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Keeping the SmallKeeping the SmallAortic Aneurysm SmallAortic Aneurysm SmallJohn A. Curci, MD, FACSAssociate Professor of Vascular and Endovascular SurgeryDirector, Aortic Aneurysm Research Laboratories, Washington UniversityPrincipal Investigator [Biomarkers Core], N‐TA3CT
Markey Lecture 2012
Abdominal Aortic Aneurysms
15,000 DeathsPresent in 5 9% From Rupture
Each Year in US
Present in 5-9%Of the Population
Over 65 Years of Age
AAA45,000 Elective Operations45,000 Elective OperationsEach Year in US
OverviewOverview• Brief Clinical Background on AAA• The Development of a New Therapy
• Human Pathobiology• Lab Models• Clinical TrialsU d di h N f h Di• Understanding the Nuance of the Disease• Models
• Detailed mechanisms• Detailed mechanisms• Clinical correlation
• Systems ComplexitySystems Complexity
Etiology of AAAsEtiology of AAAs
Smoking Odds Ratio 5 57Smoking Odds Ratio 5.57Male Gender Odds Ratio 2.68Family Hx Odds Ratio 1.94A O 65 Odd R ti 1 71Age Over 65 Odds Ratio 1.71Hypertension Odds Ratio 1.15
Smoking <20 Pk-Yrs Odds Ratio 2.75Smoking >50 Pk-Yrs Odds Ratio 9.55
Lederle et al. J Vasc Surg 2003; 38:329-334
Histopathology of Abdominal Aortic Aneurysms
Chronic Transmural InflammationDestructive Remodeling of the Elastic Media
Inflammation in AAA
• a) Normal aortab AAA• b) AAA with focal infiltrate) CD3+• c) CD3+
• d) CD45+• e) CD68+• f) HLA DR, DP, DQ+
Medial SMC Depletion in Human AAAs
Normal Aorta199.5 +/- 14.9 SMC/HPF
Aortic Atherosclerosis176.4 +/- 13.9 SMC/HPF
Aortic Aneurysm50.9 +/- 6.1 SMC/HPF
Lopez-Candales et al., Am J Pathol 1997; 150:993-1007
Features of Aneurysmal Degeneration
Genetic Predisposition Proteolytic Degradation of Elastin and Collagen
Medial SMC Depletion: Apoptosis and Senescence
Atherosclerosis and Expansive Remodeling
Mural Thrombus
Impaired Connective Tissue Repair and
Inflammation,Immunity, and Infection
Mural Thrombus, Medial Ischemia, and
Neovascularization
pDiminished Tensile
Strength
Oxidative Stress and Free Radical Damage
Altered Geometry and Elevated
BiomechanicalWall Stresses
AVicious CycleA Vicious Cycle• Medial Elastic Fiber
• Typically absent• Relatively unique• Elastolytic enzymesy y• Central pathophysiology?
• Inflammatory Cells• Chronic Inflammation• Chronic Inflammation• Th1 vs Th2• Protease elaboration/activation
VSMC• VSMC• Diminished capacity for matrix repair (? Cell loss)M l b t t• May elaborate proteases
• May elaborate cytokines
Tetracycline Derivatives as MMP Inhibitors
AntibioticAntibioticActivity
DOXYCYCLINE
MMP-InhibitingActivity
DOXYCYCLINE
Treatment with Doxycycline and MMP-9 DeficiencyBoth Inhibit Elastase-Induced AAAsBoth Inhibit Elastase-Induced AAAs
Pyo et al., J Clin Invest 2000; 105:1641-1649
WT Bone Marrow RescuesAAA Resistant Phenotype
MMP-9 KO Bone MarrowConfers AAA ResistantAAA-Resistant Phenotype
of MMP-9 KO MiceConfers AAA-Resistant
Phenotype Upon WT Mice
Pyo et al., J Clin Invest 2000; 105:1641-1649
MMP Inhibition in Animal Models of Aortic AneurysmAnimal Model MMP InhibitionAnimal Model MMP Inhibition
Elastase-Induced AAAs (Rats, Mice) DoxycyclineMMP-9 KnockoutMMP 9 KnockoutChemically-Modified TCNsHydroxamates (BB94, RS132908)Indomethacin (indirect) Simvastatin (indirect)
CaCl2-Induced AAAs (Mice) DoxycyclineMMP-9 KnockoutMMP-2, MMP-12 KnockoutsCD4 Knockout, IFN-g Knockout
Angiotensin-Induced AAAs (Mice) DoxycyclineMMP-9 Knockout
Fibrillin-Deficiency (Marfan Mice) DoxycyclineLosartan
Early Clinical TranslationEarly Clinical Translation• Effects of Doxycycline in vivo, pub 2000
• Biologic alterations in established AAA
• Patients for elective open AAA w/ 7 days doxy• Reduced MMP activation
• Reduced MMP production
Early Clinical TranslationEarly Clinical Translation• Alterations in AAA morphology
• Mosorin, et. al. in 2001
• Inhibition of AAA growth after 3 months of therapy
• Effect persisted beyond initial treatment interval• Effect persisted beyond initial treatment interval
More Early Clinical TranslationMore Early Clinical Translation• Phase II Study, Baxter, et.al., 2002
• 6 months of treatment tolerable
• Hackmann, et. al., 2008• Stabilized aneurysm neck dilatation after endograft• Stabilized aneurysm neck dilatation after endograft
• May have accelerated AAA shrinking
• Reduced circulating MMP‐9
• Lindeman, et. al., 2009 JVS and Circulation• Doxy reduces aortic neutrophils and cytotoxic T‐cells
Screening with CT Scans282 Patients
National Institute on Aging
Enrollment and Biomarkers248 Patients
Follow-Up Visits Every 3 Months
124 Doxycycline124 Placebo
Biomarker and CT scan @ 6-Month Follow-UpSF-36 QOL evaluationsCommon Termination After ≈3.5 YearsMinimum Follow-Up of 2 Years
Basic StudyDesign• Prospective, Randomized, Placebo‐controlled
Basic Study Design
• Doxycycline 100 mg bid
• Include Small AAA3 5 t 5 0 i• 3.5 to 5.0 cm in men
• 3.5 to 4.5 cm in women
• CT imaging every 6 months
• Statistics to evaluate growth• Based on rank order
• Includes effect of sudden death or AAA repair• Includes effect of sudden death or AAA repair
• Sensitivity of >90% to identify a 40% effect on growth.
