Location of Cells CellDensity(cells/mm2 ) Saltzman AJ, Karas R, WaxmanS, et al. Circulation Suppl 2003
  19. 19. Intrapericardial drug delivery:Intrapericardial drug delivery: Potential pancoronary therapeutic applicationsPotential pancoronary therapeutic applications  Modulation of coronary response to injuryModulation of coronary response to injury  RestenosisRestenosis  Plaque stabilization/regression/Vulnerable PlaquePlaque stabilization/regression/Vulnerable Plaque
  20. 20. How do we get there?How do we get there?  Direct surgical approachDirect surgical approach  ““Outside” inOutside” in  SubxiphoidSubxiphoid  PerducerPerducer  ““Inside” outInside” out  TransatrialTransatrial  TransventricularTransventricular
  21. 21. PerduCer™ device for intrapericardialPerduCer™ device for intrapericardial accessaccess Courtesy of Comedicus Inc.
  22. 22. Transventricular pericardial access usingTransventricular pericardial access using a helical tipped cathetera helical tipped catheter March, KL. Clinical Cardiol 1999
  23. 23. Transatrial Access into Pericardial SpaceTransatrial Access into Pericardial Space Verrier, Waxman, et al, Circulation 1998;98:2331; Waxman et al, Cath Cardiovasc Interv 2000;49:472
  24. 24. Transatrial Access into Pericardial SpaceTransatrial Access into Pericardial Space  Guide positioning inGuide positioning in right atrial appendage.right atrial appendage.  Puncture of appendagePuncture of appendage with 2 wire systemwith 2 wire system
  25. 25. Transatrial Access into Pericardial SpaceTransatrial Access into Pericardial Space  Advancement of infusionAdvancement of infusion catheter into pericardialcatheter into pericardial spacespace  Confirmation:Confirmation: fluoroscopy andfluoroscopy and pericardial fluidpericardial fluid aspirationaspiration
  26. 26. Implantable chronic deliveryImplantable chronic delivery systems?systems?
  27. 27. Use of polymers in the pericardial space for drugUse of polymers in the pericardial space for drug deliverydelivery Waxman et al, Circulation 2001;104 (Suppl):II-729
  28. 28. ConclusionsConclusions  The pericardial space may be an appropriate platformThe pericardial space may be an appropriate platform for local pancoronary therapy for VP:for local pancoronary therapy for VP:  Localized effectsLocalized effects  Small dosesSmall doses  High efficiencyHigh efficiency  Mounting evidence suggests that pharmacologicalMounting evidence suggests that pharmacological and biological agents may be delivered via thisand biological agents may be delivered via this approach to exert a local coronary vascular effect.approach to exert a local coronary vascular effect.
  29. 29. Intrapericardial DeliveryIntrapericardial Delivery ChallengesChallenges  What agents?What agents?  How practical is it? How do we get there?How practical is it? How do we get there?  Possible need for repeated dosesPossible need for repeated doses  Penetrability of therapeutic agent in tissuesPenetrability of therapeutic agent in tissues  Is there a need for “booster treatment”?Is there a need for “booster treatment”?  Patient selectionPatient selection
  30. 30. AcknowledgementsAcknowledgements  Center for TranslationalCenter for Translational Cardiovascular Research, Tufts-Cardiovascular Research, Tufts- NEMCNEMC  Sung Choi, MDSung Choi, MD  Alexandra DabreoAlexandra Dabreo  Fumiyuki Ishibashi, MDFumiyuki Ishibashi, MD  Adam Saltzman, MDAdam Saltzman, MD  Eric WeissEric Weiss  Molecular Cardiology ResearchMolecular Cardiology Research Institute, Tufts-NEMCInstitute, Tufts-NEMC  Wendy BaurWendy Baur  Flore CelestinFlore Celestin  Richard Karas, MDRichard Karas, MD  Beth Israel DeaconessBeth Israel Deaconess Medical CenterMedical Center  Richard Verrier, PhDRichard Verrier, PhD
  31. 31. Distribution ofDistribution of 125125 I bFGF after 5 differentI bFGF after 5 different routes of deliveryroutes of delivery Lazarous DF et al. Cardiovascular Research 1997;36:78-85
  32. 32. Luciferase expression at 3 days following geneLuciferase expression at 3 days following gene transfer with intrapericardial delivery, Av1Lu.transfer with intrapericardial delivery, Av1Lu. March KL et al, Clinical Cardiol 1999;22 (Suppl I):23-29

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