• Biorepository (imaging and serum/plasma)
BEYONDMATRIXMETALLOPROTEASE:Details and Nuance of the Mouse Model
BEYOND MATRIX METALLOPROTEASE: MECHANISMS OF ELASTOLYSIS
Suppression of Elastase-Induced AAAs byTreatment with a Cysteine Protease Inhibitor (E64)Treatment with a Cysteine Protease Inhibitor (E64)
Neutrophil Proteases in Elastase-Induced AAAs
Significant Suppression in Mice Deficientin Dipeptidyl Peptidase I (DPPI)in Dipeptidyl Peptidase-I (DPPI)
Pagano et al., Proc Natl Acad Sci USA 2007; 104:2855-2860
Suppression of Aortic Wall Inflammation and ElastinDegradation by Cathepsin Inhibition and Cat-S DeficiencyDegradation by Cathepsin Inhibition and Cat S Deficiency
Angiotensin II(AT1 R )(AT1 Receptor)
Oxidative Stress andOxidative Stress andPro-Inflammatory Signaling
Increased Vascular Wall MMP Production
Localized Disruption of Elastic LamellaeWith Focal Dissection
Chronic Inflammation & MMP Expression
Aneurysm Formation
Adding Tobacco SmokeAdding Tobacco Smoke• Multifactor Model for a Multifactor Disease
• Exposure to Tobacco Smoke• Up to 500%‐1000% increase in incidence of AAA.
• Compares to “only” 150% 200% increase in coronary disease• Compares to “only” 150%‐200% increase in coronary disease.
• Risk persists long after smoking cessation.
• Models of Pulmonary Emphysema• Used smoke exposure of mice for months.
• Opened new ways of considering the disease processes.
AMore Clinically RelevantModelA More Clinically Relevant ModelModified Smoking Model of AAA
100
150
200
cre
as
e0
50
100
iam
ete
r In
c0
- - +
Inactive Elastase
Low dose elastase
Low dose elastaseP
erc
en
t D
i
Elastase elastase elastase
2 cigs/day6 days/week.
Start 2 weeks before perfusion
Bergoeing, JVS 2007, 45(6)
Cured . . . or Not?Doxycycline effects overcome with Tobacco Smoke.
Jin & Arif, et. al., ATVB, in publication
Smoke Enhances Model Independently ofMMPIndependently of MMP
Smoke =Smoke larger model aneurysms.y
* P<.05 cf. non-ksmoke
† P<.05 cf. wild-typeyp
Jin & Arif, et. al., ATVB, in publication
Non‐MMPEnzymes and SmokeNon MMP Enzymes and Smoke
• No inhibition with other enzyme classes• Cathepsins – Cathepsin S• Cathepsins Cathepsin S
• Serine Proteases –Neutrophil Elastase
Eff t t t d• Effect appears to transcend simple single enzyme inhibition.
Jin & Arif, et. al., ATVB, in publication
Smoking CessationSmoking Cessationgg
• 6 Weeks of Smoke Exposure• 6 Weeks of Smoke Exposure for all Mice then stopped.
V i d i t l b t• Varied interval between smoke exposure and aortic perfusion
• All animals harvested 2 weeks after perfusion.
* P < 0.05 Smoke v. Smoke-free
Jin & Arif, et. al., ATVB, in publication
UNDERSTANDINGTHEROLEOFTHERole of the Parenchymal Cells in an Inflammatory Disease
UNDERSTANDING THE ROLE OF THE SMOOTH MUSCLE CELL IN AAA
Expression Profile of VSMCExpression Profile of VSMC
Source of SMC: AAA = Abdominal Aortic Aneurysm, NAA = Non-dilated Abdominal Aorta, CEA = Atherosclerotic Plaque
SummarySummary• Elastolysis of AAA is relatively unique and remarkably anatomically localized
• Matrix destruction results from both chronic inflammationand VSMC dysfunctionand VSMC dysfunction
• Inhibition of elastolytic enzymes may inhibit the progression of small aortic aneurysms
• Care must be taken to recognize the limitations of animal models of complex human diseases
• No single model is adequate for evaluation of all aspects of g q ppathobiology and all potential therapeutics
ContributorsContributors• Michel Bergoeing, MD
Lif li R id t R h• Lifeline Resident Research Award
• Nathan Airhart, MD• Amy Hackmann MD• Amy Hackmann, MD• Paqui Fernandez‐Garcia, MD• Batool Arif• Jianping Jin• Jianping Jin• Kathy Grapperhaus
• RW Thompson MDFinancial Support
• RW Thompson, MD• Kathy Raman, MD, MS• Elaine Davis, MDR b t M h MD
NIH/NHLBI K08AVA Lifeline/ACS
FAMRI YCSA• Robert Mecham, MDAHA BGIA